Shimizu's Textbook of Dermatology (Hokkaido University Press) PDF

Preface
Welcome to Shimizu's Textbook of Dermatology. This is an upgraded edition of Japan's

best-selling dermatology textbook. I spent 5 years completing the Japanese-language
edition, which sold more than 10,000 copies in the first one year after publication in 2005.
The popularity of the Japanese edition owes to its coverage of all the basic information
necessary for dermatology practice, presented with clear descriptions and accompanied by
more than 1,000 high-quality clinical photos.
This is not a color atlas, but a complete textbook of dermatology for dermatologists, medical
students and educators, and other medical workers. There are many similar dermatology
textbooks of similar size and weight. But the unique point of this textbook is that I have
included all major diseases seen in dermatology practice, while minimizing the book's size
and weight by avoiding vague or excessive descriptions.
I hope readers will bring this textbook with them to the clinic and the classroom.
Thanks to the Internet, anyone can read any chapter as a PDF file for free. Those who wish to
buy the hardcopy, with high-quality clinical photos, can order the textbook by Hokkaido
University Press
I hope you enjoy and appreciate Shimizu's Textbook of Dermatology as a tool for education,
everyday reference and refining your dermatological expertise.
Hiroshi Shimizu
July 2007
Go Back to the Top To Order, Visit the Purchasing Page for Details
1
Chapter
1 Structure and Function of the Skin
The skin is the human body’ s its largest organ, covering 1.6 m2 of surface area and accounting for approximate-
ly 16% of an adult’s body weight. In direct contact with the outside environment, the skin helps to maintain four
essential bodily functions: ① retention of moisture and prevention of permeation or loss of other molecules, ②
regulation of body temperature, ③ protection of the body from microbes and harmful external influences, and ④
sensation. To understand cutaneous biology and skin diseases, it is very important to learn the structure and
functions of normal human skin.
A. Skin surface
The skin surface is not smooth, but is laced with multiple net-
works of fine grooves called sulci cutis. These can be deep or
shallow. The slightly elevated areas that are surrounded by shal-
crista cutis
lower areas of sulci cutis are called cristae cutis. Sweat pores fed
by the sweat glands open to the cristae cutis (Fig. 1.1).
The orientation of the sulci cutis, which differs depending on
body location, is called the dermal ridge pattern. Fingerprints and sulcus cutis
patterns on the palms and soles, which are unique to each person,
are formed by the sulci cutis. Elastic fibers also run in specific
directions in deeper parts of the skin, with the direction depend- a b c d e f g h
ing on the site. Some skin diseases, such as epidermal nevus, are
known to occur along specific lines distributed over the body, the
Blaschko lines (Fig. 1.2). These lines are thought to be associated
a b c d e f g h i
a b c d e f g h i j
Fig. 1.1 Appearance of the skin surface.
a: Cristae cutis (triangle) and sulci cutis (arrows).
b: Nevus-cell nevus along the cristae cutis. c:
Fig. 1.2 The Blaschko lines. Sweat pores fed by sweat glands open to the
Many dermatological disorders appear along these lines, such as epider- cristae cutis (arrows).
mal nevus and linear scleroderma (Bolognia JL, et al. J Am Acad Derma-
tol 1994; 31:175-90).
1
2 1 Structure and Function of the Skin
1
hair
arrector pili muscle

sweat pore
apocrine sweat gland
epidermis
dermal papilla horny cell layer
epidermal rete ridge
papillary dermis
subpapillary dermis
epidermal basement membrane infundibulum
eccrine sweat gland
dermis
sebaceous gland reticular dermis
hair bulge
hair follicle
dermal hair papilla
hair bulb
hair matrix
subcutaneous tissue
subcutaneous
fat
fascia
muscle
Fig. 1.3 Structure of the skin.
(Nakagawa H, editor. Dermatological disorders. In: Symphonia Medica Nursing (Vol.19). Nakayama-Shoten; 2001. p.3).
with the direction in which the differentiated cell clones extend

during fetal skin development.
Skin generally consists of a three-layer structure: the epider-
mis, dermis and subcutaneous tissues (Fig. 1.3). At the boundary
between the epidermis and dermis are finger-like projecting
structures (the dermal papillae) that project into the overlying tis-
sue (the epidermis) (Fig. 1.30). The portion of the epidermis that
projects into the dermis is called the epidermal rete ridge, and the
portion of the dermis that projects into the epidermis is called the
dermal papilla.
B. Epidermis
a. Structure and cells of the dermis
horny cell layer (10-20 layers)
The epidermis is on average about 0.2 mm thick, and 95% of granular cell layer (2-3 layers)
the cells composing it are epidermal keratinocytes that proliferate
suprabasal cell layer (5-10 layers)
and divide in the epidermal basal layer and move up to the upper
layers as they mature (to form cornified cells). In the epidermis, basal cell layer (1 layer)
epidermal keratinocytes at different stages of maturation are
arranged in layers that can be divided into four levels (Figs. 1.4
and 1.5). The period between the production of daughter epider-
mal cells and their exfoliation from the outer surface of the epi- epidermal basement membrane
100 mm
dermis is called the turnover time, which is approximately 28
days in normal skin.
Fig. 1.4 The four layers of the epidermis:
basal cell layer, suprabasal cell layer,
1. Basal cell layer granular cell layer and horny cell layer.
The basal cell layer is a single layer consisting of basal cells
including the epidermal stem cell subpopulation. Basal cells
vary in shape from cubic to columnar. They contain basophilic
(or darkly staining) cytoplasm and an elliptical nucleus that is cell nucleus
rich in chromatin. The basal cells have desmosomes (for cell- suprabasal
cell attachment), gap junctions (for cell communication), and cell layer
basal
cell layer
epidermal
dermis basement membrane
Fig. 1.5 Ultrastructural anatomy of the epi-

dermis.
desmosome gap basement hemidesmosome

junction membrane
Fig. 1.6 Intracellular positions of desmosomes, gap junction and

hemidesmosomes.
1
hemidesmosomes (for connection with the extracellular matrix
horny cell layer and underlying basal membrane) (Fig. 1.6). Cell cytokeratins
(keratin filaments, tonofilaments) are abundant in the cytoplasm
of many epidermal keratinocytes and are distributed in bundles at
the periphery of the nucleus, from where they distally connect
with hemidesmosomes and desmosomes to form a rigid and
robust cellular cytoskeleton.
2. Suprabasal cell layer

horny cell layer cornified cell envelope
The suprabasal cell layer is composed of five to ten layers that
appear connected to each other by prickle-like structures.
Suprabasal (prickle) cells are polygonal in the lower layer and
flattened in the upper layers. They are larger than basal cells and
contain a small amount of chromatin in their circular nucleus.
keratin
pattern The part that gives the appearance of a prickle corresponds to the
desmosome (a form of intercellular bridge).
granular cell layer 3. Granular cell layer

Fig. 1.7 Horny cell layer. The granular cell layer is composed of two or three layers of
cells containing basophilic keratohyalin granules. The cells and
horny cells nuclei in the granular cell layers are even flatter than those in the
suprabasal layer. Spherical lamellar granules, each with a diame-
ter of approximately 300 nm (also known as Odland bodies or
ketatosomes), can be observed in the granular cell layers by elec-
tron microscopy. The main component of lamellar granules is
released into the intercellular space of horny cells as stratum
corneum lipid.
4. Horny cell layer

Fig. 1.8 Ultrastructural image of the epider- The horny cell layer, also called the stratum corneum, is com-
mis between the granular cell layer and posed of about ten sub-layers. Enucleated dead keratinocytes
the horny cell layer, with cornified cell
envelopes and lamellar granules (arrows). become membranous and multilayered, resembling fallen leaves,
and exfoliate sequentially, beginning with the outer layer, in what
is commonly called grime. The horny cell layer is very thick in
the palms and soles. Horny cells are flat, and their cytoplasm is
filled with aggregated keratin fibers. Directly above the granular
cell layer, the horny cell structure appears as an eosinophilic
layer. The horny cells gradually change into membranous struc-
tures in the upper layers. By electron microscopy, the contrast
between electron-dense interfibrous substance and the low-elec-
tron-dense keratin fibers is clear; this contrast is called the keratin
pattern.
The cell membranes are thicker in the horny cell layer than in
the other layers. The lining structure is called a cornified cell
envelope or a marginal band (Figs. 1.7 and 1.8). The protein,
component of the cornified cell envelope, is extremely stable
against physicochemical degradation.
B. Epidermis 5
1
5. Other cells
Keratinocytes account for 95% of the cells within the epider-
mis. The remaining 5% are melanocytes, Langerhans cells, a-
dendritic cells and Merkel cells, which are involved in melanin
formation, antigen presentation, and sensation, respectively.
b. Adhesion of keratinocytes
The epidermal basement membrane plays a key role in dermal-
epidermal adhesion. Even when normal skin is rubbed, the epi-
dermal basement membrane keeps the epidermis and dermis
from separating.
The epidermal basement membrane zone, which lies immedi-
ately under the epidermis, stains by periodic acid Schiff (PAS)
under the light microscope. The complicated structure of the
basal membrane includes the lamina densa (LD) and the lamina
lucida (LL), which are observed by electron microscopy (Figs.
1.9 and 1.10).
The lamina densa is 60 to 80 nm thick and consists mainly of
fibronectins, heparan sulphate proteoglycan, type IV collagen
and laminin 5 (including laminin 332). Under the electron micro-
scope, it appears to be an electron-dense lattice network struc-
ture. Hemidesmosomes play an important role in adhesion
between the basal cells and the lamina densa. Although the
hemidesmosome resembles a desmosome that has been cut in
half, the molecular components of hemidesmosomes and desmo-
somes are very different. Keratin fibers within basal cells link
hemidesmosomes, to maintain and anchor the structure of the cell
(Fig. 1.11).
The lamina lucida includes the component laminin 332. Type
Fig. 1.9 Ultrastructural anatomy of the base-
XVII collagen (BP180; 180kDa bullous pemphigoid antigen) ment membrane zone.
bridges the lamina lucida to connect hemidesmosomes directly TF: tonofilament. HD: hemidesmosome. LL:
with the lamina densa. lamina lucida. LD: lamina densa. AF: anchoring
fibril.
Anchoring fibrils, which form semi-circular loop structures,
form firmly connections around type I and III collagens in the
Blister formation MEMO
dermis linking it to the lamina densa. caused by congenital change
or autoantibody deposition
A congenital change or attachment of an
1. Adhesion between keratinocytes autoantibody to the peripheral basal mem-
brane may weaken the dermal-epidermal
Epidermal keratinocytes adhere to each other by desmosomes junction, leading to blister formation. When
and structures such as adherens junctions, gap junctions and tight autoantibodies are produced against BP180
junctions. and BP230, which comprise hemidesmosomes,
the disease bullous pemphigoid occurs. If a
The desmosome is composed of an attachment plaque (com- congenital abnormality is caused in K5, K14,
prising inner and outer plaques), a structure that penetrates mem- BP180, laminin 332, or collagen type VII by
branes to connect cells. The attachment plaque is mainly genetic mutation, then epidermolysis bullosa
occurs (Chapter 14). Blisters easily form after
composed of desmoplakin, to which keratin fibers connect, to weakened epidermal intercellular adhesion
strengthen the cytoskeleton. Transmembrane proteins such as resulting from production of autoantibodies
desmogleins and desmocollins are homophilically connected to against desmogleins, which are structural pro-
the same molecules by a calcium ion dependent mechanism, teins of desmosomes; this is an autoimmune
bullous disease called pemphigus.
which makes connections between cells possible (Fig. 1.12).
1
keratin 5/14
basal cell
enlarged hemidesmosome
BP230
plectin
integrin
a6 integrin
b4
basement
basal cell lamina lucida membrane
BP180 (LL)
lamina
densa (LD) laminin 332 lamina densa
type I/III collagen (LD)
N N N N N N
anchoring fibril
(type VII collagen)
type I/III collagen
Fig. 1.10 Microstructure of the basement membrane zone.
keratin intermediate filaments
plectin
BPAG1e
erbin a6b4integrin
BP180
CD151/PETA-3 laminins
fibrin 2
NC-1
NC-1
NC-1
type IV collagen nidogen laminins
fibronectin
type I or II collagen in the dermis
Fig. 1.11 Electron micro-

scopy of the basement
type VII collagen membrane zone.
The gap junction which is composed of connexin subunits,

mechanism, has a structure in which cell plasma membranes
associate with each other such as to leave a 2- to 3-nm space.
Connexin is involved not only in connecting cells but also in
transporting small molecules and ions between cells (Fig. 1.13).
The cell membranes of keratinocytes in the granular cell layers
are connected to each other by a tight junction network character-
ized by membrane proteins called occludins and claudins, to pre-
vent bodily fluids from leaking between cells in that the layer
(tight conjugation).
1
electron micrograph
c. Keratinization
The horny cell layer acts like a film of plastic wrap, allowing
the body to retain moisture and protecting it from invasion by
foreign substances. If the horny cell layer is lost or defective, a
human being can survive for no more than 24 hours due to loss of
liquid components leading to dehydration. The layer comprises
various substances such as keratins, produced by the epidermal
keratinocytes, and lipids. The epidermal keratinocytes divide in plakophilin
the basal layer, produce keratins and differentiate, and migrate to
Ca2+
the upper layers as they mature. This process is called keratiniza- desmoglein 1 desmoglein 1
tion. Recent studies have proved that epidermal keratinocytes Ca2+
secrete various cytokines. desmoglein 3 desmoglein 3
Ca2+
desmocolin desmocolin
1. Keratin keratin fiber keratin fiber
desmoplakin
Keratin forms tonofilaments that act as a cytoskeleton to main-
tain the structure of the keratinocyte. Keratins are classified as cell membrane
type I (acidic) or type II (neutral to basic). Type I and type II ker- Fig. 1.12 Ultrastructural image and illustra-
atins bind to each other in pairs to form intermediate filaments. tion of the desmosome.
Pairs of keratins with characteristic molecular characteristics
cytoplasm
form, depending on the keratin pairs and state of differentiation
of the keratinocytes. For example, K5/K14 pairs in basal cells
and K1/K10 pairs in the suprabasal cell layers to form the cell
cytoskeleton (Table 1.1, Fig. 1.14).
When keratinized, keratin fibers in the granular cell layer
aggregate with help from the protein called filaggrin to form the cell membrane
characteristic condensed keratin pattern. Profilaggrins, abun-
dantly found in keratohyalin granules, decompose into filaggrins
by the action of the protease peptidylarginine deiminase during cell membrane
keratinization (Fig. 1.15). Released filaggrins aggregate keratin cytoplasm connexon
fibers in the horny cell cytoplasm and keratins decompose into
amino acids, for example, in the horny cell upper layer. The
connexin
Table 1.1 Expression regions of main keratin pairs, and congeni- N C second messenger, ion, etc.
tal disorders from mutations of keratins.
Keratins Main area of expression Genetic disorder Fig. 1.13 Molecular components of the gap
junction.
K1, K10 Keratinocytes in the suprabasal Bullous congenital
cell layer and granular cell layer ichthyosiform erythroderma
K2e Superficial epidermis Ichthyosis bullosa of Siemens
K3, K12 Anterior epithelium of the cornea Juvenile epithelial corneal
dystrophy (Meesman)
K4, K13 Mucosa White spongy nevus
(on tongue)
K5, K14 Keratinocytes in the basal cell Epidermolysis bullosa simplex
layer
K6, K16 Nails Pachyonychia congenita
K9 Keratinocytes in the suprabasal Palmoplantar keratodsis
cell layer and granular cell layer (Vörner)
on the palmoplantar region
1
horny decomposed filaggrins, which function in moisture retention and
cell layer ultraviolet absorption are called natural moisturizing factors
type of
keratin: (NMF).
granular
cell layer
2. Cornified cell envelope
suprabasal
K1 & K10
cell layer The cornified cell envelope (marginal band) is an extremely
large and strong, insoluble structure lining the horny cell mem-
brane. It appears under the electron microscope as an electron-
basal K5 & K14
cell layer
dense structure at the periphery of the horny cells (Fig. 1.16).
The main structural components of the cornified cell envelope
Fig. 1.14 Expression of keratin types in the
epidermis. are involucrins, produced in the lower keratinocyte suprabasal
cells, and loricrins, produced in the granular layer keratinocyte
cells. The cornified cell envelope forms when these proteins are
profilaggrin
successively cross-linked by enzymes such as transglutaminases
calcium binding
domain filaggrin domain during keratinization. Transglutaminases are calcium dependent
and are activated by the influx of calcium ions into the cells
N-terminal
accompanying cell death after keratinization.
leader linker
phosphorylation of serine 3. Horny layer (stratum corneum)

/ threonine residue intercellular lipids
C-terminal
More than 50% of the lipids in the horny cells are ceramides,
decomposition dephosphorylation
followed in decreasing order of abundance by cholesterols, free
fatty acids and cholesterol sulfates. Lamellar granules are abun-
dantly found in the cytoplasm of the granular cell layers. These
granules are released from cells when the cells become apoptotic,
keratin fiber forming horny layer intercellular fat. The enzyme ABCA12 plays
keratin
pattern a significant role in the release of lipid from lamellar granules
keratin fiber
from granular cells. Ceramides are released from lamellar gran-
decomposition
ules, and free fatty acids are secreted from granular cell mem-
natural moisturizing factor: small molecule peptide
branes. Cholesterol sulfates connect and stabilize the layered
Fig. 1.15 Keratohyalin granules.
Profilaggrin is composed of linearly arranged
filaggrin domains that connect with each other by cornified cell envelope
linker proteins. These filaggrin domains have horny layer intercellular fat loricrin involucrin
many serine-threonine residues, which are kept
phosphorylated. During keratinization these horny cell
domains are cut by proteases and are dephospho- layer
rylated to form filaggrin, which aggregates cell
(hence:“fil”for filament, and“aggrin”for aggre- membrane
gate) keratin filaments. The filaggrin degrades
into small peptides, which act to moisturize and keratin
to absorb UV rays (quoted from; Iizuka H. pattern
Hyperkeratosis. In: Arata J, editor. General Der-
matology. 7th ed. Igaku Shoin; 2004).
granular
cell
Ceramide and its MEMO lamellar nuclear
moisturizing function granule
The ceramide content in the horny cell layer
is reduced in patients with atopic dermatitis. keratohyalin
Ceramide is thought to relate to dry skin and granule
to disorders of skin barrier function.
Fig. 1.16 Cornified cell envelope.
B. Epidermis 9
1
lipid structures between horny cells. The horny layer intercellular Ichthyosis caused by MEMO
fat is important in preventing excessive transepidermal water loss. enzyme deficiency
Transglutaminase is an enzyme that connects
the cell membranes to protein molecules such
4. Exfoliation of horny cells as loricrin, involcrin, cystatin-a, and small
proline-rich proteins. Without this activity,
As horny layer intercellular lipids move upward with the horny normal cornified cell envelopes do not form.
cell layers, they gradually get more decomposed by lipases, a When ABCA12 is lacking, lamellar granules
are not normally produced, and formation of
group of catabolic lipid enzymes, and steroid sulfatases. Subse- intercellular lipid is incomplete, resulting in
quently, adhesion between keratinocytes is disrupted by proteas- the onset of harlequin ichthyosis. The mecha-
es from the upper skin surface, which causes gradual exfoliation nism of onset is thought to be thickening by a
compensative increase in number of horny
of horny layer cell. layer cells or by inhibition of the normal exfo-
liative process. A lack of steroid sulfatase,
d. Melanocytes and melanin synthesis which restores sulfate cholesterol to choles-
terol, inhibits normal exfoliation of horny
cells, which causes sex-linked recessive
1. Form and distribution of melanocytes ichthyosis (Chapter 15).
Melanocytes (pigment cells) are neural crest (ectoderm)-

derived dendritic cells found in the basal cell layer and hair
matrix (Fig. 1.17). Since their cytoplasm contracts during the
processes of dehydration and fixation in light microscopy, such
as in HE staining, melanocytes, as well as Langerhans cells, are
called clear cells. Melanocytes stain a characteristic brownish
black in DOPA (Fig. 1.17). Approximately 1,000 to 1,500
melanocytes are seen per square millimeter of skin. Dense
melanocytes are found in sun-exposed sites of the body, such as
the face, and in physiologically pigmented sites, such as external
genitalia.
The Golgi apparatus develops in a cell and contains various
melanosomes in various formative stages (stages I, II, III and Activities of vitamin A MEMO
IV). Melanin is produced from the amino acid tyrosine in the Vitamin A inhibits cholesterol sulfotrans-
ferases and decreases cholesterol sulfates,
melanosome. Mature melanosomes are packaged and transported which is considered to stimulate exfoliation of
to the neighboring basal cells and suprabasal cells. Basal cells the horny cell layers.
that are provided with melanosomes aggregate them in the upper
part of the cytoplasm over the nucleus, forming a melanin cap to
protect their DNA from UV rays.
Racial differences in skin color are determined by the number
and size of melanosomes. There is no difference in the distribu-
tion or density of melanocytes between races.
2. Biosynthesis of melanin
Melanin is a generic term for a group of polymer pigmented
molecular phenolic substances. The melanins in human skin are
various indole compounds synthesized from tyrosines through
polymer formation (Fig. 1.18).
Melanins in humans are roughly classified as eumelanin, 50 mm
which is black (intrinsic melanin), or pheomelanin (yellow

melanin). Melanins in human skin and hair are complexes of Fig. 1.17 Melanocytes.
these two types, and their ratio determines hair color. Melanocytes are seen as clear cells (arrows)
under hematoxylin and eosin staining, because
Tyrosines, supplied by the blood, are oxidized by tyrosinase, the cytoplasm of melanocytes shrinks during the
which contains copper, and are metabolized into dopas and then process of fixation.
1
into dopaquinones. Tyrosinase is the enzyme that catalyzes these
HO N COOH two reactions. This metabolism is the rate-limiting reaction in the
H2 synthesis of melanins (Fig. 1.18).
tyrosine Dopaquinones are automatically oxidized to become indole
tyrosinase compounds that are connected to each other to synthesize eume-
lanins. If cysteins are involved at this stage, dopaquinons connect
HO with cysteins and change into 5-S-cysteinyl dopa (5-S-CD),
HO N COOH which polymerizes to synthesize pheomelanins.
H2
dopa
3. Melanosome
tyrosinase
The melanosome is a subcellular organelle, enclosed by a lipid
O
double membrane, in which melanins are exclusively produced.
O N COOH When tyrosinases, which are synthesized by the Golgi apparatus.
H2
are carried to premelanosomes, which are isolated from the
dopaquinone cysteine
agranular endoplasmic reticula, melanin synthesis begins. As the
amount of synthesis increases, melanosomes enlarge. The forma-
tion of melanosomes is divided into stages I to IV by the degree
of melanin deposition (Fig. 1.19). A melanosome in stage IV is
dopa chromium 5-S-cysteinyl 500 nm to 700 nm along its major axis, football shaped, and sup-
dopa
plied from the dendrites to the neighboring epidermal ker-
atinocytes.
indole
derivative
eumelanin pheomelanin
4. Functions of melanin
(black) (yellow)
The most important role of melanin is protecting the skin from
Fig. 1.18 Biosynthesis of melanin.
UV rays and preventing the occurrence of malignant tumors and
sunlight injury to the skin. The darker the skin of a particular
MEMO
race, the lower is the incidence of skin cancer caused by UV
Causes of enhanced
pigmentation light.
ACTH (adenocorticotropic hormones), MSH Exposure to sunlight darkens the skin. This darkening may
(melanocyte-stimulating hormones), thyroid occur immediately after exposure and may be temporary, when
hormones, estrogens, ultraviolet rays, and X-
rays are known to increase pigmentation of
melanins are oxidized temporarily, or it may occur after several
the skin. days of exposure, when there is an increase in melanin synthesis
and mature melanosome formation.
MEMO
Melanins can also act to absorb harmful active enzymes, met-
Association of
tyrosinase with albinism als and drugs.
A child that has a congenital lack of tyrosi-
nase is born with pale skin, from the lack of e. Langerhans cell
melanins (oculocutaneous albinism). In
patients with Menkes disease, there is an
extreme deficiency in copper, which causes The Langerhans cell is a bone marrow-derived dendritic cell
tyrosinase activity to decrease and these specific to stratified squamous epithelia such as the skin. Langer-
patients to have less pigment. hans cells are frequently seen isolated in the middle and upper
suprabasal cell layers (Fig. 1.20). The cells are distributed at a
Increase of 5-S- MEMO density of 400/mm2 to 1,000/mm2. They lack tonofilaments and
cysteinyl dopa (5-S-CD) in serum cell attachment structures, such as desmosomes, and they
Generally in malignant melanomas, pheome-
lanins are vigorously synthesized, and 5-S-
migrate. By electron microscopy, a few fibrillary components
cysteinyl dopas in the blood and urine and Birbeck granules, whose cross-section is a characteristic ten-
increase. Therefore, the increase of 5-S-CD in nis racquet shape, are observed in the cell cytoplasm (Fig. 1.21a).
the blood indicates metastasis of a malignant Birbeck granules are known to be Golgi-apparatus-derived or
melanoma and its degree of spreading.
membrane-derived, and carry antigens in the cells.
B. Epidermis 11
1
Langerhans cells present antigens to T cells (see Chapter 3 for
immune reactions in the epidermis). Since the Langerhans cell is
ATPase positive, CD1a positive and S-100 protein stain positive,
it is easily distinguished from other kinds of cells.
f. a-dendritic cell
The a-dendritic cell is found in the epidermis. It resembles a
Langerhans cell because of its lack of adhesive intercellular
50 m
mm
m
structures such as desmosomes; however, it can be distinguished
by its lack of Birbeck granules. Although the origin and function
Fig. 1.20 Langerhans cell (immunostaining
of a-dendritic cells are unknown, these cells may be precursors against CD1a).
of Langerhans cells or otherwise related to Langerhans cells.
g. Merkel cell
The Merkel cell is a tactile cell found in the basal cell layer.
Greater numbers of Merkel cells are seen in the fingers, oral
mucosa and trichodis areas (the hair roots). With angular plasma
membrane projections, Merkel cells are connected to adjacent
keratinocytes by desmosomes (Fig. 1.21b). Multiple dense-core
granules called Merkel cell granules are found in Merkel cells, to
which the sensory (free) nerve endings are connected by synaps-
es beneath the cell. After physical stimulation, neurotransmitters
are secreted from Merkel cell granules, and the tactile informa-
tion is transmitted to the sensory nerve.
a b c d e f g h
neural crest cell melanin

cap
migration epidermis
dermis
melanoblast
migration of melanosome to a horny cell
differentiation
melanocyte
a b c d e f g h i
nuclear
division Ⅳ
Fig. 1.21 Histopathology of Langerhans cell
and Merkel cell.
Ⅲ a: Birbeck granules of Langerhans cell (arrows).
b: Dense-core granules of Merkel cell (arrows).
Ⅱ
Four stages
mature stageⅠ of melanin in a Langerhans cell MEMO
melanocyte melanosome, divided histiocytosis (LCH)
by melanin pigmentation This used to be called histiocytosis X, a dis-
ease in which a malignancy occurs from
formation of melanosome excess proliferation of Langerhans cell histio-
cytes.
Fig. 1.19 Maturation of melanosomes.
C. Dermis
a. Structure of the dermis
The dermis is the structure beneath the epidermis, and the two
are separated by the basal membrane (Fig. 1.3). The dermis is
approximately 15 to 40 times as thick as the epidermis. It consists
of three layers.
Papillary layer: The dermal area that projects into the intervals
between the epidermal ridges. The fiber components are thin and
richly supplied with capillaries, sensory nerve endings and cyto-
plasm.
Subpapillary layer: The area underlying the epidermis, contain-
ing the same components as the papillary layer.
Reticular layer: Accounts for the largest part of the dermis and
has dense connective tissue comprising fiber components. The
cellular components
lymphatic vessel blood capillary nerve mast cell fibroblast histiocyte plasma cell
basement
Meissner corpuscle
membrane
epidermis
papillary layer
subpapillary
layer
reticular dermis dermis
subcutaneous
tissue
Pacinian corpuscle collagen fiber elastic fiber ground substance
dermal matrix
Fig. 1.22 Structure of the dermis.

C. Dermis 13
1
lower part comes into contact with the subcutaneous fatty tissue.
There are blood vessels and nerves in some parts. ★
The components of the dermis comprise the fibrous tissue and
the dermal matrix formed by cells in the interstitial components
(Fig. 1.22). The major components mainly consist of collagen ★
fibers (mainly types I and III), with smaller amounts of elastic
fibers, reticular fibers and matrix. This matrix generally compris-
es the extra-cellular matrix and ground substance made up of ★
proteoglycans and gelatin. Fibroblasts, macrophages, mast cells,
plasma cells, vascular channels and nerves are common cellular
components.
b. Interstitial components
1. Collagen fibers
Collagen fibers account for 70% of the weight of dry dermis
(Fig. 1.23) and appear white to the naked eye. The collagen
fibrous component is poorly extensible; however, it is extremely
a b c d e f g h
tough and especially resistant to tension parallel to the fibers.
This characteristic is important in maintaining the dynamic
strength of skin.
Collagen fibers form from aggregations of thin fibrils. The
more fibrils there are in the fiber, the thicker and stronger the
fiber. Thin collagen fibers are sparsely seen in the papillary lay-
ers and subpapillary layers; however, collagen bundles, with fully
developed thick collagen fibers, are densely distributed in the
reticular dermal upper layers.
In light microscopy, the proteinaceous collagen fibers stain
well in eosin solution; they stain red in Van Gieson and blue after
Mallory staining. The fibril is observed by electron microscopy
as being very long, 100 nm to 500 nm in diameter with cross stri-
ations that repeat at intervals of 60 nm to 70 nm (Figs. 1.23 and
1.24). Fibrils become collagen fibers by aggregating with glyco- g
a b c d e f h i
proteins. A thick collagen bundle can reach 2 mm to 15 mm in
Fig. 1.23 Histopathology of the dermis.
diameter. a: Collagen fibers (stars) and elastic fibers
Collagen fiber molecules are produced in the rough endoplas- (arrows). b: High-power magnification of colla-
mic reticulum of fibroblasts. Helical procollagens with three a- gen fibers. Stripes approximately 60 nm to 70 nm
chains are secreted and the molecular ends are cut by procollagen in width are seen.
peptidase to become tropocollagens. The molecules are cross- 60~70 nm tropocollagen
linked to each other with a regular gap that forms the striped col- molecule
lagen fiber (Fig. 1.23b).
Twenty subtypes of collagen molecules with a-chains of dif-
ferent molecular structures are known to exist (Table 1.2); how-
ever, type I collagen accounts for 80% of the collagen fibers that
make up the dermis. Reticular fibers, which distribute in the
perivascular regions as thin argyrophilic fibers and do not form
thick fiber bundles, are type III collagen, and these account for
about 15% of all fibers. Most of the remainder is thought to be Fig. 1.24 Stripes of collagen fibers.
Fine fibrils (tropocollagens) have cross-links,
type V collagen. Types IV, VII and XVII are mainly found in the giving the fibers a striped appearance.
basal membranes, associated with epidermal keratinocytes.
1
Table 1.2 Types of collagen fibers.
Fiber Type
2. Elastic fibers
Fibrillar I, II, III, V, XI The elastic fiber is not as tough as the collagen fiber; however,
Basement membrane IV it is extremely elastic and found abundantly in the dermis of the
Anchoring fibril VII scalp, face and the extensible organs such as arteries and tendons.
Network forming VIII, X
In the dermis, the deeper the elastic fiber, the thicker it is. In
the reticular layers, elastic fibers are scattered among collagen
FACIT IX, XII, XIV, XIX, XX
bundles running parallel to the skin surface. The closer the elastic
Microfibril VI
fiber is to the papillary layer, the thinner it is and the more per-
Multiplexin XV, XVIII pendicular it is to the skin surface. It forms an arch shape in the
Other XIII, XVII papillary layer from which thin fibers are produced that perpen-
FACIT: fibril associated collagen with interrupted dicularly reach the lamina densa. Elastic fibers are also connected
triple helix to the lamina densa of glands, sweat ducts, smooth muscle,
nerves and blood vessels.
Elastic fibers are 1 mm to 3 mm in diameter. They cannot be
differentiated from collagen fibers by HE staining. Elastic fibers
stain dark blue to black in Weigert resorcin fuchsin, red-violet in
aldehyde fuchsin, and brownish black in orcein. In elastic fibers,
the characteristic striped pattern of collagen fibers is not
observed by electron microscopy (Fig. 1.23). A skeletal fiber is
10 nm to 15 nm in diameter and its main content is fibrillin. The
homogeneous substances are highly elastic structural proteins
called elastins.
3. Ground substance, Matrix

Ground substance, a gelatinous amorphous substance of sugar
and proteins, is observed in between fibers and between cells in
the dermis.
The components of ground substance are principally proteo-
glycans and glycoproteins whose molecular weight is 150,000 to
250,000 and whose sugar content is 2% to 15%. The molecules
stabilize the fibers to give flexibility to the skin. Fibronectin, one
kind of glycoprotein, contains a domain that connects fibrin,
heparin and collagen; and binds integrin receptors on the cell sur-
face are involved in cell proliferation, differentiation and wound
healing. Besides these components, blood and lymph-derived tis-
sue fluid forms the remainder of the ground substance that is
involved in the transport of substances essential to cellar activi-
ties and metabolism.
Proteoglycans are a massive molecules with a molecular
weight of 105 to 106 or more and a composition of multiple gly-
MEMO
cosaminoglycans (mucopolysaccharides) connecting with back-
Abnormality in elastic
fibers or collagen fibers bone proteins. Glycosamine, mostly produced by fibroblasts in
If elastic fibers are decreased, lost or dena- the dermis, is rich in hyaluronic acids, which are associated with
tured, dermatolysis or senile cutis rhom- moisture retention.
boidalis nuchae may occur. If fibrillin
molecules are congenitally abnormal, Marfan
syndrome results (Chapter 18). Abnormalities
in collagens, which are components of colla-
gen fibers, may lead to Ehlers-Danlos syn-
drome, which causes skin fragility.
C. Dermis 15
1
c. Cellular components
1. Fibroblast
Fibroblast differentiates from the mesenchymal cells and pro- 20 mm
duces collagen fibers, elastic fibers, and glycosaminoglycans.
Fibroblasts appear as thin spindle-shaped cells sparse in collagen Fig. 1.25 Fibroblasts (arrows).
fibers (Fig. 1.25).
By electron microscopy, multiple Golgi apparatus and granular
endoplasmic reticuli are seen in the fibroblast. When collagen
fibers are produced and the dermis matures, fibroblasts stop their
activities and become fibrocytes. At this point, the cell nuclei
shrink and have fewer endoplasmic reticuli. Adrenal cortex hor-
mones and thyroid hormones are involved in this process.
20 mm
2. Histiocyte
Fig. 1.26 Histiocytes (arrows)
The histiocyte, a kind of macrophage, is broadly distributed in
the connective tissue and intermingles with fibroblasts on the
Histiocyte, Monocyte, MEMO
outside of endocapillary cells (Fig. 1.26). A small circular nucle- Macrophage
us and a large spindle- or star-shaped cell structure is seen in a Large phagocytic cells in the living body are
histiocyte by light microscopy; furthermore, concave nuclei and called macrophages. There are two kinds.
the formation of psudopodial protrusions are observed by elec- -- Free macrophages: e.g., monocytes in the
blood, migrating macrophages in granuloma
tron microscopy. Histiocytes contain Golgi apparatus, smooth -- Fixed macrophages: e.g., histiocytes in the
and rough endoplasmic reticuli, and lysosomes. Lysosomes con- dermis and subcutaneous tissues, Kupffer
tain hydrolases and active acid phosphatases. The histiocyte cells
Histiocytes and monocytes are kinds of
releases collagenase and lysosomal enzymes containing elastase macrophages.
to digest the interstitium. It is involved in organ repair. The histi-
ocyte degrades and phagocytoses mainly foreign substances and
presents them as antigens to T cells (Chapter 3). Melanophages MEMO
Melanin granules that have exfoliated from
the epidermis to the dermis are often phagocy-
3. Mast cell tosed by histiocytes. Histiocytes that become
brownish-red after repeatedly phagocytosing
The mast cell is found in the dermis around capillaries and in melanin granules are called melanophages.
the periphery of subcutaneous tissues. The shape is roundish or
spindled, and the diameter is 10 mm (Fig. 1.27). Mast cells pro-
duce and maintain various vasodilatory and hyperlucent chemical
mediators. Mast cell granules stain red-violet in toluidine blue
and methylene blue, and present with metachromasia. Cutaneous
mast cells resemble basophils in form and function; however,
their characteristics differ slightly from those of other organs, 20 mm
because they differentiate in skin during intrauterine life.
A mast cell intracytoplasmic granule appears as a circular
structure with a diameter of 0.3 mm to 0.5 mm under electron
Histiocytes, the key to MEMO
microscopy. Multiple mast cell granules are evenly distributed in pathological diagnosis
the cytoplasm. Chemotransmitters in the granules are released Epithelioid cells, Touton giant cells, xan-
outside the cell under various stimuli, such as in type I allergic thoma cells and foreign-body giant cells in an
reactions (Fig. 1.28, Chapter 3). The main components of the epithelioid cell granuloma are histiocytes that
pathologically present in an atypical form.
released substances are histamines and heparins, followed by
1
various enzymes, including neutrophil chemotactic factors
(NCF), eosinophil chemotactic factors of anaphylaxis (ECF-A),
tryptase, chymase and tumor necrosis factor (TNF)-like sub-
stances. The mast cell may produce and release inflammatory
substances such as prostaglandins, leukotorienes and platelet-
activating factors.
20 mm 4. Plasma cell
a b c d e f g h i j k l m n o p q r
The plasma cell is a differentiated B cell that has been stimu-
lated by an antigen. It produces antibodies and is involved in
humoral immunity. The shape of the plasma cell varies from cir-
cular to pear-shaped, and the diameter ranges from 8 mm to 14
mm, which is twice as large as a leukocyte. It has a wheel-shaped
nucleus with peripheral chromatin (Fig. 1.29).
5. Dermal dendrocyte
20 mm
a b c d e f g h i The dermal
j kdendrocyte
l is m
found in
n the dermal
o upper
p layer
q (inr
Fig. 1.27 Mast cells. and between the papillary layer and the reticular layer). It is
a: Hematoxylin and eosin staining. b: Metachro- thought to be an immunocompetent cell (Chapter 3), and it is
masia is seen by toluidine blue staining. characterized by containing clotting factor XIIIa.
antigen
d. Vascular channels and nerves
second exposure
of the antigen
1. Blood vessels
nucleus nucleus Multiple branches of arteries distributed in skin (Figs. 1.30 and
histamine 1.31) are connected with each other in the dermal deep layer to
form a horizontal network (subcutaneous plexus). With numer-
ous branches ascending from the subcutaneous plexuses, the
sensitized vasodilation
mast cell arteries form a second network in the papillary lower layer (sub-
vascular
permeability papillary plexus). The arterioles ascend through the papillary
itch layer, forming capillary loops in the dermal papillaries before
moving to venules that connect to each other to form two kinds
Fig. 1.28 Sensitization by mast cells.
of plexuses, whereby the blood flows into the cutaneous veins
(Fig. 1.30). There are also characteristic plexuses in the periphery
of the cutaneous appendages. The peripheral regions of the
eccrine glands are particularly rich in vascular networks, which
control blood flow volume and body temperature by perspiration.
Moreover, hair follicles in the anagen (growth) stage are also
richly supplied with blood vessels, present in the surrounding
dermal tissue.
There is another apparatus that circulates the blood directly
from arteries to blood vessels: This is the arteriovenous anasto-
20 mm
mosis, which is controlled by sympathetic nerves. The arteriove-
nous anastomosis controls the peripheral blood flow and is
Fig. 1.29 Plasma cells (arrows).
involved in body temperature regulation. Glomus apparatuses,
which have spherical anastomotic branches, are seen everywhere
in the skin. They are particularly well developed in the fingers, at
apical ends of the toes, and below the nails. Many layers of
C. Dermis 17
1
epidermis
50 mm
Fig. 1.31 Blood vessels (hematoxylin and

eosin).
rmis
50 mm
Fig. 1.30 Distribution of blood vessels in the dermis. Fig. 1.32 Lymphatic vessels (hematoxylin
and eosin).
smooth muscle cells (epithelial cells or glomus cells) cover the
peripheral walls of the endothelial cells.
Under the electron microscope, endothelial cells, pericytes,
and the multilayered basement membrane (lamina densa) in the
peripheral interstitium may be observed in the capillaries. The
stick-shaped Weibel-Palade granule, which has a diameter of 200
nm and a length of 1 mm or less, contains factor VIII associated
with histamines and blood coagulation. It is found in the endothe-
lial cell. Pericytes have a vasoconstrictive effect, and they are Discriminating between MEMO
seen on the perimeter of the walls of the endothelial cells. blood vessels and lymph vessels
The important points in discriminating
between these are tabulated below.
2. Lymphatic vessel
Lymph
Lymph vessels are distributed around the subpapillary layer Item Blood vessel
vessel
region and extend through the postcapillary lymph vessels to the Factor VIII Positive Basically
dermal and subcutaneous lymph vessels. The endothelial cells of negative
the lymph capillaries are thin, without pericytes or lamina densa. Basal layer Extended and Intermit-
They are partly ruptured and are surrounded by loose collagen multi-layered tent
fibers and elastic fibers (Fig. 1.32). The closer the endothelium is Intercellular Developed Weak
to the dermal deep layer, the more continuous it becomes with connection
the valva in the lumen. The structure of lymph vessels is not as Lumen Round Irregular
regular as that of the blood vessels. Aggregated cutaneous lym- shape
phatic fluid passes through the regional lymph nodes and flows Elastic fiber Arteries: positive Negative
stain in the internal
into the blood vessels. elastic layer
veins: negative
1
3. Nervous system
The nerve fiber bundle is covered with a membrane in the der-
mal lower layers. The nerve fibers change from being myelinated
to non-myeliated where the nerve bundle branches into many
fibers in the dermis, and these branched fibers are distributed
within the superficial dermis and peripheral appendages (Fig.
1.33). The sensory nerves transmit tactile, pressure, pain and
50 mm temperature sensation. The autonomic nerves control the blood
a b c d e f g vessels,
h j
isweat glands and
k otherl appendages.
m n o p q r
1) Sensory nerve
The sensory nerve structures include free nerve endings sens-
ing pain, Merkel cells (described above) that perceive tactile sen-
sation in the epidermal basal layer, and nerve end bulbs that
100 mm accept tactile, pressure and vibration sensation.
a b c d e f g h ①Free
i j
nerve ending
k l m n o p q r
The free nerve endings are distributed in the dermal upper and
papillary layers. Some of them adhere to Merkel cells in the der-
mal papillary layer, whereas others infiltrate into the dermis
directly. Nonmyelinated nerves transmit pain sensations.
②End corpuscle
myelinated
The end corpuscle is a specific sensory nerve terminal covered
with a membrane. Various end corpuscles are described below.
Meissner end corpuscle: The nerve fiber spirally ascends
through the Schwann cell (inner bulb cell) in the dermal papillae
of the palms, soles, lips of the mouth, and external genitals, per-
ceiving tactile and pressure sensations (Fig. 1.34).
Pacinian corpuscle: It is seen in the dermal deep layer and sub-
nonmyelinated cutaneous tissue of the palms, soles, and external genitals. The
nerve central nerve fiber is multi-layered with concentric membranes. It
b c d e f g h i p be clearly
isj oval, kwith a lmajor maxis ofn1 mm,o and can q r
seen by
Fig. 1.33 Nerve fibers. light microscopy (Fig. 1.35). It reacts to vibration.
a: Myelinated nerve fibers. b: Unmyelinated
nerve fibers. c: Electron microscopy.
2) Autonomic nerves
The autonomic nerves are principally distributed in the sweat
glands, arrector pili muscles, blood vessels and glomus appara-
tuses, to control the functions of these organs. The cholinergic
nonmyelinated sympathetic nerves are distributed in the eccrine
sweat glands. Mitochondria, and dense core and non-core vesi-
cles containing chemical substances are observed. The adrenergic
sympathetic nerves are distributed in the arrector pili muscles and
blood vessels.
50 mm
Sympathetic nerves distributed in the MEMO

Fig. 1.34 Meissner corpuscle (hematoxylin eccrine sweat gland
and eosin). The sympathetic nerve is generally adrenergic; however, that in the
eccrine gland is exceptionally cholinergic.
D. Subcutaneous fat tissue 19
1
100 mm
Fig. 1.35 Pacinian corpuscle (hematoxylin

and eosin).
D. Subcutaneous fat tissue

The subcutaneous tissue is the layer between the dermis and
the fascia. The fat tissue acts to preserve neutral fat, cushion
against external physical pressure, retain moisture and generate
heat.
The subcutaneous tissue is largely composed of fat cells.
Assembled fat cells separated by the connective fibroid fat sep-
tum are called fat lobules. Fiber bundles produced in the dermis
and firmly connected with the fascia and periostea through the
subcutaneous tissue are found throughout this region. These fiber
bundles are called retinaculae cutis, and they strengthen the con-
nection between the dermis and deeper tissues.
The main component of the fat droplet is triglyceride, com-
posed of olein acid and palmitin acid. Since a large droplet
accounts for most of the contents of the cellular cytoplasm in the
fat cell, other cellular organelles are pushed to the edge.
Multiple smooth muscles called tunicae dartoses are character-
istically seen in the dermal deep layers and subcutaneous tissues
Fig. 1.36 Tunica dartos in the skin of the
of the scrotum, penis, labia majora and nipples (Fig. 1.36). scrotum.
The boundary between the subcutaneous tissue and skeletal
muscle is called the musculus cutaneous. It is not clear in sites
with muscles of expression, such as in the face.
The thickness of the subcutaneous tissue depends on the body
site, age and other factors. It is particularly thick in the cheeks,
breasts, buttocks, thighs, palms and soles; it is thin in the eyelids,
dorsal nose, lips of the mouth, and labia minora; subcutaneous
tissue is absent in the foreskin. Subcutaneous tissue tends to
develop and enlarge in newborn infants and in children at puber-
ty. In embryos and newborn infants, heat is produced at a rapid
rate by brown fat tissue in the dorsal region, which contains mul-
tiple fat droplets.
1
E. Appendages
hair shaft infundibulum a. Hair apparatus
epidermis The hair apparatus plays a role subsidiary to that of the sensory
hair
follicle keratinized nerves in protecting the scalp from external forces and light, and
outer root
sebaceous sheath in moderating heat in the head. Eyelids protect the eyes from dirt,
isthmus
gland
hair medulla and armpit hair and pubic hair absorb mechanical friction. The
hair
hair cortex
hair cuticle number of hairs on a person’s head averages 100,000. The hair
apparatus is found throughout the skin except on the lips of the
arrector pili muscle mouth. It consists of hair and hair follicles that enclose the hair.
hair root
hair bulge
inner root sheath fusion
lower part
sheath cuticle inner root 1. Hair follicle

Huxley’s layer sheath
Henle’s layer The layer of tissue that encloses a hair is called a hair follicle.
outer root sheath
hair bulb
hyaline membrane It is aligned obliquely to the skin surface. Part of the hair follicle
connective tissue sheath is slightly enlarged to form a hair bulge to which the base of the
melanocyte
hair matrix
arrector pili muscle is connected (Figs. 1.37, 1.38-1 and 1.38-2).
Dermal stem cells reside in the hair bulge. Sebaceous glands are
blood capillary
seen above the bulge stem cells, and apocrine glands open further
Fig. 1.37 Longitudinal section of the hair above. The bottom of the hair root during the growth stage
follicle. bulges out spherically; it is called a hair bulb and contains a hair
group of cells known as the hair papilla. The hair follicle opens
in a funnel shape (hair infundibulum).
The hair follicle is double-bounded with two layers, with an
epithelial interior and connective tissue component on the exterior.
outer longitudinal connective

layer
tissue
inner circular sheath (CTS) connective tissue sheath (CTS)
layer
basement membrane
outer root sheath (ORS)
outer root sheath (ORS)
Henle’s layer inner root sheath (IRS)

inner root
Huxley’s layer sheath (IRS)
cuticle of the cortex of hair shaft
root sheath /
sheath cuticule
cuticula of hair shaft
papilla
cortex of hair shaft
melanocyte
hair matrix cell

100 mm 50 mm
anagen metaphase hair papilla anagen early phase
Fig. 1.38-1 Structure of the hair follicle (longitudinal section).
E. Appendages 21
1
The epithelial components are the inner and outer root sheaths. connective tissue
The connective tissue component is called the connective tissue sheath (CTS)
sheath. basement
membrane
ORS
1) Connective tissue sheath (CTS) IRS
cortex of
The connective tissue sheath (CTS) covers the outside of the hair shaft
hair follicle and is a layer connected with the dermis. Collagen hair shaft
fibers run circularly inside the connective tissue sheath and longi-
tudinally outside of it. Several elastic fibers can be found among
these collagen fibers. 100 mm
a b c d e f g h
2) Outer root sheath (ORS) connective

tissue
sheath (CTS)
hair follicle
The outer root sheath (ORS) is the outermost part of the hair basement membrane
infundibulum (inner two layers). It is keratinized and comprises ORS
Henle's layer
Henle’s
keratinocytes that contrain a light cytoplasm without keratohya- Huxley's layer
Huxley’s
IRS
line granules. The outside of the outer root sheath meets the con- cuticle of the
root sheath/
nective tissue sheath at the basal membrane. The inside of the sheath cuticle
cuticula of hair shaft
hair
outer root sheath is connected by desmosomes with the Henle’s
a b 100 mmc d e f of hairgshaft h
cortex i
layer, the outermost layer of the inner root sheath. medulla
connective
tissue sheath
3) Inner root sheath (IRS) (CTS)
basement
membrane
The inner root sheath (IRS), found inside the outer root sheath, ORS
consists of capsular layers, Huxley’s layer (a double layer of IRS
cells), and Henle’s layer (a single layer of cells). The capsular
cuticles anchor and entangle each other, with the differently cuticula of
hair shaft
directed apical tips functioning as hooks to stabilize the hair. The cortex of
Henle’s layer is connected with the outer root sheath by desmo- hair shaft
somes. (medulla)
100 mm
a inter-b c d e f g hair h
papilla i j
Keratinization occurs in the inner root sheath close to the
follicular epidermis. IRS has the appearance of trichohyalin gran-
Fig. 1.38-2 Structure of the hair follicle
ules. These granules, often found in Henle’s layer and Huxley’s (cross section).
layer, stain eosinophilically. Keratinization finishes at the height a: Hair follicular isthmus. b: Lower part of a hair
of the sebaceous gland opening, and it is followed by exfoliation. follicle. c: Hair bulb (see Fig. 1.37 for the cross-
section position).
4) Hair bulb
The hair bulb is the bulge of the hair follicle, with a dermal
hair papilla at its center. The keratinocyte follicle enclosing and
covering the dermal hair papilla semi-spherically is the hair
matrix layer, where hair and inner root sheath cells grow and
extend upward. The outer root sheath forms the outermost layer
of the hair bulb. Melanocytes that provide hairs with melanins
are also found in the hair matrix.
Unusual keratinization MEMO
of the outer root sheath
2. Hair shaft When cells in the outer root sheath denucleate
and keratinize without passing through the
The hair shaft is composed of a three-layered structure. From granular layer or becoming flat, it is called
trichilemmal keratinization.
innermost to outermost, the layers are the medulla, cortex and
1
cuticula.
Tonofilaments align in the direction of the axis in the cortex,
and a pattern similar to that observed for keratin by electron
microscopy is observed at the tips of the tonofilaments. That is,
keratinization is seen in the cortex; however, unlike in the epider-
mis and inner root sheath, no formation of keratohyaline granules
or trichohyaline granules is seen. Unlike the keratins found in
other epithelial cells, the keratins that are produced in hair cortex
are rich in cystines, glycines and tyrosines. Such specific keratins
are called hard keratins, a general term, and they are also found at
other sites, including the nails.
In the hair cuticle, the cortex is covered by flat cells in a scale-
like pattern, and they are attached to the capsular cuticles of the
inner root sheath. This connection becomes the outermost layer
of the hair shaft, protecting the shaft. The cuticles may be injured
and the natural glow of hair lost if there is excessive physical
damage to hair, such as over-brushing, or excessive use of chem-
icals such as hair dyes or permanent solutions.
Hair color differs according to the size and number of
melanosomes: Large and/or multiple melanosomes are seen in
dark hair, and red hair contains large amount of pheomelanins.
3. Hair cycle
The hair has a regular period of growth (anagen), transition
(catagen), and rest phase (telogen) (Fig. 1.39). Head hair grows
for several years after it sprouts (anagen: about 80% of all head
hair), after which its growth rate slows for 2 to 3 weeks (catagen:
about 1% to 2%) and then stops. The hair remains for several
months after it stops growing (telogen: about 15%). As a new
hair is produced, hair within the same follicle in the telogen
phase falls out. Hair in the catagen period grows 0.3 mm to 0.5
mm per day.
When hair follicles in the anagen phase repeat cell division
and transition to the catagen phase, they begin to contract and
cell division stops. The hair follicle cells lose their ability to
divide in the telogen phase and ascend to the elevated part of the
hair. The hair root presents a stick-like shape called club hair. In
the telogen phase, macrophages phagocytose melanin pigments
fixed and cell fragments in the hair papilla.
part
As the anagen phase comes around again, cell division begins
at the surface of the hair follicle. A hair papilla forms and a new
hair bulge growing hair grows in the hair matrix. It pushes out the club hair, which
The part part exfoliates.
hair papilla deeper than
this point Only the part of the hair with stem cells below the hair bulge
recedes. expands and contracts in the hair cycle. That area is called the
anagen catagen telogen fluctuation area, and the upper area is called the fixation area.
(6-8 years) (2 weeks) (3-4months) The human hair cycle differs for each hair; however, the overall
quantity of hair remains roughly constant.
Fig. 1.39 Hair cycle.

E. Appendages 23
1
b. Arrector pili muscle

The arrector pili muscle is a smooth muscle bundle between
the outer root sheath and the dermal upper layer. The hair stands
vertically after contraction of the arrector pili muscles. This
slightly elevates the peripheral hair follicles (causing goose
bumps). Controlled by the adrenergic sympathetic nerves, the
arrector pili muscle is contracted by cold stress and emotional
stresses including fear and surprise. The formation of goose
bumps may accompany shivering that occurs to raise the body
temperature.
c. Sebaceous gland
The sebaceous gland produces sebum (Fig. 1.40) that mixes
with moisture such as sweat and is emulsified on the skin surface
to form fatty acids that coat the skin. The coat is an acidic bacte-
ricide with a pH of 4 to 6 (acid mantle). Sebum and sebaceous
glands prevent invasion and infection by pathogens and toxic
substances. Additionally, the sebaceous glands control water loss
from the skin and maintain moisture in the horny cell layers.
The sebaceous glands are widely distributed throughout the
skin, except in the palms and soles and some mucous mem-
branes, but most of them open to the upper hair follicles at hair
follicle sites. Sites where multiple individual sebaceous glands
congregate are called sebaceous zones. They are seen in the scalp,
face (the “T zone,” which includes the forehead, regions of the
glabella and the nasolabial groove), sternal regions, armpits, naval,
and external genitals. The seborrheic zone is very densely distrib-
uted with sebaceous glands (400/cm2 to 900/cm2). Sebaceous
glands open directly to the skin surface at hairless sites, which
are distributed in the lips of mouth, buccal mucosa, areola
acrosyringium
straight duct
coiled duct
sebaceous
secretory unit gland
apocrine sweat
gland free sebaceous gland
hair
eccrine sweat gland
Fig. 1.40 Sweat glands, hair follicles and sebaceous glands.
1
mammae, vagina, labia pudendis, glans penis and foreskin inner
plate. These glands are called free sebaceous glands, because
they are not attached to hair follicles. Meibom glands in the eye-
lids are a type of free sebaceous gland.
The sebaceous gland is composed of sebaceous lobules and a
duct that carries sebum to the hair follicle. The daughter cell, pro-
duced by cell division, migrates into the lobule as it matures, to
produce fat droplets. As they migrate, sebocytes are filled with
exocytosis fat droplets and the cells rapture, resulting in secretion of the
(eccrine secretion) cytoplasm and fat, which is called holocrine secretion (Fig. 1.41).
The amount of fat secretion changes with age. Large amounts
of fat are produced in newborn infants, and small amounts in
children. Production begins to increase again from puberty. The
secretion of fat peaks in women in their second and third decades
of life, and in men in their third and fourth decades of life,
decreasing thereafter. The amount of fat secretion is controlled
predominantly by sex hormones: testosterone in men, and adrenal
androgens in women. Hormones derived from the mother are
apocrine serection
thought to be important in newborn infants.
(beheading secretion)
d. Sweat glands
Human sweat glands are either eccrine, distributed throughout
most of the body, or apocrine, found at specific sites of the body
and producing and discharging sweat to the body surface. Both
are hair follicle-associated glands consisting of a secretory part
and a sweat duct. The secretory parts are coiled and surrounded
holocrine secretion
by fat tissues in the deep dermal layer and subcutaneous tissue
(Fig. 1.40).
Fig. 1.41 Types of secretion.
1. Eccrine sweat glands
Eccrine sweat glands are found over the entire body, especially
in the palms, soles, and armpits, at a density of 130/cm2 to
600/cm2. They are known to number approximately 3 million.
Perspiration is enhanced by thermal stimulation, which is asso-
ciated with body temperature control, but it may be stimulated by
mental strain or gustatory stimulus (gustatory sweating). The
total amount of perspiration in a day is controlled by acetyl-
cholines and is known to average 700 ml to 900 ml (in adults).
Two-layered secretory cells with a circular nucleus and periph-
100 mm eral flat myoepithelial cells are observed in the secretory area by
a b c d e f g light
h microscopy
i j (Fig.k 1.42-1).
l Cellsmon thenbasal-layer
o p con-q
side r
Fig. 1.42-1 Errcine sweat gland. tain few subcellular organelles and a large amount of glycogens.
a: Cross section. Since these cells secrete large amounts of serous sweat by eccrine
secretion (Fig. 1.41), they are also called serous cells. Cells on
the luminal side secrete mucus. The myoepithelial cell is a
smooth muscle cell that pushes the accumulated sweat out of the
lumens to the sweat ducts by contraction.
The sweat duct ascends perpendicularly in the dermis (straight
duct) through the coiled duct that extends from the secretory area
E. Appendages 25
1
(Figs. 1.40 and 1.42-2). The sweat duct contains two cell layers,
consisting of intraluminal cells and peripheral cells, and it lacks
myoepithelial cells. The sweat that is produced in secretory areas
(as precursor sweat) is slightly hypertonic; therefore, sodium ions
and chlorine ions are re-absorbed by intralluminal cells in the
coiled ducts, and hypotonic sweat is finally secreted.
2. Apocrine sweat glands

Apocrine sweat glands, which number fewer than eccrine 100 mm
glands, are degenerated pheromone-producing mammary glandsa b c d e f g h i
found in the armpits, external ear canals, areola mammae, exter-
nal genitals and anus. They develop in conjunction with hair
apparatuses, temporarily slow in development after birth, and
accelerate with development again during puberty. Perspiration
from these glands is considered to be adrenergic and is caused
mostly by emotional stimulation. Mammary glands and Moll’s
glands are kinds of apocrine sweat glands. Although sweat is vis-
cous and odorless, its components such as glycoproteins and fat
are broken down by microbes resident on the skin surface, which
produces odor. Glandular development is associated with sex
hormones; the glands are thought to be involved with sexual
function.
The secretory portion of the apocrine gland is larger than that
of the eccrine gland. Secretory cells are aligned as a single-layer
epithelium surrounded by myoepithelial cells (Fig. 1.43). The
part of the cytoplasm that faces the lumen of the sweat duct
bulges, blebs and separates from the cell (apocrine secretion;
100 mm
Figs. 1.41 and 1.44).
a g j
The sweat ducts do not open to the skin surface directly, butb c d e f h i
open on to the upper parts of the sebaceous glands (Fig. 1.40). Fig. 1.42-2 Eccrine sweat gland.
b: Longitudinal section (epidermis). c: Longitudi-
nal section (dermis).
e. Nail
The nail is a portion of keratinized epithelial tissue and com-
posed of the nail plate, nail matrix, nail folds and nail bed. Each
of these parts comprises several more detailed structures (Fig.
1.45). The nail differentiates from the epidermis in the third
month of fetal development. Recent studies have shown that the
nail has characteristics of both dermis and hair. The fingernail
grows 0.1 mm per day, and it takes about 6 months to re-grow an
entire nail plate. The growth of nails is slower in the elderly,
whose nails tend to be thick and brownish. Nails are important in
protecting the digits and in assisting subtle sensation in the fin-
gertips.
100 mm
1. Nail plate
Fig. 1.43 Apocrine sweat gland (cross sec-
The nail plate is a rectangular horny plate on the dorsal tip of tion).
the digits consisting of top nail, middle nail and undernail. In the
proximal area, the nail plate is ingrown and covered by the
1
proximal nail fold, where the nail matrix exists. Cells that prolif-
erate are keratinized in the nail matrix to form the nail plate. Ker-
atohyaline granules are not involved in this keratinization. An
opaque white half moon shape (lunula) may appear at the root of
the nail plate from inadequate keratinization.
2. Nail matrix
Keratinocytes are produced in the nail matrix. The cells that
differentiate and proliferate in the nail matrix extend and kera-
tinize to form the nail plate; however, the undernail of the nail
plate is considered to form in the nail bed.
Fig. 1.44 Apocrine secretion of the sweat

gland. 3. Nail fold
The nail folds are the skin lesions that cover both sides of the
nail plate and nail bed. The cuticle is the horny layer that extends
and partly covers the nail plate.
nail bed
4. Nail bed
nail plate nail groove
The nail bed is seen at the bottom of the nail plate. Its compo-
nents are the same as those of the epidermis, except that it lacks a
lateral nail fold
nail matrix
lunula granular layer and is continuously keratinized to connect with the

nail plate.
proximal nail fold
cuticle
Fig. 1.45 Anatomy of the nail.
Bleeding in cuticle MEMO

Hemorrhagic punctums in the cuticle may be
found in collagen diseases (e.g., systematic
lupus erythematosus, dermatomyositis, scle-
roderma). It is thought to be caused by the
mechanism of angiitis in the microvessels. It
may be a risk factor for systemic angiitis.
Chapter
2
2 Histopathology of the Skin
Skin biopsy is the most frequently used and important test for dermatological diagnosis. In a biopsy, a sample of
skin is collected for observation under the microscope. There are many cases in which it is impossible to make
a diagnosis based only on the clinical symptoms. A blister, for example, may be caused by various pathomech-
anisms, including viruses, bacteria and autoimmune diseases, or by heredity. It is often difficult to diagnose a
blister just by naked-eye observation and disease history. To specify the cause of the disease and reach a final
diagnosis, dermatopathological examination is essential.
A. Skin biopsy
In skin biopsy, a biopsy site is selected, a skin specimen is
removed, and the sample is fixed and stained. It is necessary to
select a site that is without secondary changes and that is cosmet-
ically acceptable. In inflammatory diseases, it is recommended to
include the peripheral normal skin for comparison with the
lesion. When a disease presents various lesions, it is preferable to
collect multiple skin samples from different stages of inflamma-
tion.
After local anesthesia, a biopsy specimen is removed (Figs.
2.1-1 and 2.1-2). The main methods for removing a sample are
punch biopsy (clipping of a round sample), incisional biopsy
(removal of a spindle-shaped sample with a surgical knife), and
excisional biopsy (removal of the entire site). Shave biopsy (sam-
ple excision by razor blade) is another method for observing a
lesion in the epidermis. The removed sample is fixed immediate-
ly with 10% formaldehyde to avoid secondary degeneration. The
sample may be divided for cryo fixation or 2% glutaraldehyde
fixation for an immunofluorescence test or electron microscopy.
A skin specimen is prepared for hematoxylin-eosin (HE) stain-
ing. As shown in Table 2.1, various staining methods, known
collectively as special staining procedures, are often used in com-
bination. Immunostaining using monoclonal antibodies is also
effective for diagnosis.
Preparation of a skin biopsy MEMO

Skin biopsy may scar the site to varying degrees; therefore, the site and
biopsy method should be chosen carefully, especially when it is per- Fig. 2.1-1 Procedure of skin biopsy.
formed on cosmetically important sites or on patients with a keloidal Punch biopsy.
tendency. It is essential to record clinical conditions by photographing
the biopsy site, as well as to obtain the patient’s informed consent by
thoroughly explaining the necessity of the biopsy.
27
28 2 Histopathology of the Skin
2 Table 2.1 Specific stains used in dermatology.

Stain Stained material Stained color
Hematoxylin and eosin Entire skin Blue (nucleus), magenta
(HE) (cytoplasm, etc.)
Elastica van Gieson Collagen fibers Red
Elastic fibers Black
Azan Mallory Collagen fibers Blue
Masson trichrome Collagen fibers Green
Periodic acid-Schiff Basement membrane Red
(PAS)
Glycogen Red
Neutral mucopolysaccharides Red
Fungi Red
Fig. 2.1-2 Procedure of skin biopsy.
Incisional biopsy with a surgical knife. Toluidine blue Mast cells Purple (metachromasia)
Acid mucopolysaccharides Blue
Alcian blue Acid mucopolysaccharides Blue
Sudan III Fats Orange-red
Congo red Amyloids Red
Dylon Amyloids Orange-red
Berlin blue Hemosiderins Blue
Kossa Calcium Black
Grocott Fungi Black-purple
Ziehl Neelsen Mycobacteria Red
B. Dermatopathology
When observing a pathological specimen, it is necessary to
identify the abnormality in the specimen by comparison with nor-
mal findings (Figs. 2.2-1 and 2.2-2). This section introduces fun-
damental terms for skin pathological changes and diseases.
a. Epidermis
1. Acanthosis (epidermal hyperplasia)

Acanthosis describes thickening of the epidermis. It is classi-
Fig. 2.2-1 Normal skin (hematoxylin and fied into flat (the entire site thickens moderately; e.g., in chronic
eosin staining).
a: Normal skin of the forearm. A basket-weaved eczema), proriasiform (epidermal protrusions are extended),
horny cell layer is seen. Gaps between the stained papillomatous (the epidermis projects upwards; e.g., with viral
horny cell layers are lipids that dissolved during warts or seborrheic keratosis), and pseudocarcinomatous (pseu-
fixation. These gaps indicate that the skin is well
protected by moisturizing lipids. dosquamous cell carcinomas project irregularly downward; e.g.,
chronic ulcer margin, deep mycoses) (Figs. 2.3 and 2.4).
2. Epidermal atrophy (epidermal hypoplasia)

Epidermal atrophy (epidermal hypoplasia) is caused by reduc-
tion of keratinocytes (Fig. 2.5). It leads to thinning of the epider-
mis. As a result, the papillary processes are diminished or lost. It
B. Dermatopathology 29
2
normal
flat
psoriasiform
papillomatous
pseudocarcinomatous
b c d e f g h i j k l m n o p q r
Fig. 2.3 Patterns of acanthosis.
c d e f g h i j k l m n o p q r
Fig. 2.2-2 Normal skin (hematoxylin and eosin staining).
b: Normal skin of the sole. A thick horny cell layer is seen. c: Scalp.
Many follicles can be seen. d: Face. Sebaceous glands are abundant. Fig. 2.4 Acanthosis.
Chronic eczema.
is often found in senile skin, discoid lupus erythematosus, lichen

planus and actinic keratosis.
3. Hyperkeratosis
The horny cell layer becomes abnormally thick. This is seen in
psoriasis vulgaris, ichthyosis and callus (Fig. 2.6). In ichthyosis,
hyperkeratosis is due to detachment and exfoliation of the horny
cell layer, a process called retention hyperkeratosis. Keratiniza- Fig. 2.5 Epidermal atrophy.
tion associated with hair follicles is called follicular keratosis. Dermatomyositis.
4. Parakeratosis
Parakeratosis is caused by incomplete keratinization in which
nuclei remain in the cells of the horny cell layer (Fig. 2.7). In
normal skin, keratinocytes denucleate when they reach the horny
2 cell layer; however, keratinocyte formation in inflammatory dis-

eases such as psoriasis vulgaris or in tumorous diseases such as
actinic keratosis and Bowen’s disease takes place so quickly that
most of the nuclei remain in the horny cell layer. It is frequently
accompanied by hyperkeratosis and hypogranulosis. The nuclei
remain physiologically in the mucous membranes.
Wedge-shaped or columnar parakeratosis, called cornoid
lamellae, is observed in porokeratosis (Chapter 21).
5. Dyskeratosis
Fig 2.6 Hyperkeratosis.
Chronic eczema. Dyskeratosis occurs when some keratinocytes keratinize
abnormally before they reach the horny cell layer (Fig. 2.8). The
keratinocytes become apoptotic and necrotic. The nuclei shrink
and contain eosinophilic cytoplasm. Since intercellular bridges
between the peripheral keratinocytes are lost, the cells become
round. Dyskeratosis is often found with inflammatory diseases
and malignant tumors. It is termed “grains” in Darier’s disease
and “individual cell keratinization” in Bowen’s disease.
6. Hypergranulosis
Fig. 2.7 Parakeratosis.
Psoriasis vulgaris. Hypergranulosis is a thickening of the granular cell layers to
four or more layers from the normal one to three layers (Fig.
2.9). It is often found in lichen planus, viral warts and congenital
ichthyosis.
7. Granular degeneration, Epidermolytic

hyperkeratosis
In granular degeneration, numerous vacuolated cells contain-
ing large keratohyaline granules appear in the granular cell layer
and suprabasal cell layer (Fig. 2.10). It is characteristic of Vörner
palmoplantar keratosis and bullous congenital ichthyosiform ery-
throderma (Chapter 15). It may also be found in epidermal nevus
Fig. 2.8 Dyskeratosis. and even in normal skin.
Bowen’s disease.
8. Spongiosis, Intercellular edema

Spongiosis occurs when the spaces between neighboring ker-
atinocytes are enlarged by intense edema. As a result, the inter-
cellular space becomes extended and distinct (Fig. 2.11). When
aggravated further, intradermal blisters (spongiotic bullae) form.
It is found in eczemas and dermatitises such as contact dermati-
tis, atopic dermatitis and acute eczema.
9. Intracellular edema (ballooning

degeneration)
Fig. 2.9 Hypergranulosis.
Parapsoriasis. Intracellular edema is the infiltration of cytoplasm into ker-
atinocytes (Fig. 2.12). As the swelling develops, the cells deform
and become spherical (ballooning degeneration). If the cytoplasm 2

swells even further, the cells break and the membranes remain in
a network pattern (reticular degeneration). It is found in eruptions
caused by viral infections such as that of the herpes simplex
virus.
10. Acantholysis
Acantholysis is the dispersion of keratinocytes resulting from
the dissociation of keratinocyte intercellular adhesion, particular-
Fig. 2.10 Granular degeneration.
ly that of desmosomes. Intercellular spaces and blisters form, Bullous congenital ichthyosiform erythroderma.
with acantholytic cells (spherical keratinocytes that have lost
their intercellular adhesion) floating inside. Acantholytic cells
have a tendency to become dyskeratotic (Fig. 2.13). The phe-
nomenon is found in pemphigus, Hailey-Hailey disease and Dari-
er’s disease, and it may also be found in part of the lesions of
actinic keratosis, keratoacanthoma, warty dyskeratoma and squa-
mous cell carcinoma.
11. Blister, Bulla

Blisters, whose contents are cytoplasm and infiltrating cells,
are divided into intraepidermal and subepidermal, according to
the histological findings (Fig. 2.14). Intraepidermal blisters are Fig. 2.11 Spongiosis.
classified by formation mechanism into severe spongiosis Acute eczema.
(eczema/dermatitis group), prominent acantholysis (e.g., pemphi-
gus vulgaris), reticular degeneration (e.g., herpes infection) and
basal cell degeneration (e.g., burns, epidermolysis bullosa sim-
plex).
Causative diseases of subepidermal blistering are autoimmune
bullous diseases such as bullous pemphigoid, epidermolysis bul-
losa acquisita, dermatitis herpetiformis (Duhring) and epidermol-
ysis bullosa, and burns (Chapter 4).
12. Pustule
A pustule is a blister containing purulent components (mainly
Fig. 2.12 Intracellular edema.
neutrophils). A small pustule below the horny cell layer is called Herpes simplex.
Munro’s micro-abscess, which characterizes psoriasis vulgaris
(Fig. 2.15). A multilocular pustule, also called a spongiform pus-
tule, is caused by damage to keratinocytes from neutrophilic
infiltration in which intercellular junctions are retained. It resem-
bles the network formation that is found in pustular psoriasis
(Kogoj’s spongiform pustule) (Fig. 2.16). Pautrier’s micro-
abscess is produced by infiltration of tumorous lymphocytes and
is not a genuine pustule (refer to the following section).
13. Exocytosis (cell infiltration into the

epidermis) Fig. 2.13 Acantholysis.
Exocytosis is the infiltration of inflammatory cells and Pemphigus vulgaris.
2 erythrocytes into the dermis. It is mostly found in spongiotic

space. Infiltration of lymphocytes is seen in epidermal inflamma-
tory diseases such as contact dermatitis and atopic dermatitis.
Infiltration of multinucleated leukocytes is observed as a pustule
in impetigo contagiosa, palmoplantar pustulosis and psoriasis.
In cutaneous T-cell lymphomas such as mycosis fungoides,
tumorous T cell may infiltrate into the epidermis forming a mass
that does not become spongiform; it is called Pautrier’s microab-
scess for its resemblance to an abscess (Fig. 2.17). Langerhans
Fig. 2.14 Bulla. cells infiltrate into the epidermis in Langerhans cell histiocytosis.
Bullous pemphigoid.
b. Dermo-epidermal junction
1. Vacuolar degeneration (hydropic

degeneration)
Vacuolar degeneration occurs when the dermo-epidermal junc-
tions become vacuolated and ill defined as a result of basal cell
degeneration (Fig. 2.18). It is often accompanied by edema and
lymphocyte infiltration, and the basal membranes are lost at the
site. It is an inflammation that mainly occurs at the dermo-epider-
Fig. 2.15 Munro’s microabscess. mal junction. When further aggravated, subepidermal blisters
Psoriasis vulgaris.
form. Melanin granules contained in basal cells may permeate
into the dermis, a condition called incontinentia pigmenti histo-
logica. The macrophages phagocytose melanin granules. Dysker-
atosis caused by necrotic keratinocytes is seen in erythema
multiforme, lichen planus, lupus erythematosus and graft-versus-
host disease (GVHD). An eosinophilic Civatte body with a diam-
eter of 10 mm may be found immediately beneath the dermis
(Fig. 2.9).
Fig. 2.16 Kogoj’s spongiform pustule.

Pustular psoriasis. 2. Melanin synthesis abnormality
Production of melanin pigment in the basal epidermal layer is
increased by exposure to ultraviolet radiation. When pigment is
lost, leukoderma is observed. Generally, to diagnose melanin
synthesis abnormality, a DOPA test or an immunohistological
test is performed.
Albinism: A congenital abnormality of melanin synthesis.
Melanin loss can be identified by Fontana Masson staining, for
example.
Idiopathic guttate hypomelanosis: Melanocytes experience
functional reduction by aging.
Nevus of Ota: Ectopic melanocytes are found in the dermis.
Chloasma: Melanocytes and melanin pigments increase.
Freckles: Melanocytes experience functional increase.
Fig. 2.17 Pautrier’s microabscess.

Mycosis fungoides.
2
c. Dermis
1. Inflammatory cell infiltration

Inflammatory cell infiltration occurs when inflammatory cells
such as neutrophils, eosinophils, lymphocytes, plasmacytes,
macrophages and mast cells infiltrate around the blood vessels
(perivascular infiltration). There are several infiltration patterns,
such as lichenoid infiltration (the cells infiltrate in a band resem-
bling that in lichen planus), vasculitis (the cells cause fibrinoid
degeneration, blood clots, or bleeding in the blood vessels), and
nodular infiltration.
The principal infiltrating cells and the causative diseases are
shown in Table. 2.2.
2. Granuloma
A granuloma is a thick aggregation of histiocytes (mostly
macrophages) that form focal chronic infiltration. The
macrophages in granulomas are called epithelioid cells. Besides
macrophages, in granulomas one can observe lymphocytes, Fig. 2.18 Vacuolar degeneration.
fibroblasts, degenerated connective tissue, and blood vessels. Graft-versus-host disease. Dyskeratosis is also
Granulomas are classified according to the distribution patterns seen, from the apotosis of the epidermal ker-
atinocytes.
and subtypes of inflammatory cells, as below.
Sarcoidal granuloma: The main components are epitheliod cells
Table 2.2 Diseases with inflammatory infiltration into the skin.

Infiltrated
Disorders
cells
Neutrophils early-stage inflammation; irritant contact dermatitis,
erythema nodosum, etc.
infections; impetigo, candidiasis, etc.
disorders associated with reactions of immunocomplex and
complements; cutaneous small-vessel vasculitis, Sweet’s
disease, Behçet’s disease
Eosinophils early inflammation; incontinentia pigmenti
Fig. 2.19 Sarcoidal granuloma.
autoimmune diseases; pemphigus, bullous pemphigoid,
Cutaneous sarcoidosis. In sarcoidosis, epithelioid
etc.
cell granuloma is accompanied by few inflamma-
type I allergy tory cell infiltration, which is also called “naked
malignant diseases; mycosis fungoides, Langerhans cell granuloma.”
histiocytosis
Lymphocytes inflammations; allergic diseases, etc.
Plasma cells infections; syphilis, lymphogranuloma venereum deep
fungal infection
actinic keratosis, syringocystadenoma papilliferum, etc.
Histiocytes granulomatous diseases; sarcoidosis, granuloma annulare,
etc.
Mast cells inflammations; atopic dermatitis, chronic eczema, lichen
planus, etc.
other; wounds (especially during healing), neurofibroma, etc.
2 and giant cells. It contains a few necrotic foci and slight lympho-
cytic infiltration. This is the typical epithelioid cell granuloma
observed in sarcoidosis (Fig. 2.19).
Tuberculoid granuloma: Epithelioid cell granuloma with
caseous necrosis in the center and abundant lymphocytic infiltra-
tion at the periphery is observed.
Palisading granuloma: The granuloma contains degenerated
collagen fibers and mucin deposition in the center, with peripher-
al macrophages in a palisade or circular pattern. It is found in
granuloma annulare and rheumatoid nodules.
Suppurative granuloma: An abscess (neutrophilic infiltration)
surrounded by macrophages and lymphocytes, it is found in deep
mycoses.
Foreign-body granuloma: Macrophages, neutrophils and lym-
phocytes accumulate around an extrinsic body (e.g., glass, suture
thread, animal hair, plant fiber) or an intrinsic body (e.g., elastic
fiber, calcium deposits, cholesterin crystal). It is a normal reac-
tion to foreign bodies (Fig. 2.20). Giant cells that have phagocy-
tosed a foreign body are often observed; however, the foreign
substance becomes buried in fibrous tissues over time.
Fig. 2.20 Foreign-body granuloma. Choles- 3. Giant cell

terin deposition (arrows).
Giant cell is the general term for cells that contain a character-
istically large nucleus. Most giant cells derive from macrophages
and are multinuclear from the fusion of macrophages or repeated
nuclear division (Fig. 2.21). Ballooning observed in viral dis-
eases and Reed-Sternberg cells found in Hodgkin’s disease are
types of giant cells.
foreign body giant cell Langhans giant cell
These are other types:
Foreign-body giant cell: Macrophages grow large by phagocy-
tosing foreign substances The nuclei are irregularly arranged
(Fig. 2.20).
Langhans giant cell: Syncytial macrophages with regularly
arranged nuclei in a circular or horseshoe-shaped arrangement.
These often found in tuberculosis, sarcoidosis, and lichen nitidus.
Touton giant cell Touton giant cell: These macrophages phagocytose fat tissue.
The eosinophilic cytoplasm at the center of the cell is surrounded
Fig. 2.21 Giant cells originating from histio-
cytes.
by a nucleus that is further surrounded by foamy light cytoplasm.
Touton giant cells are found in juvenile xanthogranuloma and
xanthoma.
4. Changes in connective tissue

Fibrosis (irregular proliferation of fibroblasts and collagen
fibers such as in scarring and dermatofibroma) and sclerosis
(decrease of fibroblasts, swelling or homogenization of collagen
fibers, radiation dermatitis, scleredema) are observed in changes
of collagen fibers. Elastic fibers decrease in size and number,
fracture, and degenerate in senile skin and pseudoxanthoma elas-
ticum. Edema with detachment of connective tissue and accumu-
lation of serous fluid (scleredema) and dermis elevation caused 2
epidermis
by projected dermal papillae (papillomatosis) are also changes of
connective tissues.
5. Deposition of foreign substances
dermis
Substances that deposit in the dermis include amyloids (e.g., in
macular amyloidosis, lichen amyloydosis), mucins (e.g., myxede-
ma, lupus erythematosus), calcium (e.g., in carcinosis cutis, pseu-
subcutaneous tissue
doxanthoma elasticum, CREST syndrome), hemosiderins (e.g., in
bruising, angiitis, hemochromatosis), uric acid, porphyrin and
hyaline.
d. Subcutaneous fat tissue

septal panniculitis
1. Panniculitis
epidermis
Panniculitis is an inflammation of the subcutaneous fat tissue
(Figs. 2.22 and 2.23). It is categorized by the site of inflamma-
tion. In septal panniculitis, inflammation occurs mostly in the
dermis
septa of the subcutaneous fat tissue, such as seen in erythema
nodosum. In lobular panniculitis, inflammation occurs in the lob-
ules of the fat tissue, such as seen in erythema induratum. Panni-
culits can also occur in acute pancreatitis from the fat necrosis subcutaneous tissue
that occurs as a complication.
2. Other changes in fat tissue

Lipogranuloma, lipoatrophy, liponecrosis, lipolysis, lipoma
lobular panniculitis
and liposarcoma are other changes of fat tissue.
Fig. 2.22 Differences between septal panni-
culitis and lobular panniculitis.
Black dots are the infiltrated inflammatory cells.
Fig. 2.23 Septal panniculitis.

Erythema nodosum.
2
C. Immunohistochemistry
Table 2.3 Monoclonal antibodies frequently Immunohistochemical techniques are used to identify sub-
used in dermatology. stances in tissue by marking them with specific antibodies. They
Marker
Positive skin component/ are widely used in dermatology for identification of antinuclear
disorder antibodies, autoantibodies of autoimmune blistering diseases, and
cytokeratin (CK) epithelial cell infiltration of malignant lymphoma cells. The methods of label-
CAM 5.2 (CK8, sweat gland, mesothelioma ing are immunofluorescence using fluorescent pigments, and an
CK18, CK19) immunoenzyme method. Antibodies frequently used in dermatol-
cytokeratin 20 Merkel cell ogy are listed in Table 2.3.
epithelial mem- epithelial cell
brane antigen
(EMA) 1. Immunofluorescence (IF)
vimentin mesenchymal cell
Immunofluorescence (IF) is an immunological staining
desmin striated muscle, smooth method that uses antibodies labeled with fluorescent material
muscle
such as fluorescein isothiocyanate (FITC) to detect the molecule
a smooth muscle striated muscle, smooth
actin (SMA) muscle
connected to the antigen. It is used to detect antigens, antibodies,
complements and causative factors of diseased tissues and to
neuron-specific Schwann cell, melanocyte,
enolase (NSE) cartilage examine serologic reactions. IF techniques are classified by the
S-100 protein nerve fiber, paraganglionic
labeled antibody reactions into direct fluorescent antibody test,
cells, melanocyte indirect fluorescent antibody test and complement fixation test
HMB45, MELAN A malignant melanoma (Figs. 2.24 and 2.25).
carcinoembryonic sweat gland
antigen (CEA), 1) Direct IF
CD66e
Ki-67 (Mib-1) proliferation marker of tumor A fluorescent-labeled antibody is used to detect the antigen.
cell When the labeled antibody detects the tissue, fluorescence
factor VIII endothelial cell of the vessel appears at the site with the target substance, and that fluorescence
factor XIII endothelial cell, dendritic cell can be observed by fluorescent microscopy. This type of test is
gross cystic dis- sweat gland used for detection of the autoantibody in vivo, mainly in autoim-
ease fluid protein mune diseases such as lupus erythematosus, pemphigus vulgaris
(GCDFP)-15 and bullous pemphigoid. Direct IF is also used for detection of
CD1a Langerhans cell pathogenic microbes in tissues.
CD3 T cell
CD4 helper T cell
2) Indirect IF
CD8 cytotoxic T cell
CD20 (L26) B cell Indirect IF is a two-phase technique whereby an unlabeled pri-
CD30 (Ki-1) Hodgkin’s disease, anaplastic
mary antibody reacts against a target substance, and a labeled
large-cell lymphoma secondary antibody is reacted against the primary antibody. In
CD31 endothelial cell, fibrous tumor dermatology, it refers to detection of an antibody, especially in
CD34 endothelial cell, hemangioma,
the patient’s blood.
dermatofibrosarcoma In bullous pemphigoid, for example, an IgG antibody circulat-
protuberans ing in the bloodstream reacts directly with the basal membrane of
CD56 natural killer cell the patient. Direct IF is used to detect the antibody reacting in a
CD68 macrophage, myeloid cell patient’s skin in vivo. In indirect IF, a patient’s serum is reacted
CD79a B cell against normal skin, and then a labeled anti-IgG antibody is
cyclin D1 mantle cell lymphoma
reacted. If the IgG anti-basal membrane antibody is present in the
serum, fluorescence is observed on the basal membrane zone.
Indirect IF is widely used not only in dermatology but in other
fields for various tests, including detection of antibodies and
C. Immunohistochemistry 37
2
A. direct IF
antigen labeled antigen-specific fluorescence

antibody
B. indirect IF
＋＋
antigen antigen specific anti-IgG antibody labeled fluorescence (+)

antibody (IgG) with fluorescent
C. complement IF
＋＋＋
antigen antigen complement labeled anti-complement fluorescence (+)

specific antibody antibody
Fig. 2.24 Mechanisms of the immunofluorescence technique.

(Ueki H, et al, editors. Atlas of immune tissues in dermatology. Nankodo; 1996).
syphilis FTA-ABS tests (Chapter 27) using normal skin as the

substrate.
3) Complement IF
An unlabeled primary antibody is reacted against the target
substance and is provided with complement components. Then a
labeled secondary antibody (labeled anti-C3 antibody) is reacted
against the target substance. a b c d e f g h
2. Immunoenzyme method
In the immunoenzyme method, an enzyme rather than a fluo-
rescent material is labeled with an antibody. Antigens,
immunogloblins and complements can be detected using the
enzyme reaction. Enzymes such as peroxidase are labeled with
an antibody to react against the target molecules in the tissue in
the same way as in the IF technique. The presence of the target
substance and its distribution are indicated by the presence and
a b c d e f g h i
distribution of the pigments.
Immunoenzyme method has the following advantages over IF: Fig. 2.25-1 Examples of immunofluorescent
staining pattern.
the enzymatic reaction makes electron microscopic observation a: Epidermal basement membrane (bullous
possible, the reaction is easy to observe and has a high detection pemphigoid). b: Intercellular space of the ker-
range, and the samples can be stored longer than those of IF. It atinocyte (pemphigus vulgaris).
2 can also be used for electron microscopic section.
Fig. 2.25-2 Examples of immunofluorescent
staining pattern.
c: Perivascular area (anaphylactoid purpura).
D. Electron microscopy (EM) and immuno EM

The electron microscope is a device that generates enlarged
images of a specimen by emitting electron beams instead of visi-
ble light. Electron microscopy (EM) and immuno EM achieve
magnifications of 1,000 times and greater, so they can be used to
observe fine intracellular and intercellular structures (e.g., Bir-
beck granules in Langerhans cells) that are not visible by light
microscopy.
The transmission electron microscope exposes an ultra-thin
a b c d e f g specimen
h i to anj electron
k beam. l It is m
possible
n to achieve
o magnifi-
p q r
cations of 500,000 times.
Immuno EM, a combination of immunostaining and electron
microscopic observation, has greatly contributed to the develop-
ment of dermatological science, such as in the identification of
autoantigens in autoimmune blistering diseases (Fig. 2.26). In
scanning EM, electron beams reflected from an exposed object
are detected. It is effective in revealing three-dimensional struc-
ture; however, the magnifying power is not as high as that of
a b c d e f g h transmission
i j EM.
k l m n o p q r
Fig. 2.26 Immunoelectron microscopy of
the bullous pemphigoid (BP) proteins in
normal skin.
a: BP180, a transmembrane protein in the base-
ment membrane zone. NC16a, the most impor-
tant domain of BP pathogenesis, is in the basal
cell membrane. b: BP230 is immediately inside
the basal cell membrane, a component of the
hemidesmosome.
Chapter
3 Immunology of the Skin
3
The recent rapid progress in immunology has had a great influence on dermatology. Many diseases are now
understood thanks to increased knowledge of immunology. Furthermore, it has come to be known that the skin
itself plays a major role in the immune system. This chapter introduces the fundamental mechanisms of
immunology and the pathophysiology of various skin diseases.
A. Basics of immune reactions

hematopoietic stem cell
a. Immune system
Immunity is crucial in protecting the human body from patho-
genic microorganisms. Skin physically prevents foreign microor- multipotent progenitor cell
ganisms from invading the body. The human body coexists with
microorganisms on the surface of the skin, in the intestines and in
mucous membranes. It thereby maintains a balance; however, if common lymphoid common myeloid
the balance collapses for whatever reason, the microorganisms progenitor cell progenitor cell
begin to harm the body, and the immune system is activated.
The immune system performs the following functions:
●Distinguishing between “self” and “non-self.”

B cell T cell NK cell
●Excluding “non-self.”
●Remembering what has invaded (immunologic memory).
These functions are performed by the immunocompetent cells,

such as lymphocytes and antigen-presenting cells, both of which
macrophage granulocytes
are derived from bone marrow (Fig. 3.1). How these cells act
against various pathogens is briefly described below.
neutrophil
b. Reaction pattern eosinophil
basophil
cytotoxic helper
Foreign substances (antigens) including bacteria, viruses, T cell T cell
transplanted organs and certain proteins are distinguished as
“non-self” by the immune system. The receptor, also called the
major histocompatibility complex (MHC), plays a critical role in
plasma cell
identifying whether a substance is self or non-self. In humans, it
is called HLA (human leukocyte antigen), because it was discov-
ered in leukocytes. HLA is classified as class I (HLA-A,B,C) or
Fig. 3.1 Myelogenous cells composing the
class II (HLA-DP,DQ,DR)(Fig. 3.2). Every human has a differ- immune system.
ent HLA pattern that identifies what is non-self. Some diseases
that are thought to occur in individuals with specific HLA have
been revealed (Table 3.1).
A cell or a protein recognized as non-self is phagocytosed by a
histiocyte (macrophage) or a dendritic cell, such as a cutaneous
Langerhans cell. The phagocytosed substance is processed, and
39
40 3 Immunology of the Skin
#6 chromosome HLA part of it is recognized by lymphocytes as antigenic information

associated with MHC class II molecules. The cells that actively
3 engulf the foreign substance and transmit the information to T
cells by MHC class II molecules are called antigen-presenting
cells (APC). Cells infected by latent viruses degrade the virus-
DP DQ DR B C A
derived proteins and transmit the information to T cells by the
class II class III class I function of MHC class I molecules. The information of the anti-
antigen antigen antigen
gen is conveyed by the combination of a T-cell receptor (TCR)
Fig. 3.2 HLA (human leukocyte antigen) and MHC, resulting in immune activation and reaction (Fig. 3.3).
genes on the short arm of chromosome 6.
Genetic recombination causes the HLA pattern to
differ for each individual. c. Humoral immune reaction
1. Antibodies
The antibodies, proteins produced by B cells, react against
infectious agents or pathogenic proteins (antigens) to inhibit
infections and neutralize protein toxicity. Numerous specific B
cells and antibodies corresponding to the antigens exist in the
body. There are five immunoglobulins in descending order of
concentration from IgG, IgM, IgA, IgD, to IgE (Table 3.2). IgG,
produced at the time of infection or in the late stage of infection,
accounts for 75% of immunoglobulins and plays a central role in
the humoral immune reaction (Fig. 3.4). IgM appears preceding
IgG at the early stages of infection and strongly activates protein
complements. IgA is seen abundantly in exocrine secretions,
such as mucus, where it prevents invasion of causative factors.
IgE reacts to basophils and mast cells to evoke type I allergy.
Table 3.1 Association between HLA complex and skin diseases.

Associated HLA in Associated HLA
Disorder Chapter
ethnic Japanese in Caucasians
Behçet’s disease B51 B51 11
Systemic lupus A11, B40, DR2, B8, DR2, DR3 12
erythematosus DRW9
Neonatal lupus DW12 12
erythematosus
Sjögren syndrome DR3, DW3 12
Rheumatoid arthritis DR4 DR4 12
Pemphigus vulgaris A10, DR4 A10, B13 14
Herpes gestationis A1, B8, DR3 14
Epidermolysis bullosa B8 14
acquisita
Dermatitis herpetiformis B8, DW3 14
(Duhring)
Pustular psoriasis B27 15
Psoriasis vulgaris Cw6 Cw6 15
A. Basics of immune reactions 41
MHC class Ⅰ MHC class I molecule T-cell receptor

CD8
perforin 3
Fas-Fas L apoptosis of the infected cell
B7 CD28 Fas
infected cell cytotoxic T cell
delayed hypersensitivity
MHC class II molecule T-cell receptor IFN-g reaction against
MHC class Ⅱ
CD4 infected cells, etc.
IL-12 macrophage
Th1 IL-2 cytotoxic efffect

B7 CD28
antigen-presenting helper T IL-4
cell (Th) cytotoxic T cell
cell
Th2
IL-4 antibody production
(kills pathogen)
B cell
Fig. 3.3 Immune reactions classified by MHC class.

Each class of MHC presents antigen information to different types of T cells.
2. Complements
The complements, proteins contained in serum, are classified
into nine types from C1 to C9, and can be subclassified. In the
classical pathway, C1 reacts to IgG or IgM antibodies, followed
by continuous reaction of complements, and finally the antigen binding sites
pathogens and infectious cells are penetrated. In the alternative
pathway, the reaction is evoked mostly by bacterial components, N terminus
which directly activate C3, factor B and factor D.
ＶＨ H chain
ＳＳ
ＳＳ
Table 3.2 Basic characteristics of immunoglobulins.
ＳＳ
ＳＳ
Fab ＣＨ１ＶＬ
ＳＳ
IgG IgM IgA (secretory) IgD IgE

ＳＳ
F（ab´）2
ＳＳ
proteolysis by papain
ＳＳ
Molecular weight 150,000 970,000 160,000 184,000 188,000 L chain ＣＬ

Ｓ
(390,000)
Ｓ
Ｓ
Ｓ
Serum concentration 12.0 1.5 3.0 0.03 0.00005

ＳＳ
ＳＳ
proteolysis by pepsin
(mg/ml)
Half-life in blood 21 5 6 3 3 hinge
ＳＳ
ＳＳ
(days) ＣＨ２
Fc
Antigen type of heavy g m a d e
chain
ＳＳ
ＳＳ
ＣＨ３
Transport across the (+) (-) (-) (-) (-)
placenta
Activity of (+) (+) (-) (-) (-)
complement fixation C terminus
Basic structure (monomer)
Fig. 3.4 Basic structure of human
immunoglobulin (IgG).
(dimer) secretory piece Fab: Fragment antigen binding. Fc: Crystalliz-
able fragment. VL: Variable light chain. CL:
J chain Constant light chain. VH: Variable heavy chain.
J chain
CH: Constant heavy chain.
Clinical symptoms MEMO

resulting from abnormalities of
3 complements
Various skin diseases, including those with
systemic lupus erythematosus (SLE) like
symptoms, Raynaud’s syndrome, angioneu-
rotic edema and opportunistic infections, may
be caused by congenital abnormalities and
deficiencies of complementary proteins.
B. Immunocompetent cells
a. Immunocompetent cells in general
1. T cells
T cells express T-cell receptors that recognize the antigen
information associated with MHC molecules (Fig. 3.3). T cells
are produced in the bone marrow and develop in the thymus. T
cells are classified by function into CD4 positive helper T cells
(helper T lymphocyte; Th) and CD8 positive cytotoxic T lym-
phocytes (Tc).
Th contains CD4 on the cell surface, by which Th adheres to
MHC class II. Therefore, Th reacts against antigen-presenting
cells and B cells, which contain MHC class II. Th differentiates
into subtype Th1 or Th2, depending on the surrounding cytokine
environment (Fig. 3.3). Th1 secretes cytokines such as IL-2 and
IFN-g , activating histiocytes (macrophages) primarily, and it
induces cellular immunity by evoking various inflamatory reac-
tions. Th2 secretes IL-4 and IL-5, activates antibody production
in B cells, and inactivates foreign substances (humoral immuni-
ty). It is known that Th1 is involved mostly in type IV allergy
while Th2 is involved in type I allergy (atopic diseases).
Tc contains CD8, by which Tc is associated with MHC class I
to initiate cytotoxic immunity (Fig. 3.3); in this way, non-self
cells and virus-infected cells are destroyed. Tc is important in
transplantation immunity, tumor immunity and viral infections.
Recently, the presence of another subtype – regulatory T cell
(Treg) – has been identified. Treg is considered to be involved in
immune control, including suppression of autoimmune disease
onset. It is also known that some Th and Tc circulate in the blood
after an immune reaction to guard against re-infection.
2. B cells
B cells derive from hematopoietic stem cells in the bone mar-
row, after which they differentiate. They react against foreign
antigens in lymph nodes, the spleen, and peripheral tissues to dif-
ferentiate into antibody-forming cells (plasma cells); B cells pro-
duce antibodies in this process. B cells contain MHC class II and
B. Immunocompetent cells 43
activate T cells as antigen-presenting cells. Immunoglobulins Th1/Th2 balance MEMO

expressed on the surface of B cells react to the corresponding tar- Th1 is involved in cytotoxic immunity,
geted antigens to convey information to T cells. When activated, including apoptosis; Th2 is involved in 3
most of the B cells differentiate into antibody-producing cells humoral immunity, including type I allergy.
Th1 and Th2 release mutually inhibitive
that provide antibodies against the antigens and die in the course cytokines; it is thought that this maintains a
of time – except for some that differentiate into memory B cells balance between the two (Th1/Th2 balance).
so that they are able to produce antibodies immediately upon re- In recent years, various allergies and malig-
nant tumors have been explained by the con-
infection. cept of Th1/Th2 imbalance. For example,
atopic dermatitis and type I allergy are
thought to be caused by a Th2-dominated
3. Histiocytes (macrophages) immune reaction, and organ-specific autoim-
mune diseases and arterial sclerosis are
Histiocytes (macrophages) are bone marrow-derived cells that thought to result from a Th1-governed
have intense phagocytic reactivity. There are dermal-originated immune reaction.
histiocytes and monocytes circulating in the blood. Histiocytes
degrade phagocytosed antigen proteins into peptides and present
the antigen information to T cells by MHC class II (Fig. 3.3). In
inflammation, histiocytes proliferate, migrate to loci, leave vari-
ous cytokines, and induce phagocytosis of causative factors and
injure the infected cells. Histiocytes may fuse to form enlarged
cells. They are the main cells to form granulomas in chronic
inflammation (Chapter 2).
4. Mast cells
Mast cells play a central roll in type I allergy. They contain
high-affinity IgE receptors (FceRI) and considerable amounts of
histamines. When binded with IgE and further cross-linked by an
antigen to react to IgE, mast cells are activated to release inflam-
matory cytokines that lead to dermal edema in erythema or
urticaria. Mastcytosis is caused by tumorous proliferation of mast
cells. 20 m m
5. Eosinophils Fig. 3.5 Eosinophil.

The cytoplasm is eosinophilic (stained red in
Eosinophils have phagocytic and cytotoxic functions. They are Hematoxylin-Eosin). Note the multiple nuclei.
associated with atopic diseases (type I allergy), autoimmune blis-
tering diseases, and parasitic infections. Eosinophils are activated
by Th2-derived IL-5. Morphologically, they are characterized by
having multiple eosinophilic granules (Fig. 3.5). They do not
usually exist in normal skin.
6. Neutrophils
Neutrophils are phagocytic and play a large role in fighting
bacterial infections (Fig. 3.6). They are hardly ever found in nor-
mal skin. They are also activated in inflammatory diseases. Neu- 20 m m
trophilic infiltration (pustule) is observed in psoriasis vulgaris
and Sweet’s disease.
Fig. 3.6 Neutrophil.
In skin, cytoplasm of neutrophils is less
eosinophilic than that of eosinophils. A neu-
trophil has a multiple segmented nuclei.
7. Basophils
3 Like eosinophils and neutrophils, basophils are also granular
leukocytes, and they contain multiple basophilic granules. They
contain histamines in the granules and have FceRI on the surface.
They are involved in type I allergy. The functions of basophils
are similar to those of mast cells.
b. Immunocompetent cells specific to skin
1. Langerhans cells
Langerhans cells are bone marrow-derived cells and appear as
dendritic cells. They contain the characteristic racquet-shaped
Birbeck granules in the cellular cytoplasm (Figs. 3.7 and 3.8).
Langerhans cells are antigen-presenting cells that are specific to
the skin. Langerhans cells adhere to the epidermal keratinocytes
by E-cadherins, functioning as sentinels against foreign antigens.
When presenting an antigen to T cells, Langerhans cells are
Fig. 3.7 Langerhans cell electron micro- known to detach from the epidermis to reach the regional lymph
graph. nodes through the lymphatic vessels (Fig. 3.9). On the surface of
the human Langerhans cells are MHC class II, CD1a, and S-100
proteins; this is useful for identifying them. With stimulation by
antigens, they express CD80 and CD86 by the functions of GM-
CSF and TNF-a secreted from keratinocytes to strongly activated
T cells.
Langerhans cells disappear in lesions in graft-versus-host dis-
ease (GVHD).
2. Keratinocytes
Keratinocytes are involved not only in cornification but also in
skin immunity. They produce and secrete various cytokines to
stimulate immuno-incompetent cell activation (Table 3.3). IL-1
a is particularly abundant in keratinocytes. When keratinocytes
are destroyed by inflammation or injury, IL-1a is released to
evoke activation of lymphocytes, histiocytes (macrophages), and
vascular endothelial cells, which induces an inflammatory reac-
Fig. 3.8 Birbeck granules (arrows).
High-power magnification of Fig.3.7. Birbeck tion.
granules look like tennis racquets in sectional
image.
3. Dermal dendrocytes
Dermal dendrocytes are bone marrow-derived cells found in
the upper dermal layers. Since dermal dendrocytes are character-
ized by expressing the factor XIIIa on their surface and have anti-
gen-presenting ability, dermal dendrocytes are considered to be
Langerhans-related cells in the dermis. They increase in number
in inflammatory diseases and Kaposi sarcoma.
C. Immunity, Allergic reactions 45
Table 3.3 Main cytokines secreted by keratinocytes.

Classification, cytokines Main functions
Multifunctional cytokines 3
Interleukin (IL) Induction of secondary cytokines
6444447444448
IL-1a Modulation of adhesion molecules
IL-6 Modulation of activation and migration of T cells, B
cells and macrophages
IL-7
Activation of endothelial cells and fibroblasts
IL-12
Modulation of activation and migration of Langerhans
IL-15
cells (IL-1a, TNF-a)
IL-18
Induction of fever and acute inflammatory proteins
TNF-a
MIF
Chemotactic factor: associated with leukocyte migration
IL-8 Activation and migration of T cells and neutrophils
Colony stimulating factor: associated with leukocyte proliferation
GM-CSF Activation of granulocytes, macrophages, T cells and
Langerhans cells
G-CSF Proliferation of granulocytes
M-CSF Proliferation of macrophages
Growth factor: associated with local cutaneous reactions
TGF-a Proliferation of keratinocytes
b-FGF, PDGF Proliferation of fibroblasts and endothelial cells
Suppression factor: modulates immunity
TGF-b Suppression of keratinocytes and endothelial cells
IL-10 Suppression of immunity through Th1 cells
IL: interleukin, TNF: tumor necrosis factor, MIF: macrophage migration

inhibitory factor, GM-CSF: granulocyte macrophage colony-stimulating fac-
tor, G-CSF: granulocyte colony-stimulating factor, M-CSF: macrophage
colony-stimulating factor, TGF: tumor growth factor, b-FGF: basic fibroblast
growth factor, PDGF: platelet derived growth factor
C. Immunity, Allergic reactions

Skin is a major organ where immune/allergic reactions occur.
Various skin diseases have been increasingly understood by the
concept of immunity and allergic reactions, which are generally
classified into the four categories established by Coombs & Gell
(Table 3.4).
1. Type I allergy
Type I allergy is caused mainly by mast cells. Since a reaction
occurs 5 to 15 minutes after an antigen (allergen) is administered,
it is also called an immediate hypersensitivity. Mast cells with
IgE on the surface react to antigens, and chemical mediators such
as histamines and leukotrienes are then secreted by the mast cells
(Chapter 8). These chemical mediators enhance vascular perme-
ability, to produce edema; in addition, they induce migration of
eosinophils, to evoke inflammation. Therefore, nasal discharge,

pruritus, and bronchial asthma are induced, and blood pressure is
3 decreased, by vascular dilatation. A patient with these symptoms
may undergo anaphylactic shock in serious cases. The symptoms
are transient and usually subside within several hours.
Typical skin diseases caused by type I allergy are urticaria and
certain types of drug eruptions (urticarial reaction). Other factors
are involved in atopic dermatitis; however, IgE plays a pivotal or
even solo role in the pathogenetic process. Additionally, allergic
rhinitis (hay fever) and allergic bronchial asthma are common
diseases caused by type I allergy.
2. Type II allergy
In type II allergy, antibodies are produced against the antigen
on the cell surface to which complements and cytotoxic T cells
have been activated, thereby injuring the cells. Type II allergy
induces cutaneous diseases such as autoimmune blistering dis-
eases. In bullous pemphigoid, autoantibodies bind to BP180
(BPAG2) in the basal cell hemidesmosomes, and the basal cells
are injured by Type II allergy, resulting in blisters (Chapter 14).
A drug may function as a hapten to bind with epidermal cells
or blood cells to cause Type II allergy. Drug-induced hemolytic
anemia, thrombocytopenic purpura, and toxic epidermal necroly-
sis (TEN) occur by this mechanism.
Table 3.4 Classification of allergy.
Coombs classi-
Type I Type II Type III Type IV
fication
Type of Anaphylaxis (immediate Cytolytic reaction Immune complex reaction Cellular immunity
reaction hypersensitivity) (delayed hypersensitivity)
Associated IgE IgG, IgM IgG, IgM -
antibodies
Associated Histiocytes, basophils, Cytotoxic T cells, macrophages Multinuclear leukocytes, Sensitized T cells,
immune cells mast cells macrophages macrophages
Complement Unneeded Needed Needed Unneeded
Target Skin, lung, intestines Skin, erythrocytes, leukocytes, Skin, vessel, joint, kidney, Skin, lung, thyroid gland,
tissues/cells platelets lung central nervous system,
etc.
Disorders Urticaria, drug eruption, Bullous pemphigoid, hemolytic Cutaneous small-vessel Allergic contact dermatitis,
asthma, pollinosis, anemia, idiopathic vasculitis, serum sickness, erythema induratum,
anaphylaxis thrombocytopenic purpura, TEN, glomerulonephritis GVHD
transfusion incompatibility
Illustration of cytotoxic antigen effector
reaction T cell T cells
antigen immune
IgE FC IgG or complex
receptor IgE IgM complements
APCs
cytolysis IgG secretion of
cytokines
complements such as IFN-g
secretion of chemical
mediators such as surface antigen phagocytes
histamine tissue activated macrophage
C. Immunity, Allergic reactions 47
Blood group incompatibility from transfusion, autoimmune Hapten MEMO

hemolytic anemia, and Goodpasture syndrome are also Type II Phagocytic cells engulf antigens that contain
allergies. proteins of 10,000 molecular weight or 3
greater (complete antigen) and carry the infor-
mation of the antigens to lymphocytes. That
3. Type III allergy is, non-protein substances of small molecular
weight (e.g., carbohydrates, fats, organic
Type III allergy occurs when antigen-antibody complexes compounds, metallic molecules) cannot be
antigens themselves; they are called haptens,
(immune complexes) deposit in the blood vessels and specific or incomplete antigens. Although antibodies
sites of tissue. An infection or a drug induces immune complex react to haptens individually, lymphocytes
deposition, where an allergic reaction causes fibrinoid degenera- produce such antibodies only in combination
with other proteins.
tion and neutrophilic infiltration; this is called cutaneous small-
vessel vasculitis (Chapter 11).
Serum sickness disease, glomerular nephritis and lupus nephri-
tis are also type III allergies.
4. Type IV allergy
Type IV allergy is inflammation caused by a reaction between
an antigen and the corresponding T cells (Th1 in particular).
There are two stages in type IV allergy: sensitization, and an
effector phase. After an initial invasion, the antigen is engulfed
by antigen-presenting cells to activate T cells in the regional
lymph nodes. At this time, memory T cells along with effector T
cells are produced in order to enable them to respond promptly to
the secondary invasion of the antigen (sensitization). In the sec-
ondary and later invasions, memory T cells are activated by the
antigen-presenting cells, and inflammation is evoked that peaks
48 hours after antigenic challenge (effector phase). Since it takes
a long time for the reaction to occur, Type IV allergy is also
① first contact with antigen ② contact with the same antigen

(sensitization: about 1 week) (challenge phase: 24-48 hrs)
allergen (antigen)
papules, vesicles
spongiosis
Langerhans cell cytokines

migration to
lymph node
edema
antigen presenting inflammatory-cell infiltration
T cell memorization by Langerhans cell telangiectasia
presents effector
antigen information T cell (Th 1)
lymph node
Fig. 3.9 Mechanism of allergic contact dermatitis.

called delayed hypersensitivity (Fig. 3.9).

Typical lesions caused by type IV allergy are allergic contact
3 dermatitis and graft-versus-host disease (GVHD).
D. Immune abnormality
1. Autoimmune diseases
Immunity is a mechanism whereby self is distinguished from
non-self to exclude non-self. Therefore, autologous proteins do
not usually induce immune reactions. If there is a disturbance in
the body, antibodies (autoantibodies) are produced against autol-
ogous proteins and the immune mechanism tries to exclude self;
this phenomenon is called autoimmunity, and the diseases caused
by it are called autoimmune diseases. Autoantibodies are thought
to appear by the following mechanisms.
●Organs that have been isolated from the immune system since
the embryonic phase are exposed to the immune system for an
unknown reason and are recognized as non-self (e.g., sympa-
thetic opthalmia, azoospermia).
●Normal tissues are degenerated by viruses or bacteria, and
antibodies are produced against the degenerated proteins (e.g.,
mycoplasma pneumonia).
●Antibodies that have been produced against specific bacteria
react with similar self antigens (cross-reaction) (e.g., rheumatic
fever).
●Immunologic homeostasis becomes dysfunctional somehow,
and lymphocytes that react against autoantigens (forbidden
clones), which are excluded in a normal state, are not excluded
(some autoimmune diseases, including systemic lupus erythe-
matosus (SLE)).
●Regulatory T cells suffer reduced function for some reason,
and immune reactions to self become uncontrolled (some
autoimmune diseases, including SLE).
The major autoimmune diseases that are treated in dermatolog-

ical practice include SLE, systemic sclerosis (SSc) and autoim-
mune blistering diseases such as pemphigus and pemphigoides.
2. Immunodeficiency
Immunodeficiency is subclassified into congenital and
acquired. In congenital immunodeficiency, the immune factors
are congenitally lacking. In acquired immunodeficiency the
cause is secondary – the result of a disease or treatment. Different
factors are dysfunctional in each disease, resulting in immunode-
ficiencies such as hypogammaglobulinemia, lymphocytopenia
and the decrease of compliment titer.
In congenital immunodeficiency diseases, the infection is often
D. Immune abnormality 49
by bacteria, viruses, or fungi. The infection tends to become seri-

ous. Specific cutaneous findings may be present in each disease,
such as the eczematous lesion observed in Wiskott-Aldrich syn- 3
drome, and the oculocutaneous albinism and photosensitivity
reaction distinctively observed in Chédiak-Higashi syndrome.
Secondary immunodeficiency is caused by collagen diseases
such as SLE, malignant lymphoma, immuno-proliferative dis-
eases such as leukemia, HIV (human immunodeficiency virus),
HTLV-I (human T-lymphotrophic virus 1), and immuno-sup-
pressive treatment (e.g., by anti-cancer drugs, steroids, radiother-
apy). The main symptoms are opportunistic infections, including
bacterial and viral infections. In patients with AIDS, besides
these symptoms, seborrheic eczema, psoriatic rash, purpura,
tumor masses and Kaposi sarcoma may also occur (Chapter 23).
Chapter
4 Skin Lesions
4
The most fundamental and important methods of medical examination for skin diseases are visual inspection
and palpation. The recent development of biochemical and immune system examination methods has made
diagnosis more accurate. However, naked-eye and dermoscopy inspection and palpation are always the most
important in acquiring information on the nature of skin lesions, including their distribution, form, color, shape
and firmness.
A skin lesion is generally called an eruption. Eruptions are divided into primary lesions, which occur in normal
skin, and secondary lesions, which are caused secondarily by other eruptions. This chapter briefly discusses
the terminology for describing the characteristics of various types of eruptions.
A. Primary skin lesions

An eruption that occurs in normal skin without any preexisting
eruptions is called a primary lesion. These include patches, where
the only change is color; papules, nodules and tumors, which are
elevated; blisters, cysts and pustules, which contain serum, kera-
tinized substances, pus, etc.; and urticaria, which is temporarily
Clinical images are available in hardcopy only. elevated.
1. Erythema
Erythema is patchy redness produced by vasodilation and
hyperemia in the dermal papillae and the subpapillary layer
Fig. 4.1 Erythema. (Figs. 4.1 and 4.2). In erythema, although the blood volume
Annular erythema in a patient with Sjögren syn- increases in the dermal blood vessels, there is no blood leakage
drome. into the extravascular dermis. Thus the bloody color fades under
the pressure of a glass plate (diascopy). Erythema produced at the
periphery of other eruptions such as papules, bullae and pustules
is described as a red halo.
2. Purpura
Purpura is purple to bright red hemorrhaging in the skin (Figs.
4.2 and 4.3). The color of the blood does not fade in diascopy,
erythema purpura pigmented macule leukoderma
Unusual erythema and MEMO

purpura
Bleeding may occur in the superficial epider-
mis, making the epidermis appear red. The decrease of
red does not fade by diascopy, unlike in the telangiectasia extravasation melanin deposition melanin
usual erythema. Vasodilation may occur in
the dermal deep layer, making that layer
appear purple. Fig. 4.2 Skin lesions.
Macule colors and their respective changes.
50
A. Primary skin lesions 51
because hemorrhage causes blood leakage into the dermis, which

distinguishes it from erythema. A purpura of 2 mm or less in
diameter is called a petechia. A purpura that is larger than a
petechia is called ecchymosis, and an even larger elevated purpu-
ra is called a hematoma. The red of a purpura is fairly bright 4
shortly after bleeding begins (from the hemoglobin) but becomes Clinical images are available in hardcopy only.
brownish (from hemosiderin) over time. When macrophages
phagocytose and decompose the leaked blood cells, the color
fades.
3. Pigmented macule
Fig. 4.3 Purpura.
A pigmented macule is a patch of brown, yellow, blue or other Henoch-Schönlein purpura.
color, depending on the deposited substance (Figs. 4.2 and 4.4).
It is most commonly caused by deposition of melanin, the next
most common causes being deposition of hemosiderin, carotin,
bile pigment, drugs or other foreign substances (e.g., metal, char-
coal).
The macule color changes from brown to blackish brown with
increased melanins in the epidermal basal layer, and ranges from Clinical images are available in hardcopy only.
gray to purplish brown in the papillary dermis. It becomes blue
with deposition in the deep dermal layer. The sites of melanin
pigmentation in various diseases are listed in Fig. 4.5.
Fig. 4.4 Pigmented macule.

Senile freckle.
a b c d e
epidermis
dermis
Site of melanin deposition and disorder

Site of deposition Color of lesion Disorder Clinical images are available in hardcopy only.
a) Intraepidermis~ Black nevus-cell nevus

dermo-epidermal junction (compound), malignant
melanoma
b) Basement membrane Deep brown Melasma, nevus spilus,
café-au-lait spot
c) Basement membrane~ Brown to black nevus-cell nevus
the middle of the epidermis (junctional)
d) Dermal papilla Violaceous to brown Lichen planus, inconti-
nentia pigmenti, fixed
drug eruption
Fig. 4.6 Leukoderma.
e) Deep dermis Bluish Mongolian spot, blue Vitiligo vulgaris.
nevus, Ota's nevus
Fig. 4.5 Association between the site of melanin deposition and

the color of the lesion.
52 4 Skin Lesions
keratotic serous solid perifollicular papule

papule papule papule
Fig. 4.7 Various papules.
4. Leukoderma
Clinical images are available in hardcopy only.
Leukoderma is a white patch produced by depigmentation or
local anemia (Figs. 4.2 and 4.6). Depigmentation is caused by
abnormal production of melanins, such as in vitiligo vulgaris
(Chapter 16). Nevus anemicus causes local anemia leading to
leukoderma (Chapter 20). Leukoderma in the periphery of an
Fig. 4.8 Papule. eruption is called a white halo.
Lichen nitidus.
5. Papule
A papule is a localized elevated lesion of 10 mm or less in
diameter (Figs. 4.7 and 4.8) with a hemispheric or flat shape. It is
characterized by a surface that can be smooth, eroded, ulcerative,
hyperkeratotic or crusted. It may be caused by a proliferative or
Clinical images are available in hardcopy only. inflammatory change in the epidermis, or by dermal edema.
Papules are distinguished by naked-eye observation as serous
(with a vesicle on the top; e.g., eczema and dermatitis), solid
(without blistering; e.g., neoplastic lesions, dermal edema), fol-
licular (associated with hair follicles) or non-follicular (not asso-
ciated with hair follicles).
Fig. 4.9 Nodule.

Dermatofibrosarcoma protuberans. 6. Nodule, Tumor
A nodule is a localized lesion that appears as a papule with a
diameter of 10 to 20 mm (Fig. 4.9). It can have various causes,
such as tumor formation, granulomatous change, inflammation or
edema. An intensely proliferative nodule with an elevation of 30
mm or more in diameter is called a tumor.
7. Blister
A blister is a skin elevation of 5 mm or more in diameter
enclosed by a membrane and containing transparent fluid that is
mainly plasma and cellular material. A small blister with a diameter
A. Primary skin lesions 53
intraepidermal
bulla subepidermal bulla vesicles
4
Fig. 4.10 Blisters.
a b c d e f g h
of less than 5 mm is called a vesicle (Figs. 4.10 and 4.11). A
hemorrhagic blister containing serum mixed with blood is
referred to as a bloody bulla.
A blister with a flaccid covering (flaccid bulla) breaks easily.
A flaccid bulla is often produced by exfoliation of the suprabasal
cell layer (e.g., in pemphigus or impetigo contagiosa). A bulla Clinical images are available in hardcopy only.
with a thick, tight covering formed under the epidermis is called
a tense bulla (e.g., pemphigoid, dermatitis herpetiformis). It does
not break as easily as a flaccid bulla. During an infectious
episode, a variolar bulla is observed; this is a bulla with a central
concavity. a b c d e f g h i
Blocked by the thick horny cell layer, a blister on the palms or Fig. 4.11 Blisters.
soles does not elevate, but presents a droplet-like appearance. a: Bullous pemphigoid. b: Insect bite.
Such a blister is called a pompholyx. When it occurs in the
mucous membrane, the covering of the aphtha breaks sponta-
neously. Pompholyx with painful erosion and peripheral erythe-
ma are included in aphthae (Fig. 4.21).
8. Pustule
A pustule is a yellowish blister with purulent contents (neu-
trophils) (Figs. 4.12 and 4.13). It may be produced by bacterial
infection or by leukocytes that migrate for some other reason
(sterile pustules). Diseases that produce multiple sterile pustules
are generally called pustuloses (Chapter 14).
Fig. 4.13 Pustule.

Palmoplantar pustulosis (localized pustular psori-
asis).
pustule cyst wheal (urticaria)
neutrophils edema
Fig. 4.12 Pustule, cyst and wheal.

54 4 Skin Lesions
9. Cyst
A cyst is a closed tumorous lesion covered by a membranous
lining, which does not always elevate above the skin. The cover-
4 Clinical images are available in hardcopy only. ing consists of epithelial tissue or connective tissue containing
keratinous substances (observed in epidermal cysts, for example)
or fluid components (e.g., in eccrine and apocrine hydrocys-
tomas) (Figs. 4.12 and 4.14).
Fig. 4.14 Cyst. 10. Wheal, Urticaria

Epidermal cyst.
Urticaria is localized edema that disappears in a short period of
time (usually within several hours, and always within 24 hours).
It usually appears light pink with a slightly flat elevation. It is
accompanied by itching and heals without scarring in most cases
(Figs. 4.12 and 4.15). “Wheal” and “urticaria” are often use syn-
Clinical images are available in hardcopy only. onymously, although the former is the name of an eruption and
the latter is a condition presenting these eruptions.
Fig. 4.15 Wheal.

Acute urticaria.
B. Secondary skin lesions

A secondary lesion is an eruption that occurs secondarily after
a primary or other skin lesion.

1. Atrophy
Skin atrophy is when skin becomes thin or has a smooth or
finely wrinkled surface (Figs. 4.16 and 4.17). The secretory func-
tion is reduced, and the skin surface dries. Aging leads to skin
atrophy, including subcutaneous lipoatrophy, striae atrophicae
Fig. 4.16 Atrophy. caused by steroids (Chapter 18), kraurosis vulvae and macular
Widespread striae atrophicae.
atrophy.
epidermis
dermis
subcutaneous atrophy hypertrophic scar

tissue
Fig. 4.17 Atrophy and hypertrophic scar.
B. Secondary skin lesions 55
2. Scaling
Scaling is the abnormal thickening of the skin surface and for-
mation of scaly white lamellae from the accumulation of horny
cell layers. Detachment of scales from the skin surface is called 4
desquamation. Since the normal horny cell layers exfoliate indi-
vidually, individual desquamation lamellae cannot be seen by the Clinical images are available
naked eye. Scales are observed when multiple horny cell layers in hardcopy only.
pathologically exfoliate in diseases such as psoriasis (Fig. 4.18).
Fine scaling is called pityriasis, slightly larger scaling is sim-
ply called scaling, and even larger scaling is called large lamellar
scaling. Thick silver-gray scales, called micaceous scales, visible
in psoriasis and fish-scale-like large scaling, are called ichthyosi-
form scales.
There are two mechanisms of scale formation: retention hyper-
keratosis and proliferation hyperkeratosis. In retention hyperker- Fig. 4.18 Scaling.
Psoriasis vulgaris.
atosis, such as in ichthyosis, horny cell layers are too cohesive to
exfoliate normally; they exfoliate only after accumulating abnor-
mally. In proliferation hyperkeratosis, such as in psoriasis, the
epidermis exfoliates abnormally from over-proliferation. Blisters
and pustules may become scales secondarily.
3. Crust
Crust is solidified keratin and exudate that forms on an erosion
or on ulcerous skin (Fig. 4.19). A crust of clotted blood is called
a bloody crust (commonly called a scab). a b c d e f g h
4. Callus, Tylosis
A callus (tylosis) is localized, proliferated, and thickened epi-
dermal horny cell layers. It is commonly called a corn (Chapter Clinical images are available in hardcopy only.
15).
5. Clavus a b c d e f g h i
In clavus, the horny cell layer becomes wedged into the skin Fig. 4.19 Crusts.
by prolonged physical stimulation, such as pressure produced by a: Epidermolysis bullosa simplex. b: Psoriasis vul-
garis.
wearing shoes for long periods of time. It is commonly called a
corn (Chapter 15).
6. Scar, Keloid
A scar is the reactive proliferation of dermal collagen after the Clinical images are available
skin is injured (Fig. 4.17). Healing usually leaves a flat scar. in hardcopy only.
Sometimes the scar is hypertrophic, or thickened, but confined to
the margin of the wound. A keloid, by contrast, starts some time
after the injury and extends beyond the wound site (Fig. 4.20).
This tendency to spread into surrounding areas that weren’t
injured distinguishes keloids from hypertrophic scars.
Fig. 4.20 Keloid.
56 4 Skin Lesions
7. Excoriation
Excoriation is partial damage to the epidermis by injury or
rubbing (Fig. 4.24). The symptoms vary by the depth of excoria-
4 tion. When it occurs within the horny cell layer, it heals by scal-
ing. When it occurs in a deeper site, blood or other fluids may be
exuded. In both cases, healing is without scarring.
8. Erosion
Fig. 4.21 Erosion. Erosion is epidermal excoriation down to the basal cell layer.
Bullous pemphigoid.
It often develops after breakage of a blister or pustule (Figs. 4.21
and 4.24). It appears red and is infiltrated with serous fluid in
most cases. It frequently forms in the lips and oral mucosa, from
their lack of keratinocytes. Healing is without scarring. It fre-
quently occurs in diseases that cause intraepidermal blistering,
such as impetigo contagiosa, pemphigus, epidermolysis bullosa
Clinical images are available in hardcopy only. and herpes simplex, and in diseases that cause subepidermal blis-
tering, such as pemphigoid, burns and spontaneous intensely
itchy eruptions (e.g., Duhring dermatitis herpetiformis, atopic
dermatitis).
9. Ulcer
Fig. 4.22 Ulcer.
Chronic radiation dermatitis. An ulcer is the complete deficiency of tissue at sites deeper
than erosion, reaching from the dermis to subcutaneous tissues
(Figs. 4.22 and 4.24). In healing, an ulcer is repaired by granular
tissue and scarring is left. The bottom of an ulcer often has bleed-
ing, serous exudation, and a crust that includes part of the previ-
ous lesion. Ulceration occurs secondarily in many cases after
blood circulation disorder (e.g., stasis dermatitis, collagen dis-
ease, vasculitis, blocked arteries, diabetes), infection and malig-
nant tumor.
10. Fissure
A fissure is a thin linear cleavage running through the deep
epidermal layer and the dermis. It is commonly called a crack
(Figs. 4.23 and 4.24). It may accompany another lesion, includ-
Fig. 4.23 Angular cheilitis (perlèche).
ing chronic eczema in the hands and feet, psoriasis and angular
excoriation erosion ulcer fissure
Fig. 4.24 Excoriation, erosion, ulcer and fissure.

D. Lesions with elevation of skin 57
cheilitis. It tends to occur in the hands and feet, joints, intertrigo,

and mucocutaneous junctions.
C. Enanthema 4
An enanthema is a lesion of the mucous membranes, such as

the oral mucosa, conjunctiva and external genitalia. Specific
types are listed below.
1. Aphtha
An aphtha is a painful, sharply circumscribed, round erosion
with a diameter of 1 cm or less in the mucous membrane (Fig.
4.25). It is accompanied by peripheral inflammatory flush. Heal- Fig. 4.25 Aphtha.
ing is without scarring. Deep ulcers are not included in aphtha. Patient with Behçet’s disease.
Major diseases that cause aphtha are viral infections (e.g., herpes
simplex, varicella, hand-foot-and-mouth disease) and Behçet’s
disease.
2. Leukoplakia Clinical images are available in hardcopy only.

Leukoplakia is abnormal keratinization of the mucosal epithe-
lium. It appears white (Fig. 4.26) and may be benign or precan-
cerous (Chapter 22).
Fig. 4.26 Leukoplakia.

Squamous cell carcinoma with leukoplakia at the
center.
D. Lesions with elevation of skin
1. Lichen
Lichens are multiple aggregated papules of 5 mm or less in
diameter that persist longer than one month without progressing Clinical images are available in hardcopy only.
to another type of lesion (Fig. 4.27). Lichens are classified into
lichen planus, lichen nitidus, lichen pilaris, lichen spinulosus,
lichen amyloidosus, lichen sclerosus et atrophicus, lichen
myxedematosus, lichen scrofulosorum and lichen striatus. Atypi-
Fig. 4.27 Lichen.
cal lichen-like skin lesions are called lichenoid eruptions Lichen amyloidosis.
2. Lichenification
Lichenification is the thickening and hardening of skin that
results from chronic disease. The sulci cutis and cristae cutis are
clearly observed (Fig. 4.28). Lichenification is found in chronic
eczema, lichen simplex chronicus and atopic dermatitis.
58 4 Skin Lesions
3. Plaque
A plaque is a broad, flat, elevated skin lesion with a diameter
of 2 cm to 3 cm, sometimes more (Fig. 4.29). It presents as flat or
4 Clinical images are available in hardcopy only.
papillomatous, according to the type of elevation; moreover, the
shape is described as round, oval, atypical or circular. These
descriptions are useful not only for individual lesions with a flat
elevation, but also for flat, elevated lesions of aggregated fused
papules.
Fig. 4.28 Lichenification.
Atopic dermatitis.
4. Papilloma
A papilloma is a papillary tumor that is covered by epidermis
and mucosal epithelium. Connective tissue containing capillaries
Clinical images are available in hardcopy only. is present. Since it is protrusive, papilloma is susceptible to injury
and infection.
Elevated lesions on the glandular epithelium are usually called
polyps.
5. Condyloma
A condyloma is an aggregation of soft nodules with a papillary
or granular surface (Fig. 4.30). It is mostly seen in the mucous
membranes, such as those of the external genitalia. Typical
condylomas are condyloma acuminatum caused by human papil-
loma virus (HPV; Chapter 23), and condyloma lata (caused by
a b c d e f g h syphilis;
i j Chapter
k 27). l m n o p q r
Fig. 4.29 Plaque.
a: Extramammary Paget’s disease. b: Mycosis
fungoides.
Clinical images Clinical images

are available are available
in hardcopy only. in hardcopy only.
Fig. 4.30 Condyloma.

left: Condyloma aquminatum. right: Condyloma
latum.
E. Lesions associated with hair follicles
1. Acne
Acne is an inflammatory change, such as an erythema or pus-
tule, at a hair follicle (Fig. 4.31). It is usually accompanied by
F. Lesions with color changes 59
black-headed papules (comedos). It frequently occurs in sebor-

rheic zones of the skin. The term acne usually refers to acne vul-
garis; other types of acne are oil acne, iodine acne (the follicle is
blocked by iodine secreted after chronic ingestion of iodine) and Clinical images are available in hardcopy only.
steroid acne (from prolonged chronic use of topical and systemic 4
corticosteroids) (Chapter 19).
2. Comedo Fig. 4.31 Acne.

Acne vulgaris.
A comedo is a black-headed papule that results from the
blockage of a hair follicle by sebum (Fig. 4.32). The hair follicle
at a site with a comedo is open. A plaque of multiple aggregated
comedos on the face is Favre-Racouchot disease. Clinical images are available in hardcopy only.
3. Sycosis
Sycosis is the formation of a nodule or pustule in a hair folli- Fig. 4.32 Comedo.
cle, found as a plaque at sites with terminal hair (Fig. 4.33). The Solitary giant comedo.
main types are sycosis vulgaris and sycosis trichophytica.
Fig. 4.33 Sycosis.

Sycosis vulgaris.
F. Lesions with color changes
1. Erythroderma, Erythrodermia
Erythroderma (erythrodermia) is the condition in which the
Clinical images are available
skin has a systemic flush on more than 90% of the body surface in hardcopy only.
(Fig. 4.34). Often accompanied by scaling, erythroderma may
also be called exfoliative dermatitis (Chapter 9).
Fig. 4.34 Erythroderma.

2. Melanosis Patient with Hodgkin’s disease.
Melanosis is large, vaguely margined pigmentation, including
Riehl’s melanosis and friction melanosis (Chapter 16).
3. Livedo (livedo reticularis) Clinical images are available

in hardcopy only.
Livedo is a large network of reddish lesions caused by hypo-
tonicity of the venous network and overactivity of the arterial
network in the junction of the dermis and subcutaneous fat tis-
sues (Figs. 4.35-1 and 4.35-2). Livedo is mainly classified as Fig. 4.35-1 Cutis marmorata (physiologic
cutis marmorata (physiologic livedo reticularis), idiopathic and livedo reticularis).
60 4 Skin Lesions
primary livedo reticularis, and secondary livedo reticularis.

The most frequent type, cutis marmorata, occurs as a rosy net-
work of persistent erythema in a shape of a closed ring, mostly in
the knees. It is mainly caused by cold and is often seen in other-
4 wise normal women and children. It tends to disappear when the
outside air temperature rises, without leaving pigmentation, or
when pressed by glass (diascopy).
Idiopathic and primary livedo reticularis occurs in the extremi-
ties as peach bloom dendritic persistent erythema in the shape of
an open ring. It tends to accompany systemic organic changes
Fig. 4.35-2 Idiopathic livedo and primary such as vasculitis.
livedo reticularis on the dorsum of the feet.
G. Lesions accompanied by multiple blisters and pustules
1. Herpes
Herpes is a lesion in which there are aggregated vesicles and
small pustules (Fig. 4.36). Presently the term usually refers to
herpes simplex or herpes zoster, which are infections caused by
the herpes virus. In other cases, herpes may be observed as
lesions of vesicle aggregation, such as in Duhring dermatitis her-
Fig. 4.36 Herpes. petiformis and herpes gestationis. Aggregated pustules are found
Herpes zoster.
in pustular psoriasis and pustulosis palmaris et plantaris (PPP).
2. Pemphigus
Pemphigus produces acantholysis in the epidermis. The mech-
anism is autoimmune. The typical types are pemphigus vulgaris,
Clinical images are available in hardcopy only. pemphigus vegetans, pemphigus foliaceus and pemphigus erythe-
matosus (Chapter 14). Bullous pemphigoid and dermatitis her-
petiformis are considered to be separate diseases; they are
excluded from the category of pemphigus.
Fig. 4.37 Impetigo. 3. Impetigo

Impetigo contagiosa.
Impetigo is a combination of pustules and crust, which may be
accompanied by erythema and small blisters (Fig. 4.37). Impeti-
go contagiosa and bacterial dermatitis are typical of impetigo
(Chapter 23).
H. Lesions with a change in the horny cell layer
1. Pityriasis
Pityriasis is characterized by fine scaling caused by abnormal
keratinization (Fig. 4.38). It includes pityriasis rosea (Gibert),
I. Lesions accompanied by other changes 61
pityriasis simplex and pityriasis circinata.
2. Xerosis
Xerosis is dry skin whose surface is rough and muddy. It is 4
caused by diminished secretion of sebum and perspiration. Pity-
roid scales and shallow cracks may develop, giving an
ichthyosis-like appearance and mild itching. Hereditary xeroder-
ma pigmentosum and secondary xeroderma, both of which occur Fig. 4.38 Pityriasis.
Pityriasis rosea (Gibert).
after the onset of a preexisting eruption, are included in xerosis
(Chapters 13 and 19).
3. Ichthyosis
Ichthyosis is thin dry scaling on the skin that resembles glued- Clinical images are available in hardcopy only.
on fish scales (Fig. 4.39). Various types of ichthyoses are known,
including congenital and acquired (Chapter 15).
Fig. 4.39 Ichthyosis.

Lamellar ichthyosis.
I. Lesions accompanied by other changes
1. Poikiloderma
Poikiloderma is a lesion that shows the combined features of
atrophoderma, pigmentation, depigmentation and telangiectasia
(Fig. 4.40). It is often observed at the terminal stages of various
lesions. Poikiloderma occurs in dermatomyositis, scleroderma, Clinical images are available in hardcopy only.
systemic lupus erythematosus (SLE), mycosis fungoides, chronic
radiodermatitis and xeroderma pigmentosum. Congenital poikilo-
derma is called poikiloderma congenitale (Chapter 18).
2. Sclerosis
Fig. 4.40 Poikiloderma.
Sclerosis is thickening of the skin caused by proliferation of Dermatomyositis.
connective tissues such as collagen and extracellular matrix (Fig.
4.41). It is found in scleroderma, scleredema adultorum and scle-
romyxoedema. Pathologically, the number of fibroblasts decreas-
es, and collagen fibers become swollen or uniform in size.
3. Seborrhea
Seborrhea is a condition in which sebum accumulates on the
skin surface in great amounts, as a result of increased secretion.
This tends to lead to bacterial infection, acne, eczema infantile
and seborrheic dermatisis (Chapter 7); however, seborrhea itself
62 4 Skin Lesions
does not present inflammatory symptoms. Sites that are densely

distributed with sebaceous glands, such as the head, face, precor-
dial region, center of the back, armpits and external genitalia are
called seborrheic zones.
4 The severity depends greatly on genetic factors and predisposi-
tion. Androgens are known to enhance sebum discharge. Physio-
logically, seborrhea occurs in newborn infants and in adults from
adolescence.
4. Alopecia
Fig. 4.41 Sclerosis.
Morphea. Alopecia is a condition in which hair grows sparsely or not at
all (Fig. 4.42). The major types of alopecia are alopecia areata,
alopecia totalis, alopecia universalis and ophiasis.
5. Pruritus
Pruritus is itching without eruptions. Pruritus is also called
pruritus cutaneous, and it may occur secondarily in various sys-
temic disorders and local lesions, such as urogenital diseases
(Chapter 8).
Fig. 4.42 Alopecia.

Alopecia areata.
Chapter
5 Diagnosis of Skin Diseases
In dermatological diagnosis it is most important to correctly identify the nature of the skin lesion by visual
inspection. Skin lesions are often diagnosed only by naked-eye observation or by dermoscopy. Besides visual 5
inspection, diagnosis is verified by detailed history-taking (oral consultation), palpation, and olfactory examina-
tion in some cases. Various additional tests are conducted according to the symptoms.
History-taking
1. General diagnostic methods ・ Chief complaint
・ Present illness
1) History-taking (Fig. 5.1) ・ Family history
・ Past history
Diagnosis begins with questioning on previous diseases, that
is, medical history-taking. The inquiries that should always be
included in history-taking and reminders for history-taking are Inspection and palpation
listed below. ・ Dermoscopy (see Appendix)
①Chief complaint ・ Diascopy
・What is the main reason for the patient’s visit?
②Present illness
・Are there subjective symptoms? Is there a presumed cause? Other tests Olfactory examination
・ Photosensitivity test
・Are there systemic symptoms (e.g., high fever, fatigue,
・ Allergy test
aching joints, muscle pain, insomnia)? ・ Skin biopsy
・Were there precursory symptoms? ・ Etc.
・How has the lesion progressed? (Has it generally become
Fig. 5.1 General diagnostic methods.
aggravated? Does it worsen at night?)
・How has the lesion spread? (Is it spreading? Does it occur
and disappear repeatedly?)
③Family history
・Have any family members had similar symptoms? (Check
the hereditary and allergic background of the patient.)
④Past history
・What diseases and medical treatments has the patient had?
(Have topical or oral medications been used?)
In addition, the patient is asked whether there are people with
similar symptoms at home or school, or in the workplace, to
determine whether the condition is infectious or environmental.
2) Inspection and palpation

Physical examinations should be conducted in a bright room. It
is preferable to examine not only the site of the complaint, but
the entire body skin and visible mucous membranes. It should be
remembered that an eruption may show its distinguishing fea-
tures secondarily by fusion or rubbing. For accurate identifica-
tion, it is important to find and examine an eruption that has not
been influenced by any changes (individual eruption). Terms
used to describe the nature and feature of eruptions are listed
below.
Eruption type: e.g., spot, papule, nodule, blister (Chapter 4)
63
64 5 Diagnosis of Skin Diseases
Number of eruptions: single or multiple

Eruption shape: e.g., round, oval, polygonal, irregular, map-
like, linear, circular, serpiginous (Fig. 5.2)
round oval polygonal irregular
Eruption size: Numerical values (millimeters and centimeters)
are used in this text to describe the sizes of eruptions, thereby
avoiding ambiguous expressions such as coin-size, egg-size and
5 finger-size.
map-like linear circular serpiginous Shape of elevation: e.g., flat, domed, hemispherical, pedunculat-
ed, linear, umbilicated (Fig. 5.3)
Eruption surface: e.g., smooth, rough, warty, papillary, marked-
ly uneven, granular, lichenoid, shagreen-patch-like, oystershell-
band-like star-shaped araneous
like, dry, moist, exudative, hemorrhagic (bloody, bleeding),
scaly, crusty, erosive, ulcerated, cracked, atrophic, shiny, necrot-
Fig. 5.2 Shapes of lesions. ic, elevated
Eruption color: e.g., colored, depigmented, hyperpigmented,
pale, anemic, congestive colored
Eruption texture: e.g., soft, firm (stiff), fragile, tense, elastic,
undulated, movable
flat dome-shaped hemispherical
Eruption distribution: e.g., localized, widespread, aggregated,
plaque-like, diffuse, centrifugal, beaded, serpiginous, linear, sym-
metrical, asymmetrical (Fig. 5.4)
Eruption site: e.g., face, head, extremities, hand, sole, fingertip,
toe, extensor surface, flexor surface, exposed, unexposed, areas
pedunculated linear umbilicated
with pubes, mucocutaneous junction, intertrigo
Subjective symptoms: e.g., itching, pain (tenderness), numb-
ness, crispation, hyperesthesia, hypoesthesia, alganesthesia, burn-
ing, cold
acuminate verrucous papillomatous
Eruption progress: e.g., rapid or gradual, with or without recur-
Fig. 5.3 Shapes of elevation. rence, progress of an individual eruption, progress of spread, with
or without precedent eruption, treatment effect
Other: e.g., with or without mobility between the eruption and
the skin surface or the base of the eruption, sharply circum-
scribed, mildly circumscribed
aggregated (localized) disseminated (widespread)

3) Olfactory examination
Osmidrosis axillae are examined by the smell of absorbent cot-
ton or gauze with which the affected site has been swabbed. In
infectious diseases, each microbial species has a distinct smell.
arcuate beaded
Fluid and color of pus in the eruption may be keys to diagnosis.
Unfamiliar terms used to describe eruptions MEMO

serpiginous linear Some terms are more frequently used in dermatology than in other
medical fields. They are described here.
Shagreen patch: The surface is leathery, such as seen in tuberous scle-
rosis.
Oystershell-like skin: The surface is thick with rough and uneven
intermittent lemniscate crusts that resemble an oyster’s shell. It is seen in severe psoriasis and
Norwegian scabies.
Beaded skin: Multiple circular eruptions fuse to form an irregular-
Fig. 5.4 Eruption distribution. shaped eruption that resembles a map-like eruption.
2. Photosensitivity test (Chapter 13)

Various photosensitivity tests are conducted by examining the
reaction to irradiation. Ultraviolet radiation is divided into ultra-
violet A (UVA) (operative wavelength of 320 to 400 nm), ultra-
violet B (UVB) (operative wavelength of 290 to 320 nm) and
ultraviolet C (UVC) (operative wavelength of 100 to 290 nm).
5
UVA, UVB and visible light are most frequently used.
1) Photo test
The degree of photosensitivity and suitable operative wave-
length can be measured and determined by the amount of radia-
tion that causes cutaneous reactions such as pigmentation and
erythema. By testing the operative wavelength on patients, it is
possible to know which particular radiation exposure should be
eliminated.
The most widely conducted photo test is exposure to UVB
irradiation in the minimal dose that causes erythema in 24 hours
(minimal erythema dose; MED). The average dose for ethnic
Fig. 5.5 Photo test to measure minimal ery-
Japanese is 60 to 100 mJ/cm2 (Fig. 5.5). When the MED is low, thema dose (MED).
involvement of a photosensitive disease is suspected. Erythema appeared at the site of 60 mJ/cm2 irra-
Diseases of photosensitivity to UVA are rare, occurring for diation; the MED for this patient is 60 mJ/cm2.
example in some cases of chronic actinic dermatitis. Pigmenta-
tion (suntan) is caused by UVA exposure; it is called the minimal
response dose (MRD), in contrast to the MED. The normal MRD
for ethnic Japanese is 5 to 15 J/cm2. The result is determined 48
hours after irradiation.
Chronic actinic dermatitis and some cases of porphyria
cutanea tarda are diseases in which there is sensitivity to visual
light. There is no standard technique for measuring MRD for
photosensitive diseases; they are generally observed in the cuta-
neous reaction induced by exposure to slide projector light for 15
to 20 minutes.
A photo-provocation test of exposure to 2 to 3 MED for 3 con-
secutive days may be performed in the case of photosensitive dis-
eases to observe the reaction.
2) Photo-patch test
The photo-patch test is conducted to examine the influence of
rays when a chemical substance is placed on the skin. Twenty-
four to 48 hours after a material that is suspected of causing pho-
tosensitive disease is pasted on the skin, the site is exposed to UV
rays. If reddening or swelling occurs within 24 hours, the test is
considered to be positive for such disease.
3) Photo-drug test
The influence of radiation in the presence of a chemical sub-
stance can also be examined by photo-drug test. A drug that is
suspected of causing a photosensitive disease is taken orally

instead of topically. The photodrug test is generally used for
diagnosis of drug-induced hypersensitive diseases.
3. Allergy test
5 The tests for allergic reactions to a specific antigen are largely
divided into those for type I allergy (immediate) and those for
type IV allergy (delayed). A scratch test and an intracutaneous
reactivity test are conducted for type I allergy; a patch test and an
intracutaneous reactivity test are conducted for type IV allergy.
ELISA and Western blot test are performed to detect the anti-
body in autoimmune blistering diseases.
1) Patch test
The patch test, for detection of the antigen of contact dermati-
tis, is conducted by applying the antigen to normal skin to
g
observe the reaction.
j
The antigen that is suspected of causing
p q
a b c d e f h i k l m n o r
allergy is mixed in a vehicle of a topical agent such as white
petrolatum and spread on an adhesive plaster or put in a Finn-
chamber (a plaster to which an aluminum plate is affixed). The
plaster is adhered to a site of normal skin (usually the back or the
upper inner arm). After 48 hours, the patch is removed, and the
test result is determined in about 20 minutes when stimulation
caused by the plaster has subsided. If reddening, edema, papule
or erosion is produced, the test is considered to be positive for
allergy (Fig. 5.6, Table 5.1). The site may be observed after 72
hours and 96 hours for more reliable results. A series of diluted
a b c d e f g h i j p q
test substanceskis usedl for themtest. Inn casesoin which the result isr
Fig. 5.6 Patch test. positive only when the test substance is diluted to a certain level
a: The antigens are spread on adhesive plasters
that are then stuck to the back of the patient. b: In
48 hours, various allergic reactions (edematous
erythema and papules (arrows)) are seen if the
Table 5.1 Readings and interpretation of patch test reactions.
patient is allergic to the antigen.
Japanese criterion ICDRG criteron
− Negative − Negative
Faint erythema Doubtful reaction; faint
± ＋？ erythema only
Erythema Weak positive reaction;

＋＋ palpable erythema,
infiltration, possibly papules
Edematous erythema Strong positive reaction;
erythema, infiltration,
papules, vesicles
Infiltrative erythema, papules, Extreme positive reaction;
vesicles intense erythema and
infiltration and coalescing
vesicles
Fig. 5.7 Prick lancet. Coalescing vesicles Irritant reaction of different
IR types
NT Not tested
ICDRG: International Contact Dermatitis Research Group
3. Allergy test 67
or higher, it is considered the primary irritant (Chapter 7). Table 5.2 Readings of scratch test reactions.
Wheal diameter Erythema diameter
Reading
(mm) (mm)
2) Scratch test Negative (-) ＜5 ＜15
The scratch test is a simple test to detect an immediate allergen Positive (+) ≧5 ≧15
(type I allergy). The flexor surface of the forearm is scratched
with a needle or a needle-like tool without drawing blood, and
Table 5.3 Readings of intradermal test reac- 5
tions (in 15 minutes).
one drop of antigen solution is applied to the forearm (Fig. 5.7).
Wheal diameter Erythema diameter
If the patient is allergic to the allergen, reddening or swelling is Reading
(mm) (mm)
produced on the spot. The diameter of the reddening or swelling Negative (-) ＜7 ＜15
along the minor axis is measured 15 to 20 minutes after applica-
+)
Doubtful (- ＜9 ＜20
tion for identification of the allergy (Table 5.2).
Positive (+) ＜15 ＜40
A scratch test may cause shock in patients with a history of
anaphylactic shock. Therefore, the antigen solution should be Strongly ≧15 ≧40
positive ( )
tested first on normal skin to see whether urticaria is produced in
30 minutes (open test). If the result of the open test is positive, it
is unnecessary to perform a scratch test or an intracutaneous reac-
tivity test.
3) Intracutaneous test
(type I allergy test, type IV allergy test)
Type I allergens can be detected by intracutaneous test 1. In
this, 0.02 ml of a solution containing the suspected substance is
injected intradermally, and if an urticarial lesion or pseudopodia-
like projection occurs within 15 to 20 minutes, the test is deter-
mined to be positive (Table 5.3). Since there is a risk of causing
anaphylactic shock in the intracutaneous reactivity test, it is
desirable to perform a scratch test in advance to determine the
severity of the reaction.
Intracutaneous test 2 is conducted to examine the strength of
cellular immunity against an antigen. Forty-eight hours after
intradermal injection of 0.1 ml of the solution containing the sus-
pected substance, if the reddening or swelling along the minor
axis averages 10 mm or more, the result is generally considered
positive to allergy. Common intracutaneous tests are listed in
Table 5.4.
4) Drug-induced lymphocyte stimulation test

(DLST)
The drug-induced lymphocyte stimulation test (DLST) is known
to be useful in identifying drug-induced eruptions associated with
T cells; however, the involvement of a drug cannot be ruled out
even when the results are negative, because of the low sensitivity
of the test. DNA synthesis accompanying a lymphocyte prolifera-
tive reaction can be determined by 3H-thymidine after peripheral
blood lymphocytes are cultured with a drug.
Table 5.4 Typical type IV allergy tests.

Tuberculin skin test (PPD skin test)
5) Drug challenge test
A tuberculin skin test is used to detect delayed The drug suspected of causing allergy is administered to the
hypersensitivity to tuberculosis, by injecting patient to determine whether the eruptions will recur. One one-
tuberculosis antigen intradermally. 0.1 ml of
tuberculosis antigen (purified protein derivative;
hundredth to one tenth of the usual dosage is given orally. In seri-
PPD, 0.05 mg/ml) is injected into the inner side ous drug eruptions, there is a high risk that a drug challenge test
5 of the forearm. The long diameter of the will cause anaphylactic shock. The drug challenge test is the
erythema 48 hours after injection is used for
interpretation: less than 10 mm is negative, and
most reliable allergy test.
more than 10 mm as positive. Positive reaction
is sometimes categorized into weak (only
erythema), moderate (erythema and induration), 4. Skin function test
and strong (erythema with vesicles and necrosis).
Tuberculin skin test is specific to tuberculosis. Tests for measuring various skin function, such as temperature
However, patients with measles, sarcoidosis, control, secretion, and vascular regulation, are as follows.
Hodgkin’s disease, severe tuberculosis, and
serious malignancies may show weak reaction
or false negative. 1) Measurement of skin temperature
Trichophytin reaction and thermography
An antigen derived from trichophyton
(trichophytin antigen) may be used to test Thermography, which uses an infrared-camera-equipped emis-
intradermally for trichophytid and tinea profunda. sion pyrometer to express the distribution of skin temperature
Sporotrichin reaction two-dimensionally, has become widely used for diagnosing dis-
Sporotrichin antigen is injected intradermally for eases of the blood vessels, and nervous system disorders, inflam-
diagnosis of sporotrichosis. mations, tumors, and other disorders.
Ito’s reaction
Haemophilus ducreyi antigen is used for 2) Transepidermal water loss (TEWL)
diagnosis of chancroid.
Frei reaction Transepidermal water loss (TEWL) from the skin surface is
Frei reaction is an intradermal test for measured by electric hygrometer (Fig. 5.8). This test is effective
lymphogranuloma venereum. in determining the clinical condition of keratinization. The
Lepromin reaction (Mitsuda reaction) TEWL value usually is elevated in dyskeratoses, such as in
Lepromin reaction (Mitsuda reaction). ichthyosis.
Antigen derived from leproma is intradermally
injected for diagnosis and classification of leprosy.
3) Skin capillary resistance test
Kveim test
Diagnosis of sarcoidosis used to be done by a The fragility of skin capillaries can be determined by measur-
skin test whose antigen is derived from another ing ecchymosis produced in artificially pressured blood vessels.
patient’s spleen and lymph nodes. Kveim test is
rarely done today. In the Rumpel-Leede test, the upper arm is pressed by a blood
pressure manchette to congest the blood vessels. Two minutes
after pressure between the systolic and diastolic pressures is
applied to the patient’s upper arm for 5 minutes to constrict the
blood vessels, hemorrhagic spots occur. When 10 hemorrhagic
spots or more produced, the test is positive for dysfunction of
vascular regulation. It may also be positive if there is abnormality
in the capillaries or platelets, such as Henoch-Schönlein purpura
or thrombopenic purpura.
5. Fungal examination
Potassium hydroxide (KOH) is used for observation and detec-
tion of fungi and mites. Scales or blister contents are swabbed
(Fig. 5.9) and applied to a glass slide onto which 20% KOH solu-
tion is dripped, and a slide cover is placed on top. The slide is
10. Cytological diagnosis (Tzanck test) 69
heated on a hot plate at 70 ℃ to 80 ℃ for 5 to 10 minutes. The

components of skin such as the horny cell layers are hydrolyzed,
and the fungal components become easily Fig. 25.1. By similar
procedure, animals such as mites are observed. Recently, KOH
solutions to which dimethylsulfoxide (DMSO) has been added
have been frequently used, due to the short dissolution time and
the fact that there is no need to use a hotplate.
5
6. Dermoscopy (see Appendix for details)

Fig. 5.8 Electric hygrometer for measuring
Dermoscopy is a test to observe the skin surface in detail under transepidermal water loss (TEWL).
a magnifying glass with a magnification factor of ten (Fig. 5.10).
Use of jelly for echography and a bright light source reduces scat-
tering light and makes it possible to observe the lower dermal layer
as well as the horny cell layer. The technique is particularly use-
ful in distinguishing between and diagnosing pigmented lesions
(e.g., malignant tumors including malignant melanomas and nevus)
and subcorneal bleeding. Unlike skin biopsies, dermoscopy is not
invasive; it is essential and greatly useful for dermatological
examinations. Digital images of dermoscopy can also be saved.
7. Diascopy
In diascopy, a site with a skin lesion is pressed with transpar- Fig. 5.9 Diagnosing tinea pedis: Scales or
ent glass to see whether the coloration of the lesion disappears swabbed blister contents are sampled
(Fig. 5.11). If so, the diagnosis is erythema. Otherwise, the diag- from the interdigital area.
nosis is purpura. A light brown spot is characteristically seen in a Microscopic examination is made with potassium
hydrate.
granulomatous nodule such as lupus vulgaris. The test is also
effective for distinguishing between nevus anemicus and
hypopigmented macule. In the case of the latter, the whitish mac-
ule remains visible under the pressure of diascopy.
8. Needle reaction test

When the skin of a patient with Behçet’s disease is stuck with
a needle, an erythema, papule or pustule appears in 24 to 48
hours. The needle reaction test is positive for about 70% of
patients with Behçet’s disease, which reflects the skin irritability
Fig. 5.10 Dermoscopy.
of patients with this condition. Observation of skin lesion by dermoscope.
9. Wood’s lamp test

When skin with erythrasma, pityriasis versicolor, tinea capitis
or porphyria is exposed to Wood’s lamp, a 365-nm UV light, the
fluorescence has a characteristic color (Fig. 5.12, Table 5.5).
10. Cytological diagnosis (Tzanck test)

Cytological diagnosis (Tzanck test) is conducted by applying a
slide glass to the bottom of a broken blister and staining the
adhered cellular components in Giemsa (Fig. 23.8) for observation
under a light microscope. Acantholytic cells called Tzanck cells

are observed in pemphigus. In blisters of herpes simplex and her-
pes zoster, ballooning cells produced by viral infection are
a b c d e f g observed.
h i j k l m n o p q r
5 11. Dinitrochlorobenzene (DNCB) test

The strength of cellular immunity is measured by dini-
trochlorobenzene (DNCB) test. First, a patch soaked in a 1%
solution of DNCB acetone is adhered to the upper inner arm of
the subject for sensitization. After 2 to 3 weeks, a patch soaked in
0.1 to 0.01% of the same solution is adhered to a symmetrical
site on the other arm as a provocation test to observe the reaction
after 48 hours. If erythema, papule or small papule is produced,
ge
theg test is
jh
positive; that is, the subject is consideredpto haveq cellu- p q
a b ca db ec fd hf i ki l j mk nl om n o r
lar immunity. Immuno-compromised patients with cancer may
not always be sensitized by this test.
12. Dermographism
Some reactions of skin rubbed by something dull such as a fin-
gernail maybe observed. If the rubbed site becomes red and ele-
vated, it is called (red) dermographism which is a diagnostic
finding of physical urticaria (Fig. 5.13). If the site becomes
ca db ec fd ge hf ig jh white,
ki
itl jis called
mk
white
nl
dermographism;
om pn this
qo is usually
rp
seen
q in r
patients with atopic dermatitis (Fig. 5.14).
Fig. 5.11 Diascopy.
a: Transparent glass plate for diascopy. b, c: Ery-
thema disappears with pressure from the glass
plate. d, e: Purpura does not disappear with such 13. Darier’s sign
pressure.
When dermography is performed on a pigmented area of a
patient with mastocytosis (urticaria pigmentosa (Chapter 21)),
mast cells are degranulated and the site becomes markedly ele-
vated to form an urticarial lesion. This phenomenon is called
Darier’s sign (Fig. 5.15). Urticarial lesions are usually produced
g
shortly after rubbing.
j
Mastocytosis can be distinguished p
fromq
other pigmented lesions by Darier’s sign.
14. Sensory test

Sensory tests on touch (stroking with a brush), pain sensation
Clinical images are available in hardcopy only. (sticking with a needle), and temperature sensation (touching by
tubes containing warm water or ice water) are conducted on a
blindfolded patient. It is useful for the diagnosis of dissociation
disability in Hansen’s disease and neurological disorders.
Fig. 5.12 Wood’s lamp.
a: Wood’s lamp. b: Photodynamic diagnosis of
extramammary Paget’s disease. Wood’s lamp
reveals the area of the lesion, after delta-aminole-
vulinic acid ointment is applied in occlusive
dressing.
21. General internal medical tests 71
Table 5.5 Fluorescence under Wood’s lamp.

15. Nikolsky phenomenon
Disorder Fluorescence
In Nikolsky phenomenon, although the skin appears normal, Pityriasis versicolor Yellow-orange
blistering is produced by rubbing. The result is positive in pem- Erythrasma Coral pink
phigus, epidermolysis bullosa, staphylococcal scalded-skin syn- Porphyria Red
drome (SSSS), and toxic epidermal necrolysis (TEN) type drug
eruptions.
Tinea capitis Yellow green-viridian 5
16. Köbner phenomenon

From stimuli such as rubbing or sunlight, a lesion is produced
in normal skin; this is called the Köbner phenomenon, which is
seen in psoriasis and lichen planus.
17. Auspitz phenomenon

Auspitz phenomenon is the occurrence of small droplets of Fig. 5.13 Dermographism.
blood in skin. In psoriasis, when scales exfoliate, petechia is Artificial urticaria.
quickly produced (Chapter 15). However, the patient may also
test positive for Auspitz phenomenon in cases of eczema; it is not
necessarily specific to psoriasis.
18. Enzyme-linked immunosorbent assay

(ELISA)
Enzyme-linked immunosorbent assay (ELISA) is a method for
measuring the amount of specific proteins, using enzymes and
antibodies that are associated with fluorescent substances. For Fig. 5.14 White dermographism.
pemphigus diagnosis, it is necessary to identify whether there are Atopic dermatitis.
autoimmune antibodies to desmoglein 1 and 3. For bullous pem-
phigoid diagnosis, it is necessary to identify whether there are
autoantibodies to BPAG2 protein (Chapter 14).

19. Western blot
Western blot is a method to measure the amount of specific
proteins using proteins that are extracted from the epidermis to be
electrophoresed and reacted to the specific antibody (Fig. 5.16).
Fig. 5.15 Darier’s sign in mastocytosis.
It is used for detection of autoantibodies.
20. Diagnostic imaging

Diagnostic imaging using X-ray photography, CT, MRI, ultra-
sound, and scintigraphy is important for diagnosis of skin tumor
and lymph node metastasis of a skin tumor.
21. General internal medical tests

A general blood test, bacterial culture and urinalysis are gener-
al internal medical tests.
22. DNA analysis

230 kD With identification of the causative genetic mutation, accurate
diagnosis and classification of diseases are possible for hereditary
skin diseases caused by single-gene mutation (Fig. 5.17, Chapter
29). The characteristic configuration of DNA in tuberculosis and
5 atypical mycobacterial diseases is detectable by magnifying the
180 kD
DNA extracted from the lesion or reproducing it by PCR.
patient normal control
Fig. 5.16 Western blotting.

Serum of bullous pemphigoid patient reacts
against skin antigens (molecular weight of 180
kD and 230 kD).
Fig. 5.17 DNA analysis of type VII collagen

in a patient with epidermolysis bullosa.
Point mutation (C6761G, exon 86) causes non-
sense mutation; stop codon (TGA) occurs at
2261 amino acid instead of arginine (CGA).
Photodynamic diagnosis MEMO

(PDD), Photodynamic therapy (PDT)
When d -aminolevulinic acid is applied as
topical occlusive dressing therapy or when it
is locally injected or orally administered for
lesions such as those that occur in extramam-
mary Paget’s disease, basal cell carcinoma,
and actinic keratosis, there is accumulation of
protoporphyrin IX that contains red fluores-
cence. Taking advantage of this, non-invasive
diagnosis (photodynamic diagnosis; PDD)
and treatment (photodynamic therapy; PDT)
is possible. In PDD, by irradiation of Wood’s
lamp 4 to 6 hours after topical application of
d -aminolevulinic acid, red fluorescence is
observed (Fig. 5.12). In PDT, irradiation is by
100 J/cm2 630-nm excimer dye laser instead
of by Wood’s lamp.
Chapter
6 Treatment of Skin Diseases
Dermatological treatments are largely divided into external application of drugs, systemic therapies (oral admin-
istration of drugs, injections), physical therapies, laser therapies and surgical therapies. Among these treat-
ments, topical therapies are the most important treatments in dermatology. Physical therapies, including
irradiation and warming/cooling of affected sites, are also frequently applied. It is essential for dermatologists to 6
have full knowledge of various therapies and combinations of effective treatments.
A. Topical therapies
Topical therapies involve the application of a topical agent on
affected sites of skin. Topical agents are compounds of a main
agent and a vehicle (base). The main agent acts on lesions,
whereas the vehicle acts supplementarily to increase absorption
of the agent.
The horny cell layer in the outermost layer of skin is water-
repellant and dense. It prevents water from evaporating from the
body, which means it is the strongest barrier for the topical agent
to overcome (i.e., the rate-controlling step). The water-repellant
horny cell layer generally has a thin sebum membrane on the sur-
face that also functions as a barrier. The site below the granular
cell layer is characterized by hydrophilicity and ready absorption
of agents.
●Topical agents more readily permeate places where the horny
cell layer is thin, such as the face and scrotum, than places
where the horny cell layer is thick, such as palms and soles
(Table 6.1).
●The smaller the molecular weight of an agent, the more effi-
ciently the agent is absorbed. Generally, substances whose
molecular weight is 1,000 or more do not permeate normal skin.
●The absorption of a topical agent increases at a site whose
horny cell layer is injured by erosion, ulceration or the like.
Oleaginous ointments are fairly slow to show effects on these
types of lesions.
●A topical agent’s absorption tends to increase with duration of
contact. This characteristic is taken advantage of in occlusive Table 6.1 Relative absorption rate of topical
steroids by skin region (forearm=1).
therapy.
The type of vehicle and the consistency of main agent are cho- Region Relative absorption rate
sen according to the conditions and site of the eruption. Various Plantar area 0.1
vehicles and main agents and their characteristics and application Palms 0.8
on eruptions are described here briefly. Flexor side of forearm 1
Back 1.7
a. Vehicles for topical agents Scalp 3.5
Axilla 3.6
Vehicles help main agents permeate the skin. The agents have
Cheek 13
various actions, including hydration, cooling, lubrication, drying
(removal of exudate), protection, softening, purification, and itch Scrotum 42
73
74 6 Treatment of Skin Diseases
relief. A vehicle can be applied without a main agent in many

cases. Vehicles should be non-stimulating, colorless and scent-
less, stable (non-denaturing), able to retain the main agent even-
oil ly, moderately viscous, appropriately firm, and moderately
absorbable.
The same main agent may be mixed into various vehicles for
water
various types of topical agents with different applications (Figs.
6.1 and 6.2, Table 6.2). Typical vehicles and their characteristics
6 a．w/o emulsified ointment
are listed below with brief explanations.
oil
1. Ointments
water
Ointments are the most frequently used topical agents. They
are less stimulative than other vehicles and are highly protective.
b．o/w cream
They are transparent or translucent semisolids.
Fig. 6.1 Illustration of water in-oil (w/o) emul-
sified ointment and oil in-water (o/w) 1) Oleaginous ointments
cream.
a: W/o emulsified ointment. Water granules are Various oils such as olive oil, vaseline, paraffin, and plastibase
dispersed in oil by emulsion. b: O/w emulsive
cream. Oil granules are dispersed in water. are the most frequently used vehicles for oleaginous ointments.
These ointments are free of water, absorb little water, and are
insoluble in water. They are also called water-repellant oint-
ments. The vehicle itself protects and softens the skin and works
as an anti-inflammatory. Oleaginous ointments are the least stim-
ulative, and are applied on all kinds of eruptions.
(Examples: white petrolatum, zinc oxide ointment, various
steroids)
MEMO
2) Emulsified ointments
Vaseline, Petrolatum
Vaseline (petrolatum) is a semisolid com- These are water-in-oil ointments containing emulsifiers such
pound that is refined from petroleum. It is
often used as a vehicle for topical agents. It as polyethylene glycol. Because of the cooling sensation they
comes in yellow and white, the latter being bring with application, emulsified ointments are commonly
yellow Vaseline that has been bleached. called cold creams. They are more protective and less sticky than
There is no essential difference between the
two. creams (see below) and are easily washed off with water. They
are mostly applied on dry lesions.
Table 6.2 Characteristics of vehicles.

Vehicle Characteristics Drawbacks Target skin lesions
Ointment Oleaginous Least irritating, superior in skin Greasy feeling, not water absorbant Any skin lesion
protection
Emulsified Less greasy than oleaginous Less protective, contact dermatitis Lichenified lesions, nodules, etc.
ointment, readily penetrates the skin may occur due to adjunct materials
Cream Readily penetrates the skin, feels More irritating than ointments, Chronic hypertrophic lesions,
soothing after application contact dermatitis may occur due to acute-phase lesions with slight
adjunct materials oozing
Lotion No greasy feeling, easy to apply to Irritant, possible to overuse Eczematous lesions on the scalp
the scalp
Tape Strong protective effect and drug Unable to apply to wet lesions and Nodules, lichenified lesions
penetration scalp, possible to cause folliculitis
and miliaria
A. Topical therapies 75
2. Creams
Creams, also called oil-in-water emulsive vehicles, are semi-
solid mixtures of oil suspended in water containing emulsifiers.
Creams are less sticky than ointments, and the color disappears
when they are applied thinly (vanishing cream). Since they do
not stain clothes, creams are readily accepted by patients, and
compliance with application is ensured. However, they may be
6
irritating, and less protective than ointments. Although creams a b c d e f g h
are useful for erythema and papules, they should not be used on
eroded or moist sites.
3. Lotions
Lotions are liquids (usually water) with an agent mixed in.
When applied topically, the liquid evaporates, bringing cooling,
astringent and protective effects. The agent remaining on the skin
acts pharmacologically. In addition to water, the following are
g
often used as liquid vehicles for lotions: alcohol, propylene gly-a b c d e f h i
col, glycerin, and zinc oxide oil (a 1:1 mixture of zinc oxide and
olive oil). Some lotions require shaking prior to application. They
are known as shake lotions.
1) Emulsive lotions
Emulsive lotions are emulsions of oil in water. They are more
permeable in skin than are shake lotions (see below). They are
used for non-moist lesions and are often applied on the a hairyb c d e f g h i j
scalp. Fig. 6.2 Topical agents with various vehi-
(Examples: various steroid lotions) cles.
a: Oleaginous ointment. b: Cream. c: Lotion.
2) Shake lotions
Shake lotions are liquids with powdered agents mixed in. The
powder settles, so these need to be shaken before use. When
applied, a cool sensation is produced as the liquid evaporates;
shake lotions are effective on lesions that are accompanied by
fever and evaporable moisture, such as erythema and papules.
They are unsuitable for intensely exudative lesions, such as ero-
sions, because they may cause irritation.
(Examples: sulfur camphor lotion)
3) Other topical agents

Ointments MEMO
Tinctures: agents dissolved in alcohol or in alcohol and water “Ointment” in dermatology usually refers to
Aerosols: vaporized liquid agents an oleaginous ointment. However, some
water-in-oil emulsive creams (cold cream)
and oil-in-water creams (vanishing cream)
4. Gels may also be regarded as “ointments” by
patients. Care should be taken in prescribing
Gels are transparent agents that are solid to semisolid. Gelatine ointments and in explaining their use to
patients.
is dissolved in water or acetone, yielding a gelatinous product.
After application, it dries to become a thin adhesive film on the

skin. Gels with high solvent content are called jellies. These are
used on mucous membranes to protect lesions from friction.
5. Powders
The main ingredients of powders are zinc oxides, talc (magne-
sium silicate), and starches. Powders dry affected sites by absorb-
6
ing moisture. They also cool the skin, reduce friction, and smooth
the skin surface. They are effective in preventing miliaria and
intertrigo.
6. Liniments
Liniments are mixtures of water and zinc oxides, phenol or
glycerin. They dry fast on the skin. They are effective in cooling
the skin and relieving itching. Carboric acid liniments are used
for erythema and papules of, for instance, varicella; however,
they must be avoided for lesions with moist surfaces, because of
their water solubility.
7. Pastes
Pastes are highly viscous mixtures of oil-based substances and
microparticles of powder. In this they resemble oleaginous oint-
ments; however, pastes contain more powder than oleaginous
ointments do.
8. Plasters
Plasters are cloth, paper, or plastic film spread with topical
agents. One example is 30% salicylic acid plaster. They are
applied to lesions such as callus and clavus (Fig. 6.3). Adhesive
plasters containing steroids are also useful. Adhesive plasters
with nitroglycerine or fentanyl are used for systemic administra-
tion in non-dermatological medical departments, utilizing the
transdermal absorption of the skin.
9. Other vehicles for topical agents

These include compresses, soaps, shampoos and bath addi-
tives.
b. Main topical agents

The main agents are the components that have therapeutic
effects on skin. Frequently used main agents are listed below.
1. Corticosteroids (steroid)
Fig. 6.3 30% salicylic acid plaster. The main purpose of steroid topical application is to fight
Table 6.3 Topical steroids.

Brand name and form Corticosteroid Potency
Betnovate cream/ointment/lotion Betamethasone valerate 0.1% Very strong
Betnovate RD cream/ointment Betamethasone valerate 0.025% Strong
Bettamousse Betamethasone valerate 0.12% Very strong
Cutivate cream/ointment Fluticasone propionate Very strong
Dermacort cream Hydrocortisone 0.1% Mild
Dermovate cream/ointment/scalp application Clobetasol propionate 0.05% Strongest 6
Dioderm cream Hydrocortisone 0.1% Mild
Diprosone cream/ointment/lotion Betamethasone dipropionate 0.05% Very strong
Efcortelan cream/ointment Hydrocortisone 0.5%, 1%, 2.5% Mild
Elocon ointment/scalp ointment Mometasone furoate 0.1% Very strong
Eumovate eczema and dermatitis cream Clobetasone butyrate 0.05% Strong
Eumovate cream/ointment Clobetasone butyrate 0.05% Strong
Haelan cream/ointment/tape Flurandrenolone (fludroxycortide) Strong
Halciderm cream Halcinonide 0.1% Strongest
Locoid cream/ointment/lipocream/scalp lotion Hydrocortisone 17-butyrate 0.1% Very strong
Metosyn cream/ointment Fluocinonide 0.05% Very strong
Mildison lipocream Hydrocortisone 1% Mild
Modrasone cream/ointment Alclometasone dipropionate 0.05% Strong
Nerisone cream/oily cream/ointment Diflucortolone valerate 0.1% Very strong
Nerisone forte oily cream/ointment Diflucortolone valerate 0.3% Strongest
Propaderm cream/ointment Beclometasone dipropionate 0.025% Very strong
Stiedex LP cream Desoximetasone 0.05% Strong
Synalar cream/ointment/gel Fluocinolone acetonide 0.025% Very strong
Synalar 1:4 cream/ointment Fluocinolone acetonide 0.00625% Strong
Synalar 1:10 cream/ointment Fluocinolone acetonide 0.0025% Mild
Ultralanum cream/ointment Fluocortolone Strong
(Adapted from; http://www.netdoctor.co.uk/skin_hair/eczema_corticosteroids_003762.htm).
inflammation. Vasoconstriction, diminution of membrane perme-

ability, liberation and inhibition of inflammatory chemical medi-
ators, arachidonic acid reduction by phospholipase inhibition,
immunosuppression, and cell division inhibition combine to
inhibit inflammation.
Steroids for topical application are classified by strength:
strongest, very strong, strong, mild and weak (Table 6.3).
Steroid topical application may have side effects. Particular
care should be taken in facial application, because of the high
absorptiveness of the skin there. As long as the dosage and usage
of steroids are appropriate, systemic side effects are rare. Howev-
er, when strong steroids are applied on a large area for a long
period or when they are used in occlusive therapy, side effects
similar to those caused by steroid systemic administration may be
produced. Moreover, special care should be taken in administer-
ing steroids to infants, since the effects tend to be systemic.
Topical corticosteroids induce and aggravate cutaneous atro-
phy, striae atrophicae, telangiectasia, purpura, hypertrichosis,
steroid acne, rosacea-like dermatitis and infectious diseases (tinea
Table 6.4 Side effects of topical steroids. incognito and candidiasis in particular) (Table 6.4).
Systemic Intralesional steroids are used for recalcitrant dermatoses, such
Suppression of adrenal gland function as alopecia areata, keloids, scars, prurigo nodularis and lichen
Local simplex. Triamcinolone is often used, but dermal atrophy and
Atrophy leukoderma may occur.
Steroid purpura
Rosacea-like dermatitis, perioral dermatitis
Steroid acne 2. Immunosuppressants
6 Hypertrichosis
Infection (bacterial, fungal, viral) Tacrolimus (FK-506: molecular weight=822Da), a topical cal-
Contact dermatitis cineurin inhibitor, selectively inhibits T-cell functions, making it
Rebound (exacerbation of disease after sudden
cessation)
effective against atopic dermatitis as an immunosuppressant. It is
also useful as a treatment for chronic actinic dermatitis and lichen
planus.
Potency and strength of MEMO
topical steroids
Topical steroids are classified into several 3. Antifungal agents
groups according to the potency of prepara-
tion. In Japan, the clinical activity is Various types of topical antifungal agents, such as those con-
expressed in terms of strength, which is cate- taining imidazole, benzylamine or morpholine, are used. They act
gorized into five levels: strongest, very by attaching to the cellular walls of fungi and inhibiting biosyn-
strong, strong, mild and weak. However, the
English-language literature uses the term
thesis. These agents are used topically (as creams, lotions, or
“potency.” This table ranks the strengths and ointments) for superficial mycosis; however, they may be used
potencies. Note that the correspondence of orally for tinea unguium and deep fungal infections.
strength/potency is not determined strictly; it
can change with changes in the concentration
of the drug and the vehicle. 4. Antibiotics
Strength (Japan) Potency Potency Class
Topical agents containing antibiotics are used against superfi-
Strongest Very potent, class 1
super potent cial bacterial infections. Antibiotics should be effectively anti-
Very strong Potent class 2
bacterial against the targeted bacteria and have transdermal
sensitization capability. Macrolide or new quinolone antibiotics
Strong class 3
are effective against folliculitis, including acne vulgaris. As
Moderate class 4
(mid-strength)
antibiotic resistance among bacteria has been increasing in recent
Mild (medium) class 5 years, ointments containing antibiotics are not always effective in
Mild class 6 treating superficial infectious diseases.
Weak class 7
5. Vitamin D analogues
Activated vitamin D3 is used to treat hyperkeratotic and prolif-
erative diseases such as psoriasis, ichthyosis, and palmoplantar
keratosis, because of its ability to induce differentiation of the
epidermis and antiproliferation. It is the first choice of treatment
for psoriasis. Nevertheless, a prolonged large dosage of activated
vitamin D3 may lead to hypercalcemia; the dosage should be
carefully decided.
6. Urea
Urea is used as a moisturizer for its water retentivity.
Hydrophilic ointments containing 10% to 20% urea are frequent-
ly used to treat senile xerosis, ichthyosis, palmoplantar keratosis,
keratodermia tylodes palmaris progressiva, and atopic dermatitis.
Urea may produce irritation on cracked or moist sites.
7. Zinc oxide
Zinc oxide is frequently used not only as a vehicle but also as a
main agent for its actions of desiccation, astringency, anti-itch-
ing, cooling, and radiation blocking. Zinc oxide spread on cotton
lint is available commercially (Fig. 6.4).
8. Sulfur, Resorcinol 6
Sulfur and resorcinol are antibacterials and antifungals with
keratin-exfoliating action. They are effective in treating acne vul-
garis.
Fig. 6.4 Zinc oxide sheet.
9. Salicylic acid
Salicylic acid is keratolytic and is used to treat keratoderma in
the soles. A plaster containing 30% to 40% salicylic acid is used
to soften and remove callosity and clavus.
10. Phenol
Phenol has anti-itching and antibacterial effects. Because of its
corrosive effect, it may also be used in treating verruca vulgaris
and ingrown nails, and for chemical peeling.
11. Tars
Tars such as coal tar, wood tar and Glyteer have been applied
topically on moist eruptions and lichenified lesions. Because of
their peculiar odor and color, and their carcinogenicity if used for
long periods, they are rarely used now. Tars may also cause pho-
tosensitive diseases. As tars have a cellular antiproliferative
effect, they have been used in the past in combination with ultra-
violet rays (UVB) against psoriasis; this treatment is called
Goeckerman therapy.
12. Other agents

Antihistamines, retinoids (isotretinoin and adapalene), antitu-
mor drugs, sunscreen, psoralen, vitamins, sex hormones, and
nonsteroidal anti-inflammatory drugs (NSAIDs) are used as topi-
cal agents.
c. Application
Topical agents are applied as described below. Care should be
paid in the application of agents for which there are restrictions
on dosage and use frequency. For agents whose dosage is not
specified, it is necessary to determine the daily dosage for each
patient.
Instructing patients on the MEMO Direct application: A topical agent is applied directly to a skin
daily dosage of external medicine lesion. This is the most common application method.
For oral medicines, it is easy to specify the Plaster: A cloth spread with the agent is applied to a lesion. It is
precise daily dosage in the prescription. For effective in removing crusts and protecting erosions and ulcers.
topical medicines, it is not. Dermatologists
must give careful instructions not only on the Occlusive dressing therapy (ODT): A topical agent is directly
daily dosage but also on how much of the top- applied, and the site is tightly sealed with polyethylene film.
ical medicine (e.g., the number of grams, how Steroid adhesive plasters are sold commercially. They are useful
much of the tube) should be applied accord-
for treating infiltration, acanthosis, lichenified plaques, and
6 ing to the severity and size of the lesion.
hyperkeratosis. However, ODT is much more absorptive than
other topical agents; therefore, the patient should be monitored
for side effects such as systemic symptoms.
Chemical and mineral bath: Chemicals and minerals are dis-
solved in warm water, for systemic or topical soaking. The bath
may also be used for disinfecting burns. Hot spring water is rich
in minerals and has a thermo-therapeutic effect. In UV therapy,
the patient is radiated with UV rays after a chemical bath of pso-
ralen (PUVA-bath therapy).
B. Systemic treatments
Table 6.5 Common antihistamines.
Non-sedating 1. Antihistamines
Acrivastine (Semprex) There are several types of antihistamine agents that bind to
Cetirizine hydrocholoride (Zirtek) histamine receptors to inhibit their functions. H1 receptor inhibit-
Fexofenadine hydrochloride (Telfast) ing drugs, widely used in dermatological treatments, are extreme-
Loratadine (Clarityn) ly effective in treating inflammation and allergic reactions.
Mizolastine (Mistamine, Mizollen)
Second- and third-generation antihistamines, which also inhibit
the release of a chemical mediator from mast cells, may also be
Terfenadine
called antiallergic drugs. Third-generation antihistamines such as
Sedating
Loratadine, Cetirizine, and Fexofendadine have a mild depressant
Alimemazine tartrate/trimeprazine tartrate action on the central nervous system (Table 6.5), and have a long
(Vallergan)
serum half-life: Only one or two doses per day is effective in
Azatadine maleate (Optimine)
relieving itching from urticaria, eczema and dermatitis, pruritus,
Brompheniramine maleate (Dimotane) and prurigo. Drugs prompting anticholinergic action must be
Chlorphenamine maleate/chlorpheniramine avoided for patients with glaucoma and enlarged prostate.
maleate (Piriton)
Cinnarizine (Stugerone)
Clemastine (Tavegil)
2. Corticosteroids
Cyclizine (Valoid) Corticosteroids afford anti-inflammatory and anti-immune
Cyproheptadine hydrochloride (Periactin) effects. They are administered orally for long periods in collagen
Hydroxyzine hydrochloride (Atarax, Ucerax) diseases such as systemic lupus erythematosus (SLE), and in
Meclozine hydrochloride (Sea-legs) autoimmune skin diseases such as pemphigus and pemphigoid.
Promethazine hydrochloride (Phenergan)
Short-term oral use of corticosteroids may be given for extensive
drug eruptions or autosensitization dermatitis. However, systemic
Promethazine teoclate (Avomine)
administration as a treatment for chronic diseases including
(http://www.bupa.co.uk/health_information/html/
medicine/antihistamine.html).
atopic dermatitis, chronic urticaria, and psoriasis should not be
performed without careful consideration.
Oral use of steroids may cause a wider variety of side effects
than topical use. Oral use should be performed with care,
B. Systemic treatments 81
particularly for patients with an underlying disease such as dia- Table 6.6 Side effects of corticosteroids.
betes or high blood pressure; steroids may aggravate these dis- Severe Relatively mild
eases. The typical side effects of systemic steroid administration Secondary adrenal Moon face, central
are shown in Table 6.6. dysfunction obesity
Sideration and exacerbation Hyperphagia
The initial dosage of steroids is determined according to the of diabetes Leukocytosis
severity of the disease. This dosage is reduced to a maintenance Sideration and exacerbation Skin streaks
dose or stopped with the gradual diminution of symptoms (Table of hypertension Subcutaneous
Hyperlipidemia hemorrhage,
6.7). If necessary, steroid pulse therapy (500 mg to 1,000 mg of Psychiatric effects purpura 6
methylprednisolone intravenous injection per day for 3 succes- Muscular atrophy Steroid acne
sive days) is performed. Cataract, glaucoma Hypertrichosis
Gastric ulcer Alopecia
Osteoporosis Edema
3. Nonsteroidal anti-inflammatory drugs Aseptic necrosis of bone Insomnia
Susceptibility to various
(NSAIDs), analgesics, antipyretics and infectious conditions
other anti-inflammatory drugs
Most analgesics and antipyretics also have anti-inflammatory
effects, which occur from inhibition of prostaglandin synthesis.
Aspirins inhibit thromboxane A2 (TXA2) synthesis-synthesis
that is necessary for platelet aggregation. Therefore, besides anti-
inflammatory and analgesic effects, aspirins are used for throm-
botic diseases.
Gold preparations, colchicines and potassium iodide are
applied exclusively for specific inflammatory diseases. Gold
preparations that are engulfed by macrophages inhibit the func-
tions of macrophages; additionally, those preparations are
thought to inhibit cellular immunity, a characteristic that is used
in treating rheumatoid arthritis and pemphigus. Colchicines act to
inhibit neutrophil chemotactic and cell division, making them
useful in treating gout and Behçet’s disease. Potassium iodide is
effective against erythema nodosum.
4. Immunosuppressants
Azathioprines, methotrexates, cyclophosphamides, cyclosporines
and tacrolimus are known to be immunosuppressants. When it is
difficult to reduce the steroid dosage, such as in treating SLE,
dermatomyositis, pemphigus, bullous pemphigoid and Behçet’s
disease, immunosuppressants may be used in combination with
steroids. Cyclosporines may be used alone in intractable psoria-
sis; however, they tend to cause dose-dependent kidney disor-
ders and high blood pressure. Therefore, blood concentration
Table 6.7 Various corticosteroids: comparison of the duration and dose for the same effects.
Duration of action Drug Dose needed for the same effect as 5 mg prednisolone Dose per tablet
Short (within 8 hours) Hydrocortisone 20 mg 10 mg
Moderate (1 day) Prednisolone 5 mg 5 mg
Methylprednisolone 4 mg 4 mg
Long (2 days) Dexamethasone 0.75 mg 0.5 mg
Betamethasone 0.6 mg 0.5 mg
(Adapted from; Wallace J, et al, editors. Dubois’ lupus erythematosus. 5th ed. Williams & Wilkins. 1997).
monitoring is necessary when cyclosporines are administrated.
5. Antifungal agents
Antifungal agents for internal use, such as potassium iodides,
Griseofulvin, amphotericin B, nystatin, flucytosine and micona-
zole, were formerly administered orally or by injection. They
have a narrow antifungal spectrum, and side effects. Recently
6
developed itraconazole, terbinafine and fluconazole have a broad
antifungal spectrum and fewer side effects; therefore, they are
widely applied in many types of diseases. Highly keratinophillic,
these drugs are known to concentrate in a skin lesion. Moreover,
they are administered orally to patients with kerion celsi, sycosis
trichophytica, or mycosis profunda. For tinea unguium, pulse
therapy of itraconazole (400 mg per day, 1 week per month for 4
cycles) is also effective.
6. Antibiotics
Antibiotics are used to treat cellulitis and infectious skin dis-
eases such as impetigo contagiosa. Most infectious skin diseases
tend to respond to internal use of antibiotics; however, drug-
resistant bacteria such as MRSA have been frequently found in
community-acquired infections in recent years. For that reason,
before administration of antibiotics, cultivation tests (on exudate,
pus or the like) should be performed. When antibiotics are not
effective enough, the drugs may be changed according to the
results of laboratory culture test. History-taking is necessary to
avoid allergic reactions. For patients with severe liver disorder or
kidney dysfunction, the dosage and times of administration
should be reviewed in consideration of the metabolic pathway of
the drugs. Types of antibiotics and their mechanisms of action are
shown in Table 6.8.
7. Antiviral agents
Aciclovir and Ara-A (adenine arabinoside) are effective
against herpes viruses, including herpes simplex and varicella
zoster. Aciclovir may be administered orally or by injection; it is
used in outpatient treatment. Since antiviral agents are metabo-
lized by the kidney, in patients with kidney disorder the dosage
should be controlled based on creatinine clearance. Other antivi-
ral agents are ganciclovir, which is effective against
cytomegalovirus, and some kinds of anti-HIV drugs.
8. Retinoids
Retinoids are A vitamins and their derivatives. They control
the proliferation and differentiation of epithelial tissues, process-
es that are promoted by retinoic acid, a metabolite of vitamin A.
The only retinoid permitted in Japan is etretinate; however, in
B. Systemic treatments 83
Table 6.8 Common antibiotics and their mechanisms. Table 6.9 Major retinoid-responsive skin
diseases.
Antibacterial
Classification by drug structure Mechanism
effects Disorders of keratinization
Ichthyoses
Biocidal agents b -lactams Penicillin
Darier's disease
Cephalosporin Psoriasis
Monobactam Pityriasis rubra pilaris
Inhibition of cell Malignancies
Carbapenem wall synthesis Basal cell carcinoma
Squamous cell carcinoma
Penem
Mycosis fungoids
6
Fosfomycins Other
Aminoglycosides Inhibition of Acne
protein synthesis Cutaneous aging
Polypeptide antibiotics Inhibition of cell

wall synthesis
Synthetic Quinolone Inhibition of DNA
antibiotics synthesis
Sulfamethoxazole/ Inhibition of folic
trimethoprim acid synthesis
Bacteriostatic Tetracyclines
agents
Chloramphenicols Inhibition of
Macrolides protein synthesis
Lincomycins
other developed countries, acitretin, isoretinoin and all-trans

retinoic acid are permitted. Vitamin A works to decrease sulfate
cholesterols, constructional components of the horny cell layers;
that is, exfoliation of the horny cell layers is increased by vitamin
A administration. In light of these effects, retinoids are useful
against various disorders of keratinization, such as ichthyosis,
palmoplantar keratosis, Darier’s disease and severe psoriasis
(Table 6.9). Nonetheless, etretinate causes serious side effects
(teratogenesis and bone defects), and contraception of 2 years for
women and 6 months for men after the administration of
retinoids is strictly advised for patients of reproductive age. In
Europe and U.S., etretinate has been withdrawn from the market
because of its undesirable pharmacolcinetics. Today acitretin is
commonly used. Care should be taken in deciding whether to
administer retinoids to children, because of the possibility of pre-
mature closure of the epiphyseal line. Other side effects are epi-
dermal exfoliation, nail fragility, liver disorders and abnormal
lipid metabolism. In Europe and the United States, retinoid
creams are externally applied to treat acne and psoriasis.
9. DDS (4,4’-diamino-diphenyl-sulfone,
diaphenylsulfone)
DDS (dapsone), a sulfa drug that inhibits folic acid synthesis,
was originally used to treat Hansen’s disease. Since it was found
to be effective against inflammatory skin diseases whose main
symptom is neutrophilic infiltration, DDS has been adminis-
tered to treat Duhring herpetiform dermatitis and other bullous
diseases, erythema elevatum diutinum, subcorneal pustular der-

matosis, vasculitis, granuloma faciale and pustular psoriasis. The
side effects are hemolytic anemia, methemoglobinemia, leucope-
nia, liver disorders and kidney disorders; regular blood tests are
necessary. Eruptions, fever and liver dysfunction may be present
as so-called hypersensitivity syndrome in rare cases (Chapter 10):
These particular symptoms are known as DDS syndrome.
6
10. Vitamin preparations
Skin diseases caused by vitamin deficiency are ariboflavinosis
(vitamin B deficiency), pellagra (niacin deficiency), and biotin
deficiency (vitamin H deficiency). Vitamin replacement therapy
is administered. Vitamin C is given in cases of melasma and
postinflammatory pigmentation.
11. Anticancer agents

Anticancer agents may be administered for skin diseases such
as malignant melanoma, squamous cell carcinoma, Paget’s dis-
ease, and cutaneous lymphoma, depending on the stage of the
disease. Combined use of various types of anticancer agents is
conducted; however, the various anticancer agents and their
dosages should be thoroughly discussed before administration.
Most anticancer agents have more serious side effects than drugs
in general, and they can even be fatal (Table 6.10). Nausea, vom-
iting and leucopenia are diminished by anti-serotonin and G-CSF
drugs. CHOP therapy (for lymphoma) and DAV-feron therapy
(for malignant melanoma) are frequently administered in derma-
tology (Chapter 22).
12. Biologic (molecular-targeted) therapies

Biologic (molecular-targeted) therapies, in which mono-
chrome antibodies such as infliximab, adalimumab, etanercept
Table 6.10 Main side effects of anticancer agents.

Side effects
Drug
Myelosuppression Nausea/vomiting Alopecia other
Cyclophosphamide +++ ++ +++ Hemorrhagic cystitis, SIADH
Cisplatin ++ +++ + Renal dysfunction, hypacusis, neuropathy
Dacarbazine + +++ ++ Flu-like syndrome, hepatic vein dysfunction
Methotrexate ++ + + Hepatic dysfunction, renal dysfunction, neuropathy
Fluorouracil ++ + + Diarrhea, aphtha, cerebellar ataxia, myocardial infarction
Doxorubicin +++ +++ +++ Cardiac dysfunction
Bleomycin + + ++ Interstitial pneumonia, fever, allergic reaction
Vincristine + + ++ Neuropathy, constipation, SIADH
Etoposide +++ ++ +++ Allergic reaction, hepatic dysfunction, neuropathy
Docetaxel +++ + ++ Edema, eruption, allergic reaction
C. Laser therapies 85
Table 6.11 Biologic (molecular-targeted) agents.

Target
Drug Indication
molecule
Rituximab CD20 B-cell lymphoma, pemphigus vulgaris
Infliximab TNF-a Crohn’s disease, rheumatoid arthritis, psoriasis
Etanercept TNF-a Crohn’s disease, rheumatoid arthritis, psoriasis
Alefacept CD2 Psoriasis
Efalizumab CD11a Psoriasis 6
and alefacept are administered, have recently been developed to

treat lymphoma, collagen diseases, autoimmune bullous diseases
and psoriasis (Table 6.11). In contrast to anticancer drugs and
immunosuppressants, there are fewer and less severe side effects
with biologics. Particularly beneficial effects on severe psoriasis
and psoriatic arthritis have been reported, and widespread use of
biologic therapies is expected in the future. However, secondary
infections such as tuberculosis have occurred in some cases.
These therapies should be applied carefully.
C. Laser therapies
1. Basics and theory of laser therapy

“Laser” is an initialism for “light amplification by stimulated
emission of radiation.” Molecules are excited in a xenon flash
tube or by electric discharge. When they return to their base state, Clinical images are available in hardcopy only.
the molecules emit light. The light is amplified in the resonator.
Laser beams are distinguished by their monochromaticity, direc-
tivity, and high energy density. Light energy is absorbed in tis-
sues by heat transfer, and cells and tissue are destroyed as a
result. The part of a visibly colored molecule that absorbs light in a b c d e f g h
the visible range is called a chromophore. It is found in melanins
and hemoglobins of normal skin. The application of a laser with
a wavelength that affects melanin- or hemoglobin-containing
cells causes the temperature to increase and thermal diffusion to
be produced, which in turn causes the cells to burn. In this way,
blood capillaries are cut off, and the unwanted color tone of the
cells fades. To prevent degeneration of the skin surface by thea b c d e f g h i
destructive heat, apparatuses equipped with cooling systems may Fig. 6.5 Laser therapy.
be used. a: Dye laser for vascular lesions. b: Alexandrite
As a cohesive theoretical understanding and trial results have laser for pigmented lesions.
been accumulated, it is now possible to determine the most effec-
tive wavelength for each case. The main laser therapies are sum-
marized in Table 6.12. Examples of laser therapy are shown in
Fig. 6.5, and the laser apparatuses that are frequently used are
listed in Fig. 6.6.
The wavelength that is most effectively absorbed by each
lesion is selected for irradiation. O 2 -hemoglobins absorb
Table 6.12 Common lasers.

Laser Wavelength Absorbed by... (chromophore)
Carbon dioxide 10600 nm Water
Dye 577-585 nm Hemoglobin
Ruby 694 nm Melanin, tattooing pigments
Alexandrite 755 nm Melanin, tattooing pigments
Nd: YAG 1064/532 nm Melanin, hemoglobin,
6 tattooing pigments
lights most effectively at 418 nm, 542 nm, and 577 nm. Light with
a wavelength of 577 nm reaches the deep area of skin (Fig. 6.7).
For melanins, the proper wavelength varies depending on the
depth between the pigmented site and the epidermal layer. More-
a b ac bd ce df eg
over, the
fh gi duration
hj
of irradiation
ik j l maykm
need to
ln
be changed
mo
accord-oq
np pr
ing to the color of the targeted lesion. Lasers with a pulse on the
order of nanoseconds (10-9 second) or shorter are used to destroy
melanosomes; lasers with a pulse on the order of microseconds
(10-6 second) are used to destroy the cells completely.
Heat damage to the epidermis may result in adverse reaction
such as blistering, scarring and dyspigmentation. To reduce the
risk, some lasers have cryogen spray cooling equipment (dynam-
ic cooling device).
2. Laser therapy on pigmented skin lesions

Ruby laser (694 nm) and alexandrite laser (755 nm) are used to
b ac bd ce df eg fh gi htreat
j pigmented
ik j l skin km
lesions.ln Lightmoat those
np wavelengths
oq pr is notq r
absorbed by hemoglobins, and it reaches the depth of 1.5 mm.
Fig. 6.6 Lasers.
a: Carbon dioxide laser. b: Dye laser. c: Alexan- The Q-switched ruby laser has a 20- to 30-ns irradiation duration,
drite laser. d: Ruby laser. and its beams can be concentrated on melanosomes effectively.
Reduction of pigmented cells is observed in 80% or more cases
molar extinction coefficient (X105l / mole・cm)
with nevus of Ota, a kind of dermal melanocytosis. Laser therapy

1.4 Hb (H2O)
is effective only against pigmented lesions in nevocellular nevus
HbO2 (H2O)
1.2 and blue nevus. The color tone of nevus fades in proportion to
1.0
the number of irradiations; however, the therapy does not work
on elevated, slightly pigmented skin lesions. Basically, laser ther-
0.8 apy is not performed in such cases; if necessary, the possibility of
0.6 bilirubin (CHCl3) pathological malignancy should be ruled out. Laser therapy is
performed on ectopic Mongolian spots, senile lentigo, and nevus
0.4
dopamelanin (H2O) spilus.
0.2 It is also used to remove tattoos; nonetheless, the effectiveness
0 depends on the depth and the pigment color. For multicolored tat-
300 400 500 600 700 toos, a different laser should be applied for each color.
wavelength (nm)
Fig. 6.7 Optical absorption spectrum in
human skin. 3. Dye lasers for vascular lesions
(Anderson RR et al. The optics of human skin. J
Invest Dermatol 1981; 77: 13-9). Dye lasers (577 nm to 585 nm) are used to treat hemangiomas.
With hemoglobins targeted, the vascular endothelium is
destroyed by destruction of erythrocytes and subsequent emission
of heat. These lasers are effective in treating hemangioma simplex,
D. Physical therapies 87
strawberry marks, and telangiectasia.

Photodynamic therapy (PDT) is also conducted. In this thera-
py, a tumorous lesion is exposed to red fluorescence with appli-
cation of d -aminolevulinic acid, and then it is irradiated by laser.
D. Physical therapies
6
1. Phototherapies
Phototherapies are largely divided into those using ultraviolet
rays and those using infrared rays.
1) Ultraviolet (UV) light

Ultraviolet (UV) light is classified into three wavelength
ranges. From longest to shortest, they are UVA (320 nm to 400
nm), UVB (290 nm to 320 nm) and UVC (200 nm to 290 nm).
The shorter is the wavelength, the lower is the penetration and
the greater is the energy of the light. UVC light that affects only
the skin surface is chiefly used for sterilization lamps, because of
its high cytotoxicity. The UV phototoxic reaction of UVA and
UVB light are used in dermatological laser therapies. UVA and
UVB directly or indirectly damage DNA by exciting UV absorb-
ing molecules, or they produce free radicals that injure cells.
①Psoralen-ultraviolet-A (PUVA) therapy
Psoralen-ultraviolet-A (PUVA) therapy (Fig. 6.8) is a typical
UV therapy that uses UVA, which is deeply penetrative but has
little energy. After oral or topical application of psoralen, a pho-
totoxic substance, the site is irradiated with UVA. The patient is
given radiation in combination with 8-MOP (8-methoxypsoralen)
or TMP (4,5’,8-trimethylpsoralen). This treatment is applied in
cases of psoriasis vulgaris, vitiligo vulgaris, mycosis fungoides,
palmoplantar pustulosis, atopic dermatitis, alopecia areata and
prurigo nodularis. As a side effect, sunburn may be caused by
excessive irradiation of long-wavelength UV rays. It should be
performed carefully, so that successive irradiations over a long
period of time do not cause cataracts or cutaneous malignant
tumors. Clinical images are available in hardcopy only.
②UVB therapy
UVB is known to be immunosuppressive by inhibiting the
functions of Langerhans cells. Currently, UVB irradiation thera-
py is performed to treat atopic dermatitis, pityriasis lichenoides
chronica, and pruritus in dialysis patients. For patients with psori-
asis vulgaris, frequent sunbathing is strongly advised, as the
UVB in sunlight is expected to be beneficial (heliotherapy).
③Narrow-band UVB therapy
Narrow-band UVB has a wavelength of 311 nm ± 2 nm. It is
thought to be more effective than broadband UVB as a treatment
for skin diseases. It is effective against psoriasis, atopic dermati- Fig. 6.8 UV irradiation instrument (narrow-
tis, the early stages of mycosis fungoides, and vitiligo vulgaris. band UVB).
④UVA1 therapy
UVA with a long wavelength of 340 nm to 400 nm is called
UVA1. It is applied mainly to treat atopic dermatitis. It is effec-
tive against scleroderma.
2) Infrared (IR) irradiation

The patient is subjected to infrared (IR) radiation at a wave-
6
length of 760 nm or longer so as to raise the temperature,
improve blood circulation, and achieve anti-inflammatory action.
The transmissivity through skin is high, with a reach of several
centimeters in depth from the skin surface. This allows the thera-
py to act directly on blood vessels, nerves, lymphatic vessels and
other tissues. It is effective in treating frostbite, chilblains, and
ulcers of the lower thigh.
2. Radiotherapy
Radiotherapy was once used to treat benign diseases such as
chronic inflammatory diseases. In consideration of its side
effects, which include carcinogenesis, it is rarely performed for
this purpose nowadays. Instead, linac ultrahigh X radiation, 60Co
g radiation, or electron radiation generated by linac or betatron
are the main forms of radiation used for therapy. These forms of
radiation strongly ionize molecules, and the generated free radi-
cals damage DNA directly or indirectly, leading to cell death.
The proper type of radiation should be chosen in suitable dose for
each case.
1) Electron beams
These are b rays generated by betatron or linac. They evenly
Skin types MEMO
irradiate lesions to a certain depth, and the energy is not attenuat-
Reaction to sun exposure differs for each
individual. Some people sunburn easily,
ed in the superficial layers. They are used for treating lymphomas
whereas others tend to suntan. Fitzpatrick and keloids.
classified human skin into six types according
to such differences. Japanese skin falls under
type III xanthoderm. 2) Soft X-rays
Fitzpatrick Japan Soft X-rays are low-voltage, low-energy X-rays (about 20 kV).
type I A device called a dermopan is used to generate X-rays in derma-
（pale white） sunburn type I（15%）
reddening（＋＋）
tology. However, their application is limited to superficial lesions
type II suntan（−） (e.g., intraepidermal carcinoma, malignant lymphoma, hemagio
（white） blastoma) because of the low energy. Soft X-rays are rarely used
Japanese
skin type
type III falls within type II（70%） nowadays.
（white） this range of reddening
type III.
suntan（＋）
type IV
（light brown） 3. Cryotherapy, Cryosurgery
type III（15%）
type V suntan mainly Cryotherapy is a method of freezing cells using a cryogenic
（brown）
suntan
source such as liquid nitrogen. It is frequently used to remove
type VI warts, and it may be used to treat nevus, hemangioma, alopecia
（black）
and other diseases. There are several methods of cryotherapy,
E. Skin surgery 89
including the swab method (a cotton swab dipped in liquid nitro-

gen at -196.8℃ is brought into contact with a lesion (Fig. 6.9),
and the spray method (liquid nitrogen is sprayed on a lesion at a
pressure of 0.1 kg/cm2 to 0.5 kg/cm2 (Fig. 6.10).
4. Thermotherapy, Hyperthermia
In thermotherapy, a lesion is warmed to 42 ℃ to 47 ℃ with
6
warm water, a body warmer, a medical exothermic sheet or the
like. This is effective in treating sporotrichosis, chromomycosis Fig. 6.9 Cryotherapy (using stype).
and infections of atypical mycobacteria. It may be performed as a
treatment for malignant skin tumors in conjunction with
chemotherapy or irradiation therapy.
5. Hyperbaric oxygen (HBO) therapy

The aim of hyperbaric oxygen therapy (HBO) is to increase
oxygen dissolved in the blood and to increase the partial pressure
of oxygen in the tissues. It may be used for peripheral circulatory
disorders such as ischemic anaerobic infections (e.g., gas gan-
grene), or postoperatively on skin grafts.
Fig. 6.10 Cryotherapy (using spray).
E. Skin surgery
Skin surgery may be performed to treat various types of nevus,
benign and malignant tumors, burn scars, intractable ulcers,
chronic pyoderma, and tattoos. Before operation, medical indica-
tion for surgery should be carefully evaluated (particularly as to
whether the lesion is malignant,). Also, the physical capability of
patients to tolerate surgery should be thoroughly examined. It is
important to conduct surgeries for satisfactory functional and
cosmetic results. Before the use of local anesthesia, the complete
medical history should be taken, and an intracutaneous test may
need to be performed. Sufficient explanation about the surgery
should be given to the patient in advance; moreover, it is essen-
tial to gain the patient’s written consent.
Practical techniques of suturing, skin grafting, and dermabra-
sion are introduced briefly below. Refer to textbooks on dermato-
logical surgery and plastic surgery for greater detail.
1. Excision and suturing

A comparatively small lesion is removed and the periphery is
sutured (Figs. 6.11 and 6.12). The basic method is spindle-
shaped excision and suturing (Fig. 6.12). If the long axis of exci-
sion is not long enough, the ends may rise in what are called
dog-ears, from their shape. This is a cosmetic problem. For that
reason, the long axis needs to be at least triple the width. In the
event that a lesion cannot be sutured in one operation, it may be
excised in two or more operations (serial excision). The skin may

Clinical be extended using silicon prior to surgery (skin expansion), or
images are skin graft may be performed. Excision is basically performed
available in along the line of a wrinkle; however, excision lines are decided
in hardcopy only.
hardcopy
only.
carefully, according to cosmetic concerns, especially when the
excision is long or in the face.
6 2. Skin graft
When a lesion is too large for excision and suture, a skin graft
is performed. Skin grafts are roughly divided into free skin grafts
and pedicle grafts.
Free skin grafts: Skin grafts are removed from the donor site
(Fig. 6.13) and fixed (tie-over method, Fig. 6.14). The removed
skin remains ischemic for approximately 4 or 5 days, until blood
flow returns. Depending on the thickness of the dermal area,
grafts are full-thickness (the epidermis and all of the dermal lay-
ers) or split-thickness (the epidermis and partial layers of the der-
mis) (Fig. 6.15). In a split-thickness graft, removed skin is
Clinical images are available in hardcopy only. processed into a mesh to raise the graft survival rate (mesh skin
graft). Since skin is one of the organs that are most likely to pro-
duce immunologic rejection, the patient’s own normal skin is the
only possibility for a permanent graft. Allogenic graft, dermato-
heteroplasty, and biological dressing of freeze-dried pigskin are
sometimes performed to temporarily cover the body.
Pedicle flaps: Skin and subcutaneous tissues are not complete-
ly separated from the living body for a graft. The flaps themselves
Clinical images are available in hardcopy only. supply the blood (Fig. 6.16). Although local flaps are usually
used, distant flaps may also be used.
3. Dermabrasion, Skin abrasion

Dermabrasion is a method of scraping away the skin surface
with a high-speed grinder or dermatome. Depending on its depth,
dermabrasion may produce keloids, recurrent lesions, or pigmen-
Clinical images are available in hardcopy only. tation; therefore, skillful performance is required. Instead of a
Fig. 6.11 Excision of keratoacanthoma.

Skin defect was closed by V-T flap.
B
A
A B B A
Fig. 6.12 Various incisions and flaps.

E. Skin surgery 91
6
Fig. 6.13 Split-thickness skin graft was obtained using silver knife.
Clinical images are available Clinical images are available Clinical images are available Clinical images are available
in hardcopy only. in hardcopy only. in hardcopy only. in hardcopy only.
Fig. 6.14 Skin grafting and tie-over.
high-speed grinder or dermatome, a carbon dioxide gas laser is

often used to treat epidermal nevus, seborrheic keratosis, tattoos, split-thickness
skin graft
lichen amyloidosis, porokeratosis, Darier’s disease and Hailey- (STSG)
dermis epidermis
Hailey disease.
4. Chemical peeling
With application of chemicals (e.g., salicylic acid, glycolic
flap
p
acid, trichloroacetic acid) to a lesion, the surface of the skin exfo-
subcutaneous
full-thickness
liates. In many cases, cosmetic effects of chemical peeling are skin graft
tissue
expected on lesions such as acne and senile lentigo. As the pene- (FTSG)
tration depth can be varied so as to limit the treatment to the
horny cell layer or to apply it to epidermal layers, the method
muscle
most suitable for the disease or purpose should be chosen accord-

ing to the chemical and the duration of activity.
Fig. 6.15 Skin thickness and various graft
procedures.
5. Electrosurgery, Iontophoresis
The main electrosurgeries are electrocoagulation, in which B B
120° E
heat generated by an electric scalpel coagulates tissues (Fig. 6.17), A 60° C A F C
and electrolysis, in which blood and tissue fluids are degenerated G
D E D
by direct-current electricity applied to the body. Iontophoresis is G
the process of introducing salt ions in solution through the skin
F
into the tissues, and it may be effective in treating palmoplantar
and axillary hyperhidrosis. Several iontophoresis devices are Fig. 6.16 Pedicle flap (Limberg flap).
commercially available.
6. Laser knife
Laser knives cauterize tissue using heat produced by laser.
Carbon dioxide gas lasers are the principal lasers used for sur-
gery. The advantages of surgical lasers are that there is no direct
contact and that they can be used without electricity, thus making
them applicable for patients with pacemakers. A surgical laser is
useful for treating seborrheic keratosis and epidermal nevus;
6
moreover, the depth is easily controlled, and injury to normal tis-
sues is minimal.
Fig. 6.17 Electrocoagulation.
Chapter
7 Eczema and Dermatitis
Eczema and dermatitis are synonyms for a disease that is the most commonly seen in dermatology practice.
Eczema/dermatitis has the symptoms of itching, reddening, scaling, and edematous papules, and the condition
progresses in a specific inflammatory reaction pattern. Eczema/dermatitis is histopathologically characterized by
intercellular edema called spongiosis, which can be caused by extrinsic factors, such as irritants or allergens, or
by intrinsic factors, such as atopic diathesis. These factors interact in complex ways, and extrinsic and intrinsic
factors are seen together in many cases. There is no international agreement on the subcategories of eczema.
7
If the cause is not identified, eczema may be called acute, subacute or chronic, depending on the clinical and
pathological features.
Eczema
Synonym: Dermatitis
Outline
● Eczema and dermatitis are synonymous.
● Pathologically, eczema is accompanied by itching, red-
dening, scaling, and edematous or serous papules.
● Histopathologically, it is characterized by intercellular
edema (also called spongiosis).

● It accounts for one-third of all dermatology cases.
● Extrinsic and intrinsic factors are simultaneously involved
in its onset. Clinical images are available in hardcopy only.

● The first-line treatment is topical steroid application.
Clinical features
Itchy edematous erythema forms, on which papules and serous
papules are produced. After the formation of vesicles, pustules,
erosions, crusts and scales (Fig. 7.1), the condition begins to sub-
side. The progress of eczema is illustrated in the chart (Fig. 7.2).
In the acute stage, these symptoms are present singly or together.
In the chronic stage, acanthosis, lichenification, pigmentation and
depigmentation are found, in addition to the symptoms of the
acute stage.
Pathogenesis
Both extrinsic and intrinsic factors are involved in eczema
(Fig. 7.5). When an extrinsic agent such as a drug, pollen, house
dust, or bacteria invades the skin, an inflammatory reaction is
induced to eliminate the foreign substance. The severity and type
of reaction vary according to intrinsic factors such as seborrhea,
dyshidrosis, atopic diathesis, and the health condition of the patient.
Pathology Fig. 7.1 Eczema.

Eczema is characterized by intercellular edema (spongiosis) (Fig. 16-year-old Japanese woman with acute eczema
7.3). In the acute stage, it is accompanied by exocytosis of lym- on the legs. Scaly erythema with scales, papules
and vesicles are scattered, partly forming oozy
phocytes and spongiotic bulla. In the chronic stage, hyperkeratosis, crusts and pustules.
93
94 7 Eczema and Dermatitis
acute extrinsic intrinsic

eczema factors factors
pustule chemical agents health condition

bacteria sebum secretion
other allergens sweating
drugs existence of allergy
vesicle wetness
chronic
eczema
lichenification,
papule crust pigmentation
7
eczema
erythema scaling cure

Fig. 7.5 Various factors causing eczema.
Extrinsic and intrinsic factors interact, resulting
Fig. 7.2 Course and symptoms of eczema. in eczema formation.
parakeratosis, irregular acanthosis, and elongation of rete ridges

are observed. Spongiosis and spongiotic bulla are less severe in
chronic eczema than in acute eczema.
Classification
Eczemas are generally classified by cause (Table 7.1). These
causes interact in complex ways and are not always clearly iden-
a b c d e f g tifiable.
h i The name
j ofk the disease
l may differ
m n from
o country
p toq r
country.
a. Eczema with unidentified cause

When the cause is not identified, eczema is simply called
acute, subacute or chronic, according to the clinical findings, the
course of the eruption, and the pathological findings. There is no
clear definition of eczema. Lesions in various stages often exist
Fig. 7.3 Histopathology of eczema.
a: Acute eczema. Spongiosis (arrows) has formed
from intercellular edema. Lymphocytic infiltration Table 7.1 Eczema classified by pathogenesis.
is also seen. b: Chronic eczema. Hyperkeratosis,
regular acanthosis and elongation of epidermal rete Contact dermatitis
ridge are noted. Spongiosis is not severe (arrows). Housewives hand eczema
Keratodermia tylodes palamaris progressiva
Diaper dermatitis
Atopic dermatitis
Seborrheic dermatitis
Nummular eczema
Lichen simplex chronicus，lichen Vidal
Autosensitization dermatitis
Stasis dermatitis
Other
Fig. 7.4 Acute eczema. Pompholyx, dyshidrotic eczema
Itchy edematous erythema and infiltrated small Pityriasis simplex faciei
papules are seen. Small vesicles also appear. Perioral dermatitis
1. Contact dermatitis 95
together on the same individual. Eczema with unidentified cause

is usually considered contact dermatitis with the involvement of
an extrinsic substance. Topical steroids and oral antihistamines
are applied as the first line of treatment for eczema at all stages.
1. Acute eczema
Acute eczema is accompanied by exudative erythema, edema,
and sometimes vesicles (Fig. 7.4). It is newly produced eczema
only several days after its onset. Intercellular edema (spongiosis), Clinical images are available in hardcopy only. 7
intense dermal edema, and inflammation occur. Acanthosis usu-
ally does not.
2. Subacute eczema
Subacute eczema has a severity between that of acute and that
of chronic. Such eczema is accompanied by erythema and edema,
and it is slightly lichenoid. Mild edema is produced in the epider-
mis. Acanthosis and parakeratosis are observed.
3. Chronic eczema
Chronic eczema is characterized clinically by lichenification.
When acute eczema continues for more than one week after
onset, it is likely to appear lichenified, and the diagnosis is chron-
ic eczema. Acanthosis and parakeratosis are noticeable
histopathologically (Fig. 7.6); however, there is less infiltration
of inflammatory cells into the epidermis than with acute and sub-
acute eczema.
b. Eczemas with more specific names

according to their distinguishing Fig. 7.6 Chronic eczema.
Hyperkeratosis is severe, as in tylosis. Erythema
features and fissures are seen.
1. Contact dermatitis
Outline
● Contact dermatitis is localized to the site of extrinsic stim-
ulation by foreign substance or allergic reaction.
● Eczema reactions such as reddening and blistering
occur at the contact site.
● There are specific types of contact dermatitis, such as
diaper dermatitis and housewive’s hand eczema.

● The causative substances include certain plants, chemi-
cal agents, and nickel, mercury and other metals.

● Patch testing is useful for diagnosis. Topical steroid
a b c d e f g h
application is the first-line treatment. The causative agent
should be eliminated. Fig. 7.7-1 Contact dermatitis.
a: “Ginkgo nut dermatitis.” This patient touched
his face without washing his hands after gather-
ing ginkgo nuts.
Clinical features
Erythema, serous papules, vesicles, erosions and crusts are
localized at the contact site of the causative agent (Figs. 7.7-1 to
7.7-3). The eczematous lesions are relatively sharply circum-
scribed and are intensely itchy. Although only localized areas are
Clinical images are available in hardcopy only. affected, erosive lesions may become widespread when the
causative agent is spread by rubbing and scratching. If the
inflammation spreads over the entire body, systemic symptoms
such as fever may arise. When the causative agent is highly stim-
7 ulative, it may cause necrosis of the skin and ulceration.
Atypical cases of contact dermatitis
①Pseudoatopic dermatitis: When the skin is repeatedly stimu-
lated by a causative agent, symptoms closely resembling those
of adult atopic dermatitis may appear.
②Melanosis Riehl: Ingredients of cosmetics are converted by
light into allergens that cause pigmentation without noticeable
Clinical images are available inflammation (Chapter 16).
in hardcopy only. ③Systemic contact dermatitis: When an individual is sensitized
by contact allergy and inhales an antigen, a systemic allergic
reaction is induced. Mercury is well known as such an antigen.
④Gold dermatitis caused by earrings: Readily ionized metals
such as nickel often cause dermatitis. In recent years, the num-
ber of cases caused by gold earrings has increased significant-
ly. They are characterized by intractable induration where the
b c d e f g h i j p q
ear isk pierced.
l A lymphoid
m n follicle-like
o structure may r form
(Fig. 7.8).
Pathogenesis
Primary irritant contact dermatitis is an inflammatory reaction
caused by lysosomes or various cytokines that are released from
Clinical images are available in hardcopy only. keratinocytes when the keratinocytes are injured by substances in
the causative agent. With a certain level of irritation, contact der-
matitis may occur in anyone from the very first contact.
Allergic contact dermatitis basically occurs as a type IV aller-
gic reaction (Fig. 3.9). The causative agent invades the body per-
c d e f g h i j k l
cutaneously m is captured
and n p
o by Langerhans q r which are
cells,
epidermal antigen-presenting cells. It moves to the regional
lymph nodes and transmits information about the antigen to thy-
mus-derived T cells. Those T cells proliferate in the lymph nodes
(sensitization). If the causative agent reinvades the body after
Clinical images are available in hardcopy only. sensitization, the sensitized T cells become activated to release
various cytokines, which leads to a prompt inflammatory reaction
that causes dermatitis. This reaction is not produced by the first
contact, but it is produced in previously sensitized persons even
d e f g h i j k l contact
by m withn a minute p
o amount ofqthe antigen
r (that is, there is
Fig. 7.7-2 Contact dermatitis. no threshold amount of a causative agent that causes contact der-
b: Contact dermatitis from a bra. c: From aller- matitis).
genic plants. d: From an unknown cause, proba-
bly soap. e: “Shiitake dermatitis.” When eaten Almost anything, from plants to cosmetics to detergents to
raw, shiitake mushrooms sometimes cause very chemicals in workplaces and homes, can be an allergen (Table
itchy, systemic contact dermatitis. 7.2).
1. Contact dermatitis 97
Table 7.2 Main allergens in allergic contact Table 7.3 Contact dermatitis: locations and main causes.
dermatitis.
Location Cause
Heavy metals Chrome, nickel, cobalt
Dcalp Shampoos, hair dyes, hair restorers, hats
Plants Poison oak, primrose, orchis,
ginkgo, chrysanthemum, aloe Face Cosmetics, medicinal agents, perfumes, eyeglasses,
plants
Foods Tomatoes, lettuce
Neck Necklaces, cosmetics, perfumes, medicinal agents, clothes
Hair dyes Paraphenylendiamine (PPD)
Body, extremities Clothes, cleansers, metals, medicinal agents
Perfumes
Hands and feet Rubber, leather, plants, medical agents, cleansers,
Medicinal agents Ointments, disinfectants cosmetics, metals
Preservatives Paraben Genital region Clothes, cleansers, condoms, contraceptive devices 7
Synthetic resins Latex
Laboratory findings, Diagnosis

Each causative agent causes a particular distribution of erup-
tions; the agent in each case is easily identified by the distribu-
tion and history-taking. Substances that frequently cause contact Clinical images are available
dermatitis are listed by the location on the body in Table 7.3. The in hardcopy only.
causative substance is determined by patch testing (Chapter 5).
Treatment
The irritant should be avoided. Topical steroids and oral anti-
histamines are the first-line treatments. Although desensitization
a b c d e f g h i j k l m
therapy is performed at some institutions, the efficacy varies
from case to case. Fig. 7.7-3 Contact dermatitis.
f: Contact dermatitis from tattooing. Red pigment
is thought to be the allergen.
Note
There are more specific names for contact dermatitis according
to types of patients and particular locations on the body.
①Diaper dermatitis: This occurs where the diaper comes into
contact with the skin (Fig. 7.9).
②Housewive’s hand eczema: This affects the hands of those
who frequently work with water. Keratodermia tylodes pal- in hardcopy only.
maris progressiva is included in this category.
③Dyshidrotic eczema: Small vesicles (also called pompholyx)
and desquamation occur frequently on the palms and soles,
and they often worsen during the summer.
Fig. 7.8 Contact dermatitis from gold earrings.
Varieties of contact dermatitis MEMO

Contact dermatitis may be diagnosed as ginkgo nut dermatitis, rhus
dermatitis, mercury dermatitis, or shiitake dermatitis. The diagnosis
depends on the allergen.
Fig. 7.9 Diaper dermatitis.
2. Atopic dermatitis
Outline
● Atopic dermatitis is chronic eczema/dermatitis caused by
an atopic condition (allergic asthma, rhinitis, conjunctivi-
tis).
● Exudative eczema occurs on the face and ear pinna. It is
in hardcopy only. characterized by eruptions of dry pityriatic scales.
● The patient tests positive for white dermographism. The
7
IgE value is high.
● Filaggrin gene mutation is a key predisposing factor for
atopic dermatitis.
● These complications can occur: Kaposi’s varicelliform
eruption, cataract, and retinal separation.

● Topical steroids, topical immunosuppressants such as
tacrolimus and pimecrolimus, oral antihistamines, and
moisturizers are the first-line treatments.
General information
In atopic dermatitis, chronic eczematous/dermatitis lesions are
caused by various acquired stimulative factors, under conditions
in which the skin barrier function is congenitally low and IgE is
in hardcopy only.
easily produced. The Japanese Dermatological Association
defines atopic dermatitis as “a disease whose main lesion is itch-
ing eczema with recurrent remissions and exacerbations, and
most patients have some atopic condition.” Type I allergy (an
atopic condition, such as asthma, allergic rhinitis, or conjunctivi-
tis) and type IV allergy are involved in most cases.
Clinical features
Atopic dermatitis is classified into three age periods: infantile
(age 2 months to 4 years), childhood (early childhood to puber-
ty), and adolescent/adult. Different eruptions characterize each
period (Figs. 7.10-1 to 7.10-3). Atopic dermatitis is accompanied
by intense itching in all the periods, with recurrent remissions
and exacerbations. It tends to worsen when the skin is dry and
Clinical images are available during the summer. Although it most frequently occurs in infan-
in hardcopy only. cy, its incidence in patients beyond infancy, including adults, has
been increasing greatly in recent years.
1) Infantile atopic dermatitis

In the early stage of atopic dermatitis in infancy, erythema,
Fig. 7.10-1 Atopic dermatitis.
a: In childhood. Widespread eczematous lesions Atopy MEMO
with severe excoriation. b: Adult man. Edema- Atopy is the word for a concept that Coca et al. proposed in 1923. The
tous, infiltrated plaques with exudation are seen term means “abnormal hypersensitivity.” Atopic patients tend to suffer
on the face and neck. c: Adult woman. Licheni- congenitally from bronchial asthma and hay fever. Atopic dermatitis is
fied papules are seen on the face. often hereditary.
2. Atopic dermatitis 99
scales, and serous papules are produced on the head and face and
these gradually spread to the trunk. The condition becomes
exudative: erosions form, with crusts and scales attached to the
surface. It resembles seborrheic dermatitis. Thick crusts on the
head and ear notch, and lesions around the mouth and lower jaw Clinical images are available in hardcopy only.
(produced by causative agents in baby food) are also observed.

The trunk and extremities become dry, and follicular papules
aggregate, appearing as goose bumps. Scaly erythematous
a b atopicc d e f g h i j k
plaques form on these lesions and progress to childhood
dermatitis. 7
2) Childhood atopic dermatitis
In childhood atopic dermatitis the skin becomes dry. Licheni-
fied plaques occur on the cubital fossa and popliteal fossa. Clinical images are available in hardcopy only.
Cracks are often found in the auricle area (ear notch). Multiple
follicular papules occur on the dry skin of the trunk. This der-
matitis is accompanied by intense itching, and it progresses
quickly to eczematous crusty lesions.
a b c d e f g h i j k l
3) Adolescent and adult atopic dermatitis

The symptoms are similar to those in childhood dermatitis, but
the lichenified plaques progress and enlarge. Rough, dry, dark
brown atopic dermatitis occurs all over the upper body. The
lesions are more severe and widely distributed than those of Clinical images are available in hardcopy only.
childhood dermatitis. Thinning of one-third of the lateral eye-
brow is present (Hertoghe’s sign, Figs. 7.10-1b and 7.10-1c). In
serious cases, diffuse erythema occurs on the face, and a mottled
appearance is seen on the neck and upper chest (poikiloderma
lesion, dirty neck, Fig. 7.10-2d).a Atopic b prurigo
c may d occure f g h i j k l m
repeatedly on the extremities.
Pathogenesis
There have been many studies on skin physiology and immune
function in atopic dermatitis; however, the pathogenesis has not
been fully clarified.
Abnormality of skin physiology: A defective skin barrier is Clinical images are available in hardcopy only.
important for the pathogenesis of atopic dermatitis. Filaggrin
gene mutations have been shown to be a key predisposing factor
for atopic dermatitis. Abnormality in vascular response can be
tested by white dermographism (skin with atopic dermatitis
becomes white when scratched, whereas normal skin becomes
g j
red) (Fig. 7.11). Dyshidrosisa and decreased
b c d
content e
(particularlyf h i k l m n
a decrease in ceramides) of lipid in the horny cell layer, facial Fig. 7.10-2 Atopic dermatitis.
d: “Dirty neck.” Poikilodermatous pigmentation
pallor, dry skin and multiple small follicular papules are present is seen on the neck and upper chest. e: Adult
(atopic skin). The atopic skin is vulnerable to extrinsic irritation; atopic dermatitis. Severely excoriated plaques are
intensely itchy eczema is easily produced by slight irritation, or seen. f: Erythrodermic atopic dermatitis. g: Pruri-
go will occur as a result of longtime scratching.
even by perspiration or contact with animal fur, wool or chemi-
cals.
Immune function abnormality: Atopic conditions such as allergic
asthma, allergic rhinitis, conjunctivitis and atopic dermatitis are

found in the family and patient’s history. Patients with atopic
dermatitis readily produce IgE antibodies. When there is a high
IgE value and positive intracutaneous reactions to various aller-
gens, a congenital immune abnormality of some sort is regarded
Clinical images are available in hardcopy only. as being involved in atopic dermatitis.
Complications
Eye diseases such as cataract (in 10% of severe adult cases),
7 keratoconus, and retinal separation develop as complications of
g h i j k l m n atopic
o p q Eye-rubbing
dermatitis. r from the itch and prolonged oral
steroid use are thought to be the cause; however, this has not
been confirmed. Infectious diseases including Kaposi’s varicelli-
form eruptions, molluscum contagiosum, and impetigo conta-
giosa may also be caused. Patients with atopic dermatitis may be
hypersensitive to drugs and insect stings.
Laboratory findings
in hardcopy only. The serum IgE value is high; IgE RAST for mites and house
dust is positive in most cases. There is an increase in eosinophils
in the peripheral blood. Although white dermographism is highly
sensitive in detecting atopic dermatitis, it has low specificity.
Diagnosis
When there are the clinical findings described above, atopic
h i j k l m n o p q is easy
dermatitis r to diagnose. In diagnosis, it is also important to
consider any family history of the condition. Atopic dermatitis in
adolescents and adults has been increasing in recent years. Infant
seborrheic dermatitis closely resembles infantile atopic dermati-
tis.
Clinical images are available Treatment
in hardcopy only.
Topical steroid application is the primary treatment for the
intense cutaneous symptoms. The application method and dosage
of steroids are chosen according to the degree and course of the
lesion. Ointments containing immunosuppressants such as
i j k l m n o p tacrolimus
q r and pimecrolimus have become widely used dermato-
Fig. 7.10-3 Atopic dermatitis. logical treatments (Chapter 6). These drugs are not used for ero-
h: Atopic dermatitis with severe hand eczema. i, sions or ulcers; however, they are helpful for systemic lesions
j: Severe erythema is sometimes seen on the flex- including those on the face, and they are frequently used interna-
or of the lower legs.
tionally as first-line treatments. Moisturizer is helpful in treating
mild symptoms. Oral antihistamines are effective at preventing
The “atopy industry” MEMO

Patients with atopic dermatitis have become the target of commercial
ventures in recent years in Japan, not all of which are medically justi-
fied. This is called the atopy industry or atopy business, which has
become a social problem. In light of this, some medical institutions
such as university hospitals are providing educational hospitalization
for atopic dermatitis, so that patients can learn correct knowledge of
the clinical state and its treatments.
2. Atopic dermatitis 101
the eruptions from becoming aggravated by rubbing and scratch-

ing. Oral steroids are usually unnecessary for mild symptoms of
atopic dermatitis.
Besides these medical treatments, improvement of the living Clinical images are available in hardcopy only.
environment (e.g., removing carpeting, keeping the temperature
and humidity low to reduce perspiration), and skin care (avoiding
contact with causative agents, keeping the skin clean) are impor-
tant.
Prognosis
7
Atopic dermatitis tends to be chronic and recurrent. It mostly
resolves spontaneously by the time the patient reaches age 10;
however, the symptoms do not improve in some patients until
they reach adolescence or adulthood. The incidence of adolescent Clinical images are available in hardcopy only.
and adult atopic dermatitis has been increasing in recent years.
3. Seborrheic dermatitis
Synonym: Seborrheic eczema
Fig. 7.11 White dermographism in a patient
Outline with atopic dermatitis.
● Seborrheic dermatitis occurs on sites of skin where
sebum is actively secreted. It is characterized by erythe-
matous lesions accompanied by yellowish scales.
● This is one of the most common skin diseases, occurring
in infants, adolescents and adults.

● Pityrosporum fungus resident in the skin is a factor in the
occurrence.
● Skin care and application of topical steroids and antifun-
gal agents are the main treatments.
Clinical features
There is some controversy as to whether seborrheic dermatitis
in infants, adolescents and adults is the same disease, because
there are minor differences in the clinical courses (Fig. 7.12).
Dermatitis appears as follicular eczema on seborrheic sites or
intertriginous areas in the head, face, axillary fossa, neck and
external genitals. The main features of the lesions are oleaginous
scales and erythematous plaques that may be slightly itchy.
In infants, yellowish crusts begin to form on the scalp, eye-
brows and forehead. In infants, scaly erythematous plaques may
also form 2 to 4 weeks after birth. In most cases they resolve 8 to
12 months after birth. In adolescents and adults, pityroid scales
(commonly called dandruff) increase and scaly erythematous
Pityriasis simplex faciei MEMO

Partially hypopigmented macules accompanied by pityriasis scales are
produced on the face in later childhood. It is most commonly observed
in boys and may appear as a symptom of atopic dermatitis. It heals nat-
urally in several years, in most cases.
lesions form on the eyebrows and nasolabial groove. Seborrheic

dermatitis is chronic and recurrent.
Pathogenesis
Clinical images are available in hardcopy only. Triglycerides in sebum are decomposed by microbes resident
in the skin to produce free acid. The free acid reacts to cause seb-
orrheic dermatitis. It has been reported that over-proliferation of
Pityrosporum fungi such as Malassezia furfur aggravates sebor-
rheic dermatitis.
7 Differential diagnosis
Dry seborrheic dermatitis closely resembles psoriasis vulgaris.
It is also important to differentiate seborrheic dermatitis from
Clinical images are available in hardcopy only. pityriasis rosea and parapsoriasis en plaque. In infants, differenti-
ation from atopic dermatitis is essential.
Treatment
a b c d e f g h i Proper
j facialk cleansing
l with
m soap n
and hairo washing
p withq sham-r
poo are basic for keeping the seborrheic regions clean. Regulat-
Fig. 7.12 Seborrheic dermatitis.
a: Scalp. Erythema with thick white scales. b: ing daily life is also helpful. Middle class topical steroids are
Scaly erythema on the chest. applied. Topical antifungal agents and antifungal shampoos are
effective at resolving seborrheic dermatitis accompanied by dan-
Infantile eczema MEMO druff in adolescents and older adults, which is often caused by
Eczema tends to occur in infants 2 to 3 weeks overproliferation of Pityrosporum fungi.
after birth, or sometimes up to several months
after birth. It can generally be referred to as
infantile eczema. Infantile eczema includes
the diseases listed below. Differentiation
4. Nummular eczema (eczema nummulare)
among these diseases is difficult, especially in
newborns.
①Seborrheic dermatitis in infancy: See text. Outline
②Early-stage atopic dermatitis: In intractable ● Round, relatively large eczematous plaques are pro-
cases of infantile eczema.
③Contact dermatitis: e.g., lick dermatitis
duced.
● Nummular eczema may occur at any site on the body,
(dermatitis caused around the mouth by saliva
and food), diaper dermatitis. and it tends to progress to autosensitization dermatitis.
④Food allergy: Eruptions caused by baby ● Topical steroids are the first choice of treatment.
food or by changes in breast milk from health
problems including nutritional imbalance in
the mother. Clinical features, Epidemiology
⑤Other disorders: Tinea, candidiasis. Wiskott- Nummular eczema is frequently seen in the winter. Multiple
Aldrich syndrome, Netherton syndrome and
Langerhans cell histiocytosis are rare; howev- round eczematous lesions occur, mostly on the extremities (par-
er, it is necessary to distinguish infantile ticularly on the extensor surface of the lower extremities), trunk,
eczema from these diseases. hips and buttocks (Fig. 7.13).
At the periphery of the lesions, serous papules aggregate, in
the center of which exudative erythema is produced with scales
on the surface. Most cases are accompanied by intense itching
and multiple scars from rubbing and scratching. As the lesions
Clinical images are available progress, they may produce dispersal eruptions (id dermatitis) to
in hardcopy only. progress into autosensitization dermatitis.
Pathogenesis
Scratched insect bites may develop urticarial lichens that,
when rubbed, progress to nummular eczema. Or nummular
eczema may result from asteatotic eczema in the elderly, or it
3. Seborrheic dermatitis 103
may appear as a symptom of atopic dermatitis.
Treatment
Topical steroids (containing ODT) are effective. In cases in
which infiltration and exudation are intense, the application of
topical zinc ointment sheets is also effective. Oral antihistamines
are helpful in relieving the itching.

5. Lichen simplex chronicus
7
Synonyms: Lichen Vidal, Circumscribed neurodermatitis
Lichen simplex chronicus is chronic eczema in which round,

intensely itchy lichenified plaques form on the nuchal region and
extensor aspect of forearms and lower legs of middle-aged
women. Pigmentation or depigmentation is present in many
cases. Warty eruptions may proliferate (Fig. 7.14). When skin is
repeatedly stimulated by the friction of clothing or by metal aller-
gens and the site is rubbed and scratched for a long period of
time, it leads to the occurrence of chronic eczematous lesions.
Topical steroids and oral antihistamines are first-line treatments
for the itching.
6. Autosensitization dermatitis
Outline
● Multiple small papules and erythematous lesions accom-
panied by itching occur systemically. They are caused by
sudden aggravation of a localized lesion. Fig. 7.13 Nummular eczema.
Round patches of eczema, 1 cm to 3 cm in diam-
● This dermatitis is caused by endogenous allergic reac-
eter, are disseminated on the trunk and legs.
tion (id reaction).
Clinical features
Reddening, swelling and acute aggravation of exudation occur
in the lower extremities as primary lesions of autosensitization
dermatitis (in 50% to 60% of cases). Two weeks to several weeks
after acute aggravation of reddening, swelling and exudation, dis-
persed eruptions appear. In most cases, the eruptions (id dermati-
tis) are erythema, papules, serous papules, or pustules of 2 to 5 Clinical images are available
mm in diameter dispersed symmetrically on the extremities, in hardcopy only.
trunk, and face. These are often accompanied by intense itching
(Fig. 7.15). Systemic symptoms such as fever and fatigue may
occur.
Pathogenesis
Autosensitization dermatitis arises from endogenous allergic
reaction (id reaction). Decayed proteins, bacteria, fungal compo-
Fig. 7.14 Lichen simplex chronicus (lichen
nents, and toxins produced by injured tissues in a primary lesion Vidal).
are considered to be the antigens. These may spread through the Long-time friction from clothes is a cause. It is a
entire body such in blood flow from the primary lesion, or they chronic eczema.
may spread by rubbing or by an accidental dose of the causative

substance (orally or intravenously). Autosensitization dermatitis
is caused by sensitization against the antigens. The primary
lesions can be nummular eczema, stasis dermatitis, contact der-
matitis, atopic dermatitis, tinea pedis, or eczematization of a
burn.
Treatment
Topical steroids are applied and oral antihistamines are admin-
7 Clinical images are available in hardcopy only. istered, in addition to whatever treatment is given for the under-
lying lesion. In severe cases, oral steroids are also administered.
7. Stasis dermatitis
Outline
● Edematous erythema or eczematous plaques form on
the lower thighs as a result of varicose veins or conges-
tion in the lower extremities.
● This disease tends to affect those who work standing,
the elderly, and obese women.

● It may progress to autosensitization dermatitis.
● Elastic bandages and varicose vein phlebectomy are
effective in reducing congestion.

Clinical features
Edematous erythema occurs on the lower third of the leg, par-
ticularly at the upper ankles. The site gradually presents a dark
red, scaly, eczematous plaque, pigmentation or whitish atrophie
blanche (Fig. 7.16). Minor trauma may induce ulceration. Treat-
ments for stasis dermatitis may induce allergic contact dermatitis
as a complication, from the application of an antiseptic or a topi-
cal agent (lanoline, antibiotic agent, preservative). Aggregated
serous papules often progress to autosensitization dermatitis.
Epidemiology
Stasis dermatitis is frequently found in those who work stand-
ing for long periods of time. Pregnancy may trigger stasis der-
matitis as a complication of varicose veins.
Pathogenesis
Congestion in the cutaneous blood vessels is caused by impair-
ment of venous outflow, which leads to bleeding from the capil-
lary vessel loop in the dermal upper layer. Hemosiderins deposit
in tissues, and the skin takes on a blackish-brown appearance.
The keratinocytes are injured by further impairment of blood
flow. Atrophy and scaling occur in the epidermis and there is ten-
dency of ulceration. The skin looses its function as a barrier and
becomes more reactive to extrinsic irritation, leading to eczema-
Fig. 7.15 Autosensitization dermatitis.
Disseminated eczematous eruptions are seen. tous lesions in many cases.
8. Asteatotic eczema 105

Stasis dermatitis is easy to diagnose from the varicose veins
and the characteristics and distribution of the eruption. A Doppler
test and angiography are performed on the varicosity to examine
the physical potential of patients for surgical treatment. A patch
test is performed if allergic contact dermatitis is suspected.
Treatment
Topical steroids are effective in treating eczematous lesions.
When there is ulceration, it is cleansed and dressed. Induced 7
allergic contact dermatitis is carefully avoided during treatment.
Intravenous circulatory impairment is treated to prevent stasis
dermatitis from progressing. Pressure that is greater than that of
elastic bandages and socks should not be given to the patients.
They should take bed rest and keep the lower extremities elevat-
ed. Surgery such as sclerotherapy, ligation, and removal of vari-
cose blood may be necessary for cases with severe varicosity.
8. Asteatotic eczema
Skin dryness (asteatosis, xerosis) occurs when sebum decreas-
es as a result of aging or excess washing. When the horny cell
layer is destroyed, the skin is vulnerable to extrinsic irritation.
When asteatosis becomes inflamed and eczematous, the condi-
tion is called asteatotic eczema (Fig. 7.17). This mostly affects
the lower extremities of elderly in dry seasons, especially winter.
For those who have a habit of excessively washing or rubbing the
body with a towel, lifestyle guidance to avoid such behavior has
therapeutic effects. Use of moisturizer prevents skin dryness.
Eczema is treated with topical steroids. Skin care with moisturiz- Clinical images are available in hardcopy only.
er is helpful afterwards (Chapter 19).
9. Wiskott-Aldrich syndrome
Outline
● The three major characteristics of this disorder are
immunological deficiency (T-cell dysfunction), thrombo-
cytopenia, and intractable eczema.
● It is hereditary (X-linked recessive).
● There are decreased levels of immunoglobulins.
Fig. 7.16 Stasis dermatitis. Edematous, dark-
● Bone marrow transplantation may be performed.
red erythema with scales.
Chronic vein insufficiency is a pathophysiology.
Clinical features Ulcer formation is also seen.
Wiskott-Aldrich syndrome is characterized by eczema or pur-
pura that occurs in newborn babies within 6 months after birth.
The eczema that occurs on the head, face, buttocks and extremi-
ties appears similar to atopic dermatitis and seborrheic dermatitis
(Fig. 7.18). Purpura is caused by thrombocytopenia. Immune-
deficiency-derived infections occur repeatedly as the patient
grows. Infections are caused by various factors including bacteria,
viruses, fungi and protozoa. Impetigo contagiosa (Staphylococcal

infection), pseudomonas infection, herpes simplex, varicella (her-
pes virus infection), and candidiasis are particularly likely to
accompany this syndrome, and they tend to become aggravated
and persistent. Systemic symptoms such as bloody diarrheic
stool, internal organ hemorrhage, infection (e.g., tympanitis,
paranasal sinusitis, pneumonia) are seen recurrently.
Pathogenesis
7 Wiskott-Aldrich syndrome is caused by abnormality of a
WASP gene at Xp11.22-11.23. The function of the WASP pro-
tein is unknown; however, it is thought to be associated with the
cell viability and functional activation of T cells and platelets.
Treatment, Prognosis
Born marrow transplantation may be conducted as a treatment.
Fig. 7.17 Asteatotic eczema.
Treatments for atopic dermatitis are given for skin lesions pro-
duced by Wiskott-Aldrich syndrome. Patients with the syndrome
may not survive, because of bleeding and infection in infancy
(until about age 10); nevertheless, long-term survival is possible
if the patient survives this period. In long-term survival cases,
autoimmune disease and malignant lymphoma may arise as com-
plications.

in hardcopy only.
Fig. 7.18 Wiskott-Aldrich syndrome.

Eczematous eruption on the scalp.
Chapter
8 Urticaria, Prurigo and Pruritus
This chapter discusses urticaria, prurigo and pruritus cutaneous, which have severe itching in common. Each
condition has its own mechanism, clinical features and histopathological findings.
Urticaria
8
1. Types of urticaria
Outline
● Urticaria is transitory localized erythema or wheals
accompanied by itching.
● Acute urticaria occurs in episodes shorter than 6 weeks;
chronic urticaria occurs in episodes of 6 weeks or longer.

● Vascular permeability increases. Edema forms in the
dermal upper layer.

● In factitious urticaria, dermographism is positive.
● Oral antihistamines are the first-line treatment.
Clinical features
A slightly elevated, sharply circumscribed wheal or reddening
with a circular, oval or map-like pattern suddenly appears,
accompanied by intense itching (Fig. 8.1). Edema, the primary
event in the dermal upper layer, may occur at any site on the
body, especially at sites subjected to rubbing or pressure. Wheals
may occur not only in skin but also in mucosa. When formed in
the pharyngeal region, urticaria causes hoarseness and breathing
difficulty. Urticaria usually begins to subside within several
hours and usually disappears within 24 hours. In some cases, ery-
thema and slightly infiltrative lesions remain for several days.
Pathogenesis, Classification
Chemical mediators such as histamines released from mast Clinical images are available in hardcopy only.
cells enhance vascular permeability, which causes edema to form
in the dermal upper layer (Fig. 8.2). Even thorough examination
is unable to detect the cause of urticaria in about 90% of cases
(idiopathic urticaria). For that reason, urticaria is often classified
by duration of episode. Urticaria in episodes shorter than 6 weeks Fig. 8.1 Typical eruption of urticaria.
It is characteristically itchy, with slightly elevat-
is called acute; that in episodes of 6 weeks or longer is called ed erythema and wheals.
chronic. When there is an identifiable cause, the urticaria is
named after that cause (discussed later).
Diagnosis, Examinations
It is easy to diagnose urticaria by the clinical findings. History-
taking on suspected causative agents of urticaria, such as
107
108 8 Urticaria, Prurigo and Pruritus
wheal mechanical stimuli, the cold, foods and drugs, is helpful. Since
epidermis urticaria sometimes accompanies systemic diseases, including
plasma collagen diseases, determination of the primary disease is neces-
dermis sary. Dermographism is positive (when the skin is rubbed, the
site turns red; Fig. 8.3). Tests such as that for serum IgE levels,
IgE RAST (radioallergosorbent test), intradermal allergic test and
drug-induction test are conducted.
physical allergen
stimuli Treatment
IgE
Antihistamines are the first-line treatment. When the cause is
identified, it should be removed. Oral or intravenous steroids are
8 effective in severe cases, such as glottic edema. Urticaria
resolves in several days in most cases; however, it may progress
chemical mediators to chronic urticaria.
mast cell (histamines)
Types of urticaria
Fig. 8.2 Mechanism of urticaria.
Chemical mediators such as histamines from Typical types are described below.
mast cells induce vascular hyperpermeability,
which causes intradermal edema.
1) Acute and chronic urticaria
Urticaria is divided by duration of episode into acute (less than
6 weeks) and chronic (6 weeks or longer).
2) Contact urticaria
Contact urticaria occurs at sites where a foreign substance
comes into contact with and permeates the skin or mucosa. It is
classified into allergic contact urticaria and nonallergic contact
urticaria.
Patients with allergic contact urticaria have had previous con-
tact with the substance and are sensitized to it. Nonallergic con-
tact urticaria is caused by the first contact with a substance
(MEMO).
3) Physical urticaria
Physical urticaria is an eruption caused by physical stimula-
tion. It disappears in 30 minutes to 1 hour. It is divided into sev-
eral subtypes according to cause. Factitious urticaria, also called
Clinical images are available in hardcopy only. mechanical urticaria, is produced by rubbing. Dermographism is
positive in factitious urticaria. Solar urticaria is caused by sun-
light. Cold urticaria is caused by exposure to the cold, such as
cold water or wind.
4) Cholinergic urticaria
Cholinergic urticaria occurs when the body perspires after the
body temperature rises from exercise or bathing (Fig. 8.4). The
cholinergic nerves are thought to be involved.
Fig. 8.3 Dermographism.
Mechanical stimuli such as rubbing cause wheals
(urticaria).
Urticaria / 2. Angioedema 109
Allergic reaction as a disease name MEMO

The diseases listed below cause urticarial eruptions; however, they are often described as kinds of allergies.
The tests and treatments for these diseases are the same as for urticaria. For cases with severe respiratory
symptoms or anaphylactic shock, epinephrine administration and systemic management are necessary.
◆ Food allergies
Food allergies are reactions (mainly type I allergy) to certain foods, such as eggs, milk, chicken, rice, wheat,
soybeans, fish, shellfish, buckwheat flour, peanuts, chocolate, kiwi fruit and papayas, or to antigens contained
in the additives of these foods. They frequently occur in children, causing edema in the oral mucosa. Digestive
symptoms (nausea, vomiting, abdominal pain, diarrhea), respiratory symptoms (bronchial asthma, nasal dis-
charge, glottic edema), and migraine are also found. They cause anaphylactic shock in severe cases, which can
be fatal.
◆ Latex allergy
Latex allergy is caused by contact with products made of natural rubber. Latex may have cross-reactions with
certain kinds of foods, such as bananas and avocados; latex allergy is also called latex-fruit syndrome*. The 8
symptoms, which have various severities, include erythema accompanied by itching at the contact site, mild
wheals, urticaria on the whole body, wheezing, and anaphylactic shock.
◆ Insect allergies
IgE reacts to histamines and phospholipases, which are the main components in the venom of bee stings and
which are the allergen in moth bodies; type I allergy is induced. Insect allergic reactions are most often trig-
gered by bee stings, followed by respiration of substances from moths, and stings/bites from mosquitoes, gnats
and, more rarely, fleas, ants and centipedes. Besides the main symptoms of urticaria and flushing on the whole
body, there may be systemic edema, edema of the larynx, bronchial stenosis, abdominal pain, diarrhea, and
shock that may lead to death. Generally, insect allergic reactions develop within 15 minutes after the sting/bite
or other exposure to the allergen. The sooner the symptoms appear and the older the patient is, the more severe
the symptoms tend to be.
◆ Occupational allergies
Occupational allergies are caused in workers with specific occupations by exposure to antigens. For example,
beauticians, pharmacists, buckwheat noodle-makers, and workers at oyster shell crushing sites, factories,
sawmills and egg farms are likely to develop occupational allergies. The main symptoms are eczema, dermati-
tis and urticaria. Allergic contact dermatitis and solar photosensitivity may also be caused by various work-
place drugs, chemicals and materials. Bronchial asthma and allergic rhinitis are frequently produced by various
kinds of dust.
*Type I allergy predominates among in food allergies. Specific IgE antibodies are sensitized against specific foods by
oral ingestion, and food allergic reaction occurs. Recent study has identified another type of food allergy in which a
specific antibody can be sensitized by food intake through non-oral routes; the cross-reaction occurs with a wider range
of foods (class II food allergy). Latex allergy and oral allergy with the involvement of pollen allergen (oral allergy syn-
drome; OAS) are typical class II food allergies.
2. Angioedema
Synonyms: Quincke’s edema, Angioneurotic edema Clinical images are available
in hardcopy only.
Outline
● Angioedema is caused by increased vascular permeabili-
ty in the subcutaneous tissue at sites deeper than those a b c d e f g h
of urticaria.
● The pathogenesis can be hereditary or nonhereditary.
● The eyelids and lips of mouth are the most frequently Clinical images are available
in hardcopy only.
affected.
● The treatment for nonhereditary angioedema is the same
a b c d e f g h i
as for urticaria.
Fig. 8.4 Cholinergic urticaria.
a: Small, multiple wheals are seen. b: Sweating
Clinical features test reveals that wheals appear at locations of
Localized edema suddenly occurs and remains for several sweat glands.
hours to several weeks. The size of the angioedema varies, with

the diameter ranging from 1 cm to 10 cm. It is sharply circum-
scribed, and itching is not usually present. Although it may occur
at any site on the body, the most frequently affected areas are the
eyelids, lips and genitalia (Fig. 8.5). Angioedema may be pro-
duced not only on the skin surface but also in the glossopharyn-
geal areas, nasal cavity, bronchial mucosa, gut mucosa,
a b c d e f g intracranial
h i region,
j heart
k or kidneys.
l It can be
m n fatal.o p q r
Pathogenesis, Classification
Angioedema is produced by the increased vascular permeabili-
8 ty in the subcutaneous tissue that results when histamines are
Clinical images are available in hardcopy only. released from mast cells in the dermal lower layer or the subcuta-
neous tissue or when some hereditary factor comes into play.
Angioedema is divided into hereditary and nonhereditary. Non-
hereditary angioedema is thought to be deep-seated urticaria.
a b c d e f g h i Hereditary
j angioneurotic
k l edema,
m caused
n by
o congenital
p absence
q r
of C1 esterase inhibitors (C1INH) is autosomal dominant in most
cases and is rare in Japan. Because of the absence of C1INHs,
there is activation of C1, kallikrein, Hageman factor (antihe-
mophilic factor XII) and plasmin, which results in the production
Clinical images are available in hardcopy only. of C2 kinin or bradykinin. Angioedema is caused by a resulting
increase in vascular permeability.
Diagnosis
b c d e f g h i j Andioedema
k l is easymto diagnose
n p
o medical
from q
history r clin-
and
ical features. Serum C1 inhibitor activation assay is effective in
diagnosing hereditary angioedema.
Treatment
The treatments for nonhereditary angioedema are the same as
those for urticaria. For hereditary angioedema, the following are
Clinical images are available in hardcopy only. administered: C1 inhibitor; androgen, which enhances expression
of the C1 inhibitor; or C1 inactivator, which strongly inhibits the
action of C1.
Prognosis
Nonhereditary angioedema may heal naturally. Hereditary
g j
angioedema rarely subsides, and it may
p
beqaccompanied by dis-
c d e f h i k l m n o r
orders such as those of the vocal cords.
Fig. 8.5 Angioedema.
a: Severe swelling on the right palpebra. b:
Severe edema on the lower lip. c: Edema on the 3. Urticarial vasculitis
upper lip, particularly on the right side. d:
Angioedema on the right side of the tongue. Urticarial or erythema multiforme-like eruptions that persist
for more than 24 hours recur and heal with purpura or pigmenta-
tion. Urticarial vasculitis most frequently occurs in women. Sys-
temic lupus erythematosus (SLE) like symptoms and decreased
complement value are seen. Leukocytoclastic vasculitis is found
histopathologically in many cases (Chapter 11). The etiology is
unknown. It is divided into idiopathic urticarial vasculitis and sec-
ondary urticarial vasculitis, the latter of which occurs secondarily
Prurigo 111
to a primary disease such as SLE, rheumatic arthritis or hepatitis

B. Unlike in ordinary urticaria, type I allergy is not involved in
urticarial vasculitis. However, the immune complex that indicates
the involvement of a type III allergy is present.
4. Food-dependent exercise-induced
anaphylaxis (FDEIA)
Physical stress – from exercise, for example – 1 to 4 hours
after ingestion of certain foods may cause anaphylaxis and
urticaria simultaneously. In Japan, food-dependent exercise-
induced anaphylaxis (FDEIA) is most often caused by wheat, fol- 8
lowed in frequency by shrimp, oysters and celery. Since exercise
or ingestion of specific foods alone does not cause FDEIA, an
induction test is necessary to confirm and diagnose FDEIA.
Prurigo
Outline
● Prurigo is a condition in which there are independent
itchy papules or small nodular eruptions.
● It is induced by insect bite, allergy, or atopic condition.
● It may be aggravated by rubbing, whereby small in hardcopy only.
intractable nodules form.
Clinical features, Classification

In prurigo, papules or small urticarial nodules are accompanied
by intense itching that becomes chronic. These nodules are called
pruritic papules (Fig. 8.6). There are various etiologies and clini-
cal features; however, the condition is thought to be a specific
inflammatory reaction. Prurigo is characterized by exudative
inflammatory lesions (Fig. 8.7) and by its failure to develop into Clinical images are available
the other types of eruptions that are seen with eczematous and in hardcopy only.
dermatitis lesions. Prurigo remains as chronic papules and nod-
ules. It is often categorized as acute or chronic.
Pathogenesis
Prurigo is exudative inflammation that occurs in the dermal
upper layer. It is accompanied by lymphocytic or neutrophilic
infiltration. It is thought to be induced by specific inflammatory
reaction (pruritic reaction); however, the causative agent is
unknown in many cases. Insect bites, mechanical or electrical in hardcopy only.
stimulation, certain kinds of foods, and chemical stimulation
such as by histamines are thought to be causative factors. Prurigo
may also accompany malignant tumor, leukemia or Hodgkin’s
disease. Atopic dermatitis can also cause prurigo.
Fig. 8.6 Prurigo nodularis.
Small, severely itchy nodules of 5 mm to 20 mm
in diameter are noted. Excoriation is also seen.
1. Acute prurigo
Synonym: Strophulus infantum
Clinical features
Urticarial erythema or wheals appear and become exudative
papules, usually in small children. Secondary infection may be
caused by rubbing and scratching brought on by intense itching.
Although acute prurigo tends to last only several weeks, it tends
to recur. Symptoms do not appear after the patient reaches a cer-
tain age.
8
Pathogenesis
Fig. 8.7 Histopathological findings of pruri- Atopic condition and hypersensitive reaction to insect bite or
go nodularis. certain foods (e.g., eggs, soybeans, pork) are known to be associ-
Acanthosis and inflammatory cell infiltration in ated with the occurrence of prurigo. Children under age 5 are
the upper dermis are noted. Excoriation induces
even more severe acanthosis. mostly affected in the summer, when insect stings are common.
Treatment
Topical steroids and oral antihistamines are the first-line treat-
ment. Insect bites and intake of causative foods should be avoid-
ed.
2. Subacute prurigo
Synonym: Prurigo simplex subacuta
Clinical images are available in hardcopy only. An urticarial papule accompanied by intense itching occurs on
the extensor surface of the extremities or the trunk. When it is
rubbed and scratched, erosion or crust forms. Subacute prurigo is
intractable and may become chronic.
The etiology is unknown. A primary disease such as atopic
dermatitis, diabetes, liver dysfunction, lymphoma, leukemia,
Hodgkin’s disease, internal malignancy, polycythemia, gout, ure-
mia or pregnancy is often involved. Mental stress has also been
pointed out as associated with onset. The clinical features are
intermediate between those of acute and chronic urticarias. How-
Fig. 8.8 Prurigo chronica multiformis. ever, acute and chronic urticarias may be found simultaneously
in the same patient.
In addition to treatments for the primary disease, topical
steroids and antihistamines are administered as needed.
3. Chronic prurigo
Classification
Chronic prurigo is subdivided into prurigo chronica multi-
formis, with aggregated individual papules that tend to form a
a b c d e f g h j
i lesion; p q
lichenoid andk prurigo
l nodularis,
m n with o
large nodular r
Fig. 8.9-1 Prurigo pigmentosa. papules that form sparsely and individually.
a: Chest lesion in a young male patient.
Pruritus cutaneus 113
Clinical features
Prurigo chronica multiformis occurs most frequently in the
trunk and legs of the elderly (Fig. 8.8). Exudative or solid
papules aggregate to form invasive plaques. The lesions are
rubbed as a result of intense itching, and exudate and crusts form Clinical images are available in hardcopy only.
to present intermingled pruritic papules and lichenoid lesions.
The condition is often chronic, with recurrences and remissions.
Prurigo nodularis most commonly affects adolescents and
older women (Fig. 8.6). Papules and nodules occur in the extrem-
ities, accompanied by intense itching. When rubbed they developa b c d e f g h i
erosion and bloody crusts, resulting in dark brown solid papules
or nodules. These are isolated and do not coalesce to form 8
plaques. They persist for several years.
Treatment
Topical steroids or ODT is applied as a local therapy. Applica-
tion of a zinc ointment sheet over topical steroids is effective.
Oral antihistamines are helpful in relieving itching. Oral steroids
and cyclosporines may be applied for a short period of time in
severe cases. Local injection of steroids and phototherapya areb c d e f g h i j
also conducted. Fig. 8.9-2 Prurigo pigmentosa.
b: Prurigo pigmentosa in a female patient in her
20s. Fresh-red erythema are mixed with old
4. Prurigo gestationis lesions, which are seen as reticular hyperpig-
mented macules. c: Erythematous macules
Prurigo gestationis appears on the extremities or trunk of (arrows) are seen at the center of reticular hyper-
pigmentation. It is a recurrence of prurigo pig-
women in their 3rd or 4th month of pregnancy and subsides after mentosa.
delivery. It is increasingly likely to occur with each successive
pregnancy. Differentiation between prurigo gestationis and
PUPPP (pruritic urticarial papules and plaques of pregnancy) is
controversial; however, the former occurs in the early stages of
pregnancy, whereas the latter occurs in the later stages of preg-
nancy.
5. Prurigo pigmentosa (Nagashima)

Prurigo pigmentosa (Nagashima) is urticarial erythema accom-
panied by intense itching. Pruritic erythematous papules recur
and heal with reticular pigmentation (Figs. 8.9-1 and 8.9-2). It
most frequently occurs on the back, neck and upper chest of ado-
lescent women. The pathogenesis is unknown. Minocycline and
DDS (dapsone) are extremely effective treatments.
Pruritus cutaneous
Outline
● In pruritus cutaneous there is no obvious eruption; only
itching is present.
● It is often accompanied by dry skin (xerosis).
● Eruptions, lichenification and pigmentation may be
Table 8.1 Causes of pruritus cutaneous. produced secondarily by rubbing and scratching.
Diffuse pruritus cutaneous ● Oral antihistamines and psychological counseling are
Visceral disorder helpful.
Endocrinologi- Diabetes mellitus, diabetes
cal dysfunction insipidus, thyroid disorder, Clinical features, Classification
parathyroid disorder The disease is classified by distribution into pruritus univer-
Metabolic Hepatitis, cirrhosis, salis and pruritus localis.
dysfunction carcinoid syndrome, biliary
atresia, gout, etc.
Pathogenesis
Renal disorder Chronic renal failure,
uremia Pruritus cutaneous occurs secondarily to various underlying
Hematological Erythrocythemia, iron
diseases, including liver dysfunction and renal failure (Table
8 disorder deficiency anemia 8.1). Scarring, thickening of the skin, lichenification and pigmen-
Malignancy Various carcinomas, multi- tation often develop secondarily by rubbing and scratching. The
ple myelomas, malignant disease is accompanied by dry skin (xerosis). It tends to occur
lymphoma (in particular, when the skin is sensitive to external stimulation, especially in
Hodgkin’s disease and
mycosis fungoides), chron- winter and at bedtime.
ic leukemia
Parasitosis Ascariasis, ancylostomiasis
Differential diagnosis
Neurological Myelophthisis, thalamic Systemic examinations such as blood test and renal function
disorder tumor test are necessary for diagnosis. When the genitalia are affected,
Environmental Mechanical stimuli, dry pruritus cutaneous should be differentiated from scabies and can-
factor conditions, spicy foods didiasis.
Drug Cocaine, morphine,
bleomycin, and drugs to Treatment
which the patient has
hypersensitivity
Treatment focuses on the underlying disease, if detected.
Application of antihistamines and moisturizer, and UV irradia-
Food Seafood (mackerel, tuna,
squid, shrimp, clams, etc.), tion are conducted as symptomatic therapies. It is also important
vegetables (aroids, bamboo to eliminate pruritus-inducing factors such as alcohol, coffee and
shoots, eggplant, etc.), spices. Bathing to keep the body clean, wearing cotton clothes,
pork, wine, beer, chocolate
avoiding dryness, and eliminating emotional stress are also help-
pregnancy In the third trimester
ful. Topical steroid application is effective against secondary
psychogenic Excessive stress, compul- eruptions; however, it is ineffective against pruritus itself.
factor sive neurosis and other
psychogenic disease
skin dryness senile xerosis 1. Pruritus universalis
Localized pruritus cutaneous
Itching is present on the whole body surface. As shown in
Pruritus on the Prostatic hypertrophy,
Genital region urethral stricture, vaginal
Table 8.1, it usually accompanies other diseases. In the elderly,
trichomoniasis, etc. pruritus may be present without a disease because of dry skin and
Pruritus on the Constipation, diarrhea, anal age-related processes; this is called senile pruritus.
perianal region prolapse, hemorrhoid, etc.
(Adapted from; Miyachi Y. Minimum dermatology. 2. Pruritus locaris
Bunkodo; 2000).
Itching appears locally in the anal region or genitalia. Pruritus
locaris in the anal region, which accounts for most cases of pruri-
tus, frequently affects young and middle-aged men. It may be
caused by constipation, diarrhea, hemorrhoids and anal prolapse.
Pruritus localis of the genitalia is commonly found in middle-
aged women. The labia majora and minora are most commonly
affected. Pruritus localis needs to be differentiated from parasitic
infection.
Chapter
9 Erythema, Erythroderma (Exfoliative
Dermatitis)
Erythema is caused by telangiectasia or hyperemia in the papillary and reticular dermis. The color disappears
with application of pressure. Erythema is a component of a very large number of cutaneous diseases including
eczema, urticaria, psoriasis, infectious diseases, blistering diseases and lymphomas. This chapter is devoted to
well recognized patterns of erythematous eruptions, with a focus on erythema multiforme, annular erythema and
erythroderma (exfoliative dermatitis).
Erythema
9
A. Erythema multiforme and related diseases
1. Erythema multiforme (EM)

Synonym: Erythema exsudativum multiforme (EEM)
Outline Clinical images are available in hardcopy only.

● Multiple circular edematous erythema of 5 mm to 20 mm
in diameter occurs multiply and symmetrically on the dor-
sal hands and the extensor surfaces of the joints.
● EM may occur in patients of all ages, but it occurs pre-
a b c d e f g h
dominantly in adolescents and young adults.
● Infection by the herpes simplex virus or mycoplasma
pneumoniae is the dominant causative factor of EM, but

drug-sensitivities are also an important cause.
● Topical or oral corticosteroids are effective for the treat-
ment of EM. Recurrence may occur.
Classification
Erythema multiforme (EM) is largely classified into localized
cutaneous lesions (EM minor) and mucosal lesions with systemic
involvement (EM major). EM major is thought to be the same as Clinical images are available in hardcopy only.
Stevens-Johnson syndrome. Both EM minor and EM major are
transitory. These prototypes are well defined, but their distinction
may be difficult in practice because of their overlapping features.
Clinical features, Epidemiology

Eruptions occur symmetrically on the extensor aspects of the
joints (e.g., the dorsal hands, elbows, knees) as erythematous
papules or edematous erythema, and they spread centrifugally in
about 48 hours to form sharply circumscribed, round or irregular-a b c d e f g h i
ly shaped erythema (Figs. 9.1-1 and 9.1-2). The center of the ery- Fig. 9.1-1 Erythema multiforme (EM).
thema is concave, presenting either as a target lesion or iris Well-demarcated edematous exudative erythema
disseminates on the dorsal hand (a) and elbow
formation, also called exudative erythema. The affected area (b). The size is up to 2 cm. Note the central con-
simultaneously shows new and old lesions that may fuse into cavities.
115
116 9 Erythema, Erythroderma (Exfoliative Dermatitis)
map-like patterns. EM may be accompanied by blistering (bul-

lous EM) and erosions of the oral mucosa.
EM frequently occurs in the young and middle-aged, and it
tends to appear during the spring and summer. Infectious symp-
toms including high fever and pharyngodynia may precede the
onset. In cases caused by herpes simplex infection, EM tends to
occur 1 to 3 weeks after the onset of the herpes simplex symp-
toms (post-herpetic EM).
Pathogenesis
As shown in Table 9.1, EM is caused by various factors, such
as viral or bacterial infections (by herpes simplex or Mycoplasma
pneumoniae), and drugs and malignant tumors. It is estimated
9 Clinical images are available in hardcopy only. that EM is a cell-mediated immuno reaction leading to the
destruction of keratinocytes expressing various antigens. Howev-
er, the underlying pathomechanism is not known.
Pathology
In the early stages of epidermal EM, there is lymphocytic infil-
tration into the dermo-epidermal junction and vacuolar degenera-
tion of basal cells. As the disease progresses, lymphocytes
(CD8+T cells) infiltrate into the epidermis, and necrosis of epi-
dermal cells and subepidermal blistering are found (Fig. 9.2 and
Table 9.1 Conditions associated with erythema multiforme.

Cause Details
Fig. 9.1-2 Erythema multiforme (EM).
Infections Virus (e.g., human herpes simplex virus), bacteria
The central concavities give a characteristic iris-
(Streptococcus, Mycoplasma, Mycobacterium), tinea,
like appearance.
Chlamydia, Rickettsia
Drug reactions Antibiotics, NSAIDs, anticonvulsants, antineoplastic
agents, etc. See Chapter 10.
Collagen diseases, Insect bite, disease (especially systemic lupus erythe-
Allergic disorders matosus (SLE)), sarcoidosis, Crohn’s disease
Other Physical stimulation (e.g., cold), hematopoietic
malignant disorders, pregnancy, etc.
Table 9.2 Histopathological classification of erythema multi-

forme.
Classification Main histopathological findings
Epidermal In the early stage, lymphocytic infiltration and ballooning
degeneration in the dermo-epidermal junction. As the
Fig. 9.2 Histopathology of erythema multi- disease progresses, infiltration of CD8+ lymphocytes into the
forme (EM). epidermis, resulting in keratinocyte necrosis and
Necrosis of epidermal cells (staining strongly red subepidermal blistering. Decrease of epidermal Langerhans
by eosin), vacuolar degeneration of the basal cells and overexpression of ICAM-1 on keratinocytes.
layer, inflammatory cell infiltration and edema in
the upper dermis are noted. Dermal Perivascular monocytic infiltration in the upper dermis;
edema in the dermal papilla. It is now said that erythema
multiforme is always accompanied by at least some change
in the epidermis.
Mixed Epidermal changes (vacuolar degeneration of the basal
layer, satellite cell necrosis); dermal changes (perivascular
lymphocytic infiltration).
Erythema/A. Erythema multiforme and related diseases 117
Table 9.2). Table 9.3 Erythema multiforme: differential

diagnosis.
Laboratory findings Disorder Difference from erythema multiforme
Because of inflammation, CRP may be positive and the ery- Urticaria Itching is more severe. Each lesion
usually disappears within 24 hours.
throcyte sedimentation rate is elevated. The herpes simplex virus Dermographism rubrum occurs.
antibody titer, Mycoplasma antibody titer and antistreptolysin O
SLE Systemic symptoms occur (renal,
(ASO) titer may be elevated in some cases. In cases involving arthritic, etc.). Laboratory findings of
bacterial infection, there is an increase in neutrophils. antinuclear antibodies, etc.
Erythema multiforme sometimes
Diagnosis, Differential diagnosis occurs in association with SLE.
Bullous Direct/indirect immunofluorescence
EM is relatively easy to diagnose by its characteristic clinical pemphigoid reveals antibodies against basement
features and by the distribution of the eruptions. History of previ- membrane.
ous diseases, such as infectious diseases, supports the diagnosis.
Refer to Table 9.3 for differential diagnosis. 9
Identifying the pathogenesis is important not only for treatment
but also for prevention of recurrence. The underlying infectious
disease should be treated. Topical steroids, oral antihistamines,
NSAIDs and potassium iodides may also be used. Severe cases
need the application of systemic corticosteroids. EM regresses
spontaneously within 2 to 4 weeks. When caused by herpes sim-
plex infection, acyclovir administration may be effective; howev-
er, EM tends to recur. Clinical images are available in hardcopy only.
2. Stevens-Johnson syndrome (SJS)

Synonyms: Mucocutaneous ocular syndrome, EM major
Outline
● SJS is a severe acute mucocutaneous reaction with sys-
temic symptoms such as fever and arthralgia.
● It may develop into toxic epidermal necrolysis (TEN).
● When the symptoms are severe, systemic corticosteroids a b c d e f g h
is administered. Steroid pulse therapy and systemic
management may also be adopted.
Classification
Stevens-Johnson syndrome (SJS) is EM major with oculo-
mucous lesion and systemic symptoms including liver and renal Clinical images are available in hardcopy only.
dysfunction. Nevertheless, well-defined findings on the differ-
ences between EM major and SJS have not been obtained. Drugs
are clearly the leading causative factor of SJS. The disease occurs
1 to 6 cases per million population per year. It is sometimes diffi-
cult to draw an absolutely clear distinction between SJS and toxica b c d e f g h i
epidermal necrolysis (TEN) (Chapter 10). Fig. 9.3-1 Stevens-Johnson syndrome (SJS).
a, b: Erythema multiforme rapidly spreads on the
Clinical features entire body. Some lesions overlap to form large
EM occurs suddenly, with systemic symptoms such as high plaques on the back. A bull’s-eye pattern, charac-
teristic of erythema multiforme, is seen at the
fever, general fatigue, arthralgia, myalgic pain, chest pain and border of a plaque.
gastrointestinal distress (Figs. 9.3-1 and 9.3-2). Intense edematous
EM major, accompanied by blistering and bleeding, develops and

tends to be severe. The extensor surface of the extremities and
the entire body surface including the face and trunk are affected.
Mucosal sites are involved and may be severe. Erythema, hemor-
rhagic bullae, and erosions accompanied by pus and bloody
Clinical images are available in hardcopy only. crusts occur in the eyes, oral cavity, nose, perineal regions, and
genital mucosa. Patients sometimes cannot eat or excrete because
of severe pain. Systemic treatment is essential for cases with
involvement of hepatopathy and renal dysfunction. Conjunctival
inflammation, adhesion, corneal opacity and ulceration occur in
b c d e f g h i j eyes.
the k Whenl it heals,
m SJS nmay leave p
o serious q
aftereffects,
r such
as loss of eyesight. Dense fibrous adhesion (symblepharon)
between the conjunctival linings is also seen. Ocular involvement
9 in SJS requires early consultation with an opthalmologist.
Pathology
Clinical images are available in hardcopy only. Refer to the section on erythema multiforme. Necrotic degen-
eration is found mostly in the epidermis. Vacuolar degeneration
of the basal membranes and dermal edema are also present.
Diagnosis, Differential diagnosis

c d e f g h i j k SJS isl characterized
m n by severe
o lesions
p in
q the mucocutaneous
r
Fig. 9.3-2 Stevens-Johnson syndrome (SJS). junction, erythema over the entire body surface, blisters, erosions
c: Large plaques. d: Erosions and ulcers are seen and systemic symptoms, and histopathologically by epidermal
on the oral mucosa and tongue, with severe pain. necrotic degeneration. A detailed medical history is needed to
identify the cause. Antibody titers of HSV, Mycoplasma, pharynx
culture and chest X-ray are performed. Sudden enlargement on
MEMO the entire body suggests progression to TEN.
Differentiation between
SJS and TEN
Both Stevens-Johnson syndrome (SJS) and Treatment
toxic epidermal necrolysis (TEN) produce Early diagnosis and treatment are important for improving the
necrotic lesions over the skin and mucous
membranes on the whole body. When the area prognosis. Systemic steroid administration (orally or by pulse
ofepidermolysis is 10% or less, the disease is therapy) is especially important in the early stages. The causative
called SJS; when it is 30% or more, the disease drug should be discontinued immediately. The skin and mucous
is called TEN.
membranes should be protected by ointment application.
Prognosis
Unless the patient is treated appropriately, SJS may develop
into TEN, and the patient may die of pneumonia or renal dys-
function. In severe cases, it leaves corneal opacity and conjuncti-
val adhesion.
Erythema/A. Erythema multiforme and related diseases 119
3. Sweet’s disease
Synonyms: Acute febrile neutrophilic dermatosis, Neu-
trophilic dermatosis
Outline
● In Sweet’s disease, painful erythema with elevated bor-
ders occurs on the face and joints.
● Fever, neutrophilia and arthralgia appear simultaneously.
● Histopathologic features are edema of dermal papillae Clinical images are available in hardcopy only.
and dense infiltration of leukocytes in the dermis.
● It is associated with hematologic malignancies (common-
ly acute myelogenous leukemia and myelodysplastic

syndrome (MDS)). 9
● The treatments of systemic corticosteroids, colchicines
and potassium iodides are effective.
Clinical features
Sweet’s disease occurs most frequently on the face, neck, fore-
arms and dorsal hands of middle-aged women. Several days to 4
weeks after upper respiratory tract infection, multiple painful and
sharply circumscribed dark reddish edematous erythema 10 mm
to 25 mm in diameter occur suddenly, accompanied by high fever
(Fig. 9.4). The surface of the eruptions is rough and granular, and
the eruptions are surrounded by vesicles and pustules. Central Clinical images are available in hardcopy only.
clearing may lead to annular or accurate patterns. When Sweet’s
disease occurs on the lower thighs, it resembles erythema
nodosum. Differentiation from Behçet’s disease may be neces-
sary if oral aphtha is found.
Pathogenesis
Fig. 9.4 Sweet’s disease.
Hypersensitive reaction occurs against Streptococcus and other
pathogens in certain circumstances, such as the presence of a
hematopoietic malignant tumor, solid tumors, or various autoim- Table 9.4 Disorders associated with Sweet’s
mune disorders. Sweet’s disease is caused by abnormally activat- disease.
ed neutrophils; the details of the pathomechanism are not known. Disorder type Details
Hematological Myelodysplastic syndrome (MDS),
Complications leukemia, myelofibrosis, etc.
Sweet’s disease often accompanies the diseases listed in Table Autoimmune Sjögren syndrome, rheumatoid
arthritis, subacute cutaneous
9.4. 10% to 15% of the Sweet’s disease is reported to be associat- lupus erythematosus, ulcerative
ed with hematologic malignancies. colitis, etc.
Other Other malignancy, pyoderma gan-
Pathology grenosum, etc.
The main and most striking feature is a massive infiltration of
neutrophils in the dermis and dermal edema (Fig. 9.5). Changes
on the epidermis and vasculitis (fibrinoid necrosis) are not
observed. In the chronic stage, lymphocytic perivascular infiltra-
tion occurs instead of neutrophilic infiltration.

Peripheral leukocytosis with neutrophilia is the characteristic
laboratory finding. An elevated erythrocyte sedimentation rate

and high CRP levels are also present. Sweet’s disease is often
associated with an underlying disease. It is necessary to deter-
mine whether the primary disease is lymphoma (myelodysplastic
syndrome, leukemia), malignant internal-organ tumor or autoim-
mune disease.
Treatment
Oral administration of corticosteroids, potassium iodides,
NSAID and colchicines are the main treatments. Antibiotics are
ineffective.
Fig. 9.5 Histopathology of Sweet’s disease.
Dense neutrophilic infiltration on the entire der- Prognosis
mis without apparent vasculitis.
9 Without treatment, the eruption may persist for weeks or even
months. Patients with cancer may see frequent recurrences.
4. Palmar erythema
Clinical features
Palmar erythema is observed in several conditions.
Pathogenesis
Palmar erythema is a vascular acrosyndrome with multiple eti-
ologies. Best known in pregnancy, liver diseases and collagen
diseases (e.g., erythematosus, dermatomyositis, rheumatic arthri-
tis), it can occur in a variety of other systemic disturbances. Pal-
mar erythema may be related to elevated serum estrogens and
related 17-cetosteroid hormones. In rare cases it occurs hereditar-
ily in otherwise healthy people.
Refer to Chapter 18 for erythema nodosum and erythema
induratum.
B. Annular erythema
Annular erythema is a general term for diseases in which small
erythema appear and then spread centrifugally. It begins with
small erythema that enlarge centrifugally while resolving in the
center, resulting in a ring shape. It may involve an underlying
disease, such as an infectious disease, malignant tumor, drug
eruption or collagen disease. Annular erythema is classified
according to the underlying disease and the clinical features
(Table 9.5). Refer to Chapter 12 for Sjögren syndrome and the
annular erythema associated with LE.
Erythema / B. Annular erythema 121
Table 9.5 Classification of annular erythema.

1. Erythema annulare centrifugum (EAC)
Eythema annulare centrifugum
Synonyms: Darier’s erythema annulare centrifugum Annular erythema associated with infection
・Erythema chronicum migrans
Clinical features Annular erythema associated with collagen
Erythema annulare centrifugum (EAC) most commonly affects disease
・Annular erythema associated with Sjögren
young middle-aged adults. Infiltrated papules slowly enlarge and syndrome
form a ring as the central area flattens and fades (Figs. 9.6-1 and ・Neonatal lupus erythematosus
9.6-2). The disease may persist for many years. ・Subacute cutaneous lupus erythematosus,
annular/polycyclic
・Erythema marginatum rheumaticum
Pathogenesis
Annular erythema associated with neoplasms
It may involve interaction among inflammatory cells, their ・Erythema gyratum repens
mediators and ground substances, as foreign antigens diffuse ・Necrolytic migratory erythema
through the skin. 9
Pathology
The vessels of the upper and mid-dermis show dense perivas-
cular lymphocytic sleeving.
Treatment
A search for the underlying cause is the primary goal of treat-
ment. The systemic or topical application of corticosteroids and
oral antihistamines may help.
a b c d e f g h
2. Erythema marginatum rheumaticum
Clinical features, Pathogenesis

Erythema marginatum rheumaticum occurs in 5% to 30% of
patients with active rheumatic fever. It begins as an erythematous
macule or papule that extends outward while the skin in the cen-
ter returns to normal. The edge of the eruption elevates slightly.
The eruption is symptomless. The lesion fade in a few hours, or
at most in 2 to 3 days. Recurrent crops may appear at intervals
for many weeks. Deposition of antibodies and complements on
the blood vessel walls suggests an association with immunoreac-
tion. Although children are the most commonly affected by ery-
thema marginatum rheumaticum, there are cases in adults.
a b c d e f g h i
Treatment Fig. 9.6-1 Erythema annulare centrifugum
The treatments for rheumatic fever (systemic administration of (EAC).
a: On the abdomen. b: On the trunk. Edematous,
antibiotics in very large doses) is effective. slightly elevated erythema 1 cm to 5 cm in diam-
eter. These sometimes expand centrifugally to 5
Prognosis cm to 20 cm in diameter. The margins are usually
elevated. Erythema annulare centrifugum pres-
The eruptions disappear spontaneously. The prognosis of rheu- ents one or more lesions on the entire body.
matic fever depends on coronary damage.
3. Erythema chronicum migrans (ECM)
Clinical features
Within 1 month after a tick bite, a papule or erythema occurs
on the bitten site. It quickly enlarges centrifugally to form a char-
acteristic ring-shaped eruption: The edge is scarlet and may ele-
Clinical images are available in hardcopy only. vate, and the center partly or totally fades. It is asymptomatic.
The eruption may reach 40 cm in diameter. Erythema chronicum
migrans (ECM) is the cutaneous hallmark of Lyme disease (refer
to Chapter 28 for other symptoms and treatments of ECM).
Pathogenesis
9 ECM can be attributed to infection by Borrelia burgdorferi, a
spirochete whose usual hosts are ticks of the genus Ixodes.
Fig. 9.6-2 Erythema annulare centrifugum
(EAC). 4. Erythema gyratum repens
c: On the upper arm.
Cutaneous eruptions of concentric raised erythematous bands
move in waves over the body surface in a “wood grain” pattern.
Accompanied by intense itching, they enlarge quickly (Fig. 9.7).
The eruption is associated with internal malignancy. Immunoglob-
ulin and immune complex deposit in the dermo-epidermal junc-
tion, suggesting the involvement of immunoreaction.
5. Necrolytic migratory erythema

Necrolytic migratory erythema is a marker for glucagonoma. It
typically involves the face and the intertriginous areas. There is a
cyclic pattern in the course of the eruption. Vesicles and pustules
Fig. 9.7 Erythema gyratum repens.
tend to become confluent. Irregular centrifugal expansions of the
annular lesions coalesce into a map-like serpeginous pattern.
Erythroderma
Outline
● Erythroderma is the term applied to any inflammatory
skin disease with erythema and scaling which affects
more than 90% of the body surface.
● The causes are various.

Erythroderma is often of sudden onset. Patchy erythema which
rapidly generalizes may be accompanied by desquamation
(Table 9.6, Figs. 9.8-1 and 9.8-2). The underlying dermatologic
disorder is often impossible to identify, but in some causes,
patients have the specific clinical features of the original
causative disorder. Intense itching is present. When the palms
and soles are affected, erythroderma may cause acanthosis,
Erythroderma / 1. Eczematous erythroderma 123
hyperkeratosis, and fissures in the horny cell layer. The scalp hair Table 9.6 Causative conditions of erythro-
derma.
may be shed and the nails become ridged. The skin becomes
shiny and pigmented in the chronic stages of the eruptions. These Inflammatory disorder
may be accompanied by fever, shivering and malaise. Eczema, atopic dermatitis
Drug eruption
Psoriasis
Pathology Erythema multiforme
There are no characteristic pathological findings for erythro- Viral eruption (measles, rubella)
Pityriasis rubra pilaris
derma, because the findings vary depending on the underlying Reiter’s syndrome
disease. In most cases, histopathologically, there are hyperkerato- Congenital ichthyosiform erythroderma
sis, parakeratosis, acanthosis and chronic inflammatory infil- Bullous pemphigoid
trates. The submission of multiple biopsy specimens from a Pemphigus foliaceus
Dermatitis herpetiform (Duhring)
patient enhances the accuracy of histopathologic diagnosis. Hailey-Hailey disease
Lupus erythematosus
Laboratory findings Dermatomyositis 9
Sarcoidosis
In cases in which the underlying disease is not identified, labo- Fungal infections
ratory findings are referred to for diagnosis (Table 9.7). Scabies
Staphylococcal scalded-skin syndrome
Treatment Ofuji papuloerythroderma
Graft-versus-host disease
Oral antihistamines and topical steroids are useful; neverthe- HIV infection
less, side effects from topical agents tend to occur as a result of Neoplasm
enhanced skin barrier function, which accelerates percutaneous Mycosis fungoides
absorption. Systemic corticosteroids are needed in severe cases. Sézary syndrome
Treatment in hospital is advisable for cases with systemic symp- Adult T-cell leukemia/lymphoma
Leukemia
toms, including protein or electrolyte imbalance. Malignant lymphoma, especially Hodgkin’s
disease
Multiple myeloma
1. Eczematous erythroderma Other malignant disorder
Eczematous erythroderma accounts for about 50% of all ery- Table 9.7 Examinations for diagnosis and
throderma cases. Although it most frequently affects elderly men, severity of erythroderma.
it may occur in patients of other ages with atopic dermatitis. Examination Points
Atopic dermatitis and various types of eczema generalize to Complete blood Essential for the diagnosis of
become erythroderma under the influence of intrinsic or extrinsic count, blood infections, malignant lymphoma,
factors. Intrinsic factors include dysfunction of T cells, liver or picture leukemia and Sézary syndrome.
kidney; paranephros; and autonomic dystonia. Extrinsic factors In atopic dermatitis, drug
eruption and eosinophil levels
include inappropriate treatments for eczema, home remedies and are elevated.
environmental changes. Edematous redness and scaling are pres- Liver function Liver dysfunction suggests drug
ent over the entire body skin. This is accompanied by intense reaction or collagen disease
itching and, sometimes, indolent lymphadenopathy, particularly such as dermatomyositis.
of the inguinal lymph nodes. Systemic symptoms such as fever, Skin biopsy Underlying disorder (mycosis
dehydration, protein loss, body temperature instability and oppor- fungoides, psoriasis, etc.) may
be found by repeated skin
tunistic infection may be found. Skin atrophy, pigmentation, pity- biopsy.
roid scaling and skin glossiness become noticeable as the Bacteriological Bacterial culture and potassium
eruptions become chronic. Eczematous erythroderma is often examination hydrate (KOH) from scales/
caused by atopic dermatitis, contact atopic dermatitis, seborrheic pustules may reveal underlying
dermatitis and autosensitization dermatitis. Topical steroids are disorders.
extremely effective as a treatment. Antihistamines are useful. Plasma protein Indicates hypoalbuminemia
fraction from scaling and skin metabolic
Oral administration of steroids should be avoided as much as dysfunction.
possible.
Renal function, Indicates dehydration and
cardiopulmonary edema.
function,
electrolytes
2. Drug-induced erythroderma
Drug-induced erythroderma accounts for about 10% of all ery-
throdermas. It is most frequently caused by antibiotics,
antiepileptic drugs and NSAIDs (Table 9.8). After intake of any
of those drugs, the disease starts as erythematous papules. These
spread rapidly until bright red erythema affects the entire skin
surface. Causative drugs should be discontinued. Oral steroids
and pulse therapy are effective at the early stages. Although most
cases resolve relatively soon after the causative drug is discontin-
ued, lichenification may continue for a long period. Drug-
induced hypersensitivity syndrome (DIHS, Chapter 10) is a
persistent severe drug eruptions with organ failure; the disorder
9 may also cause erythroderma.
3. Psoriasis erythroderma
Psoriatic exfoliative dermatitis can occur in association with
Clinical images are available in hardcopy only. the use of steroids, and phototherapy, alcohol and stress. Typical
psoriatic eruptions often partly remain in erythroderma. Nail
deformity frequently occurs. The treatment of oral cyclosporine
or etretinate (a vitamin A derivative) is required as treatments in
many cases.
4. Tumorous erythroderma
T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome),
adult T-cell leukemia, Hodgkin’s disease, or chronic lymphocytic
leukemia may occur as the primary diseases of tumorous erythro-
derma (Figs. 9.8-1 and 9.8-2). Systemic examination is necessary
to detect internal lesions. Erythema with intense itching spreads
over the whole body surface, and the lymph nodes swelling. The
primary disease should be identified and treated.
5. Other potential cause of erythroderma

①Bullous dermatosis: Pemphigus foliaceus (and erythematous),
herpetiformis dermatitis may progress to erythroderma. A
histopathological examination and a direct immunofluorescent
antibody test are useful for diagnosis.
②Hereditary keratosis: In nonbullous congenital ichthyosiform
Clinical images are available in hardcopy only. erythroderma, diffuse erythema, scaling and hyperkeratosis occur
at the time of birth or within several weeks after birth. Keratotic
follicular papules are produced on the extensor surface of the
joints in pityriasus rubia pilaris, and these may diffuse and
progress to erythroderma.
③Infectious disease: Erythroderma tends to occur in immuno-
Fig. 9.8-1 Erythroderma associated with compromised patients, such as those with AIDS. Scabies (Nor-
Hodgkin’s disease.
Flushing and marked scaling are seen on the wegian scabies, particularly), tinea, candidiasis, and viral
entire body. The severity of the skin lesions mir- infections such as of measles and rubella may also produce ery-
rors that of the Hodgkin’s disease. throderma. In children, staphylococcal scalded-skin syndrome
Erythroderma / 5. Other potential cause of erythroderma 125
(SSSS) sometimes progresses to erythroderma.

Graft-versus-host disease: Erythroderma may occur as a symp-
tom of graft-versus-host disease (GVHD) after transfusion. It is
fatal. About 10 days after transfusion, edematous erythema,
fever, diarrhea, liver disorder, pancytopenia and edematous ery-
thema occur and become erythroderma. Postoperative erythroder-
ma can be prevented by X-radiation of blood products before
transfusion.
Ofuji papuloerythroderma: Ofuji papuloerythroderma is an Clinical images are available in hardcopy only.
uncommon entity of unknown etiology, characterized by a prurit-
ic eruption of flat, widespread, reddish-brown papules that pro-
gresses to spare skin folds. Some cases may be associated with
an internal malignancy or T-cell lymphoma.
9
Fig. 9.8-2 Erythroderma associated with

Hodgkin’s disease.
With regression, normal skin areas appear on the
abdomen and shoulder (arrows).
Table 9.8 Causative drugs of erythroderma.

Antibiotics
NSAIDs
Allopurinol
Lithium
Phenytoin
Calcium channel blockers
Carbamazepine
Cimetidine
Gold
Quinidine
Other
Chapter
10 Drug-Induced Skin Reactions and GVHD
Skin and mucocutaneous lesions induced by a drug or by its metabolites are called drug eruptions. Some cuta-
neous drug reactions present a specific morphological pattern. However, most drug eruptions can present the
appearance of any cutaneous lesion. It is necessary for dermatologists to take a detailed patient’s history of
medication use as well as a medical history. It is clinically important to differentiate drug-induced skin reactions
from viral rash and graft-versus-host disease (GVHD); this differentiation is sometimes difficult.
A. Drug-induced skin reactions

10
Outline
● Drug-induced skin reaction or drug eruption is a general
term for eruptions in the skin and mucosa induced by a
drug or its metabolites.
● Drug-induced skin reactions show various morphologies.

General information
Maculopapular or morbilliform eruptions may be the most com-
mon of all cutaneous drug reactions. It is also known that cuta-
neous drug reactions present the specific morphological patterns.
(Figs. 10.1-1 and 10.1-2). In diagnosing skin diseases, it is essen-
tial to consider drugs as a possible cause of any eruption, because
drug eruptions can take the form of any skin lesion. Drug eruptions
may be accompanied by general symptoms including fatigue,
a b c d e f g h
fever, i
lymph j
node k l disfunction
enlargement, m nof the internal
o porgansq r
such as liver, kidneys or bone marrow, hypotension and shock.
Classification, Pathogenesis
Drug eruptions are roughly divided into immunologic and non-
immunologic. The pathogenesis is unclear in some cases. The
eruptions are often classified by their clinical features (Table
10.1, Figs. 10.2-1 and 10.2-2).
Treatment
It is essential to discontinue the causative medication. In seri-
ous cases, such as anaphylactic shock, systemic management
using steroids in large doses including antihistamines, epineph-
rines, and steroids in large doses, including by pulse therapy.
a b c d e f g h i a. Classification
j k l ofmdrugn eruptions
o p by q r
Fig. 10.1-1 Drug-induced skin reaction. pathogenesis (Table 10.2)
a: Diffuse edematous erythema on the back. Each
eruption is an erythema multiforme-like erythe-
ma of 1 cm to 2 cm in diameter that gradually 1. Immunologic drug reactions
enlarged and tended to coalesce. b: Edematous
itchy erythema coalesced into a large plaque. A drug or the complex of a drug and a serum protein becomes
126
A. Drug-induced skin reactions 127
Table 10.1 Drug-induced skin reactions and their typical causative drugs.
Type of eruption in drug-
Causative drugs
induced reactions
Maculopapular Iohexol, iomeprol, ampicillin, amoxicillin, carbamazepine, mexiletine, tiopronin
Photosensitive Sparfloxacin, fleroxacin, lomefloxacin , piroxicam, ampiroxicam, griseofulvin, mequitazine, ketoprofen
Fixed-drug eruption Allylisopropylacetyl urea, mefenamic acid, ethenzamide, barbital, minocycline,
sulfamethoxazole, piroxicam, fluorouracil
Erythema multiforme Iohexol, carbamazepine, amoxicillin, tiopronin, phenytoin, diltiazem, mexiletine
Lichenoid Tiopronin, captopril, interferon a, cyanamide, oxatomide
Urticarial Cefaclor, minocycline, iohexol, aspirin, cetraxate, mefenamic acid
Toxic epidermal necrolysis Cefzonam, penicillin, phenobarbital, chlormezanone, carbamazepine, methazolamide, acetaminophen,
(TEN) allopurinol, diclofenac
Stevens-Johnson syndrome Penicillin, chlorpromazine, sulfamethoxazole, sodium aurothiomalate, phenytoin
Erythrodermic Carbamazepine, sodium aurothiomalate, cyanamide, allopurinol, ampicillin
Vesiculo-bullous D-penicillamine, tiopronin, captopril, bucillamine, alacepril
10
Eczematous Penicillin, chlorpromazine, chlorthiazide, promethazine
Purpuric Sodium aurothiomalate, sulfamethoxazole, penicillin, aspirin
antigenic, causing a drug eruption that results from immunologi-

cal processes. That is, a drug eruption occurs in specific individu-
als whose antibodies and lymphocytes react against specific
antigens. Although type I, II, III, and IV hypersensitivities are
thought to cause drug eruptions (Coombs and Gell classification),
the details of the pathogeneses are unknown.
IgE mediated type I allergy: Within 2 hours after exposure to
an antigen (e.g., penicillin or some NSAIDs), urticaria or anaphy-
lactic shock occurs. Clinical images are available
Type II allergy: Complements are activated by an antigenic drug in hardcopy only.
that connects with tissues, resulting in hemolytic anemia and

thrombocytopenia. It is observed in some cases of purpura-like
eruptions.
Immune complex-associated type III allergy: Immune com-
plex deposits in tissues, causing disorders. Vasculitic eruptions
are thought to be caused by this mechanism.
Type IV allergy: A delayed hypersensitivity reaction is induced
g j
by T cells that have been sensitized to drug antigens. It isa knownb c d e f h i
that many types of drug eruptions, such eczema-like eruptions,
are produced by type IV allergy or by T-cell mechanisms that
resemble type IV allergy.

in hardcopy only.
2. Non-immunologic drug-induced skin
reactions
Drug-induced skin reactions without an immunologic patho-
genesis may affect anyone, regardless of whetherathere has
b beenc d e f g h i j k
sensitization.The pathogenesis of drug-induced skin reactions can Fig. 10.1-2 Drug-induced skin reaction.
also be classified pharmacokinetically. c: Drug-induced erythema enlarged and coa-
Pharmacologic effects: Drug-induced skin reactions may be pro- lesced to form erythroderma. d: Drug eruption
caused by tegafur.
duced by essential pharmacological action of the drug. Hair loss
128 10 Drug-Induced Skin Reactions and GVHD
Table 10.2 Drug-induced skin reactions classified by mechanism.

Immunologic
Type I hypersensitivity (via IgE antibodies; acute onset within 2 hours
after drug intake)
Type II hypersensitivity (eruption caused by thrombocytopenia and
hemolysis resulting from complement activation)
Type III hypersensitivity (immunocomplex deposition in skin components)
Clinical images are available Type IV hypersensitivity (reactions caused by activated T cells)
in hardcopy only.
Non-immunologic
Pharmacological effects
Accumulation
Drug interaction
Patient-specific conditions
caused by anticancer agents and exfoliation in palms and soles
10 caused by retinoids are examples.
Accumulation: A drug accumulates in the skin or mucous mem-
branes from prolonged use (arsenic melanoderma and argyria are
Clinical images are available examples of accumulation disorders).
in hardcopy only. Drug interaction: One drug may inhibit another drug’s metabo-
lism or excretion, or it may influence protein binding, leading to
the same symptoms as those in drug overdose.
Specific condition of patients: Inherited enzyme deficiency may
a b c d e f g h i
cause j
drug k
reactions; l m reaction
excessive n o
occurs p
against a qminuter
amount of drug (intolerance). An unexpected action of the drug is
caused (idiosyncrasy).
b. Classification of drug eruptions by

characteristic skin features
Although maculopapular eruption (multiple edematous ery-
thema on the extremities and trunk) are the most common;
Clinical images are available drug-induced skin reactions can appear as any kind of cuta-
in hardcopy only.
neous lesion (Table 10.1). When seeing patients with any
types of eruption, dermatologists should always carefully con-
sider the possibility of precedent drug reactions.
c. Methods of identifying the causative

drug
History is taken on drug-induced skin reactions and on exacer-
g p
b c d e f h i j
bation k remission
or l ofmeruptions
n influenced
o by useqor discontinu-
r
Fig. 10.2-1 Various types of drug-induced ation of a drug. If the eruption is suspected to be drug-induced
skin reaction.
a, b: Erythema multiforme-like. Although uni-
reactions, tests listed below are conducted for identification
formly colored erythematous plaques are mainly (Chapter 5).
seen, newly formed erythema is seen at the ①Skin test (scratch test, prick test, intradermal test)
periphery, some parts of which show the target- ②Patch test
like appearance that characterizes erythema mul-
tiforme. c: Purpuric. Dark red macules up to 1 ③Drug lymphocyte stimulation test (DLST)
cm in diameter are observed. These do not disap- ④Rechallenge test (absolutely contrainidicated in severe forms
pear by diascopy pressure, which indicates that of drug reactions)
the eruption is purpura.
d. Specific types of drug-induced skin

reactions
1. Fixed drug eruption (FDE)
Definition
Fixed drug eruptions (FDEs) are eruptions that recur at the
same site each time the same drug is administered. They fre- Clinical images are available in hardcopy only.
quently occur at mucocutaneous junctions.
Clinical features
FDEs frequently occur at mucocutaneous junctions, such as in
the perioral area, lips and genitalia, and in the extremities. They
are characterized by a single or a few sharply demarcated red or 10
purple patches (Fig. 10.3), with a diameter of 1 cm to 10 cm.
Multiple patches may also occur. They may appear as blistering
or erosion. Itching and pain are common. The lesions appear sev-
eral minutes to several hours after the administration
a b of thec d e f g h i j k
causative drug. They heal in 2 to 5 weeks, leaving pigmentation.
If the same drug was administered repeatedly, the dark brown
pigmentation intensifies from inflammation in the basal layer,
and subsequent melanin deposition in the dermis (post-imflam-
matory pigmentation).
Pathogenesis
FDEs are caused by the activation of cytotoxic T lymphocytes
in the basal layer by drugs. Common causative drugs are
NSAIDs, tetracyclines, sulfa drugs, phenacetin, hypnogenics and Clinical images are available in hardcopy only.
food additives.
Diagnosis
FDEs are diagnosed by detailed history-taking on drugs and
the course of the eruptions. A patch test performed on the site
where an eruption has occurred is positive with high frequency; it
is diagnostically meaningful.
Treatment
The causative drug should be discontinued.
Fig. 10.2-2 Various types of drug eruption.
d, e: Urticarial drug eruptions. Edematous erythe-
2. Adverse drug reactions in skin that can ma resembling urticaria is seen on the trunk and
palms.
result in death
There are several specific clinical types of drug-induced skin Generalized bullous MEMO
reactions that may lead to death. Toxic epidermal necrolysis fixed drug eruption
Blistering may be present in some fixed drug
(TEN) has the highest mortality (30-35%); Stevens-Johnson syn- eruptions, and it may spread on the whole
drome and transitional forms correspond to the same syndrome, body surface, becoming severe. Generalized
but with less extensive skin detachment and a lower mortality (5- bullous fixed drug eruption may be catego-
rized with toxic epidermal necrolysis (TEN),
15%). which is described in the following section.
Hypersensitivity syndrome, sometimes called drug-induced

in hardcopy only.
a b c d a e b f c g d h e i f j g k h l i m j n k o l p m q n r o
Clinical images are available in hardcopy
only.
10 Clinical images are available

in hardcopy only.
b c d ae bf cg dh ei af j gk
b h
cl dim ejn kfo glp hq
m ni r oj p
k
Fig. 10.3 Fixed drug eruption (FDE).
a: Early FDE on the right eyelid. Early lesions are edematous erythema without pigmentation. b:
FDE on the abdomen. Repeated intake of the causative drug results in a severely pigmented FDE
lesion. c, d: FDE on the thigh. The center of the lesion shows characteristic pigmentation caused
by chronic inflammation. The periphery is erythematous, which suggests recent intake of the
causative drug. e: FDE on the interdigital area. Erythema and bullous lesions are seen.
hypersensitivity syndrome (DIHS) or drug reaction with

eosinophilia and systemic symptoms (DRESS), has a mortality of
about 10% or less.

1) Toxic epidermal necrolysis (TEN)
Synonym: Lyell’s syndrome

Toxic epidermal necrolysis (TEN) is one of the severest drug
eruptions. It is accompanied by fever, and erythema and blister-
ing on the whole body surface. It leads to marked epidermal
necrosis and exfoliation (Figs. 10.4-1 and 10.4-2). It is closely
related to Stevens-Johnson syndrome (SJS) (Fig. 10.5). TEN is
classified into several types according to the clinical course.
TEN developing from SJS: Most cases of TEN develop from
Clinical images are available in hardcopy only. SJS. Vaguely outlined, small, dark red edematous erythema
sparsely appear on the whole body and gradually spread. They
subsequently increase and form blisters and erosion. Typical pri-
mary lesions are characterized by so-called target lesions with
dusky centers. Severe erosion develops in the oral mucosa, and
systemic symptoms such as fever and fatigue are seen. SJS is
Fig. 10.4-1 Toxic epidermal necrolysis (TEN). characterized by the transformation of erythema into blistering
fixed drug
generalized TEN SJS EM
eruption
FDE
(FDE)
Fig. 10.5 The pathogenic association of fixed drug eruption (FDE),

toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome
(SJS) and erythema multiforme (EM).
and erosion with dark red patches at the periphery (Chapter 9). Fig. 10.4-2 Toxic epidermal necrolysis (TEN).
Rapid extensive type: This is the type that Lyell first reported.
Two to 3 days after intake of the causative drug, erythroderma
and extensive erosions occur on the whole body surface without
preceding macules, and the skin exfoliates easily; it is similar to a 10
large burn (second-degree). This type accounts for several per-
cent of all TEN cases (Fig. 10.6).
Pathogenesis
It is widely accepted that the cellular functions of cytotoxic T
cells are abnormally enhanced by certain drugs, including sulfa
drugs, penicillin, barbituric acids, aspirins, pyrazolone drugs, and
anticonvulsants, and epidermal necrosis and subepidermal sepa- Clinical images are available in hardcopy only.
ration occurs as a result. Fas-Fas ligands, which induce apoptosis
in epidermal cells, are thought be involved in the occurrence of
TEN.
Treatment
Use of the causative drug should be discontinued immediately.
Systemic glucocorticosteroids in high doses, including pulse ther-
apy, are widely known to be useful in the early stages of TEN, but
not in the late stage of the disease course. Intensive care with top-
a b c d e f g h
ical treatment and body fluid management similar to the patients
with burns are essential. Plasma exchange may be conducted, and
large doses of immunoglobulins may also be applied. The causative
drug must not be readministered.
2) Drug-induced hypersensitivity syndrome Clinical images are available in hardcopy only.
Synonyms: Drug hypersensitivity syndrome, Drug reaction

with eosinophilia and systemic symptoms (DRESS)
There is still controversy on the naming of this newly proposed

g
concept of the disease condition, but each different disease namea b c d e f h i
may indicate the same or similar condition which is induced by Fig. 10.6 Diffuse erythematous toxic epider-
mal necrolysis (Lyell's syndrome).
drug. Drug-induced hypersensitivity syndrome (DIHS) is proposed a: The causative drugs here are antituberculosis
by a group of Japanese dermatologists which holds that skin lesions drugs, which were used for tuberculosis associat-
are caused by a combination of drug allergy and reactivated latent ed with AIDS. Generalized shedding of the epi-
dermis on the whole body is seen. The dermis is
viral infection, specifically human herpes virus 6 (HHV 6) infec- pink where the skin exfoliates. b: Severe erosions
tion. Two to 6 weeks after administration of a specific drug, fever and ulcers in the oral region.
Table 10.3 Diagnostic criteria for drug-induced hypersensitivity

syndrome (DIHS).
1. Maculopapular rash develops more than 3 weeks after starting a certain
drugs.
2. Lymphadenopathy
3. Fever (>38˚C)
4. Leukocytosis (>10 × 109/L)
a. Atypical lymphocytosis
b. Eosinophilia
5. Hepatitis (ALT >100 U/L)
6. HHV-6 reactivation
The diagnosis is confirmed by the presence of five of the six criteria above.
(Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS):
a reaction induced by a complex interplay among herpes viruses and antivi-
ral and antidrug immune responses. Allergology International 2006; 55: 1-8).
and generalized maculopapular erythema occurs (Fig. 10.7), which

10 results in erythroderma in some cases. Enlargement of superficial
lymph nodes, liver dysfunction and hematological abnormalities
(leukocytosis, appearance of atypical lymphocytes, increase of
eosinophils) occur. There is also a report that suggests the
involvement of cytomegalovirus and human herpes virus (HHV-
7) in DIHS. The diagnostic criteria are listed in Table 10.3 (also
refer to Chapter 23 for viral infections).
Drug reaction with eosinophilia and systemic symptoms
(DRESS) is thought to be the same or similar syndrome, which is
mainly used by European dermatologists group. The important
point is that dermatologists should be aware of these systemic
drug-induced reactions in association with marked eruption, and
that routine laboratory examination is necessary when a drug
eruption is suspected.
Fig. 10.7 Drug-induced hypersensitivity
syndrome (DIHS). The treatements include systemic corticosteroid and termina-
tion of the causative drug.
B. GVHD and viral eruptions
1. Graft-versus-host disease (GVHD)
Outline
● After bone marrow transplantation, other organ trans-
plantation or transfusion, donor lymphocytes are stimu-
lated by major and/or minor histocompatibility locus
antigens and subsequently target host tissues for cyto-
toxic damage.
● The skin, intestinal tract and liver are the main affected
organs.
● In acute GVHD, erythematous macules occurs on the
palms and spread over the whole body. In chronic GVHD,

lichen-planus-like and scleroderma-like eruptions are
found.
B. GVHD and viral eruptions 133
Definition, Pathogenesis
When donor-derived blood cells circulate in the patient’s skin
after transplantation, the immunocompetent donor, T cells, may
recognize the foreign hosts histocompatibility locus antigens
(HLA). Subsequently, an immune reaction against the host’s
organs occurs. It may also be caused by general blood transfusions.
Classification
As shown in Table 10.4, graft-versus-host disease (GVHD) is
categorized by the onset. The skin, digestive tract and liver are
the main organs affected, and the symptoms are mainly seen in
those organs. Post-transfusion GVHD occurs about 10 days after
a transfusion and has a poor prognosis. Congenital GVHD occurs a b c d e f g h
after birth, and intractable dermatitis, diarrhea, opportunistic
infections, and disturbance in growth are caused by lymphocytes
transferred from the mother. 10
Clinical features
Acute GVHD: In most cases, 10 to 30 days after a graft, edema-
tous erythema appears on the extremities and trunk. It may be
accompanied by slight itching. In severe cases, the eruptions coa-
lesce and may develop into erythroderma, blistering or erosion
(Figs. 10.8-1 and 10.8-2). Symptoms of acute GVHD may Clinical images are available in hardcopy only.
remain longer even after the first 100 days or more after trans-
plantation, as a result of recent improvements in immunosuppres-
sive drugs.
Chronic GVHD: This includes lichenoid forms and scleroder-
moid forms. The lichenoid forms multiple purplish-red plaques
resembling lichen planus, and the sclerodermoid forms sclerotic
lesions resembling scleroderma.
The severity of GVHD is classified according to the severity
of the skin lesions and other organ disorders (Table 10.5). g
a b c d e f h i
Pathology
GVHD pathologically presents a lichenoid reaction. Intrader-
mal lymphocyte infiltration, necrosis of the epidermal cells, and
Table 10.4 Classification of graft-versus-host disease (GVHD). Clinical images are available in hardcopy only.
Duration after
Type of
transplantation/ Symptoms
GVHD
transfusion
Hyperacute 7 to 14 days Fever, diarrhea, erythrodermic skin erup-
tion, pulmonary edema, heart failure
a b c d e f g h i j
Acute Up to 100 days Triad (fever, diarrhea and liver dysfunction).
Poorly demarcated erythema seen on the Fig. 10.8-1 Acute graft-versus-host disease
face and palmoplantar area. In severe (GVHD).
cases, TEN and erythroderma. a: Diffuse erythema on the back after bone mar-
Chronic More than 100 Various skin lesions like those in collagen row transplantation. Differential diagnosis from
days diseases and lichen planus. Liver dysfunc- drug eruption is almost impossible clinically. b,
tion, oral symptoms, ocular symptoms. c: Severe acute GVHD. Severe exfoliation simi-
lar to toxic epidermal necrolysis is seen.
Transfusion- About 10 days Resemble those of hyperacute GVHD.
associated Prognosis is poor.
Table 10.5 Clinical staging and grading of GVHD.

Liver findings
Stage Skin findings Gut findings
(mg/dL bilirubin)
1 Maculopapular rash on 2 to 3 Diarrhea 500 to
<25% of body surface 1000 mL/d or
persistent nausea
2 Maculopapular rash on 25% 3 to 6 Diarrhea 1000 to
to 50% of body surface 1500 mL/d
3 Generalized erythroderma 6 to 15 Diarrhea >1500
Clinical images are available mL/d
in hardcopy only.
4 Desquamation and bullae >15 Severe abdominal
pain or ileus
Stage
Overall Grade
Skin Liver Gut Functional impairment
0 (None) 0 0 0 0
I (Mild) 1 to 2 0 0 0
10
II (Moderate) 1 to 3 1 1 1
c d e f g h i j k l
III (Severe) m n3
2 to 2oto 3 p2 to 3 q r 2
IV (Life-threatening) 2 to 4 2 to 4 2 to 4 3
(Adapted from; http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cmed6.table.
17337).
vacuolar degeneration of the basal cell layer are found (Chapter

2). The number of Langerhans cells decreases.
Clinical images are available GVHD needs to be differentiated from drug-induced skin reac-
in hardcopy only.
tions, eruptions of peripheral lymphocyte recovery accompany-
ing a graft (generally 10 to 14 days after transplant), and viral
infections.
Treatment
Immunosuppressants (cyclosporine, tacrolimus, azathioprine,
cyclophosphamide) and steroids are administered orally, Post-
transfusion GVHD can be prevented by irradiating the blood to
d e f g h i j k l m n o p q r
be transfused.
Fig. 10.8-2 Acute graft-versus-host disease
(GVHD).
d, e: Diffuse small erythema coalesce into red 2. Viral eruption
plaques.
When maculopapular erythema appear abruptly on the whole
body of a febrile patient who has been adiministered NSAIDs or
any other medicine for that condition, a drug reation or a viral
infection are the two most likely diagnoses. In those cases, differ-
entiation between drug-induced eruption and viral eruption is
often difficult, even with thorough examination. Drug-induced
hypersensitivity syndrome (DIHS) is thought to be caused by
causative drug as well as re-activation of latent viral infection.
Refer to Chapter 23 for details on viral infections.
Chapter
11 Vasculitis, Purpura and Other
Vascular Diseases
Vasculitis is divided into several types according to the diameter of the artery or vein at the principal site of
inflammation (Fig. 11.2). In cutaneous vasculitis, there is frequently purpura or ulceration. Purpura may be an
early sign of vasculitis.
Purpura is a general term for reddish-purple skin lesions produced by bleeding in the dermis or subcutaneous
tissues. It is classified by the size of bleeding into petechia (diameter up to 2 mm) or ecchymosis (diameter larg-
er than 2 mm). The major causative factors are ① vascular abnormality (from vasculitis or mechanical injury), ②
blood flow abnormality (e.g., hypergammaglobulinemia, which often accompanies a systemic disease), ③
decrease or functional abnormality of platelets, and ④ coagulopathy (e.g., DIC). However, the etiology is
unknown in many cases. This chapter discusses diseases with the symptoms listed above and diseases caused
by circulatory disorder of the arteries, veins and lymphatic vessels.
Vasculitis 11
A. Vasculitis in small vessels
1. Cutaneous small-vessel vasculitis (CSVV)

Synonyms: Leukocytoclastic vasculitis, Necrotizing vasculi-
tis, Allergic vasculitis, Cutaneous allergic vasculitis
Outline
● This is a group of diseases that are characterized by Clinical images are available in hardcopy only.
neutrophilic infiltration into the peripheral small dermal
blood vessels.
● Various clinical features, including erythema, purpura,
papules, blistering and ulceration, may be present,

depending on the depth and severity of the vasculitis.
● Henoch-Schönlein purpura is a variant of CSVV.
Definition Fig. 11.1 Cutaneous small-vessel vasculitis

(CSVV).
Cutaneous small-vessel vasculitis (CSVV) is a general term The skin lesion presents a mix of purpura,
for diseases that present pathological features of leukocytoclastic papules, nodules, pustules, blisters, erosion and
vasculitis, i.e., diseases with pathological perivascular neu- ulcers. It is accompanied by sharp pain.
trophilic infiltration and fibrinoid degeneration of the vascular
Allergic vasculitis, MEMO
walls (Fig. 11.1). Henoch-Schönlein purpura and urticarial vas-
Vasculitis allergica cutis (Ruiter)
culitis are included under a broad definition of CSVV; however, Cutaneous small-vessel vasculitis that occurs
they are usually treated as distinct diseases. In its more restricted mainly in the upper and middle dermal layers
sense, CSVV is considered to be a disease caused by small-vessel and is rarely accompanied by systemic symp-
toms is called allergic vasculitis. Although the
vasculitis in the dermis (in and between the middle and deep lay- term is frequently used in Japan, it is not
ers of the dermis). known internationally. For that reason, the
term allergic vasculitis is not used in this text-
Clinical features book. Instead, the term cutaneous small-ves-
sel vasculitis is used.
Purpura, urticaria, erythema-multiforme-like erythema,
135
136 11 Vasculitis, Purpura and Other Vascular Diseases
epidermis
dermis
A-1：cutaneous small-vessel
vasculitis (CSVV)
B A-2：Henoch-Schönlein
Clinical images are available in hardcopy only. purpura (HSP)
B-1：polyarteritis nodosa (PN)
B-2：allergic granulomatous
angiitis (AGA)
B--1
1 B-3：Wegener’s
subcutaneous
tissue granulomatosis
11 Fig. 11.2 Cutaneous vasculitis and the depth of the affected ves-
sels.
papules, nodules, pustules, blistering, erosion and ulceration

occur, mainly in the lower extremities (Figs. 11.3-1 and 11.3-2).
Nephritis, pulmonary infiltration, pleuritis, acute abdomen, cra-
Clinical images are available in hardcopy only. nial nerve symptoms, convulsive seizure, headache, myocarditis
and epicarditis may accompany CSVV.
Pathogenesis
An immune complex of an antigen (e.g., bacterium, virus,
drug) and the antibody against that antigen deposit on the arteri-
olovenular walls. These activate the immune system and cause
vasculitis (type III allergic reaction). Penicillin, sulfa drugs and
other drugs, chemical substances, hemolytic streptococcus bacte-
Clinical images are available in hardcopy only. ria, or viruses may be the foreign antigen. Collagen diseases and
antibodies against malignant tumors can also be causes.
Pathology
In the upper and middle dermal layer, fragments of nuclear
debris and leakage of erythrocytes are found in the peripheral
arteriola. Neutrophilic infiltration occurs in the arteriolovenous
small blood vessels and capillaries. Thickening of the blood ves-
sel walls and fibrinoid degeneration are also found in many cases
(Fig. 11.4).
Palpable purpura, Non-palpable purpura MEMO

When diagnosing purpura, it is important to distinguish between purpu-
ra caused by vasculitis and purpura caused by other factors (e.g.,
thrombocytopenia, capillary fragility). Purpura caused by vasculitis
Fig. 11.3-1 Cutaneous small-vessel vasculi- tends to be accompanied by palpable infiltration (palpable purpura),
tis (CSVV). whereas in purpura caused by factors other than vasculitis, infiltration
The disease presents various cutaneous clinical is not usually present. However, infiltration is impalpable in mild vas-
features including purpura, erythema, bloody culitis.
blisters and ecchymosis.
Vasculitis / A. Vasculitis in small vessels 137
Laboratory findings
Elevated erythrocyte sedimentation rate, increase of leukocytes
and hypergammaglobulinemia may occur. The serum comple-
ment titer often decreases. Tests for immune complex are some- Clinical images are Clinical images are
times positive. When CSVV immunocomplex is accompanied by available in available in
systemic symptoms, renal lesion tends to occur, and proteinuria hardcopy only. hardcopy only.
and hematuria are found.
Diagnosis
CSVV is diagnosed by skin biopsy. Since there are many dis-
eases that cause CSVV, special care should be taken in diagnosis.
When the cause is a drug or infection, those should be Clinical images are Clinical images are
available in available in
removed. For a lesion in the lower extremities, the legs should be hardcopy only. hardcopy only.
raised and kept warm and the patient should get bed rest. Oral
application of NSAIDs and DDS (dapsone) is effective in reliev-
ing symptoms. Systemic corticosteroid therapy and immunosup- 11
pressants are useful for severe cases with systemic symptoms.
Fig. 11.3-2 Cutaneous small-vessel vasculi-
tis (CSVV).
2. Henoch-Schönlein purpura (HSP) It presents various cutaneous clinical features
from palpable purpura to deep ulcers, depending
Synonym: Anaphylactoid purpura on the depth of the affected vessels.
Outline
● It is a specific type of cutaneous small-vessel vasculitis.
● The cause is IgA immune complex deposition on the
vascular walls. HSP is a type III allergy.
● It is a leukocytoclastic vasculitis in which there are scat-
tered nuclear fragments (nuclear dust), mainly in the

subpapillary vessels of the dermal upper layer.
● Arthritic symptoms, abdominal pain, and renal symptoms
occur.
● Bed rest and systemic steroid administration are the
major treatments.
Definition
Multiple palpable purpura occur mostly in the lower legs, and
they are accompanied by arthralgia, digestive disorder and kid-
ney disorder. Henoch-Schönlein purpura (HSP) is in the patho-
logical category of cutaneous small-vessel vasculitis (CSVV);
however, it is localized in the dermal upper layer, and there is
IgA deposition on the vascular walls.
Fibrinoid degeneration MEMO Fig. 11.4 Histopathology of cutaneous

This is deposition of eosinophilic amorphous material on the vascular small-vessel vasculitis (CSVV).
wall, and it appears in the early stages of vasculitis; the immunocom- Fibrinoid necrosis of the vessel walls in the upper
plex may be identified by fibrinoid degeneration (Fig. 11.4). dermis, hemorrhage with neutrophils, and
nuclear dust (arrows) are present.

The most severely affected organs and locations are the skin,
joints, digestive organs, and kidneys. Although children are most
commonly affected, HSP may also occur in adults. It may be pre-
ceded by a headache, pharyngeal pain, and symptoms of the
common cold. Disseminated palpable purpura of several millime-
in hardcopy only. ters to 10 mm in diameter occur, mainly in the lower extremities
and dorsum of the foot, but sometimes on the thighs, upper
extremities, and abdomen (Fig. 11.5). Blisters, ulcers, and old
and new eruptions may be present together. In some cases there
is transient edema with slight pressure pain. Arthritic symptoms
in the legs, knees, hands and elbows, sharp pain in the abdomen,
and gastrointestinal symptoms such as nausea, vomiting,
hematemesis, and melena are found. HSP may be accompanied
by renal symptoms including acute nephritis that progresses to
nephrosis. Renal symptoms are closely related to the prognosis.
11 Pathogenesis
In children, the onset is mostly after upper respiratory infec-
tion; association with hemolytic streptococcus has been pointed
Clinical images are available out. Drugs (penicillin, aspirin) and certain kinds of foods (milk,
in hardcopy only. eggs) are known to be antigens. These antigens combine with
antibodies (mainly IgA) in the body, and the immunocomplex
deposits on the vascular walls. Immunoreaction is induced to
cause vasculitis and purpura.
Pathology
Leukocytoclastic vasculitis accompanied by fibrinoid degener-
ation is seen on the vascular walls in the upper dermal layer. IgA
deposition is observed by direct immunofluorescence (Fig. 11.6).
The histology of the kidney in HSP patients often shows crescen-
tic glomerulonephritis.
Laboratory findings
Clinical images are available in hardcopy only. When HSP is caused by hemolytic streptococcal infection,
antistreptolysin O and antistreptokinase values increase. In half
of the patients, serum coagulation factor XIII decreases. In cases
with renal lesion, hematuria and proteinuria occur.
When the purpura described above occurs in youth, HSP is
suspected. History-taking should inquire into not only HSP but
also other diseases before examinations and histopathological
tests are conducted. It is necessary to differentiate HSP from
other purpura, polyarteritis nodosa, Goodpasture syndrome,
nephritis after infection caused by hemolytic streptococcus, and
systemic lupus erythematosus (SLE). In adults, differential diag-
nosis from polyarteritis nodosa is important.
Fig. 11.5 Henoch-Schönlein purpura.
Palpable purpura may be accompanied by bloody Treatment
blisters in some cases. Bed rest is the first-line treatment, followed by the administra-
Vasculitis / A. Vasculitis in small vessels 139
tion of a vessel-strengthening drug and hemostatics, and systemic

administration of steroids. When the disease is caused by
hemolytic streptococcus, antibiotics are used. Administration of
factor XIII may be effective.
Prognosis
HSP generally has a good prognosis and resolves within sever-
al weeks in most cases; however, it may recur. Serious complica-
tions may occur in other organs, such as nephritis with IgA
deposition in the mesangium area, enterorrhagia, intussusception, Fig. 11.6 Direct immunofluorescence of
intestinal perforation, or cerebral hemorrhage. Henoch-Schönlein purpura.
IgA deposition on the vascular wall in the upper
dermis is observed.
3. Urticarial vasculitis
When an urticarial eruption remains for more than 24 hours
with purpura, urticarial vasculitis is suspected. It may be accom-
panied by systemic symptoms such as fever and a decrease in
complement titer (Chapter 8). 11
4. Erythema elevatum diutinum (EED)
Erythema elevatum diutinum (EED) frequently occurs in men
and women of middle age and older. It is a skin lesion that is accom-
panied by symmetrical infiltration on the extensor surface of elbows
and knees. Although the pathogenesis is unknown, an immune reac-
Fig. 11.7 Erythema elevatum diutinum.
tion caused by deposition of immune complex in the blood ves- A specific type of erythema elevatum diutinum
sels is thought to be involved. Appearing as soft, slightly elevated, produces not only erythema but also vesicles.
purplish-red erythema at first, the eruptions gradually become
fibrotic and keloidal. There is an atypical type with blistering
(Fig. 11.7). Leukocytoclastic vasculitis occurs in the dermis. It is
nearly asymptomatic, however, it recurs repeatedly and persistently.
Oral ulcer, arthritis, lung fibrosis, IgA myeloma, and viral infec-
tion may accompany EED. DDS is an effective treatment.
5. Granuloma faciale
Granuloma faciale, a soft, infiltrative, reddish-brown plaque
with a sharp margin, occurs on the face. It is known to be a
chronic leukocytoclastic vasculitis. Deposition of immunoglobu-
lins on the vascular walls has been reported, from which the pos-
sibility of an immunoreaction resembling that of EED has been
pointed out. Granuloma faciale is intractable. Liquid nitrogen
cryotherapy, local injection of steroids, and dye laser treatment
have been used in recent years.
B. Vasculitis in medium-size and large arteries
1. Polyarteritis nodosa (PN)

Synonym: Periarteritis nodosa
Outline
Clinical images are available in hardcopy only. ● Itaffects muscular arteries the most severely. PN is clas-
sified into cutaneous (only the skin is affected), systemic
(systemic symptoms occur), and microscopic (renal
symptoms caused by affected arteries occur, and respi-
ratory symptoms occur).
● Histopathologically, it is
a b c d e f g h i j k l leukocytoclastic
m n ovasculitis
p inq r
small and medium-size arteries.
● Cutaneous findings include subcutaneous nodules, live-
11 do reticularis, and erythematous ulceration.

Polyarteritis nodosa (PN) most frequently occurs in men and
women in their 30s to 60s. There are no significant differences in
Clinical images are available cutaneous manifestations between systemic PN and cutaneous
in hardcopy only.
PN, and cutaneous symptoms are seen in 10% to 60% of sys-
temic PN cases. Palpable subcutaneous nodules of 1 cm to 2 cm
in diameter, purpura, livedo and ulceration occur mainly parallel
to the superficial arteries (Fig. 11.8). Tenderness may be present.
PN becomes chronic with repeated recurrences and regressions.
Urticaria and transient erythema may also occur. Livedo reticu-
a b c d e f g h laris
i (livedo
j racemosa)
k l is commonly
m nfound. o p q r
Systemic PN may be accompanied by fever, fatigue, weight
loss, arthralgia, and visceral symptoms such as renal failure, car-
diac infarction, cardiac failure, pericarditis, high blood pressure,
abdominal pain, neuritis and myalgia. The kidneys are the most
commonly affected organs, and death from renal failure is possi-
ble. Patients with microscopic PN may develop acute progressive
nephritis, interstitial pneumonia, and pulmonary hemorrhage.
The disease is highly associated with MPO-ANCA.
Pathogenesis
The etiology is unknown. The hepatitis B virus, bacterial
infectious diseases (e.g., streptococcus), and drug hypersensitivi-
ty are known to precede or induce PN.
Pathology
PN is leukocytoclastic vasculitis that is accompanied by
swelling in the tunica media of small and medium-sized arterial
b c d e f g h i j k l degeneration,
m p
nand neutrophilic
o q r
walls, fibrinoid cellular infiltration
Fig. 11.8 Polyarteritis nodosa. (Fig. 11.9). As PN progresses, thromboembolism, aneurysm and
a: Nodules with palpable, severe infiltration. b:
Coalesced purpura. c: Advanced polyarteritis
bleeding occur, leading to the formation of epithelioid cell granu-
nodosa accompanied by ulceration. loma. In cutaneous PN, these symptoms occur in the arteries in
Vasculitis / B. Vasculitis in medium-size and large arteries 141
the deep dermal layer and subcutaneous fat tissue. Lesions occur
in almost all the nutrient arteries in systemic PN; nevertheless,
the lungs are rarely affected. The thickness of the blood vessels
and the depth from the skin surface for PN and other vasculitises
are compared in Fig. 11.2.
Laboratory findings
Immune complex deposition may be found in the area with
eruptions. ANCA is generally positive in microscopic PN.
Aneurysm is frequently observed by angiography.
Diagnosis
PN is diagnosed by the clinical features, laboratory findings
and skin biopsy. It is necessary to differentiate it from systemic
lupus erythematosus (SLE), cutaneous small-vessel vasculitis,
erythema nodosum, erythema induratum and cryoglobulinemia.
Treatment 11
Cutaneous PN with mild clinical severity is treated by bed rest
with the lower extremities raised, and administration of vasodila-
tors, NSAIDs and DDS. Steroids are temporarily administered
orally during acute aggravation. For systemic PN, steroids and
immunosuppressive drugs are necessary in high doses.
Prognosis
Cutaneous PN has a good prognosis. The eruptions heal in sev-
eral weeks; however, they are persistent and recur for years. In Fig. 11.9 Histopathology of polyarteritis
nodosa.
contrast, the prognosis of systemic PN is poor, because of various Thickened vessel walls of medium-sized arteries,
internal-organ disorders (e.g., renal failure, intracranial hemor- fibrinoid degeneration, and leukocytoclastic vas-
rhage, cardiac infarction). culitis are accompanied by neutrophilic infiltration.
2. Allergic granulomatous angiitis (AGA)

Synonym: Churg-Strauss syndrome
Outline
● AGA is a vasculitis syndrome. Allergic symptoms such
as asthma, fever, and increase of eosinophils and IgE
precede AGA.
● Necrotizing vasculitis in small and medium-sized arteries Clinical images are available in hardcopy only.
and the formation of granuloma are the primary dis-

eases.
● Interstitial pneumonia and lung granuloma occur.
● P-ANCA is positive.
● Oral or pulse administration of steroids is the main treat-
ment.
Clinical features, Differential diagnosis

In most cases intractable bronchitis and other allergic diseases
Fig. 11.10 Allergic granulomatous angiitis.
occur for several months to several years before the onset of Infiltrative subcutaneous nodules, purpura and
allergic granulomatous angiitis (AGA) (Fig. 11.10). Infiltrated erythema.
Table 11.1 Main clinical symptoms and find- subcutaneous nodules, purpura and erythema frequently appear.
ings of Churg-Strauss syndrome (based
on classification criteria proposed by the Peripheral nerve disorder (usually mononeuropathy multiplex)
American College of Rheumatology). and gastrointestinal lesions are also found. Lung involvement is
Symptoms and
common; migrating polymorphic interstitial pneumonia resem-
Details bling Löffler syndrome is observed by chest X-ray. In compari-
findings
Bronchial Expiratory wheezing or son with PN, prodromes are common and renal dysfunction is
asthma high-pitched rales rare in AGA. The typical symptoms of AGA are summarized in
Eosinophilia Eosinophils accounting for 10% Table 11.1.
or more of the fraction of
peripheral leukocytes Pathology
Neuropathy, Numbness accompanied by In AGA, as in PN, there is leukocytoclastic vasculitis in small
mono or poly pain, with glove-stocking
distribution and medium-sized arteries and small veins. Granuloma occurs in
Pulmonary Migrating or transient pulmonary
the vascular or perivascular walls, and there is marked
infiltrates, infiltration (X-ray) eosinophilic infiltrate in the tissue.
non-fixed
Paranasal sinus Sharp pain or tenderness in Laboratory findings
abnormality paranasal sinus, or abnormal Notable increase of leukocytes, eosinophils and serum IgE are
11 findings in X-ray
seen. The patient often tests positive for P-ANCA (MPO-
Extravascular Extravascular eosinophils in the ANCA), a kind of anti-neutrophil cytoplasmic antibody (ANCA).
eosinophils skin and lung, observed
pathologically
Treatment
（Adapted from; http://www.rheumatology.org/publi-
cations/classification/churg.asp?aud=mem）. With systemic high-dose application of steroids in the early
stages, AGA subsides in a relatively short time. Their use in
combination with immunosuppressants is recommended in
intractable cases.
3. Wegener’s granulomatosis
Outline
● This rare vasculitis syndrome is preceded by upper res-
piratory symptoms such as paranasal sinusitis. It is
accompanied by fever and systemic fatigue.
● Leukocytoclastic vasculitis and granuloma are found in
the upper respiratory tract, lungs and kidneys.

● Cutaneous symptoms are the same as in PN.
● C-ANCA is positive. Multiple lung lesions are observed
by chest X-ray.
● The prognosis is improved by combined use of steroids
and cyclophosphamide.

Wegener’s granulomatosis most commonly occurs in men and
women between the ages of about 25 and 55 years. Necrotizing
granuloma lesions in the upper and lower respiratory tracts cause
foul-smelling rhinorrhea, mucosal erosion in the upper respirato-
ry tract, nasal hemorrhage, paranasal sinusitis, ocular proptosis,
hemosputum and breathing disruption. As the lesions progress,
saddle nose may be caused. The lesion gradually spreads to the
kidneys, leading to rapidly progressive renal failure.
Cutaneous symptoms are found in approximately half of all
Vasculitis / B. Vasculitis in medium-size and large arteries 143
cases. Various eruptions, such as gangrenous papules, blisters,

erythema, purpura, pustules, nodules and ulcers, are produced
symmetrically in the extremities and buttocks. In the early stages,
a skin lesion resembling pyoderma gangrenosum may be found;
it may be useful for early diagnosis (Fig. 11.11).
Pathogenesis
The etiology of Wegener’s granulomatosis is unknown; how-
ever, an autoimmune mechanism is suspected. Autoantibodies
called C-ANCA (PR3-ANCA), which are anti-neutrophil cyto-
plasmic autoantibodies, are thought to activate neutrophils and
monocytes, causing Wegener’s granulomatosis.
Pathology
Leukocytoclastic vasculitis in the upper dermal layer and gran-
uloma formation in the periphery are found. g
a b c d e f h
Laboratory findings 11
Elevated erythrocyte sedimentation rate, increases in leuko-
cytes and platelets, and elevated levels of human immunoglobu-
lins are found. Skull fracture may be observed by head X-ray. In
a chest X-ray, there is shading that closely resembles that of pul-
monary tuberculosis and pulmonary metastatic tumor, and cavi-
tary circular shading with a thin wall is seen in 30% to 50% of
cases. C-ANCA is useful for diagnosis as a specific antibody and
is associated with disease severity. The antibody titer decreases
during the course of successful treatment.
Differential findings
It is necessary to differentiate Wegener’s granulomatosis from
sarcoidosis, lymphoma, Goodpasture syndrome, malignant
g
tumor, PN, AGA and cutaneous small-vessel vasculitis. Diagno-a b c d e f h i
sis follows the diagnostic criteria of the American College of Fig. 11.11 Wegener’s granulomatosis.
a: Necrotic papules. b: Ulceration in the oral cav-
Rheumatology (Table 11.2). ity.
Systemic steroids and immunosuppressants (cyclophos-
phamide in particular) are used. Wegener’s granulomatosis was
once regarded as having a poor prognosis and usually leading to
death from renal failure or other disorder within a year after
onset. Currently, it may subside as long as it is treated in the
early stages.
4. Temporal arteritis (TA)

Synonym: Giant-cell arteritis
Outline
● TA is a vasculitis syndrome. The superficial temporal
arteries and ophthalmic arteries are affected.
● It occurs in elderly women. The typical symptoms are
Table 11.2 Criteria for the classification of unexplained fever, throbbing headache, and visual
Wegener’s granulomatosis.
impairment.
1. Nasal or oral inflammation ● Cord-like induration occurs in the temporal region, and
Development of painful or painless oral muscular pain develops (polymyalgia rheumatica).
ulcers or purulent or bloody nasal discharge
● Oral steroids are the main treatment.
2. Abnormal chest radiograph
Chest radiograph showing the presence of Clinical features, Pathogenesis
nodules, fixed infiltrates, or cavities
Temporal arteritis (TA) most frequently occurs in persons over
3. Urinary sediment
age 50, with a ratio of 1 male to 3 females. Temporal arteries are
Microhematuria (>5 red blood cells per high mainly affected. Cord-like thickening of the temporal arteries,
power field) or red cell casts in urine sedi-
ment reddening, pain and swelling are present. Throbbing headache,
4. Granulomatous inflammation on biopsy
difficulty of opening the mouth, blistering, ulceration, necrosis in
the scalp, and hair loss occur. When the lingual artery is affected,
Histologic changes showing granulomatous
inflammation within the wall of an artery or in the tongue becomes red, swollen and erosive. When the oph-
the perivascular or extravascular area thalmic artery is affected, visual impairment results, with blind-
(artery or arteriole) ness following in 10% of cases. A temporary visual disorder
For purposes of classification, a patient shall be (amaurosis fugax) may also occur. When an artery in the brain is
11 said to have Wegener’s granulomatosis if at least 2 affected, bulbar palsy and dementia occur as well.
of these 4 criteria are present.
(Leavitt RY, et al. The American College of Rheuma- The pathogenesis of TA is unknown; however, the involve-
tology 1990 criteria for the classification of ment of viral or bacterial infection, or drug allergy is suspected.
Wegener’s granulomatosis. Arthritis Rheum 1990; Since HLA-DR4 is associated with TA, genetic factors may be
33: 1101-7).
involved in the occurrence of TA.
Laboratory findings
Elevated erythrocyte sedimentation rate and increased CRP are
observed. Autoantibodies are absent. The serum complement titer
and myogenic enzyme are normal. By biopsy, TA appears as
granulomatous inflammation accompanied by cellular infiltrate
mainly caused by mononuclear cells and production of giant
cells.
Treatment
To prevent visual impairment, steroids are used systemically in
the early stages of TA. If the symptoms subside, the medication
may be discontinued.
C. Other diseases related to vasculitis in small and medium-sized blood vessels
1. Behçet’s disease
Outline
● Recurrent oral aphtha, eye symptoms (uveitis), ulcera-
tion in the genitalia, and cutaneous symptoms (erythe- Clinical images are available in hardcopy only.
ma-nodosum-like eruptions) typically occur.

● Behçet’s disease is an inflammatory disease with an
unknown cause. It occurs mostly in middle-aged men.

Severe thrombophlebitis is induced.
● A distinct, severe clinical type that involves nerves, intes- a b c d e f g h
tines and blood vessels has been reported.
● Its occurrence correlates highly with HLA-B51. It occurs
more frequently in ethnic Japanese than in people of 11

other ethnicities.
● Needle reaction test is positive.
● Administration of colchicines and immunosuppressants
are the main treatments.
Clinical features
Behçet’s disease first manifests in men and women in their 20sa b c d e f g h i
and progresses over a long period of time (Figs. 11.12-1 to Fig. 11.12-1 Behçet’s disease.
11.12-3). It occurs slightly more frequently in ethnic Japanese a, b: Recurrent aphtha in the oral cavity accom-
than in Caucasians, and in men more than women. The typical panied by sharp pain.
cutaneous symptoms are ① erythema-nodosum-like eruptions,
② thrombophlebitis, and ③ folliculitis and acne-like eruptions.
The erythema-nodosum-like eruptions most commonly occur in
the lower extremities and forearms and are accompanied by pres-
sure pain. They subside in about 1 week; however, they tend to
recur. Thrombophlebitis appears as palpable painful subcuta-
neous linear cord in the extremities, and it often migrates. Folli-
culitis and acne-like eruptions produce multiple follicular sterile
pustules; they are presumably caused by increased irritability,
and they produce a pustule where a needle has been inserted, 24
to 48 hours after insertion (needle reaction test).
The disease is also characterized by ulceration in the genitalia.
Deep ulcers with sharp margins form in the scrotum in men and
in the labia majora and minora in women. These are painful, and
they leave scarring when they heal. Aphthae in the oral mucosa
form sharply margined ulcers that are persistently painful. They
heal in about 10 days and then recur. More than 60% of patients
with Behçet’s disease experience oral aphtha as an early symp-
tom; this has diagnostic significance.
In addition, uveitis accompanied by hypopyon often occurs;
there is a high risk of blindness. Fever, fatigue, arthritic symp-
toms, gastrointestinal symptoms (in the ileocecal region, in par-
ticular), epididymitis, vasculitis symptoms, and central nervous
Human-leukocyte- MEMO system damage may also occur.

antigen (HLA) complex
This is known to be a gene cluster that influ- Pathogenesis
ences histocompatibility and is involved in The primary disease is thought to involve increased neutrophil
the strength of immunoreaction. It is thought
to have a strong association with autoimmune activity; however, vasculitis plays a central role. Behçet’s disease
and other diseases (Chapter 3). is strongly correlated with the HLA-B51 allele, and abnormality
in immunity is known to be associated with the occurrence of the
disease. The involvement of bacterial allergy (especially
hemolytic streptococcus) is suggested as an initiating factor.
Antiphospholipid antibodies and autoimmunity are thought to be
involved in the formation of thrombi.
Pathology
In erythema-nodosum-like eruptions, neutrophilic or lympho-
cytic cellular infiltration is found in the peripheral blood vessels
Clinical images are available in hardcopy only. in the deep dermal layer and subcutaneous fat tissues (septal pan-
niculitis). Unlike in erythema nodosum, vasculitis may be found.
11 In thrombophlebitis, thrombus tends to occur in the small veins
of the subcutaneous fat tissues.
Laboratory findings
Needle reaction test is positive in 70% of cases, from enhanced
b c d e f g h i j
irritability
k of the
l skin.m Positive
n HLA-B51
o pis alsoq an important
r
finding in diagnosing Behçet’s disease. Increased erythrocyte
sedimentation rate, positive CRP, increased immunoglobulins,
and leukocytosis (particularly neutrophilic) are seen from inflam-
mation. When the disease progresses, complement activity
increases.
Clinical images are available in hardcopy only. Diagnosis

Criteria for diagnosis of Behçet’s disease have been made by
Health and Welfare Ministry of Japan (Table 11.3). When the
four typical symptoms present during the course of the disease, it
is called complete Behçet’s. In recent years, complete Behçet’s
has rarely been seen; in incomplete Behçet’s there are three main
c d e f g h i j symptoms
k l or m
a combination
n o of eye
p symptoms
q and
r one main
Fig. 11.12-2 Behçet’s disease. symptom.
c, d: Deep ulceration in the genitalia.
Treatment
Specific and severe types of Behçet’s disease and ocular symp-
toms, if any, are given priority in any treatment. When
colchicines, which inhibit neutrophils and NSAIDs, are ineffec-
tive, immunosuppressants (cyclosporine A, tacrolimus) are use-
ful. Anticoagulation therapy is performed on thrombosis.
Vasculitis / C. Other diseases related to vasculitis in small and medium-sized blood vessels 147
2. Kawasaki disease
Synonyms: Mucocutaneous lymph node syndrome (MCLS),
Acute febrile mucocutaneous lymph node syndrome
Outline
● The etiology is unknown. Kawasaki disease has six char-
acteristics: 1 fever continues for more than 5 days, 2 Clinical images are available in hardcopy only.
edema, erythema and scaling occur in the distal fingers

and toes, 3 eruptions of various shapes appear on the
trunk, 4 hyperemia occurs in the bulbar conjunctivae, 5
reddening in the lips and oral cavity, flush, and strawber-
ry tongue are present, and 6 non-purulent lymph nodes
enlarge.
● It is most common in children age 4a and underb c g j
(80% ofd e f h i k l
cases).
● Aspirin and human immunoglobulins are the main treat-
ments. 11
a b c d e f g h i j k l m
Clinical features
Kawasaki disease occurs in 3 boys for every 2 girls. Pro-
dromes are not present. It begins with a fever of about 39 ℃. Clinical images are available in hardcopy only.
Sharply margined erythema occurs in the fingers and toes. Red-
dening or blistering at the site of BCG immunization appears.
Shortly after that, irregular aeruptions
b occur c on thed wholee body.f g h i j k l m n
The eruptions are mainly erythema, followed in frequency by Fig. 11.12-3 Behçet’s disease.
urticaria and by scarlet-fever-like or rubella-like eruptions in some e: Nodular erythema-like eruptions. f: Folliculi-
tis-like eruptions. g: Folliculitis-like eruptions.
cases. So-called strawberry tongue is present. The distinctive facial
features of strawberry tongue, and eruptions and firm edema on the
hands and soles are seen 3 to 5 days after the onset of Kawasaki
disease. Non-purulent cervical lymphadenopathy also occurs at
this time. Scaling occurs in the tips of the fingers and toes 10 to
15 days after onset (Fig. 11.13). Joint pain and swelling, and nail Clinical images are available in hardcopy only.
deformation are found. Myocarditis, pericarditis and coronary
vasculitis occur as complications in 70% to 80% of all cases.
Pathogenesis
It is unknown. There is a theory that superantigens of hemoly- Fig. 11.13 Kawasaki disease.
tic streptococcus and chlamydia infection are involved. Firm edema and scaling in characteristic pattern.
Laboratory findings
In the peripheral blood, leukocytosis (increase in neutrophils
and platelets, and left shift of white blood cells), platelet increase,
elevated erythrocyte sedimentation rate, positive CRP, and
increased a-2 microglobulins are seen. These findings are help-
ful for early diagnosis.
Diagnosis
Children with a persistent high fever that does not respond to
antibiotics may have Kawasaki disease. The diagnostic criteria
are those of the Kawasaki disease Research Group of the Health
Table 11.3 Diagnostic criteria of Behçet’s and Welfare Ministry of Japan.

disease.
1. Major symptoms Treatment
1 Recurrent aphthous ulceration in the oral
mucosa Aspirin is administered orally, to prevent thrombus. Human
2 Cutaneous symptoms immunoglobulin preparations given in large doses are effective
(a) Erythema-nodosum-like skin lesions in shrinking coronary artery aneurysm in the early stages (less
(b) Subcutaneous thrombophlebitis
(c) Folliculitis-like eruptions, acne-like
than 7 days after onset).
eruptions; helpful finding: enhanced
sensitivity of skin
3 Ocular symptoms 3. Pyoderma gangrenosum
(a) Iridocyclitis
(b) Retinouveitis (chorioretinitis)
(c) Symptoms that suggest past occurrence Outline
of (a) and (b), such as posterior synechia ● Small pustules and papules rapidly appear to form ulcers
of the iris, pigmentation on the lens,
chorioretinal atrophy, optic atrophy, with an elevated edge. These mostly occur in the lower
complicated cataract, secondary body.
glaucoma, or phthisis of the eyeballs ● The etiology is unknown. It is frequently associated with
4 Genital ulceration
2. Minor symptoms
primary diseases such as chronic ulcerative colitis, aorti-
11 1 Arthritis that is not accompanied by articular tis syndrome and leukemia.
deformity or rigidity, 2 Epididymitis, 3 ● Steroids and oral DDS are the main treatments.
Gastrointestinal lesions such as ileocecal
ulcer, 4 Vascular lesions, 5 Moderate or Clinical features
severe central nervous symptoms
3. Diagnostic criteria for types of Behçet’s disease Pyoderma gangrenosum occurs most commonly in the extrem-
1 Complete Behçet’s disease ities, lumbar region, and abdomen of women from about age 10
4 major symptoms during the course of the to 60. The eruptions progress through four stages. In the first
disease
2 Incomplete Behçet’s disease
stage, blisters, pustules, and small hemorrhagic papules occur. In
(a) 3 major symptoms, or 2 major symptoms the second stage, many of them coalesce into ulcers that enlarge
in combination with 2 minor symptoms centrifugally. The periphery of the ulcer is elevated in a river-
(b) A typical ocular symptom in combination bank shape. The ulcers have undermined edges and are accompa-
with another major symptom, or a typical
ocular symptom in combination with 2 nied by palpable infiltration. The bottom of the ulcer contains
minor symptoms brownish-yellow necrotic substances with mulberry pigmentation
3 Possible Behçet’s disease at the periphery. The ulcer is painful and secretes pus when
1 or more major symptoms that do not meet
the criteria for incomplete Behçet’s disease, pressed (Fig. 11.14). In the third stage, the center of the ulcer
and recurrence or aggravation of typical begins to heal and papillary granulation proliferates. In the fourth
minor symptoms. stage, the ulcer heals with scarring. The scars have the surface
4 Rare symptoms of Behçet’s disease
(a) Gastrointestinal Behçet’s disease:
roughness of fabric. These eruptions recur chronically in a cycle
Abdominal pain should be investigated, of several months.
and occult blood test should be conducted.
(b) Vascular Behçet’s disease: Impairment in Pathogenesis
large arteries, small arteries, or both large
and small veins is noted. One theory is that vasculitis is the cause, with autoimmune
(c) Neuro Behçet’s disease: headache, response as the etiology. Another is that bacterial allergy is the
paralysis, and encephalomyelopathy. cause. However, no definite cause has been identified. Injury,
Investigation should be made for
neurological symptoms. bruise, or skin biopsy may also induce pyoderma gangrenosum.
4. Helpful laboratory findings (not essential for
diagnosis) Pathology
(1) Needle reaction of skin: negative/positive Nonspecific neutrophilic infiltration and fibrin deposition are
(2) Skin prick testing (SPT) using Streptococcus
vaccine: negative/positive the major findings of pyoderma gangrenosum. Since necrotic
(3) Inflammatory response (enhanced ESR, vasculitis is not seen, it is thought that vasculitis is not involved.
serum CRP positive, increased WBC, and
elevated complement titer） Complications
(4) HLA-B51(B5) positive
From the Japan Intractable Diseases Information
Aortitis syndrome, ulcerative colitis, rheumatoid arthritis,
Center (http://www.nanbyou.or.jp/top.html). leukemia, Crohn’s disease or IgA deficiency may appear as a
complication. In pyoderma gangrenosum, various complications

develop in 75% of cases.

There are few specific diagnostic findings. As a result of
inflammation, CRP is positive, the erythrocyte sedimentation rate Clinical images are available in hardcopy only.
is elevated, and there is an elevated level of neutrophils. As pyo-

derma gangrenosum is sterile pyoderma, bacteria are not detected
in the lesions. Nevertheless, various bacteria are released by sec-
ondary infection during the course of pyoderma gangrenosum.
a b c d e f g h
Therefore, it is diagnosed by clinical features and complications.
If pyoderma gangrenosum is suspected, there should be a thor-
ough investigation for complications.
Treatment
Systemic administration of steroids and DDS are the main Clinical images are available in hardcopy only.
treatments. Pulse therapies of steroids or cyclophosphamide, and
cyclosporine are administered in intractable cases. 11
4. Buerger’s disease a b c d e f g h i
Synonym: Thromboangiitis obliterans (TAO)
Clinical features
Buerger’s disease most commonly occurs in male smokers in
their 20s or older. It is caused by arterial obstruction and contrac-
tion of small arteries, and contractive ischemia. At onset, Ray-
naud’s phenomenon appears; that is, the skin color changes from
white to purplish blue or red and sharp pain occurs in distal fingers Clinical images are available in hardcopy only.
and toes, cool sensation in fingers occur, and cyanosis is observed.
Over time, a minor injury may trigger ulceration in the fingers,
toes and peripheral nails. When a relatively large artery in the
extremities is affected, weakened arterial pulse, intermittent clau-
dication, and pain during rest may occur. It is accompanied by
migrating thrombophlebitis in 20% to 30% of cases (Fig. 11.15).
a b c d e f g h i j
Pathogenesis
Most patients with Buerger’s disease are male smokers; the
disease is strongly associated with cigarette smoking.
Laboratory findings
Multiple segmental blockages are found in the main peripheral
arteries of the lower extremities (popliteal arteries) by arteriogra-
phy.
Pathology a b c d e f g h i j k
Thickening and inflammation are seen in the tunica intima of Fig. 11.14 Pyoderma gangrenosum.
arterial walls in the medium-sized and large arteries. According- a: Ulcer with inflammation is seen (2nd stage). b:
ly, stenosis and blockage are caused by thrombosis. Necrotizing These ulcers are replaced by blood crusts and
granulomatous tissue (3rd stage). c. The lesions
of the vascular walls does not occur. heal with scarring (4th stage). d: 4th stage (scar-
ring stage).
Differentiation from arteriosclerosis obliterans is important. In
general, Buerger’s disease is differentiated by the age of onset,
sex and other factors (Table 11.4).
Treatment
Smoking should be discontinued immediately. It is important
to keep the body warm, to maintain blood circulation in the
affected sites, and to avoid external injury. Vasodilators, antico-
agulants, and prostaglandins are administered. Revascularization
or sympathetic nerve block is performed as a surgical treatment.
5. Mondor disease

Subcutaneous linear cord with a diameter of 3 mm to 10 mm
11 appears on the chest, upper abdomen and upper extremities (Fig.
Clinical images are available in hardcopy only. 11.16). Mondor disease is usually characterized by obliterative
phelebitis, and it most frequently occurs in women between the
ages of 30 and 60. However, it may also occur in men at the root
of the penis and in the coronal sulcus. The primary disease is
thrombophlebitis or lymphangitis in the subcutaneous fat tissues.
a b c d e f g h Iti is induced
j byk external
l injury
m or operation
n oin the upper
p chest,
q orr
by infection. It may be accompanied by spontaneous pain. There
may be some tenderness or discomfort, but there are often no
symptoms until the patient discovers a red linear cord running
from the lateral margin of the breast.
Clinical images are available in hardcopy only. Pathology
The lumens of the vascular channels in the lesion are narrow
and blocked by new connective tissue. Both the inner and outer
membranes become thickened and fibrotic. Cellular infiltration is
b c d e f g h i j seenk (Fig. 11.17).
not l m n o p q r
Fig. 11.15 Buerger’s disease.
a: Bluish discoloration (cyanosis) of the first toe. Treatment
b: Progressive ulceration of the first toe. c:
Necrosis of the first toe caused by impaired
The disease usually resolves naturally in several weeks. Clini-
blood circulation. cal follow-up is fundamental.
Table 11.4 Differential diagnosis of chronic
arterial occlusive disease. 6. Malignant atrophic papulosis
Thromboangiitis Arteriosclerosis
obliterans obliterans Synonym: Degos’ disease
Age of onset 30 to 50 years over 50 years Multiple rose-pink papules occur in the upper extremities. Sev-
Most common Small arteries Large or
eral days after onset, they form peculiar eruptions with atrophy or
site medium-sized telangiectasia at the center. Pathologically, lymphocytic infiltra-
arteries tion is seen in the periphery of the blood vessels. Malignant
Habits, Smoking Diabetes, atrophic papulosis has a poor prognosis, and it is known to cause
complications hypertension, cerebral infarction or perforative peritonitis several years after
hyperlipidemia
onset. Since eruptions that are pathologically similar to malignant
Arteriosclerosis - +
atrophic papulosis are seen in SLE, systemic sclerosis, rheuma-
Mobile phlebitis + - toid arthritis, dermatomyositis and Crohn’s disease, it is neces-
sary to examine the eruptions thoroughly to determine whether

there is an underlying disease. There is controversy over whether
malignant atrophic papulosis is an independent disease.
7. Thrombophlebitis
Concept
Thrombophlebitis is a disease in which thrombi form in the
small and deep veins as a result of various factors. Clinical images are available in hardcopy only.
Pathogenesis
Most cases of superficial venous inflammation treated by der-
matologists result from damage to the veins by IV line place-
ment, or from administration of vasodilators or antibiotics.
Thrombophlebitis often develops in the lower extremities when
there is infectious disease (e.g., tuberculosis), Behçet’s disease or
chronic venous insufficiency including stasis varicose vain. 11
Clinical features
Thrombophlebitis occurs mostly where IV lines are placed and
in the lower legs. Cord-like induration parallel to the veins
occurs, accompanied by tenderness and itching. Reddening is
often present. Ulceration may occur in severe cases. The lesion Clinical images are available in hardcopy only.
may change by the week depending on the pathogenesis. It may
progress and recur.

Thrombophlebitis is easily diagnosed by the distinctive clinical
symptoms. History-taking on drug administration and detection Fig. 11.16 Mondor disease.
of Behçet’s disease and tuberculosis may be necessary. Particular Subcutaneous, cordlike induration is observed.
care in differentiation should be taken for diseases in which there
is linear cord, such as Mondor disease and gnathostomiasis.
Treatment
Bed rest is most important, followed by cooling of the affected
sites. NSAIDs are necessary in many cases. When the symptoms
are severe, oral steroids may be administered.
Fig. 11.17 Histopathology of Mondor dis-

ease.
Purpura
1. Thrombocytopenic purpura
Definition, Classification
Thrombocytopenic purpura is the general term for purpura that
accompanies a decrease in platelet density. When that density is
less than 100,000 per microliter, subcutaneous bleeding is easily
produced by bruising. When it is less than 50,000 per microliter,
bleeding becomes marked and causes purpura. Thrombocy-
topenic purpura is classified by pathogenesis into idiopathic
thrombocytopenic purpura, which is caused by auto-antiplatelet
antibodies; symptomatic thrombocytopenic purpura, which
accompanies drug-induced purpura, leukemia, bone-marrow can-
11 cer, SLE, infectious diseases and DIC; and hereditary thrombo-
cytopenic purpura, which accompanies Wiskott-Aldrich
syndrome and Fanconi syndrome.
1) Idiopathic thrombocytopenic purpura (ITP)
Clinical features
Idiopathic thrombocytopenic purpura (ITP) occurs in children
during recovery from infectious disease; in adults it develops
without any particular pathogenesis. Its main symptoms are cuta-
neous petechia and ecchymosis, which are followed by bleeding
in the oral mucosa, nasal mucosa and gingiva; hematuria; mele-
na; and menorrhagia. Splenomegaly is not found.
Pathogenesis
Platelets are destroyed as a result of production of platelet-
associated IgG (PAIgG), which leads to ITP. The mechanism of
production of these autoantibodies is unknown.
Pathology
Decreased platelet density (100,000 per microliter or less) and
an extended duration of bleeding (3 minutes or longer) are
observed. PAIgG is found in the blood in more than 90% of
cases. In a bone-marrow biopsy, the megakaryocyte count is
found to be elevated from consumption of platelets. The coagula-
tion system is normal; the prothrombin time (PT), activated par-
tial thromboplastin time (APTT) and fibrinogen value are normal.

Bone-marrow biopsy and detection of PAIgG are essential for
diagnosis. ITP should be differentiated from symptomatic or
hereditary thrombocytopenic purpura listed below (Table 11.5).
Henoch-Schönlein purpura and hemophilia are also differentiated
Purpura / 2. Cryoglobulinemic purpura 153
from ITP. Henoch-Schönlein is distinguished by relatively local- Table 11.5 Causes of symptomatic throm-
bocytopenic purpura.
ized purpura in the lower extremities that results in systemic
symptoms other than cutaneous symptoms, such as arthralgia and Decreased productivity of platelets
abdominal pain; hemophilia causes deep bleeding in the joints Disease Aplastic anemia
and elsewhere. Paroxysmal nocturnal hemoglobinuria
Leukemia, lymphoma, cancer invasion
Treatment Hereditary thrombocytopenia
Oral steroids are the treatment of choice. Immunoglobulin is Causative Drugs, radiotherapy
administered in large doses for severe cases. Immunosuppres- therapy
sants and temporary platelet transfusion are also helpful. ITP sub- Enhanced consumption and destruction of platelets
sides in 80% of cases by drug therapy. For chronic cases that do Disease Diseases associated with collagen dis-
not respond to these treatments, splenectomy may be performed. eases
Disseminated intravascular
coagulation (DIC)
2) Symptomatic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Drugs, leukemia, metastasis of a malignant tumor in the bone (TTP)
marrow, SLE, viral infectious diseases, or vasculitis (Kasabach- Hemolytic-uremic syndrome (HUS)
Merritt syndrome; see Chapter 21) cause reduced production and Viral infection 11
enhanced consumption of platelets, leading to decrease of Causative Drugs, blood transfusion
platelets and the onset of purpura (Table. 11.5). therapy
3) Hereditary thrombocytopenic purpura

Wiskott-Aldrich syndrome (Chapter 7) and Fanconi anemia
(congenital aplastic anemia accompanied by malformation) are
classified as hereditary thrombocytopenic purpura.
2. Cryoglobulinemic purpura
Clinical features
Cryoglobulinemic purpura most frequently occurs in middle-
aged women. The purpura may be accompanied by petechia,
hemorrhagic papules, ecchymosis and subcutaneous nodules.
There may be necrosis. It occurs mostly on the lower legs, and
may spread to the thighs, lumbar region, and lower abdomen; it Cryoglobulin MEMO
Immunoglobulins (Ig) and similar substances
seldom appears on the trunk or face. Raynaud’s phenomenon is (e.g., Bence-Jones protein) are the essential
found in fingers. The disease typically causes renal symptoms components of cryoglobulins. Cryoglobulins
such as proteinuria, erythrocyturia, nephrosis syndrome, high are heat-labile proteins (readily changing or
blood pressure, acute or chronic renal failure, arthralgia, liver dis- denaturing at high temperatures) that precipi-
tate at 37 ˚C or cooler and denature when the
order and polyneuritis. temperature exceeds 37 ˚C. Cryoglobulins are
divided into three types.
Pathogenesis Type I: The main component is monoclonal
Ig. It is observed in multiple myeloma and
Cryoglobulinemic purpura is caused by an increase in the level chronic lymphocytic leukemia.
of cryoglobulins in the blood. Infectious diseases (viral hepatitis Type II: The main components are monoclon-
in particular), multiple myeloma, macrogloblinemia, collagen al Ig and polyclonal proteins. It is observed
in collagen diseases and various infectious
diseases (e.g., SLE, rheumatoid arthritis) or malignant tumors diseases.
may occur as complications. The elevated blood viscosity results Type III: It is associated with polyclonal Ig
in inadequate blood flow and in deposition of protein on the and complements. It is observed in colla-
gen diseases and various infectious dis-
blood vessel walls to induce necrotizing vasculitis, which causes eases.
purpura. Cryoglobulinemic purpura may appear without a primary
disease or known cause.
Pathology
Necrotizing vasculitis caused by cryoglobulin embolization in
the lesion is found in the skin lesions of cryoglobulinemic purpu-
ra. However, when type I cryoglobulin is involved in the onset,
vasculitis tends not to occur. Cryoglobulinemic purpura is char-
acterized by membranoproliferative glomerulonephritis in the
kidney.
Laboratory findings
Cryoglobulin is detected by processing the blood at 37 ˚C to
isolate the serum. Rheumatoid factor and HBs antigen are often
positive, and hypocomplementemia and hepatitis C virus anti-
bodies may be found. M proteins in the serum and Bence-Jones
proteins in the urine protein electrophoretogram may be observed.
11 Treatment
Systemic administration of steroids and removal and inhibited
reproduction of cryoglobulin by plasma exchange therapy are the
main treatments. Any underlying diseases are treated.
3. Pigmented purpuric dermatoses

Synonyms: Idiopathic pigmentary purpura, Purpura sim-
plex, Chronic capillaritis, Purpura pigmentosa chronica

Pigmented purpuric dermatoses occur most frequently in the
lower extremities of middle-aged men. They are characterized by
Clinical images are available in hardcopy only. orange/brown pigmentation (from hemosiderin deposition) that
Table 11.6 Differential diagnosis of pigmented purpuric der-

matoses.
Pigmented purpuric
Schamberg’s Majocchi’s
lichenoid dermatosis
disease disease
of Gougerot-Blum
Sex More common Slightly more Slightly more
distribution in men common in women common in men
Age of onset 20 to 59 30 to 49 30 to 49
(yrs.)
Rate of Onset Gradual Gradual Rather acute
Most Lower legs Lower legs Upper and lower
common site extremities, trunk
Clinical images are available in hardcopy only. Symptom Irregular Enlargement of Hemorrhagic brown
coalescence of petechiae, papules, aggregated
petechiae formation of coalescence of
circular lesion lichenified papules
Venous ＋＋ (sporadic) −
congestion
Pigmentation ＋＋＋＋
Fig. 11.18 Pigmented purpuric dermatoses.
Itching −/＋ (mild) − ＋
Purpura / 5. Steroid purpura 155
occurs after the onset of petechia. Pigmentation shows both clini-

cal and histological features. There are no significant systemic
symptoms (Fig. 11.18). These dermatoses are classified by distri-
bution of eruptions into three main types: Majocchi’s disease,
Schamberg’s disease, and pigmented purpuric lichenoid dermato-
sis of Gougerot-Blum. However, the main three types are the
same in essential (Table 11.6).
Pathogenesis
The etiology is unknown; however, there may be the involve-
ment of venous circulatory disorder, focal infection, or drug-
induced factor.
Pathology
Lymphocytic infiltration, vascular dilatation, and bleeding are
found in the perivascular area in the upper dermal layer. Idio-
pathic pigmentary purpura is chronic hemorrhagic inflammation.
Hemosiderin deposits are seen in old lesions (Fig. 11.19). Fig. 11.19 Histopathology of pigmented pur-
11
puric dermatoses.
Treatment Perivascular lymphocytic infiltration in the upper
dermis and deposition of hemosiderin.
Topical application of steroids and bed rest with the lower
extremities raised is the main treatment. Agents to reinforce the
blood vessels (e.g., vitamin C) are administered, as are hemostat-
ic and antiplasmin agents.
4. Senile purpura
The vascular supporting tissues weaken from age, and purpura
is easily caused even by stimulation so light the patient can
scarcely feel it. Senile purpura occurs mostly in the dorsal hands
and the extensor surface of forearms, producing sharply margin-
ed subcutaneous hemorrhagic spots.
Fig. 11.20 Steroid purpura.
5. Steroid purpura
When the vascular supporting tissues are weakened by pro-
longed topical or oral use of steroids, the capillary blood vessels
are readily broken by mechanical stimulation, leading to purpura
(Fig. 11.20). Steroid purpura occurs most frequently in the elder-
ly. Mechanical stimulation should be avoided, and steroids
should be used appropriately.
Other vascular diseases
1. Arteriosclerosis obliterans (ASO)
Clinical images are available in hardcopy only. Concept

As a result of arteriosclerosis in the extremities, distal
ischemia, skin pallor, pain and ulceration occur. The patients
often have diabetes and high blood pressure as primary diseases.
Clinical features
Symptoms caused by ischemia and poor circulation appear.
The Fontaine classification of arteriosclerosis obliterans (ASO) is
well known: In Grade I, a cooling sensation appears at the ends
of the extremities and there is mild numbness; in Grade II, there
11 is intermittent claudication (inability to walk more than a certain
Clinical images are available distance); in Grade III, there is pain even during bed rest; and in
in hardcopy only.
Grade IV, ulceration or necrosis occurs at the ends of the extrem-
ities, which are prone to ulceration. The lesion becomes enlarged
and white or purplish-red from ischemia. Pulse in the peripheral
arteries in the lesion is impalpable.

Fig. 11.21 Raynaud’s phenomenon.
Pain and ulceration are present at the ends of the extremities in
both Buerger’s disease and ASO; nevertheless, Buerger’s disease
occurs mostly in young male smokers. Pulse is often palpable in
Buerger’s disease (Table 11.4). Lumbar spinal canal stenosis is
also known to cause intermittent claudication.
Treatment
Conservative therapies using vasodilators and thrombosis
inhibitors, and physical therapies such as exercise and hot spring
bathing are the main treatments for mild symptoms of Fontaine
Grades I and II. For severe cases of ASO, surgical treatments such
as stent placement and revascularization are performed. Amputa-
tion of the extremities may be necessary at the terminal stages.
2. Diabetic gangrene
With a microvascular disorder or arterial sclerosis as the pri-
mary disease, ulcers form in toes, soles and fingers. They are
accompanied by sharp pain (Chapter 17).
3. Raynaud’s phenomenon
Synonym: Raynaud’s disease
Definition
Fingers and toes suddenly become bluish. After several min-
Other vascular diseases / 4. Stasis dermatitis 157
utes, they progress to a purplish-dark-blue hue from cyanosis and Table 11.7 Causes of Raynaud’s phenome-
non.
then return to normal color through a diffuse flushing phase.
Raynaud’s phenomenon may be induced by frigidity without a Disease, Causes
primary disease (primary Raynaud’s phenomenon), or it may Primary Raynaud’s disease
Raynaud’s
accompany a primary disease, such as a collagen disease, particu- phenomenon
larly systemic sclerosis (Raynaud’s syndrome, secondary Ray-
Secondary Physical stimulation in people who
naud’s phenomenon). Raynaud’s work with vibrating machinery
phenomenon (vibration syndrome or vibration
Clinical features white finger), pianists, typists, and
food industry workers （meat
Fingers and toes become white and there is a cool sensation, industry, fresh fish industry）
sharp pain, numbness, edematous sensation, and hypoesthesia Drugs: ergotamine, tryptamine, b-
(Fig. 11.21). Cyanosis heals with a diffuse flushing and burning blockers, oral contraceptives
sensation. The ends of the extremities are constantly cold, with or Collagen diseases: e.g., mixed
without an attack. connective tissue disease (MCTD),
systemic sclerosis (SSc)
Pathogenesis Blood disease: cryoglobulinemia,
The potential causes of Raynaud’s phenomenon are shown in cold agglutinin disease
Table 11.7. Circulatory disorders are closely associated with it. A Neurovascular disorders: 11
arteriosclerosis, Buerger’s disease,
bluish tinge is caused by reduced blood flow resulting from arterial thromboembolism, thoracic outlet
constriction. Cyanosis results from dilation of capillaries or small syndrome
veins and stasis. Diffuse flushing occurs as reactive congestion. Other diseases: malignant tumor,
hypothyroidism
Examination
Antinuclear antibody test is performed to rule out the involve-
ment of secondary Raynaud’s phenomenon. Other useful tests for
Raynaud’s phenomenon are a cold provocation test (soaking fin-
gers and toes in 4˚C water for 10 seconds) and thermography.
Treatment
Causative factors should be eliminated, and the body must be
kept warm. A vasodilator (calcium channel antagonists are the
first choice), prostaglandins, or sympatholytic agents are applied.
Smoking cessation is effective.
4. Stasis dermatitis
Synonym: Chronic venous insufficiency (CVI)
Clinical features
Stasis dermatitis usually occurs in the medial aspects of the
lower legs or ankles of obese elderly women, but it may be wide-
spread. It may develop as a complication of impaired venous
return from the lower legs. Superficial varicose veins are a fre-
quent predisposing factor. These lesions are often seen around
chronic stasis ulcers, and they are itchy, scaly, often swollen, and
hyperpigmented. Superficial veins of the lower legs including the
greater saphenous veins and lesser saphenous veins enlarge in
hose shape, nodular shape, or saclike shape and take on a serpen-
tine appearance. The skin surface appears dark blue (varicose Fig. 11.22 Varicose veins.
veins in lower legs, Fig. 11.22). As the varicosity progresses, Superficial veins of lower legs enlarge in serpen-
subjective symptoms appear. Fatigue of the lower extremities, tine, nodular or cystiform patterns.
sharp pain, edema, pigmentation, eczematous lesions and skin

induration (sclerosing panniculitis) occur. In the last stages, a
minor external injury in the lower legs may induce ulceration.
Stasis dermatitis shows the epithelial changes of spongiotic
Clinical images dermatitis and a characteristic lobular pattern of superficial
are available
in hardcopy only.
in hardcopy only.
and/or deep dermal neovascularization.
Pathogenesis
The pressure in the superficial veins is elevated, and veins are
dilated and serpentine from congenital fragility of the venous
walls and venous peripheral supporting tissues, stenosis and
obstruction of deep veins, hyperplasia of superficial veins, preg-
nancy, standing for long periods, and venous valve dysfunction.
Diagnosis
Clinical images are available in hardcopy only. Stasis syndrome is easily diagnosed by varicosity. History-tak-
ing on occupation and pregnancy is helpful. When surgical treat-
11 ment is conducted, venography is also performed.
Treatment
Standing or walking for long periods should be avoided. The
patients should be protected from extrinsic injury and infection,
and they should keep the lower extremities elevated and use elas-
tic bandages. When the condition progresses to stasis syndrome,
besides these treatments, topical steroids, oral antihistamines, and
Clinical images are available in hardcopy only. vasodilator drugs are administered. Surgical therapy including
removal of the superficial vein, ligation and sclerotherapy may
also be performed.
5. Livedo reticularis
Fig. 11.23 Livedo. Livedo reticularis is a generic term for purplish-red to pur-
plish-black discoloration with a characteristic network pattern
caused by stenosis in the veins of the dermis and subcutaneous
fat tissue junctions (Fig. 11.23). Although it can be divided into
several subtypes, the classification is not standardized. The color
deepens with exposure to cold. The condition is largely divided
Table 11.8 Livedo (reticularis).

Clinical images are available in hardcopy only. Cause Symptoms and diseases
Physiological Cutis marmorata (without an underlying disease)
Secondary Thromboembolism: e.g., cholesterol embolism,
cryoglobulinemia
Impairment in blood circulation: e.g., heart failure
Disorders in vessel walls: vasculitis (polyarteritis nodosa)
Systemic diseases: collagen diseases (e.g., rheumatoid
arthritis, SLE). Infectious diseases (syphilis, tuberculosis)
Pancreatitis, lymphoma, hyperparathyroidism, hypercalcemia
Fig. 11.24-1 Lymphedema.
Marked swelling occurrs secondarily in the lower Unknown Livedo accompanied by ulceration (livedo reticularis with
leg. summer/winter ulceration), Sneddon’s syndrome
Other vascular diseases / 8. Lymphedema 159
into cutis marmorata, in which there is no particular primary dis-

ease, and secondary livedo reticularis, in which there is a primary
disease such as collagen disease. The former transiently appears
in infants and adult women without subjective symptoms and dis-
appears when the body warms. The sympathetic nerve is thought
to be involved. Livedo that is found at birth and that is often Clinical images are available in hardcopy only.
accompanied by combined malformation is thought to be caused

by angioma-like abnormality; this condition is called cutis mar-
morata telangiectasia congenita (Chapter 21). When cutis mar-
morata occurs intermittently, the involvement of underlying
diseases such as blockage of vascular cavity, circulatory disorder
or vascular disorder is suspected (Table 11.8). Fig. 11.24-2 Lymphedema.
A skin lesion with extremely hypertrophic
changes resembles elephant skin.
6. Erythromelalgia
Synonym: Erythralgia
Erythromelalgia occurs in the extremities. It is characterized Erythema ab igne, MEMO 11

Thermal burn
by three main symptoms: paroxysmal burning sensation, flushing These are livedo caused by repeated heat
and skin temperature increase. The pathogenesis is unknown. It is exposure at the same site for a long period of
extremely painful and tends to appear when the body is warmed time. Vasculitis is not found pathologically;
however, livedo-like eruptions are present.
by exercise or bathing. It may also be caused by a primary disease
such as erythrocytosis, primary thrombocytosis, or collagen disease.
7. Lymphangitis
Concept, Pathogenesis
Lymphangitis is an inflammatory change in the lymphatic ves-
sels, usually those in the extremities. The spread of various infec-
tions (e.g., various secondary infections, cellulitis, trichophytic Clinical images are available
infection), malignant tumor (e.g., breast cancer), and parasitic in hardcopy only.
infestation (e.g., filariasis) are known to cause lymphangitis.
Clinical features
Painful, linear, soft, palpable, cord-like reddening accompa-
nied by tenderness occurs in the primary lesion and the nerve
area. Systemic symptoms such as fever (may reach 40˚C),
fatigue, and poor appetite are seen in many cases. As chronic
lymphangitis recurs, lymphatic vessels become obstructed, which
may result in lymphatic edema or elephantiasis.
Treatment
Antibiotics and analgesic drugs should be promptly applied
systemically. In the event that an abscess forms, an incision may Clinical images are available
be required. in hardcopy only.
8. Lymphedema
Lymph fluid volume increases locally from lymphatic vessel
dysfunction. Soft edema is often produced in the lower extremities
Symmetrical lividity of the MEMO and it gradually moves upwards. Soft tissues become fibrotic or
soles stiff. Papillary thickening of the epidermis and follicular dilation
This is edematous erythema produced in the are seen in the terminal stages (Figs. 11.24-1 and 11.24-2). The
footpad and sides of the feet in young people. causes of lymphatic vessel dysfunction are largely divided into
It is associated with hyperhidrosis.
congenital (e.g., hypoplasia of lymphatic vessels) and acquired
(e.g., metastasis of a tumor into a lymph node, lymph node dis-
section, filariasis, deep-lying thrombophlebitis).
9. Ataxia telangiectasia (AT)

in hardcopy only. Synonym: Louis-Bar syndrome
Outline
● AT is an autosomal recessively inherited disease involv-
ing functional abnormality of the DNA repair mechanism.
● The three main symptoms are progressive cerebellar
ataxia, telangiectasia in the auricular region and bulbar

11 conjunctiva, and T-cell immunodeficiency.
● IgA deficiency and high a-fetoprotein level are found in
Clinical images are available the serum.
in hardcopy only.
Clinical features
Telangiectasia in the skin and bulbar conjunctiva occurs in
patients 4 to 6 years old, and it extends to the auricular region,
eyelids, cheeks and extremities. Ataxia telangiectasia (AT) may
produce lesions that resemble xeroderma pigmentosum. As the
patients age, severe bronchiectasis and malignant lymphoma
occur as complications.
Pathogenesis
Disconnection or translocation of the AT gene on chromosome
11 (11q22.3) influences T cells and the Ig gene region, leading to
T-cell immunodeficiency and decreased production of
immunoglobulin.
Pathology
Peripheral blood T cells are reduced in number and function,
and serum IgA and IgE (sometimes IgG2 and IgG4) are absent or
markedly reduced. The serum a-fetoprotein value is elevated.
Brain CT and MRI show significant atrophy in the cerebellar ver-
mis. Histopathologically, denaturation of Purkinje cells is
observed.
Diagnosis
AT is diagnosed by the pathological symptoms and laboratory
findings. Diagnosis can also be made by AT gene analysis.
Treatment
Symptomatic therapy is the main treatment.
Chapter
12 Collagen Diseases
Collagen diseases share certain similarities with autoimmune diseases, because autoantibodies specific to each
collagen disease are produced. Multiple organs may be affected, and the site of the main lesion often differs
from case to case: Diagnosis of collagen diseases is mainly based on the criteria established by the American
College of Rheumatology, which include cutaneous lesions. Dermatologists play an important role in diagnosing
and treating collagen diseases.
A. Lupus erythematosus (LE)

Lupus erythematosus (LE) is a diagnostic name for diseases
that cause various systemic changes including those in the skin,
such as systemic lupus erythematosus (SLE) and neonatal lupus 12
erythematosus. The term is also used for localized cutaneous Clinical images are available in
lesions such as those seen in discoid lupus erythematosus (DLE), hardcopy only.
lupus erythematosus profundus and subacute cutaneous lupus
erythematosus. Cutaneous LE is subcategorized as acute, suba-
cute or chronic, with each subcategory having characteristic fea-
tures (Table 12.1). Since acute LE usually occurs as a
manifestation of SLE, it is discussed in the SLE section. Suba- a b c d e f g h
cute (cutaneous) LE and chronic LE are usually localized on
skin, and most cases do not meet the diagnostic criteria of SLE.
These two diseases are discussed in another section of this chap-
ter.
1. Systemic lupus erythematosus (SLE)

Clinical images are available in
Outline hardcopy only.
● Multiple organ failure occurs. The kidneys, heart, joints
and central nervous system are affected. SLE is an
autoimmune disease whose cause is unknown. Young
women are most commonly affected.
● Typical mucocutaneous manifestations are butterfly rash,
Table 12.1 Lesions of cutaneous lupus erythematosus. a b c d e f g h i

Acute Progresses in a few days
Fig. 12.1-1 Systemic lupus erythematosus
(SLE).
Butterfly rush, alopecia, palmar erythema, aphtha a: Butterfly-shaped erythema and edematous ery-
Subacute Progresses in a few weeks to a few months thema that is symmetrically spread from the dor-
sum of nose to the cheeks of a young woman in
(SCLE) Papulosquamous and annular-polycyclic lesions her teens. The skin lesion does not usually spread
Chronic Progresses over a long period of time to the nasolabial groove and lips. b: “Butterfly
rash” from the recurrence of SLE in a woman in
DLE, lupus panniculitis, lupus profundus, nodular her thirties. As SLE worsens, such rashes may
cutaneous lupus mucinosis recur.
161
162 12 Collagen Diseases
DLE, oral ulceration, solar photosensitivity and alopecia.

● The laboratory findings are antinuclear antibody positive,
anti-dsDNA antibody positive, anti-Sm antibody positive,
LE cell positive, biological false positive serological reac-
tion for syphilis, decreased complements, and pancy-
topenia.
● The diagnostic criteria are those published by the Ameri-
can College of Rheumatology.

● The main treatment is oral corticosteroids.
Epidemiology
The onset tends to be between the ages of 10 and 30. Women
outnumber men 10 to 1. Therefore, the majority of patients are
women of childbearing age.
Cutaneous features
Various cutaneous findings are observed in more than 80% of
b c d e f g h i cases.
j The
k fourl mainmsymptoms n of oSLE, which
p are
q included
r in
the diagnostic criteria (Table 12.2), are erythema on the cheeks,
12 chronic DLE, oral ulcers and photosensitivity (Figs. 12.1-1 to
12.1-3). The frequencies of occurrence of various symptoms in
SLE are listed in Fig. 12.2.
Erythema on the cheeks (Fig. 12-1-1): Also called butterfly
Clinical images are available in hardcopy only. rash, this is the most characteristic eruption. It is seen in about
90% of cases. Edematous erythema spreads symmetrically on
cheeks with the dorsal nose at the center, forming a butterfly pat-
tern. Generally, it does not extend beneath the nasolabial groove.
The margin of the erythema is relatively distinct, with slight ele-
c d e f g h i j vation.
k Blistering
l m is rarely
n present.
o The
p patients
q are rasymptomatic
or have mild subjective symptoms, such as a slight burning sen-
sation. It heals without scarring.
DLE: Discoid lupus erythematosus is sharply margined discoidal
erythema. It is seen in 30% of patients with SLE, occurring on
exposed sites such as the face, lips and ears. Scales and crusts
often form. It gradually progresses into scarring atrophic lesions
and causes alopecia when the scalp is affected (described later).
Palmar erythema: This is seen in about 50% of SLE cases. Dif-
fuse erythema occurs on the palms, the thenar and hypothenar in
particular. The lesions are hyperkeratotic and often accompanied
by scales.
Alopecia: It occurs rapidly and diffusely in the head hair. The
occurrence of short, thin, broken hairs at the front edge of the
scalp results in uneven hair length (lupus hair). The severity of
the alopecia is considered to reflect the degree of SLE progres-
d e f g h i j k sion.
l m n o p q r
Fig. 12.1-2 Systemic lupus erythematosus
Enanthema: This is seen in about 40% of SLE cases. Small
(SLE). hemorrhagic lesions with a red halo and small ulcers appear on
c: Skin lesion on fingers caused by discoid lupus the lips, oral mucosa, pharynx and pharyngeal mucosa. They may
erythematosus. Tenderness may be present. d: be found in DLE of the mucous membranes.
Diffuse erythema on the sole and toes. e: A large
ulcer in the pharyngeal region. Large oral mucos- Subcutaneous nodules: Nodules form on the face, hips and
al ulcers may be caused by SLE. upper arms. This is from inflammation of fat tissue, also called
A. Lupus erythematosus 163
Table 12.2 1982 Revised criteria for classification of systemic

lupus erythematosus.
Criterion Definition
1. Malar rash Fixed erythema, flat or raised, over the malar eminences, but
tending not to appear on the nasolabial folds
2. Discoid rash Raised erythematous patches with adherent keratotic scaling
and follicular plugging; atrophic scarring may occur in older
lesions
3. Photosensitivity Skin rash from unusual reaction to sunlight, revealed by
patient history or physician observation
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed Clinical images are available in hardcopy only.
by physician
5. Arthritis Nonerosive arthritis involving 2 or more peripheral joints,
characterized by tenderness, swelling or effusion
6. Serositis a) Pleuritis ―convincing history of pleuritic pain or rubbing
heard by a physician or evidence of pleural effusion
OR
b) Pericarditis ―documented by ECG or rub or by evidence
of pericardial effusion
7. Renal disorder a) Persistent proteinuria greater than 0.5 g per day or greater
than 3+ if quantitation is not performed
OR
a red cells,
b hemoglobin,
c d e f g h i j k l m
b) Cellular casts ―may be granules,
tubules or mixed Fig. 12.1-3 Systemic lupus erythematosus
8. Neurologic a) Seizures―in the absence of causative drugs or known (SLE). 12
disorder metabolic disorder (e.g., uremia, ketoacidosis, electrolyte f: Diffuse alopecia caused by SLE. In this case,
imbalance) discoid lupus erythematosus (DLE) is present on
OR the sites with alopecia.
b) Psychosis ―in the absence of causative drugs or known
metabolic disorder (e.g., uremia, ketoacidosis, electrolyte
imbalance)
malar rash 72
9. Hematologic a) Hemolytic anemia ―with reticulocytosis
Raynaud’s
disorder OR phenomenon 51
b) Leukopenia ―less than 4,000/mm3 total on 2 or more
alopecia 51
occasions
OR hyperesthesia 43
optica
c) Lymphopenia―less than 1,500/mm3 on 2 or more
oral ulcer 41
occasions
OR discoid rash 16
d) Thrombocytopenia―less than 100,000/mm3 in the absence
of causative drugs 0 20 40 60 80％
10. Immunologic a) Positive LE cell preparation arthritis 89

disorder OR
b) Anti-DNA: antibody to native DNA in abnormal titer fever 78
OR lymphocytopenia 73
c) Anti-Sm: presence of antibody to Sm nuclear antigen
skin lesion 72
OR
d) False positive serologic test for syphilis known to be leukocytopenia 65
positive for at least 6 months and confirmed by
thrombocytopenia 29
Treponema pallidum immobilization or fluorescent
neurologic 20
treponemal antibody absorption test disorder
11. Antinuclear An abnormal titer of antinuclear antibody by proteinuria 17
antibody immunofluorescence or an equivalent assay at any point in hemolytic
anemia 12
time and in the absence of drugs known to be associated with
drug-induced lupus syndrome pleuritis 10
The proposed classification is based on 11 criteria. For clinical studies, a person is seizure 8
said to have systemic lupus erythematosus if any 4 of the 11 criteria are present, pericarditis 7
serially or simultaneously at any time during observation (Tan EM, et al. The 1982
revised criteria for the classification of systemic lupus erythematosus. Arthritis coma 5
Rheum 1982; 25: 1271-7). 0 20 40 60 80 100％
Fig. 12.2 Main eruptions caused by sys-

lupus erythematosus profundus (described later). temic lupus erythematosus (SLE) and
Other cutaneous symptoms: These include palmoplantar ker- their frequency (% of cases).
(Hashimoto H, Miyamoto A, editors. Systemic
atosis, purpura, Raynaud’s phenomenon, erythema multiforme, lupus erythematosus. Clinical allergology. 2nd
and ulcers in the extremities. ed. Nankodo; 1998).
Table 12.3 Factors associated with onset of Systemic symptoms

SLE.
The symptoms of SLE are significantly various (Fig. 12.2).
Factor Finding The onset is an attack of fever, systemic fatigue, arthralgia and
Genetic Familial prevalence, especially in monozy- edema, accompanied by the cutaneous symptoms described
gotic twins
above.
Viral Type C viral particles are detected in the SLE
infection patient’s kidney, skin and lymph nodes. Renal symptoms: Lupus nephritis is the most critical lesion. It
The virus is persistent and forms an relates closely to the prognosis. It affects various sites and causes
immunocomplex, resulting in onset of SLE.
proteinurea, hematuria, nephrosis syndrome and renal failure.
Sex SLE frequently occurs in women of Arthralgia: This is seen in more than 90% of SLE cases. Multi-
hormone child-bearing age.
Endogenous estrogens and androgens are ple or single arthralgia occurs, transiently in many cases. Proxi-
associated with the onset of SLE. mal interphalangeal joints, knees, legs, shoulders and elbow
The SLE symptoms in model mice are
improved by androgen. joints are most frequently affected.
Extrinsic Procainamide, hydralazine, isoniazid,
Cardiac symptoms: Libman-Sacks endocarditis, pericardiac
hydantoins and other drugs may cause inflammation and cardiac tamponade occur.
skin/systemic symptoms and serological Mental and neurological symptoms: Central nervous system
findings that are similar to those of SLE.
If these symptoms are improved by (CNS) manifestations such as convulsions, impaired conscious-
discontinuation of these drugs, the condition ness, depression, schizophrenia-like symptoms or cognitive
is called drug-induced lupus. Otherwise
these symptoms are thought to be idiopathic deficit occur in about 20% of cases during the acute active peri-
SLE that was triggered by drugs. od. It may be difficult to differentiate CNS lupus from similar
12 symptoms caused as side effects by corticosteroids.
Blood abnormalities: Hemolytic anemia (mostly autoimmune
hemolytic anemia), leukocytopenia and thrombocytopenia are
present.
Pathogenesis
Hereditary predisposition, viral infection, sex hormones and
other factors are thought to interact in complex ways to cause
immune abnormality and SLE. However, the pathogenesis has
not been identified (Table 12.3). It is known that antinuclear
antibodies, anti-DNA antibodies and anti-Sm antibodies are pro-
Fig. 12.3 Lupus band test. duced and destroy tissues directly (type II allergy) or form
Normal skin in the unexposed area of a patient immunocomplexes to destroy tissues by complement cascades
with SLE, observed by direct immunofluoresc-
nce. There is linear deposition of IgG (fluores- (type III allergy), which results in inflammation in the systemic
cent green) in the epidermal basement internal organs.
membrane. The nuclei stain orange.
Complications
Differences between SLE MEMO SLE may present symptoms that meet the diagnostic criteria
and DLE for collagen diseases such as rheumatoid arthritis, scleroderma,
SLE is the diagnostic name of a condition in Sjögren syndrome and dermatomyositis (overlap syndrome).
which various lesions appear on the whole
body. DLE and LE profundus are the diag- Viral infection, such as by herpes zoster, and mycotic infection
nostic names of eruptions. Therefore, DLE result from decreased cellular immunity.
and LE profundus may occur in patients with
SLE, or they may occur without underlying Pathology
diseases associated with SLE.
Pathological findings are various, and each eruption presents
different cutaneous clinical features depending on its stage. Cuta-
MEMO
neous atrophy, keratotic plug formation, vacuolar degeneration,
Anti-ENA antibody
Nuclear proteins that are soluble in a buffer edema in the upper dermis, mucin deposition, and perivascular
solution are called extractable nuclear anti- and periadnexal inflammatory infiltration of lymphocytes are
gens (ENA). Anti-ENA antibodies include found. IgG, IgM and C3 may be found deposited in the basement
anti-RNP antibodies, anti-Sm antibodies, anti-
SS-A antibodies, and anti-SS-B antibodies. membrane zone of eruptions in unexposed normal-looking skin,
which can be identified by skin biopsy and immunofluorescence
(lupus band test; Fig. 12.3).
Laboratory findings
Anemia, leukocytopenia, lymphocytopenia and thrombocy- Clinical images are available in hardcopy only.
topenia are found. The erythrocyte sedimentation rate is elevated
as a result of the systemic inflammation; however, CRP is only
slightly increased. human immunoglobulins and IgG increase and
complements (C3, C4, and CH50) decrease. SLE is an autoim- a b c d e f g h
mune disease; various autoantibodies, such as anti-nuclear anti-
bodies, anti-DNA antibodies (especially antidouble-stranded
DNA antibodies; dsDNA) and anti-ENA antibodies are detected
in the serum. When antiphospholipid antibodies are positive, bio-
logical false positive (BFP) is observed in serological reaction for
syphilis. Clinical images are available in hardcopy only.
Diagnosis
Skin biopsy and direct immunofluorescence (IF) are necessary
for diagnosis. The diagnosis of SLE can be made when four or
more of the 11 diagnostic criteria are satisfied (Table 12.2). Even
when four criteria are not met simultaneously, the other symp-a b c d e f g h 12i
toms often appear later. Therefore, careful observation is
required.
Treatment
The primary treatment is administration of immunosuppres-
sants such as steroids, cyclophosphamides, azathioprines and
cyclosporines. Steroid pulse therapy may be performed in
intractable cases. Psychiatric treatments are also conducted for
CNS lupus. Lifestyle guidance is important; stress caused by Clinical images are available in hardcopy only.
direct sunlight exposure, over-fatigue or the cold should be
avoided as much as possible. It is known that SLE tends to
become aggravated during pregnancy.
Prognosis
SLE progresses chronically with repeated aggravation and
remission. It used to have great influence on the prognosis of
renal disorders. However, the mortality rate has been reduced by
dissemination of dialysis therapy (the 5-year survival rate
a nowb c d e f g h i j
exceeds 90%). The number of deaths from central nervous sys- Fig. 12.4-1 Discoid lupus erythematosus
tem damage and cardiac failure has been increasing. Infection (DLE).
resulting from steroid treatment can be fatal. a: The affected dorsal nose of a man in his 20s.
The skin lesion is a sharply demarcated macule
with a reddish-pink center. The periphery is
2. Discoid lupus erythematosus (DLE) brownish and accompanied by scaling. b: A
sharply margined skin lesion accompanied by
dilated hair follicles on the cheek of a woman in
her twenties. The lesion is partly erosive. c: A
Definition skin lesion spread on the whole of the right cheek
Discoid lupus erythematosus (DLE) is the name of an erup- of a woman in her thirties. Multiple DLE erup-
tion, whereas SLE is the name of a clinical condition with sys- tions of 1 cm in diameter occur and gradually
enlarge or coalesce into large plaques.
temic involvement. Some but not all patients with DLE may meet
the criteria for SLE. In other words, in many cases of DLE, the
skin is the only organ involved. Patients with SLE may have
DLE eruptions.
Clinical features
Multiple, round to oval, sharply demarcated rose-pink lesions
accompanied by scaling and follicular dilation occur on sun-
exposed sites (Figs. 12.4-1 and 12.4-2). These tend to occur on
the face, scalp and auricular region and, rarely, as individual
c d e f g h i j eruptions
k l at sites
m lowern than o the neck.
p Scaling
q and
r ulcerative
lesions may occur on the lips of the mouth. When DLE is pro-
duced in the head region, scarring alopecia may result from the
destruction of hair follicles. These eruptions are aggravated by
sun exposure, and they heal with scarring and pigmentation at the
center. Multiple DLE eruptions that occur at sites lower than the
neck region are called widespread DLE (Fig. 12.5), and these
may progress to SLE accompanied by systemic symptoms.
Pathology
d e f g h i j k l The characteristic
m n findings
o pare ① qformation
r of horny follicular
Fig. 12.4-2 Discoid lupus erythematosus plugs, ② flat atrophy of the epidermis, ③ vacuolar degeneration
12 (DLE). of the basal layer, ④ dense focal infiltration in the periphery of
d: DLE on the lips. Erythema and purple erup- the appendages and blood vessels, and ⑤ mucin deposition in the
tions are present. It should be differentiated
from lichen planus. DLE of the lips may dermis (Fig. 12.6). Linear deposition of immunoglobulins is
induce squamous cell carcinoma. e: DLE on found in the skin basement membranes of the lesion in most
the dorsum of hand and fingers. There are cases (lupus band test is positive; Fig. 12.3).
thick scales and thickening of the skin.
Laboratory findings
Lesions tend not to occur in organs other than the skin. Gener-
al laboratory findings are normal. However, in some cases (wide-
spread DLE in particular), antinuclear antibodies and anti-DNA
antibodies may appear, accompanied by hypocomplementemia
with progression to SLE.
Table 12.4 Differential diagnosis between DLE and SLE.

Patients with DLE SLE patients with DLE
eruption only eruption
Difference between sexes Almost none Women outnumber men
Common site of eruption The face, head and auricles The whole body surface
Clinical features of Discoidal Exudative erythema,
eruption disseminated plaques
Subjective symptoms None Various systemic
symptoms
Course of disease Healing with scarring in Accompanied by
Clinical images are available in hardcopy only. several years to several various systemic
decades symptoms
Prognosis Good Poor, sometimes fatal
Lupus erythematosus Negative in most cases Positive in most cases

Fig. 12.5 Widespread discoid lupus ery- cells
thematosus (DLE).
Large areas on the trunk and arms are involved. WBC count Normal or decreased Markedly decreased
Patients with DLE eruptions only are compared to those with
SLE accompanied by DLE eruptions in Table 12.4. Other erup-
tions that should be distinguished from DLE are polymorphous
light eruptions, lichen planus and cutaneous sarcoidosis.
Treatment
Patients with DLE should avoid sunlight, which tends to
aggravate the condition. Topical application of steroids and
tacrolimus are effective.
Fig. 12.6 Histopathology of discoid lupus
3. Lupus erythematosus profundus erythematosus (DLE).
There is vacuolar degeneration in the basal cell
Synonym: Lupus panniculitis layer, lymphocytic infiltration in the blood ves-
sels and peripheral skin appendages, and severe
edema and mucin deposition in the dermis. Neu-
Definition trophils and eosinophils are rarely seen.
Lupus erythematosus (LE) profundus is a subtype with major
lesions in the subcutaneous tissues. It is characterized by nonspe-
cific inflammation of fat tissue.
12
Clinical features
Lesions occur as subcutaneous induration of normal color or
rose pink, most frequently on the face, shoulders and hips (Fig.
12.7). DLE may be produced at sites with those lesions. Concave
lesions may form in the course of LE profundus, and these heal
with concave scarring. LE profundus may occur independently;
however, more than half of all cases are accompanied by SLE
and DLE.
Pathology
Perivascular infiltration of lymphocytes, mucin deposition and
dense lymphocytic infiltration are found in the subcutaneous tis-
sues. Interlobular inflammation gradually becomes fibrotic.
Deposition of immunoglobulins and complements may be seen
Fig. 12.7 Lupus erythematosus profundus.
on the blood vessel walls and at dermo-epidermal junctions. Large panniculitis in the skin of a patient with
SLE. DLE eruptions are present on the skin sur-
Treatment face.
Topical or oral corticosteroids are the main treatments.
4. Subacute cutaneous lupus erythematosus

(SCLE)
Definition
Subacute cutaneous lupus erythematosus (SCLE) is character-
ized by eruptions whose course and duration are intermediate
between those of chronic DLE and those of the acute LE seen in
SLE.
Clinical features
Multiple eruptions appear symmetrically on sun-exposed sites
of the body. There are two types of SCLE: annular-polycyclic

SCLE, with erythema whose center tends to have color degrada-
tion (Fig. 12.8), and papulosquamous (psoriasiform) SCLE, with
eruptions resembling psoriasis. Both types heal without scarring
Clinical images are available in hardcopy only. and are recurrent. About half of patients with SCLE meet the
diagnostic criteria of SLE. The disease may be accompanied by
mild systemic symptoms, such as arthralgia and fever. Severe renal
symptoms and central nervous system manifestations are rare.
a b c d e f g hPathology
i j k l m n o p q r
Characteristic findings of lupus erythematosus include epidermal
atrophy, vacuolar degeneration in the basal layers, and perivascu-
lar and adnexal lymphocytic infiltration.
Laboratory findings
Antinuclear antibodies are positive in more than half of all
cases. Since anti-SS-A antibodies and anti-SS-B antibodies are
Clinical images are available in frequently found, a correlation has been reported between SCLE
hardcopy only. and HLA-B8 or HLA-DR3.
12
Treatment
The main treatments are corticosteroids applied topically or
administered orally in small doses.
5. Neonatal lupus erythematosus

Fig. 12.8 Subacute cutaneous lupus erythe-
matosus (SCLE). Definition
a: Annular polycyclic SCLE on the back. The Annular erythema occurs in newborns whose mothers have
center of the lesion is healing centrifugally. This
condition resembles the annular erythema of SLE or Sjögren syndrome with anti-SS-A and/or SS-B antibod-
Sjögren syndrome. b: Papulosquamous SCLE. ies, even when the mother is asymptomatic for both diseases. The
Psoriasis-like papules and scaling are present. face is most frequently involved. Neonatal lupus erythematosus
is a specific type of lupus erythematosus.
Clinical features
Neonatal lupus erythematosus resembles the annular erythema
that accompanies Sjögren syndrome, or DLE-like annular erup-
tions in newborns in the first month after birth (Figs. 12.9-1 and
12.9-2), and it heals with abnormal pigmentation within 6
months. In addition to systemic symptoms associated with SLE
(fever, hepatosplenomegaly, anemia, thrombocytopenia), congen-
a b c d e f g h cardiac
ital i block j is found
k l
in some m
cases. o blockpis irre-q
Asn cardiac r
Fig. 12.9-1 Annular erythema in neonatal versible, it requires full attention.
lupus erythematosus.
a: Annular erythema on the cheek of an infant
with neonatal lupus erythematosus. It begins as Pathogenesis
erythema of 5 mm to 10 mm in diameter and Placentally transmitted anti-SS-A antibodies and anti-SS-B
gradually enlarges. The center of the lesion tends antibodies in newborns are thought to lead to neonatal lupus ery-
to regress; however, marked edema and elevation
occur at the periphery. thematosus. An anti-SS-A antibody against 52kD antigen is
strongly suspected of being involved. The cutaneous symptoms
subside in 6 months, when placentally transmitted antibodies dis-
appear from the newborns, which implies the involvement of the
B. Scleroderma 169
antibodies.
Treatment
Symptomatic therapies for the eruptions and the systemic
symptoms are the main treatments. A pacemaker may be
implanted in patients with cardiac block.

6. Nodular cutaneous lupus mucinosis hardcopy only.
Papules and nodules occur on the back and upper arms. Nodu-
lar cutaneous lupus mucinosis is a subtype of cutaneous LE.
These lesions are caused by deposition of mucin in large amounts
in the dermis, and they often accompany SLE.
7. Bullous lupus erythematosus

a b c d e f g h i
Bullous lupus erythematosus is a specific subtype of cutaneous Fig. 12.9-2 Annular erythema in neonatal
LE in which blisters form. Antinuclear antibodies in the serum lupus erythematosus.
and autoimmune antibodies against type VII collagen in the base- b: Two annular erythema on the face.
ment membranes are thought to cause blistering. Blisters may 12
form on normal skin or on LE erythematous lesions (Fig. 12.10).
Fig. 12.10 Bullous lupus erythematosus.

Bullous LE in a patient with SLE. Vesicles form
not only on the LE erythema but also on the nor-
mal looking skin.
B. Scleroderma
Scleroderma is characterized by sclerosis of the skin that fol-
lows a course of edema, sclerosis and atrophy. It is divided into
systemic sclerosis (SSc) and localized scleroderma. In SSc vari-
ous lesions occur in the internal organs, whereas in localized
scleroderma the internal organs are not involved.
1. Systemic sclerosis (SSc)

Synonym: Progressive systemic sclerosis (PSS)
Renaming from MEMO
Outline PSS to SSc
● Generalizedcutaneous sclerosis, fibrosis in the synovi- Because progressive systemic sclerosis (PSS)
is not necessarily progressive, the disease has
um and small arteries, and Raynaud’s phenomenon are come to be called systemic sclerosis (SSc).
found.
● Itaffects multiple organs, with unknown etiology.

● Anti-Scl-70 antibodies and anti-centromere antibodies
may be positive.
● Penicillamines and nonsteroidal anti-inflammatory drugs
(NSAIDs) are the main treatments.
Classification
There are two classification systems for systemic sclerosis
(SSc): Barnett’s, and LeRoy and Medsger’s. Classification is
Clinical images are available in hardcopy only. done according to the degree of hardening of the skin. These
classifications are used to describe the severity of SSc (Table
12.5).
Clinical features
SSc frequently occurs in adults aged 30 to 50. The incidence is
greater among women, with a ratio of 3 or 4 women to 1 man.
The onset is Raynaud’s phenomenon or arthralgia that becomes
aggravated in winter. The affected skin gradually hardens, begin-
ning with the peripheral skin. Skin lesions demonstrate character-
12 a b c d e f g h clinical
istic i j
features k differ
that l according
m tonthe affected
o p
site. Theq r
course is usually edema, sclerosis and atrophy.
As SSc progresses, the skin becomes impossible to pinch,
resulting in impaired finger extension. When it progresses fur-
ther, the fingers become pointy or crooked, and swollen like
sausages (sausage-like fingers). Small ulcers form on the finger
pads from circulatory failure, which results in intractable, con-
cave, worm-eaten scarring (Fig. 12.11-1). These symptoms
spread from the fingers to the upper arms (proximal scleroderma).
g Table 12.5
j Classification of systemic sclerosis (SSc).
p q
a. Barnett Classification
Type I Cutaneous symptoms are Raynaud’s phenomenon and hardening
of the fingers.
Type II Hardening of skin occurs on the extremities and face.
Type III Hardening of skin spreads to the trunk.
b. Medsger & LeRoy Classification
Limited Hardening of skin is seen only on areas distal from the elbows,
Clinical images are available in hardcopy only. cutaneous and lesions in internal organs are mild.
The prognosis is good. Most cases with anticentromere
antibody-positive are classified as this type.
Diffuse Hardening of skin spreads to proximal sites, including the trunk
cutaneous and upper arms. Visceral involvement quickly progresses to
conditions such as interstitial lung disease, oliguric renal failure,
diffuse gastrointestinal disease, and myocardial involvement.
The prognosis is poor in many cases.
Cases with anti-DNA topoisomerase I (anti-Scl-70)
b c d e f g h i j k antibody
l positive
m tend nto be classified
o p q r
as this type.
Fig. 12.11-1 Systemic sclerosis. c. Other classifications
a: There is intense sclerosis and impaired move-
ment in the fingers. b: Sclerosis leads to impaired CREST syndrome: A subtype of SSc, it is characterized by five
extension in the fingers. c: The ends of the fin- symptoms: calcinosis, Raynaud’s phenomenon, esophageal dysfunction,
gers, particularly the index finger, are lost or sclerodactylia and telangiectasia.
shortened due to necrosis from blood circulation Anti-centromere antibody (ACA) positive is serologically present. This
disorder. syndrome may be used as a synonym for limited cutaneous SSc.
B. Scleroderma 171
Telangiectasia, pigmentation, depigmentation and calcium depo-

sition are also found.
①SSc in the face (Fig. 12.11-2)
Mask-like face: Wrinkles on the face disappear from edematous
hardening. The nose becomes characteristically pointy.
Microstomia: There is difficulty in opening the mouth, which Clinical images are available in hardcopy only.
makes the mouth appear small.
Miscroglossia, tongue-tie: The tongue is difficult to stick out.
②SSc in other organs
The main symptoms found in other organs are arthralgia
(swelling), decreased esophageal peristaltic motion, dilation of
a
the lower esophagus, lung fibrosis, cardiac symptoms b c
(arrhyth- d e f g h i j k
mia, conduction disturbance), maldigestion syndrome, renal
symptoms (manifesting as malignant hypertension; severe cases
are called sclerodermatous kidney), and chronic thyroiditis
(Hashimoto’s thyroiditis).
Pathogenesis
The fundamental etiology is unknown. SSc rarely runs in fami-
lies. 12
Environmental predisposition: Patients with a silicosis
b are
c proned e f g h i j k l
to SSc. SSc-like symptoms may be found in workers who handle Fig. 12.11-2 Systemic sclerosis.
polyvinyl chloride or epoxy resin and as a side effect of the anti- d: Mask-like face. e: Microglossia.
tumor drug bleomycin.
A type of SSc called human adjuvant disease occurs in half of
those who have received silicon or paraffin injections or implants Table 12.6 Preliminary criteria for classifica-
for cosmetic purposes. The disease appears 10 years or more tion of systemic sclerosis (SSc).
after the operation. These substances are no longer in use. Major criterion
Proximal diffuse (truncal) sclerosis (skin
Pathology tightness, skin thickening, non-pitting induration)
In the early stages of SSc, collagen fibrils are swollen in the Minor criteria
middle to lower layer of the dermis. Interstitial edema, hardening 1) Sclerodactyly (only of the digits)
and lymphocytic infiltration are present. As the lesions progress, 2) Digital pitting scars or loss of substance of the
atrophy in the epidermis and appendages, deposition of collagen digital finger pads (pulp loss)
3) Bibasilar pulmonary fibrosis
fibers parallel to the epidermis, and deposition of acid
The diagnosis is given when the patient meets the
mucopolysaccharide (the major component is dermatan sulfate) major criterion or two of the three minor criteria.
are observed. Unlike in SLE, the deposition of immunoglobulins
(Adapted from; Subcommittee for Scleroderma Criteria
and complements is negative in many cases. of the American Rheumatism Association Diagnostic
and Therapeutic Criteria Committee. Preliminary cri-
Laboratory findings teria for the classification of systemic sclerosis (scle-
roderma). Arthritis Rheum 1980; 23: 581-90).
Anti-Sc1-70 antibodies are frequently seen in diffuse cuta-
neous SSc. Anti-centromere antibodies are frequently seen in
limited cutaneous SSc and CREST syndrome.
SSc findings are similar to those of other collagen diseases:
Rheumatoid factor is positive, there is biological false positive
serological reaction for syphilis, and antinuclear antibody is posi-
tive (macular or nucleolar). Nonetheless, unlike in SLE, the
patient tests negative for LE cells and anti-DNA antibodies, and
the serum complement titer is normal.

Various diagnostic criteria are consulted. In cases with typical
symptoms, the cutaneous symptoms are sufficient for conclusive
diagnosis. Otherwise, skin biopsies and the characteristic auto-
antibodies are used for diagnosis. SSc in the edematous period
should be carefully differentiated from mixed connective tissue
disease (MCTD) and overlap syndrome. The diagnostic criteria
established by the American College of Rheumatology (1980)
are shown in Table 12.6.
Treatment
Moderate doses of oral steroids are administered against hard-
ening of skin at the early stages. NSAIDs are used for arthralgia.
Various vasodilators (e.g., calcium antagonists, prostaglandin E1)
are applied for Raynaud’s phenomenon. For patients with severe
systemic symptoms, immunosuppressants and hematopoietic
stem-cell transplantation are also used. Bed rest, and warming
and massaging of the extremities are effective against cutaneous
lesions.
12
Prognosis
SSc tends to be chronic. Hardening of skin usually progresses
gradually. The prognosis depends on the severity of lesions in the
kidneys and lungs. Infection may be caused during treatment, and
it is fatal in some cases. Sudden death may be caused by heart
failure.
Clinical images are available in hardcopy only. 2. Localized scleroderma
Definition
Localized scleroderma is sclerosis of the dermis, which occurs
only on the skin. Unlike in systemic sclerosis, there is neither
Raynaud’s phenomenon nor lesions of internal organs.
Clinical features
Localized scleroderma occurs most frequently in adults aged
20 to 40 and sometimes in children. The proportion of male to
Clinical images are available in hardcopy only. female patients is 1 to 3. Raynaud’s phenomenon is not present.
Systemic symptoms are mild, if any. Localized scleroderma
includes variety of conditions.
①Morphea (circumscribed plaques)
b c d e f g h i j Localized
k round
l or m
oval indurated
n olesionspthat are
q silvery
r at the
Fig. 12.12 Localized scleroderma morphea. center occur on the trunk (Fig. 12.12). These may be surrounded
a: A sclerotic plaque of 10 cm in diameter on the by a purplish-red halo called a lilac ring. Morphea is further clas-
extensor surface of the forearm. The center of the sified by the size and number of eruptions as localized, guttate or
lesion appears ivory-colored and glossy. A lilac
ring and erythema of light color are present generalized. Generalized morphea is multiple morphea or mor-
around the lesion. b, c: Morphea on the precor- phea accompanied by other localized sclerodermatous lesions.
dial region. ②Linear scleroderma (linear morphea)
This may be accompanied by facial hemiatrophy. Linear or
band-like indurated lesions resembling morphea occur on the
C. Other collagen diseases 173
body. When the forehead is affected, it is called sclérodermie en

coup de sabre; this spreads to the scalp, leading to alopecia
(Fig. 12.13). Linear scleroderma generally penetrates to deep
sites. Lilac rings are rarely seen.
Pathogenesis
The pathogenesis is unknown. The disorder may be induced by
external injury. Involvement of Borrelia infection has been
reported recently.
Pathology, Laboratory findings

Localized scleroderma has a histopathology similar to that of
SSc. The abnormal laboratory findings that are seen in SSc are
not usually found in localized scleroderma. Rheumatoid factors
and antinuclear antibodies may be present in generalized mor-
phea.
Treatment
Steroids are topically applied or locally injected. Oral steroids
may be administered for severe cases. If no spreading tendency is 12
observed for a certain period of time, surgery may be considered. Clinical images are available in hardcopy only.
Prognosis
Patients with localized scleroderma have a good life expectan-
cy; however, the condition is usually chronic. Indurated patches
gradually shrink, and abnormal pigmentation appears.
Fig. 12.13 Linear scleroderma with facial

hemiatrophy.
Alopecia and sclerosis on the head. It resembles
the slash of a sword. Atrophy occurs in the hypo-
dermic scalp.
C. Other collagen diseases
1. Dermatomyositis (DM)
Outline
● Heliotrope rash, Gottron’s sign and unique erythema and
poikiloderma appear, and there is telangiectasia in the
perionychia.
● Muscle weakness begins in the proximal muscles. Ele-
vated levels of CPK, aldolase and urinary creatine reflect

myositis.
● Malignant tumor commonly develops as a complication.
● Interstitial pneumonia may aggravate rapidly. The prog-
nosis is poor.
● Steroids are the main treatment.
Epidemiology
There are fewer patients with dermatomyositis (DM) than with
SLE or scleroderma. It most commonly occurs in adults aged 30
to 60 and in children, with a male to female ratio of 1 to 2. DM
that does not cause cutaneous lesions is called polymyositis
(PM).
Clinical features
Cutaneous symptoms: Edematous purplish-rose patches on
the face, especially the eyelids (heliotrope rash), and flat elevated
papules with scaling (Gottron’s sign) on the extensor surface of
fingers and joints are diagnostically significant (Figs. 12.14-1
and 12.14-2). Seborrheic dermatitis-like erythema on the cheeks
and scalp often progresses to butterfly-rash-like skin lesions in
a b c d e f g children
h i (Fig. j12.15).k Intensely
l itching
m dermatitis-like
n o pdiffuseq r
edematous erythema appears on the neck and trunk, which some-
times shows linear distribution on the trunk and extremities (lin-
12 ear dermatitis). These eruptions cause abnormal pigmentation or
depigmentation, skin atrophy, scaling and telangiectasia over
time; they present as poikiloderma. Erythema in the perionychia
Clinical images are available in hardcopy only. and hair loss are also seen. Panniculitis resembling lupus erythe-
matosus profundus may be produced.
Muscular symptoms: Muscle pain (spontaneous pain, tender-
ness, gripping pain) and weakness occur symmetrically in the
trunk, the proximal regions of the extremities, and the neck. Dis-
g
order of the proximal muscles causes difficultiesp in ascending
q
a b c d e f h i j k l m n o r
and descending stairs and other walking. Weakness of the pha-
ryngeal muscle group may lead to dysphagia, dysphonia and res-
piratory disturbance.
Other symptoms: Raynaud’s symptoms, multiple arthralgia,
subcutaneous calcium deposition, pulmonary fibrosis, myocardi-
tis and sometimes interstitial pneumonia occur.
Clinical images are available in hardcopy only. Dermatomyositis in children: It may be caused secondarily
after a vaccination or a viral or bacterial infection. Muscular
symptoms are preceded by cutaneous symptoms (Fig. 12.15).
Subcutaneous and muscular calcium deposition is found in 10%
to 20% of all cases, frequently causing dyskinesia. It progresses
b c d e f g h i rather
j chronically.
k l Myoatrophy,
m n articular
o contracture
p q and rsubcu-
Fig. 12.14-1 Dermatomyositis (DM). taneous calcium deposition are seen. Fever and muscular weak-
a: Diffuse, edematous erythema accompanied by ness may occur. The patients may die from multiple ulcers of the
itching on the trunk. b: Itchy erythema on the gastrointestinal tract.
back. c: An atrophic, erythematous plaque on the
knee.
Viral infection, autoimmunity, and allergy to malignant tumors
or infection are known to be involved in DM; however, the
pathogenesis is unknown.
Complications
Malignant tumor of the internal organs is found as a complication
in 30% to 40% of adult cases. The incidence is even higher when

severe edema and intense itching are present. Stomach cancer,
breast cancer, lung cancer and malignant lymphoma are frequent-
ly caused as complications. Malignant tumor is rarely seen as a
complication in children.
Pathology
Edema in the upper dermal layer and mild thickening of the
basement membranes (staining positive in PAS) are major find-
ings in the early stages of erythematous eruptions. As the lesions
a of the
b basalc d e f g h i j k
progress, cutaneous atrophy, vacuolar degeneration
cell layer, mucin deposition, telangiectasia, swelling of collagen
fibers, lymphocytic infiltration and increase of histiocytes in the
tissue are found, and these resemble the erythematous histology
of SLE. Immunoglobulins and complement deposition on the
skin are rarely seen. In muscle tissue biopsied from a painful site,
myositis symptoms are present.
Laboratory findings
a b c d e f g h i j k
Nonspecific inflammatory reactions such as leukocytosis and 12l
Table 12.7 Classification criteria for DM and PM.

Criteria
1. Skin lesions
(a) Heliotrope rash (red-purple edematous erythema on the upper Clinical images are available in hardcopy only.
palpebra)
(b) Gottron’s sign: purplish-red erythema accompanied by hyperkeratosis
and atrophy on the dorsum of finger joints
(c) Erythema on the extensor surface of extremity joints: slightly raised
red-purple erythema over elbows or knees
a
2. Proximal muscle weakness (upper or lower b
extremities c trunk)
and d e f g h i j k l m
3. Elevated serum CK (creatine kinase) or aldolase level
4. Muscle pain on grasping or spontaneously
5. Myogenic changes in EMG (short-duration, polyphasic motor unit
potentials with spontaneous fibrillation potentials)
6. Positive anti-Jo-1 (histadyl tRNA synthetase) antibody Clinical images are available in hardcopy only.
7. Nondestructive arthritis or arthralgia

8. Systemic inflammatory signs (fever: more than 37˚C at axilla, elevated
serum CRP level or accelerated ESR of more than 20 mm/h by the
Westergren method) a b c d e f g h i j k l m n
9. Pathological findings compatible with inflammatory myositis (inflammatory Fig. 12.14-2 Dermatomyositis (DM).
infiltration of skeletal evidence of active regeneration may be seen.) d: Poikiloderma on the neck and cheek. e:
Diagnosis Intense edema and purplish eruptions on the eye-
lids (heliotrope rash). f: Multiple, scattered,
Dermatomyositis Patients presenting at least one item from the first criterion sharply margined, keratotic erythema several
and four items from the second through ninth criteria millimeters in diameter on the extensor joints of
Polymyositis Patients presenting no items from the first criterion and DIP and PIP of fingers (Gottron’s sign). g:
at least four items from the second through ninth criteria Telangiectasia of nail folds.
Differential Diagnosis
Myositis caused by infections, drug-induced myopathy, myopathy resulting
from endocrinopathy, muscular dystrophy, other congenital myopathies
(Tanimoto K. et al. Classification criteria for polymyositis and dermatomyosi-
tis. J Rheum 1995; 22 : 668-74).
elevated erythrocyte sedimentation rate are the only symptoms in

the early stages. Rheumatoid factors and antinuclear antibodies
are positive in 60% to 80% of cases. Myogenic enzymes such as
CPK, aldolase, GOT and LDH in serum are elevated, and crea-
tine in urine and myoglobin are elevated by myositis. Specific
antibodies such as anti-Jo-1 (histidyl tRNA synthetase) antibod-
ies and anti-PL-7 (threonyl-tRNA synthetase) antibodies are
found (Table 12.9). Skin and muscle biopsy findings and
myogenic changes in electromyography are also important for
diagnosis.
Diagnosis
DM can be easily diagnosed by the characteristic cutaneous
manifestations, muscular symptoms and laboratory findings.
However, in early stages it is difficult to confirm the diagnosis
only by the eruptions. The major diagnostic criteria are shown in
Table 12.7.
Treatment
12 a b c d e f g i j tumor
h If a malignant k is involved,
l mit is treated
n o p Sys-q
primarily. r
temic steroids are the main treatment. Steroid pulse therapy is
performed in severe cases. Immunosuppressants may also be
administered.
Prognosis
Clinical images are available in hardcopy only. If steroid therapy is given in the early stages, reduced muscular
symptoms and decrease of serum CPK are observed in about
80% of cases, which makes a normal life possible. However, pro-
longed steroid treatment is required in many cases. Life
expectancy depends on the severity of malignant tumors and on
a b c d e f g h heart
i orj lung complications.
k l mThe mortality
n orate ofp patients
q withr
Fig. 12.15 Dermatomyositis (DM) in children. the complication of interstitial pneumonitis is particularly high.
a: Diffuse erythema accompanied by scaling on Patients whose onset is in their youth tend to have a good life
the face and trunk. b: The cheeks are most com- expectancy.
monly show with diffuse erythema. The skin
lesion clinically resembles butterfly rash in SLE.
2. Mixed connective tissue disease (MCTD)
Outline
● Symptoms of SLE, SSc, and PM/DM are seen; nonethe-
less, it does not meet any of the diagnostic criteria of
these diseases.
● Anti-U1RNP antibodies and Raynaud’s syndrome are
Amyopathic MEMO
dermatomyosis positive. Sausage-like fingers are present.
Dermatomyosis without myositis (proximal ● Pulmonary hypertension may develop as a complication,
muscular weakness and laboratory evidence and this greatly influences the prognosis.
of myositis) but with typical cutaneous symp-
● It is internationally controversial whether MCTD is an
toms of dermatomyosis such as Gottron’s
sign and heliotrope rash is called amyopathic independent entity.
dermatomyosis (ADM). Systemic symptoms
may occur rapidly; therefore, careful observa- Clinical features
tion is required.
Mixed connective tissue disease (MCTD) most frequently
occurs in women in their 40s. The typical pathological features

are Raynaud’s phenomenon, multiple arthralgia (inflammation),
and swelling in the dorsal hands (sausage-like swelling). SLE-
like symptoms such as erythema and fever, SSc-like symptoms
such as lung fibrosis and esophageal reduction, and PM- and
DM-like symptoms such as inflammatory myositis and muscular
weakness are seen. Renal disorders and central nervous disorders
are not usually present. From these symptoms, collagen disease
may be suspected; however, most cases do not meet the diagnos-
tic criteria of SLE, SSc or DM/PM.
Laboratory findings
MCTD is characterized by high titers of anti-U1RNP antibod-
ies in serum. Collagen disease conditions cause positive rheuma-
toid factor, reduction in pulmonary diffusing capacity, elevation
of myogenic enzyme, pancytopenia and hypergammaglobuline-
mia.
Diagnosis
There are various diagnostic criteria. Those published in 1996 12
by the research division of the Health and Welfare Ministry of
Table 12.8 Guidance for diagnosis of mixed connective tissue disease (MCTD).
Concept Diagnosis
MCTD is a disease in which the symptoms and findings of 1. Positive for one or both of the common findings
SLE, SSc, and polymyositis are present. Anti-U1RNP 2. Anti-U1RNP antibody positive
antibodies are serologically observed. 3. Positive for two or more items in A, B or C of III, and at
least one item in A , B, and C
I. Common findings
MCTD is diagnosed by all three items above.
Raynaud’s phenomenon
Additional note
Swelling in fingers and dorsa of hands
1. Anti-U1RNP antibody is detected either by double immun-
II. Immunological findings
odiffusion (DID) or by ELISA. If DID is positive and ELISA.
Anti-U1RNP antibody positive is not, the DID result has priority.
III. Mixed findings 2. Diagnosis of MCTD is carefully made when the following
A) SLE-like findings labeled antibodies are positive.
1. Thrombocytopenia 1) Anti-Sm antibody
2. Lymphadenopathy 2) High titers of anti-dsDNA antibody
3. Erythema on the face 3) Antitopoisomerase I antibody (anti-Scl-70 antibody)
4. Pericarditis or pleuritis 4) Anti-Jo-1 antibody
5. Leukopenia (≦ 4000/ml） or thrombocytopenia (≦ 3. Cases of pulmonary hypertension with positive anti-U1RNP
10,0000/ml） antibody are likely to be diagnosed as MCTD in the future,
B) SSc-like findings even if other symptoms do not meet the criteria.
1. Hardening of skin in the fingers
2. Pulmonary fibrosis, restrictive ventilatory defect (%VC ≦
80%), or decreased pulmonary diffusing capacity
(%DLco ≦ 70%)
3 Diminished esophageal peristalsis, or esophageal
enlargement
C) Polymyositis-like findings
1. Muscle weakness
2. Increased myogenic enzyme (CK)
3. Electrographic finding of myogenic abnormality
(Tohjo T. A diagnostic criteria for MCTD. In: Torikai K, Kashiwagi H, Tohjo T, editors. MCTD studying group in the Ministry of Health
and Welfare in Japan. A guideline for treatment of mixed connective tissue disease. 1996: 4-9).
Table 12.9 Major specific autoantibodies in Japan are shown in Table 12.8. There is international disagree-
collagen diseases and diseases related
to collagen disease. ment on the diagnostic criteria of MCTD. They require further
deliberation and discussion.
Disease Autoantibody
SLE Anti-dsDNA antibody Treatment
Anti-Sm antibody
Systemic steroids are fairly effective. Vasodilators such as cal-
SSc Anti-Scl-70 antibody
Anti-centromere antibody (ACA) cium antagonists and NSAIDs are the main agents used for Ray-
Anti-Mi-2 antibody naud’s syndrome and arthralgia. Systemic steroids, oxygen
DM/PM Anti-Jo-1 antibody inhalation, and vasodilators are helpful for pulmonary hyperten-
Anti-PL-7 antibody sion.
Anti-Mi-2 antibody
MCTD Anti-RNP antibody Prognosis
(Anti-U1RNP antibody)
The kidneys and central nervous system are not affected, and
Overlap Anti-dsDNA antibody
syndrome Anti-Sm antibody
steroids are highly effective; MCTD generally has a good prog-
Anti-Scl-70 antibody nosis. However, when pulmonary hypertension is involved as a
Anti-Jo-1 antibody complication, the prognosis may be poor.
Anti-Ku antibody
Sjögren Anti-SS-A antibody
syndrome Anti-SS-B antibody 3. Overlap syndrome
12
Outline
● This is the name for SLE, SSc or DM/PM whose symp-
toms meet diagnostic criteria for 2 or more collagen dis-
eases. The collagen diseases do not need to occur
simultaneously.
● Many cases meet the diagnostic criteria of both SLE and
SSc.
Clinical features
92% of patients with overlap syndrome are women. When
patients have both SLE and SSc, they frequently have fever, Ray-
naud’s phenomenon, polyarthritis, ulceration of the fingertips,
and pericarditis. Vascular lesions frequently occur, resulting in
poor prognosis.
Pathogenesis
The pathogenesis is unknown. Hereditary factors are thought
to cause overlap syndrome, in conjunction with environmental
factors; however, the influential hereditary factors are unknown.
Antibodies that are detected specifically for each collagen disease
(labelled antibodies) are found independently or simultaneously.
Laboratory findings
Elevated erythrocyte sedimentation rate and polyclonal hyper-
gammaglobulinemia are seen. SLE-specific antibodies (anti-
dsDNA antibodies, anti-Sm antibodies), SSc-specific antibodies
(anti-Sc1-70 antibodies), and PM-specific antibodies (anti-Jo-1
antibodies) are positive. Anti-Ku antibodies are positive when
SSc and PM occur simultaneously (Table 12.9).
Diagnosis
The symptoms of overlap syndrome meet the diagnostic crite-
ria for various collagen diseases. When anti-U1RNP antibodies
are positive and the diagnostic criteria of MCTD are met, the dis-
ease is often diagnosed as MCTD.
Treatment
As a general rule, the most significant symptom is treated
according to the treatment guidelines for each collagen disease.
4. Anti-phospholipid antibody syndrome

(APS) Clinical images are available in hardcopy only.
Outline
● This disorder is caused by antibodies produced against
phospholipids whose antigens are various. It tends to
accompany SLE.
● Anti-phospholipid antibody is a general term that
includes anti-cardiolipin antibodies and lupus anticoagu- 12

lants.
● Thrombosis, habitual abortion, ischemic heart disease,
distal cyanosis, ulceration in the lower legs, and livedo

reticularis are caused.
Clinical features Fig. 12.16 Anti-phospholipid antibody syn-

Livedo reticularis, purpura, subcutaneous nodules, fingertip drome (APS).
Intractable skin ulcer and purpura on the lower
ulceration and gangrene are caused by thrombotic vasculitis in leg of a middle-aged postmenopausal female.
the cutaneous blood vessels (Fig. 12.16). Cutaneous vasculitis is This ulceration results from circulatory disorder
pathologically seen. SLE-like symptoms (e.g., butterfly rash, caused by angioma that is induced by anti-phos-
pholipid antibodies.
DLE, photosensitivity) may appear. Thrombophlebitis is often
found. In addition to cutaneous symptoms, the thrombosis can
cause pulmonary embolism, transient ischemic attack, cerebral
infarction, Budd-Chiari syndrome and myocardial infarction.
Another typical symptom is habitual abortion. Thrombus formed
in the placenta is known to cause the inadequate placental func-
tion that is frequently seen in the fifth or sixth month of pregnan-
cy. About 20% of habitual abortions in the absence of obvious
underlying disease are thought to result from anti-phospholipid
Anti-phospholipid MEMO
antibody syndrome (APS).
antibody syndrome (APS)
Lupus anticoagulant, an immunoglobulin that
Pathogenesis prolongs the activated partial thrombolastin
Anti-phospholipid antibodies, often abbreviated as a PL, con- time (APTT) without inhibiting coagulation
factor activation, and biologic false positive
tain anti-cardiolipin antibodies (antibodies to b -2 glycoprotein I) of syphilis are frequently observed in APS.
and lupus anticoagulants. b -2 glycoprotein I plays a role in anti- This has been recognized since the 1950s. In
coagulation, such as by inhibiting prothrombinase activity and the 1980s, extensive examination showed that
cardiolipin is the only antigen of the disease,
the formation of activated X factors. Accelerated blood coagula- and the name was changed to anti-cardiolipin
tion is thought to be caused by disruption of these functions. antibody syndrome. From further examina-
From recent studies it has been widely accepted that a complex tion, it has become clear that the antigens are
various phospholipids; the disease is now
of b -2 glycoproteins I and phospholipids (cardiolipin) accelerates called APS.
blood coagulation by connecting with a PL.
Laboratory findings
Anti-cardiolipin antibodies and lupus anticoagulants are posi-
tive. The anti-cardiolipin antibody titer increases when patients
are infected with syphilis. In serological test for syphilis, the
most reactive antibodies are anti-cardiolipin antibodies. Biologi-
Clinical images are available in hardcopy only. cal false positive is observed. Lupus anticoagulants inhibit phos-
pholipid-dependent blood coagulation reactions, leading to
prolongation of the APTT; however, the thrombin time is normal.
Since APS has a thrombotic tendency, thrombocytopenia is often
seen. Positive anti-cardiolipin antibodies in the absence of
syphilis infection is biological false positive.
Treatment
Anticoagulant therapy using heparin and warfarins is effective
for cases with thrombosis. Small doses of aspirin and simultane-
ous use of steroids are helpful in preventing abortion. It has been
reported that plasmapheresis, megadoses of human immunoglob-
ulins and megadoses of steroids are useful.
12
5. Sjögren syndrome
Synonym: Sicca syndrome
Outline
● This is an autoimmune disease which mainly targets
exocrine glands, including the salivary glands and
lacrimal glands.
● Annular erythema and purpura due to vasculitis are char-
acteristic skin features.

● Xerostomia, keratoconjunctivitis sicca and distal renal
tubular acidosis occur. Tooth decay is frequently caused

by dryness of the mouth.
● Anti-SS-A antibodies and anti-SS-B antibodies are posi-
Clinical images are available in hardcopy only. tive.

● Hashimoto’s disease (chronic thyroiditis) and B-cell lym-
phoma occur as complications.

● Symptomatic treatments and steroid administration are
the main treatments.
Classification
When there are only the characteristic symptoms of Sjögren
syndrome unaccompanied by any other collagen disease, it is
Fig. 12.17 Sjögren syndrome.
It begins with elevated, edematous erythema called primary Sjögren syndrome (sicca syndrome). Cases with
1 cm in diameter. The erythema gradually enlarges other collagen diseases such as SLE are diagnosed as secondary
and becomes ring-shaped. It occurs multiply in Sjögren syndrome.
most cases. The center of the erythema tends to
heal, and there is severe infiltration at the periph-
ery. Sjögren syndrome resembles the skin lesions Clinical features
seen in neonatal lupus erythematosus. Sjögren syndrome most commonly occurs in adults in their
30s to 50s and affects 9 females for every 1 male. The character-
istic cutaneous symptoms are annular erythema and purpura
accompanying vasculitis. Punctate hypergammaglobulinemic
purpura is recurrently seen in the lower extremities. Extended Table 12.10 Complications of Sjögren syn-
drome.
macular purpura may also occur (refer to the section on clyoglob-
ulinemic purpura in Chapter 11). Annular erythema, either ede- Other autoimmune SLE, SSc, PN, PM/DM,
diseases annular erythema, ITP
matous or urticarial, that is sharply margined and 1 cm to 5 cm in
Joints Rheumatoid arthritis
diameter is seen (Fig. 12.17). There is a close relationship
between anti-SS-B antibodies and edematous annular erythema. Thyroid Hashimoto’s disease
Annular erythema frequently occurs multiply on the face, healing Blood and lymphatic Autoimmune hemolytic
system anemia, lymphoma,
spontaneously in about 2 weeks or sometimes persisting longer. hypergammaglobulinemia,
Dry skin, telangiectasia, hair loss, butterfly rash, chilblain erythe- hypermacroglobulinemia
ma and nodular erythema also occur. Lungs Interstitial pneumonia
Eye symptoms: Keratoconjunctivitis sicca, photophobia, pain, Stomach Atrophic gastritis
itching and lacrimal disorder occur.
Pancreas Acute pancreatitis
Oral symptoms: Dryness of the mouth, dysphagia, and sharp
Liver Primary biliary cirrhosis
pain in the mouth are caused by affected salivary glands. Tooth
decay, angular cheilitis and oral candidiasis occur secondarily. Kidneys Renal tubular acidosis
Other mucosal symptoms: Lesions are found in the nasal

Table 12.11 Revised version of the European
cavity, pharynx, larynx, bronchial tubes, external genitalia and classification criteria for Sjögren syn-
alimentary mucosa. drome (2002).
Other symptoms: Raynaud’s phenomenon, arthralgia, fever, I. Ocular symptoms: a positive response to at least one
fatigue, myalgic pain, lymph node enlargement and interstitial of the following questions: 12
1. Have you had daily, persistent, troublesome dry
pneumonia occur. When B-cell lymphoma is produced, the prog- eyes for more than 3 months?
nosis is adversely affected. 2. Do you have a recurrent sensation of sand or
gravel in the eyes?
3. Do you use tear substitutes more than 3 times a
Pathogenesis day?
II. Oral symptoms: a positive response to at least one
The pathogenesis has not been identified. of the following questions:
1. Have you had a daily feeling of dry mouth for
Complications more than 3 months?
2. Have you had recurrently or persistently swollen
Sjögren syndrome tends to accompany SLE and rheumatoid salivary glands as an adult?
3. Do you frequently drink liquids to aid in swallowing
arthritis. SSc, polyarteritis nodosa, polymyositis, idiopathic dry food?
thrombocytopenic purpura, Hashimoto’s disease, autoimmune III. Ocular signs - that is, objective evidence of ocular
hemolytic anemia, primary biliary cirrhosis, renal tubular acido- involvement defined as a positive result for at least
one of the following two tests:
sis and malignant lymphoma may occur as complications (Table 1. Shirmer’s test, performed without anaesthesia (≦
5 mm in 5 minutes)
12.10). 2. Rose bengal score or other ocular dye score (≧ 4
according to van Bijsterveld’s scoring system)
Pathology IV. Histopathology: In minor salivary glands (obtained
through normal-appearing mucosa) focal
Annular erythema shows pathological features similar to those lymphocytic sialoadenitis, evaluated by an expert
of SLE and SCLE. Typically, the secretory glands are densely histopathologist, with a focus score ≧ 1, defined as
a number of lymphocytic foci (which are adjacent to
infiltrated by lymphocytes and plasma cells. Labial biopsy of normal-appearing mucous acini and contain more
minor salivary glands has prognostic value. Skin biopsy of the than 50 lymphocytes) per 4 mm2 of glandular tissue
V. salivary gland involvement: objective evidence of
purpura shows involvement of vasculitis in the small blood ves- salivary gland involvement defined by a positive result
sels. Immunoglobulin deposition may be found in the blood ves- for at least one of the following diagnostic tests:
1. Unstimulated whole salivary flow (≦ 1.5 ml in 15
sels. minutes)
2. Parotid sailography showing the presence of diffuse
sialectasias (punctate, cavitary, or destructive pattern),
Laboratory findings without evidence of obstruction in the major ducts.
Schirmer test, Rose-Bengal test and fluorescent dye test are 3. Salivary scintigraphy showing delayed uptake,
reduced concentration and/or delayed excretion of
ophthalmologically performed to identify lacrimal tear gland tracer
abnormality. Otologically, apple-tree appearance is observed by VI. Autoantibodies: presence in the serum of the
following autoantibodies:
parotid gland radiography, and salivary gland dysfunction can be 1. Antibodies to Ro (SSA) or La (SSB) antigens, or both
detected by parotid gland scintigram. Serologically, antinuclear (Vitali C, et al. Classification criteria for Sjögren’s syn-
antibodies, anti-SS-A antibodies, anti-SS-B antibodies and anti- drome: a revised version of the European criteria pro-
posed by the American-European Consensus Group.
RNP antibodies are positive. Elevated levels of immunoglobulin, Ann Rheum Dis 2002;61:554-8).
salivary amylase and rheumatoid factor may be present. Anti-SS-

A antibodies tend to show high sensitivity in Sjögren syndrome,
and anti-SS-B antibodies tend to show high specificity for
Sjögren syndrome.
Diagnosis
Currently, Sjögren syndrome is diagnosed by clinical features
according to diagnostic criteria established by European diagnos-
tic criteria (Table 12.11).
Treatment
The main treatments are symptomatic therapies, because no
effective pharmacologic therapy is available. Mouthwash, treat-
ment for periodontal disease, and administration of artificial sali-
va and of artificial tears for protection of the cornea are the main
therapies. Large doses of internal steroids and immunosuppres-
sants are administered in severe cases in which systemic angio-
pathic lesion or malignant lymphoma occurs as a complication.
12
D. Rheumatic diseases with arthritis
1. Rheumatoid arthritis (RA)
Outline
● This collagen disease causes sharp pain and swelling in
the joints.
● Rheumatoid nodules and cutaneous lesions accompany-
ing vasculitis are found.

● Chronic inflammation occurs in the synovial membranes
of joints. The articular cartridges and bones are

destroyed by synovial proliferation.
● Diseases closely related to RA include juvenile rheuma-
toid arthritis, adult Still disease, ankylosing spondylitis,

psoriatic arthritis and Reiter syndrome.
Clinical features
Fig. 12.18 Rheumatoid vasculitis.
The primary disease of rheumatoid arthritis (RA) is symmetri-
cal arthritis. In dermatology, RA is characterized by rheumatoid
nodules and cutaneous lesions that accompany vasculitis (Fig.
12.18). Rheumatoid nodules are found in 20% to 25% of patients
with RA. The nodules, 0.5 cm to several centimeters in diameter,
are painless, solid, subcutaneous nodules frequently produced on
sites where the skin is subjected to pressure, such as the knees,
hips, Achilles tendons and occipital region. They persist for a
long time, sometimes rupturing and causing secondary infection.
Ulceration on the fingertips and elsewhere, gangrene, purpura,
blistering, and livedo accompany rheumatic vasculitis. RA is usu-
ally accompanied by extracapsular symptoms, such as pericardial
D. Rheumatic diseases with arthritis 183
inflammation, interstitial pneumonitis, peripheral neuritis and Table 12.12 1987 revised criteria for the
classification of rheumatoid arthritis.
uveal inflammation.
1. Morning stiffness lasting at least 1 hour
2. Arthritis of 3 or more joint areas
Pathology
3. Arthritis of hand joints (at least 1 area swollen
Three-layered palisading granuloma is found at sites with in a wrist, MCP, or PIP joint)
rheumatoid nodules. This granuloma is fibrinoid degeneration of 4. Symmetric arthritis
5. Rheumatoid nodules
collagen fibers surrounded by histiocytes, which is further sur- 6. Serum rheumatoid factor
rounded by inflammatory cells such as lymphocytes and plasma 7. Radiographic changes
cells (Chapter 2). In rheumatic vasculitis, immunocomplex depo- For classification purposes, a patient shall be said
sition is seen on the vascular walls at sites where lesions have to have rheumatoid arthritis if he/she meets 4 of
occurred, and obstructive changes are often caused by thickening these 7 criteria. Criteria 1through 4 must have
been present for at least 6 weeks.
of endothelium and leukocytoclastic vasculitis.
(American college of Rheumatology Classification
Criteria of Rheumatoid Arthritis [1987]).
Laboratory findings
Inflammatory findings such as elevated erythrocyte sedimenta-
tion rate, leukocytosis, thrombocytosis, CRP positive, and
increases in human immunoglobulins and complement titer are
seen. Rheumatoid factors (mainly IgM antibodies that react
against abnormally produced IgG) are positive in 80% to 90% of
RA cases. The degree of progression of RA can be determined by 12
diagnostic imaging.
Diagnosis
The diagnostic criteria are listed in Table 12.12. Clinical images are available in hardcopy only.
Treatment
Besides pharmacologic therapies such as NSAIDs, treatments
for RA include disease-modifying anti-rheumatic drugs (e.g.,
DMARDs such as gold preparations, D-penicillamine, methotrex-
ate) and steroids. Biological agents such as infliximab, adali-
mumab and etanercept are now covered by health insurance in
Japan. Rehabilitation and lifestyle guidance are also important.
2. Adult Still disease

Synonyms: Subsepsis allergica, Wissler-Fanconi syndrome
Outline
● The three main symptoms are salmon-pink rheumatoid
eruptions, intermittent and remittent fever, and arthritis.
● The laboratory findings are elevated erythrocyte sedi-
mentation rate, leukocytosis, rheumatoid factor negative

and marked increase in ferritin.
Clinical features
Adult Still disease most frequently occurs in young women
aged 16 to 35. Fever, arthritis, and specific cutaneous symptoms
are found.
Cutaneous symptoms: Salmon-pink rheumatoid eruptions occur
on the trunk, extremities and face (Fig. 12.19). Itching is not usu-
ally present. Fig. 12.19 Adult Still disease.
Other symptoms: Intermittent fever persists for more than a

week, rising in the evening and at night and falling in the morn-
ing (evening spike). Arthritis occurs in the large joints (hands,
knees, feet, elbows) in all cases. Splenomegaly, lymph node
enlargement, epicarditis, and myalgic and pharyngeal pain also
occur.
Laboratory findings
Elevated erythrocyte sedimentation rate, strong positive CRP,
anemia, leukocytosis and increase of complement titer are caused
by inflammation. Negativity of antinuclear antibodies and
rheumatoid factor differentiates this disease from other collagen
diseases. Adult Still disease is characterized by elevated levels of
serum ferritin, which may be ten times the normal level. The fer-
ritin level indicates the disease’s degree of activity.
Treatment
Mainly oral steroids and NSAIDs are administered. Antibiotics
are ineffective. The effectiveness of treatment is measured by the
12 CRP and serum ferritin values.
Prognosis
The life expectancy for adult Still disease is good. Amyloido-
sis may occur.
3. Juvenile rheumatoid arthritis (JRA)

Juvenile rheumatoid arthritis (JRA) is thought to be the same
as Still disease when the patient is under age 16. The pain is rela-
tively mild. It is the most common pediatric collagen disease.
Chronic synovitis, morning stiffness and rheumatoid eruptions
are found. Since the rheumatoid factor is negative, JRA is
thought to differ in etiology from RA.
JRA is divided into systemic (Still disease; the main symptoms
are extracapsular), polyarticular (accounting for 30% of all chil-
dren with JRA; five or more joints are affected), and pauciarticu-
lar (accounting for about half of all children with JRA; four or
fewer joints are affected). In systemic JRA, intermittent and
remittent fever precedes rheumatoid eruptions or arthritis. Lymph
node enlargement, splenohepatomegaly, pericarditis and pleuritis
may also occur. Arthritis is the main symptom in both polyarticu-
lar JRA and pauciarticular JRA; other symptoms rarely occur.
Elevated erythrocyte sedimentation rate, positive CRP and
leukocytosis are present as findings of inflammation; however,
there are few findings that are specific to JRA. Seventy to eighty
percent of patients with JRA heal without any serious disorders.
Pauciarticular JRA has the best prognosis of the three types.
D. Rheumatic diseases with arthritis 185
4. Reiter’s disease
Outline
● Men aged 10 to 30 are most frequently affected. After
prodromes such as diarrhea, the three characteristic
symptoms of polyarthritis, urethritis and conjunctivitis
occur.
● Erythema, pustules, and hyperkeratosis occur in the
palms and soles. Balanitis circinata is produced.

● Reiter’s disease is closely related to HLA-B27.
● It heals spontaneously within 6 months in most cases.
Clinical features
Men in their 20s are most commonly affected. The incidence is
20 males to 1 female. Inflammatory symptoms such as urethritis
(or uterocervical inflammation; most cases are sexually transmit-
ted) and bacterial diarrhea precede Reiter’s disease. When the
prodromes subside, arthritis, conjunctivitis and cutaneous symp-
toms appear. Erythema or papules are produced in the palms and 12
soles, coalescing to form hyperkeratotic nodules. The lesions are
accompanied by pustules. Balanitis circinata (painless shallow
erosion) and keratosis in nails also occur.
Laboratory findings
HLA-B27 is positive in 90% of cases. The disease cannot be
pathologically differentiated from psoriasis. Calcification is
observed in the calcanei, fingers and phalanx regions by X-ray.
Sacroiliac articulation and ossification in the vertebral ligament
may be found. The lesions caused by Reiter’s disease are unilat-
eral; differentiation from ankylosing spondylitis is possible.
Treatment
NSAIDs are used primarily. Steroids and immunosuppressants
may be administered in severe cases.
Prognosis
Arthralgia recurs; however, most cases subside in about 6
months.
Chapter
13 Physiochemical Injury and
Photosensitive Diseases
An important role of the skin is to protect the body from extrinsic stimuli such as sunlight, heat and cold. Melanin
pigment and intercellular bridges in the epidermis prevent DNA from being damaged by sunlight and ultraviolet
rays. Perspiration and blood capillaries work to maintain the body temperature. The horny cell layer and inter-
cellular bridges protect the body from mechanical shock. Nonetheless, skin barrier functions can be destroyed
when extrinsic stimuli exceed a certain level, resulting in injury such as electrical burn, chemical burn, frostbite,
radiation damage and solar dermatitis. This chapter introduces skin disorders and photosensitive diseases with
physiochemical causes.
Physiochemical injury
1. Burns (Fig. 13.1)
Outline
13 ● Burns are injuries to cutaneous tissues caused by high
temperature. The damage is divided by depth into first,
second, and third degree.
Clinical images are available in hardcopy only. ● Burn size is measured by “the rule of nines” or “the rule
of fives.”
● The basic treatment is cooling. Systemic intensive care
or escharotomy may be necessary for severe cases.

● The first infusion, if necessary, is lactated Ringer’s solu-
tion, whose amount is decided according to the extent of

burn (e.g., by the Baxter method).
Fig. 13.1 Burn. Clinical features, Classification

Second-degree burn. Mix of superficial dermal
burn (SDB) and deep dermal burn (DDB), caused Burn severity is evaluated by depth, size and patient’s condition.
by hot water. ①Classification of burn by depth (Table 13.1)
The depth of a burn depends on the temperature of the heat
source and the contact time. Burns are classified into first-degree,
second-degree and third-degree. However, the severity is difficult
to determine immediately after a burn. A burn may deepen with
time after the burn incident.
Table 13.1 Diagnosis of burn by depth and clinical features.

Diagnosis Synonym Clinical Findings Treatment Aftereffects
First-degree burn Epidermal burn Painful erythema, edema Application of Scarring (-)
ointment
Second-degree burn Superficial dermal burn (SDB) Painful blisters with clear fluid and red Application of Heals in about 2
blister bottoms ointment weeks, scarring (-)
Deep dermal burn (DDB) Hypalagesic blisters with white bottoms Débridement, Heals in 3-4 weeks,
skin graft scarring (+)
Third-degree burn Deep burn (DB) Grayish-white or brown carbonized skin Débridement, Scarring (+)
Pain is usually absent. skin graft
186
Physiochemical injury / 1. Burns 187
First-degree burn (epidermal burn): Painful erythema and

edema occur, healing in 3 to 4 days without scarring.
Second-degree burn (dermal burn): Intense burning sensation
is present. Erythema is followed within several hours by tense
blistering (Fig. 13.2).
Second-degree burn is subclassified into superficial dermal
burn (SDB) and deep dermal burn (DDB). SDB presents as
painful blisters whose bottoms are rose pink; there is mild dam- Clinical images are available in
age to the dermis, which heals without scarring in about 2 weeks. hardcopy only.
DDB affects the deep dermal layer and heals with scarring in 3 to
4 weeks. The bottom of a DDB blister is white and has reduced
sensation. DDB often progresses to third-degree burn.
Third-degree burn (deep burn): All cutaneous layers and
sometimes even deeper areas are damaged (Fig. 13.3). The skin
appears gray-white. Blistering is not present, or the skin is car-
bonized to appear brownish. It becomes necrotic: Eschar forms and a b c d e f g h
autodestruction occurs. Proliferation of the epidermis around the
burn is the only spontaneous recovery; skin graft may be necessary.
A needle is sometimes used to examine the severity. The nee-
dle is stuck gently into the skin of the affected area; if it is
painful, the diagnosis is second-degree burn; otherwise, the diag-
nosis is third-degree burn. If hairs come out when pulled gently, 13
the diagnosis is DDB or third-degree burn.
②Estimating the burn extent
“The rule of nines” is generally adopted to determine the
extent of burns in adults; “the rule of fives” or the Lund and
Browder chart is used for children (Fig. 13.4). a b c d e f g h i
③Evaluation of burn severity
Systemic intensive care is conducted in cases of second-degree
burn on 10% or more of the body in children and on 15% or
more in adults. Cases with 15% or greater burn index score (Fig.
13.4) are treated as severe burn.
Pathogenesis
Burns are caused by high temperature. They are extremely
common in infants and children under age 10. However, low-
temperature burns caused by prolonged use of electric pads and
air heaters have been increasing among patients with cerebrovas-
a b c d e f g h i j
cular disease or diabetes (Fig. 13.5). In severe burns, histamines
and cytokines are secreted from damaged tissue, leading to an
increase in systemic vascular permeability. Accordingly, leakage
of plasma proteins and extracellular fluid loss occur, resulting in
burn shock.
Renal disorder, pulmonary edema, disseminated intravascular
coagulation syndrome (DIC), and multiple organ failure may
occur. Respiratory failure may also occur in patients with tra-
cheal edema from inhaling hot air from a fire. Extensive burns
g j
are prone to infection (sepsis), and they tend toa induceb pepticc d e f h i k
ulcer (Curling’s ulcer) within a week after the burn incident. Fig. 13.2 First- and second-degree burns
After epithelization and hypertrophic scar formation or a pro- caused by explosion of a cigarette lighter.
a: Face. b: Back. c: Palms. d: Dorsum of hand.
longed course of burn, squamous cell carcinoma may be caused.
188 13 Physiochemical Injury and Photosensitive Diseases
Clinical images are

Clinical images are available in hardcopy only. available in Clinical images are available in hardcopy only.
hardcopy only.
a b c d e f ga hb ai c bj d cke dl f emg fnh go i hp j iqk jr l

Fig. 13.3 Burns.
a, b: Second-degree burns caused by hot water. Marked blistering is present. c: The epidermis has exfoliated with the stripping of
clothes that were wet with scalding water. Third-degree burn is also present.
（back：18）（back：15）
9 5
（back：15）
15
9 9
13 18 （back：20） 10 10
15
20 10 10
20
1 10 10
20
9 9
15 15 20 20
9 9
10 10
adult infant child adult ＊

（The rule of nines）（The rule of fives）
A A
1 1
2 2 2 2
13 13 Age（years）
11
2 11
2 11
2 11
2 Area
0 1 5 10 15 Adult
21 1
2 22
1 A=1/2 of head 11 1 1 1 1 1
2％ 82％ 62％ 52％ 42％ 42％
11
4 B B 11
4
B B
B=1/2 of one thigh 2 3
4 31
4 4 41
4 42
4 43
4
C C C C C=1/2 of one lower leg 2 1
2 21
2 23
4 3 31
4 31
2
13
4 13
4 13
4 13
4
（Lund and Browder chart）

＊ Add 5% if breast or two legs are burnt.
burn index ＝ 1 ×（area of second-degree burn）＋（area of third-degree burn）
2
Fig. 13.4 Calculation of burn index score.

Physiochemical injury / 2. Chilblain (perniosis), Frostbite 189
In cases with hypertrophic scarring of the surface of joints, con-

tracture may occur.
Treatment
①Local treatment
The primary treatment for burns is cooling with running water
for at least 30 minutes to relieve pain, inflammation and edema.
In second- and third-degree burns, it is important to prevent
infection. Blister puncture may be performed. Appropriate antibi-
otic and incarnative ointments are chosen according to the skin
condition. Affected sites of DDB and third-degree burns are
removed (débridement), and a skin graft may be performed. The g
a b c d e f h
burn depth can be more clearly determined about 2 weeks after
the time of the burn, which often makes it possible to determine
whether the affected site should be treated for conservative
preservation or whether surgical treatment is necessary. In the
case of extensive burns, mesh skin grafts or fresh homografts are
applied. In the event that severe edema disturbs the blood flow in
the extremities, escharotomy is necessary to prevent necrosis.
②Systemic treatment
Airway management and infusion are primarily performed on
patients with severe burns. The Baxter method is a widely
Clinical images are available in hardcopy only. 13
applied infusion therapy (Table 13.2). Infusion fluid is controlled
by monitoring urine output, central venous pressure, and serum
sodium and potassium concentration. Antibiotics or other drugs
are applied systemically under observation if there are signs of
sepsis, peptic ulcer, cardiac failure, pulmonary edema, or renal
dysfunction.
a b c d e f g h i
2. Chilblain (perniosis), Frostbite Fig. 13.5 Third-degree low-temperature burn.
a: This burn was caused by adhering a heated pad
to the skin for a long time during sleep. Although
Outline
the burn seems small and superficial, it is deep
● Chilblains and frostbite are cutaneous disorders caused and third degree. b: Third-degree burn caused by
by exposure to the cold. a hot-water bottle during sleep. The patient has
diabetes and diminished sensation in the periph-
● Edema-like and erythema multiforme-like eruptions are
eral nerves.
caused by local vascular constriction.
● Avoidance of the cold is the basic treatment. It is impor-
tant not to warm the affected sites rapidly.
1) Chilblain, Perniosis
Clinical features
Chilblain (perniosis) occurs most commonly on the hands, fin-
gers, feet, heels, auriculae and cheeks of schoolchildren (Fig. Table 13.2 Parkland (Baxter) formula.
13.6). Chilblains are localized, usually tender, inflammatory,
erythematous, often itchy lesions that may blister or ulcerate. Lactated Ringer’ s solution [4cc x %TBSA (total body
surface area) x weight (kg)] is given for the first 24
Abnormal hypersensitive reaction is thought to be the cause; hours after the time of burn.
however, it is not clear why some people have this reaction while Half the amount is given in the first 8 hours. The
others do not. rest is given in the subsequent 16 hours.
Pathogenesis, Epidemiology
Chilblains are caused by exposure to low temperatures. Small
arteries and veins become congested by repetitive exposure to
cold, and the congestion causes inflammation. The condition
occurs more often in early winter and early spring than in mid-
Clinical images are available in hardcopy only. winter, and is seen even in regions with warm temperatures. In
addition to low temperature, moistness from perspiration and
heredity factors are closely associated with chilblain occurrence.
Treatment
Exposure to the cold should be avoided. The affected sites are
warmed and dried. Massaging is helpful. Vitamin E preparations,
topical steroids, and orally administered peripheral circulatory
dilators may be given.
2) Frostbite
Clinical features
Frostbite is acute freezing of tissues from exposure to extreme
cold. Even just a few seconds of exposure may be sufficient to
13 cause it. The fingers, ears and nose are most easily affected. It
tends to occur in those who are not accustomed to the cold, and
in the elderly. A few severe cases of frostbite in winter mountain
climbers and in drunken persons, and from occupational acci-
dents, have been reported. The skin becomes white to purplish-
red, and reduced sensory perception is accompanied by
hypoesthesia. As it progresses, blistering, necrotic ulceration, and
mummification occur. The depth classification for burns is used
to determine the severity of frostbite (Table 13.1).
Fig. 13.6 Chilblain, Perniosis.
Pathogenesis
Inadequate blood flow and thrombus formation (circulatory dis-
order) is caused when skin is exposed to the cold, leading to inter-
cellular dehydration, destruction of cellular membranes (from
tissue freezing), and blood vessel constriction. Frostbite most fre-
quently occurs at or below –12°C. The length of exposure and
the wind speed are factors in the occurrence and severity of frost-
bite. When the entire body surface is exposed to the cold for a
long period, lethargy may set in and freezing death may result.

Treatment
The affected sites are warmed gradually as an emergency treat-
ment. Rapid warming and strong friction should be avoided. The
sites are warmed with 40˚C water for 20 minutes and kept clean
and protected. Surgical removal and care to prevent infection and
necrosis are necessary. Intravenous vasodilators are useful in
cases where the frostbite is related to circulatory disorder.
Fig. 13.7 Chemical burn.

Physiochemical injury / 5. Radiodermatitis 191
3. Chemical burn
In chemical burn, cutaneous tissues are damaged by acidic,
alkaline or other escharotic chemicals (Fig. 13.7). Acid induces
coagulative necrosis. Crusts appear, and their color depends on
the causative acid (brown for sulfuric acid, yellow for hydrochlo-
ric and nitric acids, and white for hydrofluoric acid). The affected
sites should be flushed with running water immediately. Neutral-
izing agents are not applied. The treatments afterwards are the
same as those for burns.
Fig. 13.8 Electric burn.

4. Electric burn
In electric burn, cutaneous tissues are damaged by the passage
of electrical current (Fig. 13.8). These burns, called “flash
burns,” are caused on sites that come into contact with an electri-
cal current. They result in ulceration and necrosis. Flash burns
spread to become electric burns with dendritic reddening and Clinical images are available in hardcopy only.
ulceration. Lesions are caused by metal contained in electrodes
that melts and fuses to the skin. The treatments are basically the
same as those for burns.
13
5. Radiodermatitis
Synonyms: Radiation dermatitis, Radiation-induced dermati-
tis

● In radiodermatitis, cutaneous lesions are caused by radi-
ation. The condition is divided into acute radiodermatitis,
in which lesions occur immediately after exposure, and
chronic radiodermatitis, in which lesions occur later.
● The treatments are the same as those for burns.
Fig. 13.9 Acute radiodermatitis.
● Actinic keratosis and squamous cell carcinoma (radiation Blistering occurred after electron beam irradia-
cancer) may develop. Surgical removal of the affected tion.
site is also chosen as a treatment.
Clinical features
①Acute radiodermatitis
Acute radiodermatitis is caused by a single large exposure of
radiation. The symptoms vary depending on the amount of irradi-
ation, the site and the patient’s age. With a comparatively small
Kerosene dermatitis MEMO
amount irradiation (up to 5 Gy of gamma rays), erythema occurs
This dermatitis is caused by prolonged con-
several minutes after irradiation and disappears in 2 or 3 days, tact with kerosene. Kerosene dermatitis readi-
followed by edematous erythema, pigmentation, atrophy and ly occurs when kerosene clings to clothing for
telangiectasia. Blistering and erosion are caused by radiation a long period. Characteristic fresh red erythe-
ma, edema, blistering and erosion are seen at
doses between 5 Gy and 10 Gy (Fig. 13.9), and intractable ulcer- the contact site, and the symptoms are similar
ation and burn symptoms are caused by irradiation greater than to those of shallow second-degree burns.
10 Gy. Steroid application is a highly effective treat-
ment. The treatment is the same as for burns
②Chronic radiodermatitis with blistering and erosion.
Chronic radiodermatitis is commonly caused by a small
amount of fractionated radiation. It often occurs on the site where

a malignant tumor has been produced and radiation therapy has
been repeatedly performed. It is also seen in the hands of medical
professionals who deal with radiation (Fig. 13.10). There are four
Clinical images are available in hardcopy only. stages of chronic radiodermatitis: atrophy (atrophy, pigmentation,
alopecia, and telangiectasia, occurring 6 months after the irradia-
tion incident), keratinization (proliferation of horny cells), ulcera-
tion (intractable), and canceration (squamous cell carcinoma or
g basal cell carcinoma,
j
occurring 15 to 20 years after irradiation).
p q
Pathogenesis
Radiodermatitis is caused by exposure to X-rays, radioactive
materials, or corpuscular radiation. All kinds of radiation cause
cutaneous lesions of different severity. Radiation injures intercel-
Clinical images are available in lular genes by DNA degeneration and DNA synthetase inhibi-
hardcopy only. tion, which impairs cellular functions.
Treatment
The treatments for acute radiodermatitis are the same as those
for burns. For chronic radiodermatitis, the affected site is protect-
ed by ointmentk application
l m
and n
bandaging. o
Extrinsic stimulationr
13 Fig. 13.10 Chronic radiodermatitis. should be avoided. Ulcers and tumors are removed and the site is
a: Chronic radiodermatitis on buttocks exposed
to therapeutic irradiation for uterine cancer. repaired with tissue that has good blood circulation, such as by
There is atrophy of skin, pigmentation, telangiec- pedicle flap procedure.
tasia, and ulceration in some areas. The skin
lesion could become the site of origin for squa-
mous cell carcinoma. b: Chronic radiodermatitis 6. Pressure ulcer
in a man in his fifties. Chronic radiolesion-induc-
ing actinic keratosis is present on the flexor of a Synonyms: Decubitus ulcer, Pressure sore, Bedsore
DIP joint. This patient was diagnosed with tinea
manus about 30 years ago and had been treated
with therapeutic soft X-ray irradiation. Clinical features
Pressure ulcers mostly occur in the sacral division, ischial
tuberosity, and ankles (Fig.13.11). Erythema, edema and indura-
tion are produced in areas subjected to constant pressure, and
ulceration develops. Ulcers may be as deep as the bone, or spread
to joints, rectum or vagina. The periphery of the ulcer is erosive
and the lesion is often larger inside than it appears from the out-
side. The bottom of the ulcer is moist and covered by necrotic tis-
sue and accumulated pus. Secondary infection such as by
anaerobic fungi may result in sepsis.
Treatments and skin care are chosen according to the state of
the affected site; therefore, stage classification is important
(Table 13.3).
Pathogenesis
Circulation disorder caused by persistent pressure leads to
necrosis of skin and subcutaneous tissues. It most commonly
Fig. 13.11 Areas most likely to be affected occurs in bedridden elderly and patients with spiral cord injury
by pressure ulcer. who are not able to change position by themselves. Thin persons
The sacral region, ischial tuberosity, and the bony and those who have underlying diseases such as under-nutrition
areas of the skin, including the ankles, which tend to
be subjected to pressure from the body weight dur- and diabetes are also prone to pressure ulcer.
ing bed rest, are most frequently involved.
Physiochemical injury / 7. Dermatitis artefacta 193
Table 13.3 Stages of pressure ulcer.

Shea scale (1975) NPUAP (formerly IAET) stage 1988 AHCPR guidelines (1994)
Stage I In lightly pigmented skin, lesion appears as a defined Reddening persists for more than 30 Non-blanchable erythema of intact skin,
area of persistent redness. In darker skin tones, the minutes after pressure is removed. the heralding lesion of skin ulceration.
lesion may appear with persistent red, blue, or purple Damage is within the epidermis.
hues. Lesions occur within the epidermis.
Stage II Partial-thickness skin loss involving epidermis, dermis, Partial-thickness skin loss involving Partial-thickness skin loss involving
or both. The ulcer is superficial and presents clinically the epidermis dermis or both. The epidermis, dermis or both (e.g.,
as an abrasion, blister or shallow crater. ulcer is superficial and may appear as abrasion, blister, or shallow crater).
The ulcers spread to the dermis and subcutaneous fat. an abrasion blister or shallow crater.
Stage III Full-thickness skin loss involving damage to, Full-thickness skin loss involving Full-thickness skin loss involving damage
or necrosis (death) of, subcutaneous tissue that may damage to, or necrosis of, to or necrosis of subcutaneous tissue
extend down to, but not through, underlying fascia (the subcutaneous tissue, which may extend that may extend down to, but not
sheet of fibrous material overlying muscles). The ulcer down to but not through underlying through, underlying fascia (deep crater
presents as a deep crater with or without undermining fascia. The ulcer may appear as a with or without undermining). The ulcer
of adjacent tissue. deep crater with or without presents clinically as a deep crater with
The muscles are involved. undermining of adjacent tissue. or without undermining adjacent tissue.
Stage IV Full-thickness skin loss with extensive destruction, Full-thickness skin loss with extensive Full-thickness skin loss with extensive
tissue necrosis, or damage to muscle, bone, or destruction tissue necrosis or damage destruction, tissue necrosis, or damage
supporting structures (tendons, joint capsule). Adjacent to muscle bone or supporting to muscle, bone, or supporting
tissue undermining sinus tracts (an abnormal cavity in structures such as joint capsule. structures (e.g., tendon or joint capsule).
the tissue) may also be associated with this stage.
The ulcers spread to the skeletal tissue. The bones
and joints are damaged.
Treatment 13
The primary treatment for pressure ulcer is quick removal or
reduction of pressure to alleviate the impairment of blood flow.
The affected site is locally cleansed, incarnative and antibiotic
ointments are applied, and dressings are applied for protection. In Clinical images are available in hardcopy only.
the chronic stages, the affected site is cleaned with water and the
necrotic tissue is removed. Disinfectant tends not to be used
unless there is apparent infection. It is most essential not to wors-
en the condition.
7. Dermatitis artefacta Fig. 13.12 Akatsuki disease in a woman in

her twenties.
Synonyms: Multiple neurotic gangrene, Hysteric gangrene There is marked deposition of keratin. This
patient hardly ever washed her nipples for fear
that she would contract a skin disease.
Clinical features
Erythema, erosion, gangrene and ulcer occur suddenly, mostly
at sites within reach of the hands (extremities, chest and face).
Right-handed patients tend to have dermatitis artefacta on the left
side of the body. Eruptions may present different appearances Clinical images
according to the cause (e.g., fingernail scratch, knife injury, mis- in hardcopy only.
are available in
use of drug). hardcopy only.
Pathogenesis, Diagnosis
In dermatitis artefacta there are factitious lesions. Patients
with mental stress, hysteria, depression, mental disability or
Fig. 13.13 Navel stone.
schizophrenia injure themselves in the skin, nails or mucous This is so-called bellybutton lint. The patient
membranes. Most patients deny that the injury is self-inflicted. consulted a doctor on what seemed to be a black
The specific types include trichotillomania (Chapter 18) and tumor in the navel. When it was pulled out, there
was a grimey mass of keratin. This patient had
onychotillomania. Akatsuki disease (Fig. 13.12) and navel stone believed the superstition that the navel must not
(Fig. 13.13) resemble dermatitis artefacta; however, they are be washed.
caused by chronic poor hygiene.
Treatment
Cutaneous symptoms should be treated appropriately. If neces-
sary, treatment for mental imbalance may be necessary with
cooperation from a psychiatrist.
Photosensitive diseases
1. Solar dermatitis, Sunburn

Erythema and blisters are produced by prolonged exposure to
sunlight (mainly UVB). Pathologically, sunburn cells (apoptotic
epidermal cells), epidermal spongiosis, edema in the dermal
blood vessels, inflammatory cellular infiltration, necrosis and
subcutaneous blistering are present. Erythema occurs several
hours after photoradiation on the exposed site, and it gradually
13 becomes edematous (Fig. 13.14). Solar dermatitis is most severe
Clinical images are available in hardcopy only. 12 to 24 hours after irradiation, after which it gradually resolves.
Exfoliation and pigmentation occur in several days. Pigmentation
is left after healing in some cases. Application of sunscreen is
helpful for prevention. Cold compresses and steroid ointments
are effective. When blistering is present, the same treatments as
those for burns are applied.
2. Photosensitive dermatoses
a b c d e f g hOutline
i j k l m n o p q r
● Photosensitive dermatoses are cutaneous diseases that

are caused or aggravated by sunlight exposure.
● Both extrinsic factors (e.g., drugs) and intrinsic factors
(e.g., inherited diseases, metabolic disorders) may be

Clinical images are available in hardcopy only. involved.
● They are caused by direct action of drugs (phototoxic
dermatitis) or by immunological mechanism (photoaller-

gic dermatitis).
● Xeroderma pigmentosum is a hereditary photosensitive
a b c d e f g h i dermatosis
j kthat is linduced
m by intrinsic
n ofactors.
p q r
Fig. 13.14 Solar dermatitis, Sunburn.
a: Solar dermatitis caused by sleeping for 3 hours Pathogenesis
on the beach. Blistering is marked. The cuta- The two main causative factors of photosensitive dermatoses
neous symptoms are equivalent to those of first-
degree and second-degree burn. b: The normal
skin, which was under the swim trunks, differs Suntan MEMO
distinctly from the site with solar dermatitis, The skin is darkened by exposure to the sun. Oxidation of melanin
which was sun-exposed. occurs in the epidermis (primary tanning), and there is enhanced pro-
duction of melanin (secondary tanning).
Photosensitive diseases / 2. Photosensitive dermatoses 195
Table 13.4 Main drugs that induce photosensitive dermatosis.

Drug Classification Drugs
Psychoactive Chlorpromazine, promethazine, diazepam, carbamazepin, imipramine
Muscle relaxant Afloqualone
Antihistamine Diphenhydramine, mequitazine
Antibacterial agent Nalidixic acid, enoxacin, ofloxacin, ciprofloxacin, lomefloxacin, sparfloxacin, fleroxacin,
tosufloxacin, tetracycline, doxycyclin
Antifungal agent Griseofulvin, flucytosine, itraconazole
Antiinflammatory Ketoprofen, tiaprofenic acid, suprofen, piroxicam, ampiroxicam, actarit, diclofenac, naproxen
Antihypertensive agent Hydrochlorothiazide, trichlormethiazide, meticrane, clofenamide, tripamide, metolazone,
furosemide, tilisolol HCl, pindolol, diltiazem HCl, nicardipine HCl, nifedipine, captopril, lisinopril
Antidiabetic Tolbutamide, chlorpropamide, glibenclamide, carbutamide, glymidine sodium
Antipodagric Benzbromarone
Antitumor agent 5-FU, tegafur, dacarbazine, flutamide
Lipid-lowering drug Simvastatin
Prostatomegaly therapeutic agent Tamsulosin
Photochemistry therapeutic agent 8-Methoxypsoralen, trioxypsoralen, hematoporphyrin derivative
Vitamin Etretinate, pyridoxine, VB12
Antirheumatic Sodium aurothiomalate, methotrexate
(Based on: Kamide R. Photosensitive dermatosis caused by extrinsic photosensitizing substance. In: Tamaoki K, editor. New Dermatol-
ogy Vol. 16. Nakayama Shoten; 2003: 293-300).
13
Table 13.5 Classification of photosensitive dermatosis.
Classification Cause Diagnostic name Described

in...
Extrinsic Drug Phototoxic dermatitis Chapter 13

photosensitive
dermatosis Photoallergic dermatitis Chapter 13
Intrinsic Accumulation Pellagra Chapter 17
photosensitive of chromophore
dermatosis in skin Porphyria Chapter 17
DNA repair Xeroderma pigmentosum Chapter 13
defect (XP)
Cackayne syndrome
Bloom syndrome
Decrease of Albinism Chapter 16
melanin Phenylketonuria Chapter 17
Unknown Hydroa vacciniforme Chapter 13
Solar urticaria Chapter 13
Polymorphous light eruption Chapter 13
Chronic actinic dermatitis Chapter 13
(CAD)
are extrinsic chemicals and intrinsic factors (Tables 13.4 and

13.5). This section describes photosensitive dermatoses that are
caused by extrinsic factors. Extrinsic photosensitive dermatosis is MEMO
Photosensitive drug
inflammation of skin caused by the excitation of chromophores eruption
by daily exposure to radiation (mainly UVA). Chromophores In addition to phototoxic condition or pho-
reach the skin either from outside (skin lotion, perfume, fruit toallergy, drug intake may induce intrinsic
photosensitive diseases (e.g., porphyria, lupus
juice, tar) to induce photocontact dermatitis or from within the body erythematosus).
(drugs, food). The mechanisms of inflammation are phototoxic
sunlight (UVA)
chromophores
②Chromophores convert
into photoallergens.
①Contact is made
with a causative photoallergens
substance, ①Macrophages
or there is and Langerhans
intake of ③The photoallergens connect cells recognize
such substance. with biologic proteins. photoallergens
biologic proteins themselves.
intradermal area ④Macrophages and

Langerhans cells
phagocytose the conjugates
of photoallergens and
biologic proteins. in the lymph nodes ②The photoallergens
lymph ducts or intradermal are presented to
area effector T cells,
causing
inflammation that
⑤The photoallergens in peaks 48 hours
macrophages and after presentation.
regional lymph nodes Langerhans cells are
presented to T cells, and secretion of various cytokines,
sensitization occurs. localized inflammation
13 primary intake of causative secondary and further intake
substance (sensitization) of the causative substance
Fig. 13.15 Mechanism of photoallergic reaction.
Table 13.6 Phototoxic reaction and photoal- (the excited substance itself becomes toxic) and photoallergic
lergic reaction.
(the excited substance becomes an allergen that induces inflam-
Phototoxic Photoallergic mation by immunoreaction) (Fig. 13.15, Table 13.6).
reaction reaction
Incidence May occur in Immunologically
anybody mediated (Type 1) Phototoxic dermatitis
IV) only
More than one No Yes
exposure to Outline
agent required? ● Phototoxic dermatitis may occur in anyone by the combi-
Onset of reaction hours to 1 24-72 hours nation of a certain dose of drugs and sun exposure.
after exposure to day ● It may occur even at the first irradiation (usually by UVA),
agent and light
without any latency.
Clinical features Exaggerated Dermatitis ● The main causative drugs are psoralen, coal tar, thiazide
sunburn
drugs, and tetracycline.
Distribution Sun-exposed Sun-exposed
skin skin
Clinical features
Spread to No Yes (possible)
unexposed Sunburn-like symptoms are mainly seen. That is, erythema and
areas? edema are followed by exfoliation and pigmentation. Perfume
Pathologic fea- Necrosis of Spongiosis, may cause both allergic contact dermatitis and phototoxic der-
ture epidermal cell eczema matitis (Berloque dermatitis) on the neck, especially the sides.
(sunburn)
Cross reaction Almost never Yes
caused by similar (sometimes) Photocontact dermatitis MEMO
compounds? The skin comes into direct contact with the causative agent. Subse-
quent exposure to light of a certain wavelength causes photocontact
Amount of agent Large Small dermatitis. It is classified by onset mechanism as phototoxic or pho-
required for toallergic.
photosensitivity
Photosensitive diseases / 2. Photosensitive dermatoses 197
Pathogenesis
1. A test substance is
Drugs that accumulate in the skin absorb light at a certain adhered to the
wavelength. Exposure to light at that wavelength causes photo- back for 24 hours.
toxic dermatitis. Each drug affects a particular site.
Treatment
2. Half of the patch
Intake of the causative substance should be discontinued. Sun- exposed to site is exposed to a
light is avoided by sunscreen and a hat. The treatments are the a small slightly smaller
amount of amount of UVB
same as those for contact dermatitis. UVB than for the first
MED exposure
(about 70% of
2) Photoallergic dermatitis MED). If the
not substance is not a
exposed cause of
Outline to UVB photoallergic
dermatitis in the
● Photoallergicdermatitis is photosensitive dermatitis that patient, no skin
is caused by a type IV allergy reaction, which is induced lesion or erythema
will appear.
by sun exposure after topical application or intake of a
3. The patch is
drug. removed after 48
● Erythema and blistering are the main symptoms. hours. The site is
● Chlorpromazine, thiazide drugs and oral antidiabetics are examined after a
short time passes.
the main causative drugs.
13
Clinical features Fig. 13.16 Photo-patch testing.
Erythema and serous papules occur on the sun-exposed site,
progressing to edema blistering, and erosion.
Pathogenesis
60
Chromophores that somehow attach to the skin react to expo- 50
sure to light of a certain wavelength (mostly UVA, sometimes
visible light) to become allergenic, or they may convert into hap-
tens, connect with biologic proteins and become photoallergenic.
70
After sensitization, the causative substance is re-exposed to light 40
when it reaches the skin surface, where it induces type IV allergic
reaction (Fig. 13.15). This reaction does not occur without sensi-
tization; that is, inflammation is not caused by the first exposure, 30 80
nor does allergic reaction occur in everyone. A person who has
been sensitized is prone to light-induced inflammation even from
a minute amount of the substance.
20 90

Photo-patch test: The test substance is patched as in the usual 10 100 mJ/cm2
patch test. The minimal erythema dose (MED) of the patient is
also determined. After 24 hours, half of the patch site is exposed
to a slightly smaller amount of UV than that of the first MED
exposure. The other half is left unexposed. The result is deter-
Fig. 13.17 Determination of minimal erythe-
mined 48 hours after exposure (Figs. 13.16 and 13.17). ma dose (MED).
Photo-drug test: Application of the suspected drug is discontin- UVB from 0 mJ/cm2 to 100 mJ/cm2 is irradiated
ued for at least 20 days. A normal dose of a test drug is applied in increments of 10 mJ/cm 2 on areas of the
patient’s back where no eruptions have been pro-
for 2 days. The diagnosis is photoallergic dermatitis if an erup- duced. The MED in this case is 30 mJ/cm2.
tion is produced by exposure to light.
Treatment
Intake of the causative substance and sunlight exposure should
be avoided. The treatment is the same as that for contact dermati-
tis. A photosensitive disease called “persistent light reaction,”
which is categorized as a chronic actinic dermatitis (CAD), may
remain after discontinuation of the causative substance.

3. Solar urticaria
Definition, Pathogenesis, Clinical features

An allergen is intrinsically produced in skin by exposure to
light, against which type I allergy is induced. Several minutes
after light exposure (mostly the visible spectrum, but also UVA
and UVB in some cases), extremely itchy urticaria occurs; how-
ever, it disappears in several hours. Anaphylactic shock may be
a b c d e f g h
caused j
i rare cases.
in k l m n o p q r
Solar urticaria is generally diagnosed from the recurring erup-
tions caused by exposure to sunlight or to artificial light. Howev-
13 Clinical images are available in hardcopy only. er, wheals may be produced or aggravated by light shielding in
some cases; certain wavelengths in the light are thought to inhibit
wheals. In young patients, differential diagnosis from erythropoi-
etic protoporphyria may be necessary.
Treatment
The patient is shielded from the sun, and antihistamines are
applied as a symptomatic treatment. PUVA treatment may be
performed as a desensitization treatment. Immunosuppressants
and plasma exchange have been reported to be effective in severe
cases.
4. Chronic actinic dermatitis (CAD)

Chronic actinic dermatitis (CAD) most frequently occurs in
b c d e f g h i j
adult k
males. l intractable
An m n eczematous
o pchangeq whoser main
Fig. 13.18-1 Chronic actinic dermatitis. symptom is slowly progressing lichenoid plaques occurs on
a: Intractable eczema presents as lichenified exposed areas of the body and becomes chronic (Figs. 13.18-1
plaques that progress slowly. b: The skin lesion
improved significantly after topical application of and 13.18-2). In some cases, the lesions progress to erythroder-
tacrolimus for several months. c: The skin lesion ma, leading to cutaneous lymphoma-like subcutaneous nodules,
recurred after sun exposure. thickening of the skin, or facies leontina. It is hypothesized that
intrinsic antigens are produced by light exposure for some rea-
son; however, the details of the onset mechanism are unknown.
Photosensitive diseases used to be called “persistent light reac-
tion” “actinic reticuloid” or “photosensitivity dermatitis.” Now
these are categorized as forms of CAD.
Photosensitive diseases / 6. Hydroa vacciniforme 199
Pathology
Eczematous lesions are the main symptom of CAD. As CAD
progresses, lymphocytic infiltration and atypical cells are seen in
all dermal layers, and Pautrier microabscess-like lesions may
occur in the epidermis (actinic reticuloid).
Laboratory findings, Diagnosis, Treatment Clinical images are available in hardcopy only.
The minimal erythema dose (MED) for UVB is greatly

reduced. The MED for UVA and visible light is also reduced in
some cases. For differential diagnosis, the skin is subjected to
repeated UVB exposure and if eczematous lesions appear then
the diagnosis is CAD. Topical steroids are helpful. Complete g j
a b c d e f h i k
light shielding is essential. Tacrolimus ointment is also useful.
Oral steroids and immunosuppressants are effective in severe
cases.
5. Polymorphous light eruption
Clinical features
Polymorphous light eruption occurs most commonly in Clinical images are available in hardcopy only.
women between the ages of 10 to 30. Itchy erythema and papular 13
eruptions appear at sun-exposed sites. They become chronic and
tend to gradually worsen. The condition also worsens in summer
and subsides in winter.
Pathogenesis, Diagnosis
Polymorphous light eruption is thought to be an allergic reac-
a
tion to light. In practice, all photosensitive bdiseases
c withd e f g h i j k l
unknown causes and without specific symptoms of other photo- Fig. 13.18-2 Chronic actinic dermatitis (CAD).
sensitive diseases are considered to be polymorphous light erup- d, e: Chronic eczematous skin lesion accompa-
nied by intense itching on the occipital region
tion. It requires reconsideration as to whether it is an independent and dorsum of hand of a man in his 50s. It wors-
disease. ened with exposure to the sunlight. Oral
cyclosporine improved it markedly.
6. Hydroa vacciniforme
Outline
● Hydroa vacciniforme is a rare intrinsic photosensitive dis-
ease seen in infants.
● Blisters with concave centers form at sun-exposed sites
on the face and dorsa of the hands.

● Epstein-Barr viruses are involved. The disease resolves
naturally at puberty.
● Sun shading is important.

Hydroa vacciniforme first appears in infants 2 to 3 years of age
and resolves naturally at puberty. It occurs more often in males.
Erythema and blisters with concave centers are produced by
exposure to sunlight or UVB, and crusts form later on. These
leave atrophic scarring when they heal. They mostly occur in the
face, auriculae, and dorsa of hands (Fig. 13.19). The lesions are
sensitive to light and tend to worsen in summer. When the EB
virus is involved, the condition may progress to lymphoma. The
onset mechanism is unknown, and hereditary predispositions are
Clinical images are available in hardcopy only. not usually found. In cases with the involvement of the EB virus,
natural killer-cell lymphoma may develop.
Diagnosis, Examinations, Treatment

Hydroa vacciniforme is diagnosed by laboratory findings. The
symptoms may resemble those of porphyria; however, the por-
phyria level in hydroa vacciniforme is within the normal range.
Direct sun exposure is avoided. Sunscreen is helpful.
7. Xeroderma pigmentosum (XP)
Clinical images are available in hardcopy only. Outline

● XP occurs in persons with congenital failure in the DNA
repair process. The cells are easily damaged by UV.
Sunburn frequently occurs.
13 ● All types are autosomal recessive inherited.
● A malignant tumor may occur as a complication with age.
Fig. 13.19 Hydroa vacciniforme. ● Complete shading of light is an effective treatment.
Patients with xeroderma pigmentosum (XP) have a congenital
failure in repairing and eliminating DNA that is damaged by UV
exposure. The failure results in severe photosensitive symptoms.
UV causes a replication fork bypass of a pyrimidine (thymine-
thymine) dimer.
XP is classified by unscheduled DNA synthesis (UDS), a clas-
sification index, into 8 subtypes: groups A to G, and a variant
group (Table 13.7). Group A is the severest, and the variant
group is the mildest. In the variant group, UDS is normal; how-
ever, there is failure in DNA modification after synthesis. Group
A and the variant group are the most frequently occurring in
Japan, together accounting for 80% of all XP cases. All groups
are autosomal recessive and occur in 1 person out of 100,000 to
1.5 persons out of 100,000. About 30% of patients with XP are
born from consanguineous marriages. The main genes responsi-
ble for XP have been identified (Chapter 29).
Clinical features
Abnormalities are not found at birth; however, intense and
delayed sunburn in 1- to 2-month-old infants may be recognized
as the onset of XP group A. Extremely intense and persistent
sunburn recurs on sun-exposed sites such as the face and dorsa of
Fig. 13.20 Xeroderma pigmentosum (group hands and forearms. As sunburn recurs, the skin dries and
D).
Pigmentation on the face of a woman in her 20s. coarsens, presenting an unwashed appearance with ephelides-like
The cutaneous symptoms are mild. pigmented patches, exfoliation, hypopigmented macules and
Photosensitive diseases / 7. Xeroderma pigmentosum (XP) 201
Table 13.7 Comparison between types of xeroderma pigmentosum.

Average age
Severity of skin
Group MED UDS (%) Onset Neurological manifestation of skin cancer
manifestation
development
A Reduced <5 Babyhood Severe, carcinogenesis Appears at about 1 year old 9.2
B Reduced 3-7 Babyhood Severe Sometimes
C Normal 10-25 Babyhood Severe None 10.5
D Reduced 25-50 Babyhood Moderate Sometimes 35.5
E Reduced 40-60 Babyhood and infancy Mild None 41.0
F Reduced 10-20 Early childhood Mild None 47.7
G Normal <25 Early childhood Mild Sometimes 32
Variant Normal 100 Early childhood (about 5 years old) Moderate None 41.0
telangiectasia (Fig. 13.20). Seborrheic keratosis, small tumors,

UDS value MEMO
and ulcers occur in succession at the base of these lesions in UDS (unscheduled DNA synthesis), a test for
childhood. Basal cell carcinoma, squamous cell carcinoma, kera- xeroderma pigmentosum (XP), shows the
toacanthoma and malignant melanoma occur subsequently. potential degree of recovery from DNA dam-
age under UV exposure, expressed as a per-
Eye symptoms such as photophobia, blepharitis, dacryorrhea, centage compared to normal controls. Cells
and conjunctivitis occur in childhood and progress to ectropion, are scattered in a petri dish and exposed to
blindness, and malignant tumor in the terminal stages. Progres- UV. When cultured in [3H] thymidine solu-
sive neurological symptoms occur 6 months after birth, leading tion, damaged DNA is repaired, and the cells 13
absorb [3H] thymidine. The amount of [3H]
to articulatory disorder, gait disorder and intellectual impairment. thymidine is measured by autoradiography for
Disturbance in growth, such as dwarfism and spondyloschisis, comparison with normal cases; patients with
also occur. XP have reduced UDS values.
Groups E, F, and G are often overlooked due to their mild
symptoms. The carcinogenic period is the third decade of life.
Eye symptoms and neurological symptoms are rarely found in
these groups. Nevertheless, cutaneous symptoms and neurologi-
cal symptoms in some cases of groups E, F, and G closely resem-
ble those found in group A (Fig. 13.21). In the variant group,
MED is almost normal, but ephelides gradually appears after Clinical images are available in hardcopy only.
childhood. Although eye symptoms and neurological symptoms
are rarely seen, basal cell carcinoma or squamous cell carcinoma
occurs in adulthood.

XP diagnosis is confirmed by the MED level, DNA and RNA
syntheses after UV exposure, measurement of UDS, and gene
test.
Treatment
Sunlight should be thoroughly avoided by limiting outings in Clinical images are available in hardcopy only.
daytime, wearing clothes that cover the body thoroughly, keeping
the hair long, wearing UV-screening eyeglasses, sticking UV-
screening film on windows, applying shades to fluorescent
lamps, and applying sunscreen. Early detection and treatment of
cutaneous malignant tumor are important. Neurological disorders
are treated by regular listening-comprehension tests, speech train- Fig. 13.21 Xeroderma pigmentosum (Group
F).
ing, and motor ability retention training. Basal cell carcinoma on the dorsum of the nose
of a man in his 20s.
Chapter
14 Blistering and Pustular Diseases
In the strict sense, blistering and pustular diseases do not include physical injuries (e.g., burns and frostbite) or
infections (e.g., those by bacteria or by viruses such as herpes).
Diseases that are associated with blistering are divided into inherited congenital ones and acquired ones. Con-
genital blistering diseases such as epidermolysis bullosa are caused by mutation in the gene that codes for epi-
dermal basement membrane structural proteins. Ultrastructural molecular sites where the genetic mutation is
expressed become fragile, which results in blistering. Since the causative gene of epidermolysis bullosa was
identified, accurate diagnosis of disease subtypes, genetic consulting and prenatal diagnosis have become pos-
sible. Acquired blistering diseases such as pemphigus and bullous pemphigoid are autoimmune diseases.
Autoantibodies against epidermal structural proteins are produced, which leads to fragility of the epidermis and
blistering. Pustular diseases are those in which multiple sterile pustules are produced.
Blistering diseases
A. Genetic blistering diseases

14
a. Epidermolysis bullosa (EB) (Fig. 14.1)
Synonym: Epidermolysis bullosa hereditaria
Outline
● It is caused by a mutation in structural molecules of the
epidermal basement membrane.
● Shortly after birth, blisters, erosions and ulcers form at
sites of friction in newborns, whose skin is congenitally

fragile (Nikolsky’s sign).
● It is divided by the ultrastructural site of cleavage into EB
simplex (in the epidermis), junctional EB (in the lamina

lucida junctions), and dystrophic EB (in the dermis). It is
subdivided into 10 to 30 subtypes by clinical features,
inheritance patterns and causative genes (Table 14.1,
Fig. 14.2).
Fig. 14.1 What is epidermolysis bullosa? ● Identification of genetic mutation by immunofluorescence
Epidermolysis bullosa is a group of hereditary
diseases, in which blisters, erosions and ulcers (IF) to determine protein levels, and electron microscopy
easily occur by slight mechanical stimuli. This of the cleavage site are important for diagnosis.
photo shows recessive dystrophic epidermolysis ● There are no effective treatments, only symptomatic
bullosa.
treatments.
1. Epidermolysis bullosa simplex (EBS)
Outline
● The three main types of EBS are Dowling-Meara EBS
202
Blistering diseases / A. Genetic blistering diseases 203
Table 14.1 Classification of epidermolysis bullosa (EB).

Causative Inheritance pattern
3 major Immunohistochemistry and
Main subtypes protein and (autosomal Clinical features
types immunoelectron microscopy
gene chromosome)
EB Dowling-Meara (severe) Keratin 5/14 AD Blistering on the whole body surface
simplex Intraepidermal blisters, aggregation
Köbner (moderate) Keratin 5/14 AD Blistering spread to sites other than
(EBS) of keratin fibers
the palms and soles
Weber-Cockayne (mild) Keratin 5/14 AD Blistering on the palms and soles
EBS associated with Plectin AR Late-onset muscular dystrophy as a
muscular dystrophy complication
Junctional Herlitz JEB Laminin-332 AR Blistering and erosion on the whole Lamina lucida blister, absence of
EB (JEB) body at birth. Death within 1 year laminin 332
after birth
Non-Herlitz JEB Laminin-332 AR Poor development in teeth and nails Lamina lucida blister, reduced
Alopecia laminin 332 or complete absence
Type XVII AR Good prognosis of Type XVII collagen.
collagen (BP180)
JEB associated with a6b4 AR Blistering on the whole body Lamina lucida blister. Absence or
pyloric atresia integrin Congenital pyloric atresia reduced a6b4 integrin.
Poor prognosis
Dystrophic Hallopeau-Siemens Type VII AR Recurrent blistering on the
EB (DEB) recessive DEB collagen extremities and trunk. Fusion of
fingers and toes in club-shape.
Non-Hallopeau-Siemens Type VII AR Intradermal blister. Hypoplastic
Milder than Hallopeau-Siemens
recessive DEB collagen anchoring fibrils
recessive type
Autosomal dominant Type VII AD Comparatively mild
DEB collagen
(AR: autosomal recessively inherited, AD: autosomal dominantly inherited).
14
tonofilament (keratin 5/14)

basal cell
hemidesmosomes
lamina lucida
lamina densa
anchoring fibril (type VII collagen)
type I and III collagen
abnormal abnormal abnormal

tonofilaments hemidesmosomes anchoring fibrils
Are epidermolysis MEMO

bullosa hereditaria and
intraepidermal blisters in the subepidermal blisters epidermolysis bullosa different?
blisters (epidermolysis) lamina lucida (dermolysis) Epidermolysis bullosa may be called “epider-
epidermolysis junctional dystrophic molysis bullosa hereditaria” to distinguish it
bullosa epidermolysis epidermolysis from epidermolysis bullosa acquisita; howev-
simplex (EBS) bullosa (JEB) bullosa (DEB) er, the name “epidermolysis bullosa” is now
widely used for all hereditary bullosas.
Fig. 14.2 The mechanism of epidermolysis bullosa.
204 14 Blistering and Pustular Diseases
(severe), Köbner EBS (moderate), and Weber-Cockayne

EBS (mild). The disorder is caused by keratin gene
mutation (K5 or K14). It is autosomal dominantly inherit-
ed.
● Blisters form at sites prone to friction, beginning at birth
or early childhood.
● The prognosis is generally good. It subsides with age.
● EBS with muscular dystrophy (EBS-MD), a rare type of
EBS, is caused by a plectin gene mutation. Inheritance is

autosomal recessive.
Clinical features
Shortly after birth, blisters of various sizes form at sites that
are prone to friction: hands, feet, elbows, knees and so on. Blis-
tering is observed by rubbing a normal site on the skin of a
patient with severe EBS (Nikolsky’s sign). EBS heals without
scarring. It tends to aggravate in summer, from the high tempera-
ture. It subsides with age and generally has a good prognosis.
EBS is dermatologically divided by severity into three subtypes;
Clinical images are available in hardcopy only. however, there are intermediate subtypes. EBS with muscular
dystrophy (EBS-MD) is rare (MEMO).
①Dowling-Meara EBS: Ring-shaped blisters form. When it
occurs in newborns, systemic erosions and fatality may occur.
14 This is the severest subtype (Fig. 14.3).
②Köbner EBS: Blistering is present on the whole body surface.
The severity is moderate (Figs. 14.4-1 and 14.4-2).
Fig. 14.3 Epidermolysis bullosa simplex,
Dowling-Meara type. ③Weber-Cockayne EBS: Blisters form only on the hands and
Blisters form ring shapes and heal without scarring. feet. It is the mildest subtype (Fig. 14.7).
Pathogenesis
Basal cells collapse from mutation of either the K5 or K14
gene, which codes for cytoskeletons of basal cells (intermediate
Clinical images are available in hardcopy only. filaments). Cleavage occurs, resulting in blistering. Epidermoly-
sis bullosa simplex (EBS) is autosomal dominantly inherited. The
severity depends on the type and location of the mutation in the
K5 or K14 gene. The severity of clinical symptoms is measured
by the location of genetic mutation and the amino acids pro-
duced.
Pathology
Separation occurs within the cytoplasm of the epidermal basal
Clinical images are available in hardcopy only. cells, which leads to intra-epidermal blistering (Fig. 14.5).
Clumping of degenerated keratin fibers in severe Dowling-Meara
EBS is clearly observable by electron microscopy (Fig. 14.6).
Treatment
Symptomatic therapies are the main treatments. Friction and
Fig. 14.4-1 Epidermolysis bullosa simplex, warm temperatures should be avoided. Local therapies (e.g.,
Köbner type. drainage of blisters, application of antibiotic ointments) are help-
Blistering occurs on the whole body surface. The
clinical severity is between those of the Dowling-
ful. The cutaneous symptoms subside with age.
Meara and the Weber-Cockayne types.
Fig. 14.7 Epidermolysis bullosa simplex,

Weber-Cockayne type.
Blistering is localized on the hands and feet. Blis-
tering is induced by mechanical stimulation, such
as from long walks.
Fig. 14.4-2 Epidermolysis bullosa simplex, Köbner type on

hands. Epidermolysis bullosa MEMO
simplex associated with muscular
dystrophy
This specific type of epidermolysis bullosa
simplex is associated with late-onset muscular
dystrophy, a disease caused by plectin gene
mutation. Plectin is a protein found in the epi-
dermal basement membrane, hemidesmo-
somes and sarcolemma of muscle fascia. The
mutation is autosomal recessively inherited.
Epidermolysis bullosa simplex is accompa-
nied by muscular dystrophy in the fingers and 14
toes, and muscle atrophy.
☆ ☆

☆ hardcopy only.
Fig. 14.5 Electron microscopic image of epidermolysis bullosa

simplex.
The arrows indicate lamina densa. The cytoplasm of the basal cells (indi-
cated by stars) on the basement membrane is damaged, leading to blistering.
aggregated
keratin fibers
Fig. 14.6 Aggregation of keratin fibers seen in Dowling-Meara

type.
Epidermolysis bullosa MEMO 2. Junctional epidermolysis bullosa (JEB)

simplex with mottled pigmentation
Blistering is almost the same as in Weber-
Cockayne epidermolysis bullosa; neverthe- Outline
less, there is the atypical presence of small
● Blistering occurs at dermo-epidermal junctions. The dis-
pigmented patches 2 mm to 5 mm in diameter
on the lower abdomen, axillary fossa, and ease is caused by dissociation of the lamina lucida in the
extremities. Epidermolysis bullosa simplex basal cells.
with mottled pigmentation is caused by P25L ● All JEB subtypes are autosomal recessively inherited.
missense mutation in the V1 domain of the
keratin 5 gene. Epidermolysis bullosa sim- The majority patients with Herlitz JEB die within 1 year
plex-like blisters and pigmented patches are after birth. Non-Herlitz JEB has a better prognosis.
found on the trunk and axillary fossa. ● JEB with pyloric atresia, an atypical type, is caused by
genetic mutation in the integrin a 6 or integrin b 4 gene.

The prognosis is poor.
● Symptomatic therapies are the main treatments. In
recent years, genetic counseling and prenatal diagnosis

Clinical images are available in hardcopy only. have been conducted.
Clinical features
In Herlitz JEB, there is systematic blistering, erosion and
ulceration in newborns after birth. The lesions do not heal, but recur
and enlarge. Mucosal lesions and growth insufficiency of teeth and
nails are seen. Herlitz JEB is fatal, causing death within 1 year after
birth in almost all cases (Fig. 14.8). Non-Herlitz JEB has a better
14 prognosis, and patients may survive to reproductive age. Non-scal-
ing alopecia, palmoplantar keratosis, nail deformity, and aplasia of
Clinical images are available in hardcopy only. dental enamel are present (Fig. 14.9). Nikolsky’s sign is positive.
Herlitz JEB and non-Herlitz JEB are the two main subtypes of
JEB. They differ in prognosis. Herlitz JEB is caused by the com-
plete absence of laminin 332 (laminin 5). Non-Herlitz JEB is
caused by reduction of laminin 332 or complete absence of type
XVII collagen (BP180). It has a better prognosis.
JEB with pyloric atresia is caused by a genetic mutation in
Clinical images are available in hardcopy only. integrin a 6 or integrin b 4 in the membrane ligands of
hemidesmosomes. Complications associated with the disease are
systemic junctional bullosa and congenital pyloric atresia. It is
fatal soon after birth in many cases (Fig. 14.10).
Pathology
Fig. 14.8 Junctional epidermolysis bullosa,
Herlitz type. JEB presents as subepidermal blistering under light microscopy.
Intractable, erosive ulcers on the whole body sur- Blister formation is observed between the basal cell plasma
face. The ulceration gradually enlarges.
membrane and the lamina densa. Electron microscopy shows the
separation more clearly (Figs. 14.2 and 14.11).
Treatment
Lethal Herlitz junctional MEMO
epidermolysis bullosa Symptomatic therapies are the main treatments for JEB. Fric-
The disease, once called “lethal Herlitz JEB,” tion should be avoided. Local therapies and symptomatic thera-
is now simply called “Herlitz JEB,” because pies including nutrition management, topical application of
some patients have survived for more than 1
year.
ointments and antibiotic administration are conducted. Prenatal
diagnosis is also made in severe cases, such as Herlitz JEB.

hardcopy only.

hardcopy only.

hardcopy only.
Fig. 14.9 Junctional epidermolysis bullosa, non-Herlitz type.

Blistering and pigmentation occur on the whole body surface. Nonscarring alopecia also occurs on the scalp.
14
Fig. 14.10 Junctional epidermolysis bullosa

associated with pyloric atresia. Fig. 14.11 Electron microscopic image of junctional epidermoly-
Aplasia cutis congenita-like ulcer of skin and sis bullosa.
congenital pyloric atresia occur as complications. A blister (star) forms in the lamina lucida, between the plasma membrane
of the basal keratinocytes (purple arrows) and the lamina densa (black
arrows).
3. Dystrophic epidermolysis bullosa (DEB)
Outline
● There are several subtypes; however, all are caused by
a mutation in the gene that codes for type VII collagen, a
structural component of anchoring fibrils. Subepidermal
a b c d e f g h i j k p q
blistering is present over l the entire
m n
body. o r
● DEB can be autosomal dominantly inherited or reces-
sively inherited. Nikolsky’s sign is positive.
①Hallopeau-Siemens recessive DEB (HS-RDEB)

Clinical images are available in hardcopy only. Hallopeau-Siemens recessive DEB is the severest DEB. At
birth or shortly thereafter, blisters and erosions appear recurrently
on the extremities and trunk, with or without external influences.
They heal, leaving milium and scarring, which results in the club-
a b c d e f g h shaped
i j
coalescence
k ofl fingers
m and toes
n (Fig. p Lesions
o 14.12). q arer
mostly seen in nails, oral mucosa and esophageal mucous mem-
branes, and there is a tendency for esophageal atresia and dys-
phagia to occur. The symptoms do not subside with age. When
patients reach adolescence or older, a malignant tumor (squamous
Clinical images are available in cell carcinoma, in particular) often occurs. Expression of type VII
hardcopy only. collagen is completely absent. Recessive Hallopeau-Siemens is
14 extremely serious and may cause death in young patients.
②Non-Hallopeau-Siemens recessive DEB (non-HS-RDEB)
Type VII collagen is reduced, but not completely absent. The
b c d e f g h i j
clinicalk symptoms
l m lessnsevereo than p
are those ofq Hallopeau-
r
Siemens (Fig. 14.13).
③Autosomal dominant DEB
This DEB occurs in newborns and infants. Multiple blisters form
Clinical images are available in hardcopy only. on the extensor surfaces of the extremities. The disease may cause
esophageal atresia, or papules on the trunk. It heals with scarring (Fig.
14.14). Deformation of nails is present. It tends to subside over time.
Pathogenesis
Dystrophic epidermolysis bullosa (DEB) is caused by a muta-
tion in the gene that codes for the type VII collagen, a main com-
ponent of anchoring fibrils that is essential in connecting the
dermis and the epidermis. Subepidermal blistering occurs from
hypoplasia of anchoring fibrils (Fig. 14.2).
Pathology
Subepidermal blistering (dermolysis) is present. Dissociation
d e f g h i j k isl observed
m immediately
n o below
p theq laminar densa by electron
Fig. 14.12 Dystrophic epidermolysis bul- microscopy (Figs. 14.15 and 14.16). It is characterized by
losa, Hallopeau-Siemens type. hypoplasia of anchoring fibrils.
a: Blistering and ulceration are relatively mild at
birth. b: Intractable blisters form as patients Laboratory findings, Differential diagnosis
grow. c, d: Marked blistering is present on the
whole body. Adhesion is seen in the fingers and DEB is diagnosed by findings obtained by clinical examina-
toes due to recurring scarring. e: Hypoplasia of tion, electron microscopy and immunofluorescence (IF). DNA
teeth is present. tests are conducted to determine whether it is autosomal
Clinical images are available in Clinical images are available in

hardcopy only. hardcopy only.

Fig. 14.13 Dystrophic epidermolysis bullosa, non-Hallopeau-Siemens type.

Scarring blisters, crusts and adhesion occur in the fingers; however, these are milder than in the Hallopeau-Siemens type.
Expression of collagen type VII remains.
14

Fig. 14.15 Light microscopic image of dys-
trophic epidermolysis bullosa.
Typical subcutaneous blistering and slight
inflammatory cellular infiltration are present.
a b c d e f g h i j k l m n o p q
Fig. 14.14 Dominant dystrophic epidermolysis
bullosa. Fig. 14.16 Electron microscopic image of dystrophic
a: Blistering and scarring occur on areas subjected epidermolysis bullosa
to friction, such as knees. b: Deformity in the toe- Blistering is observed immediately beneath the lamina densa
nails. (arrows).
dominant or recessive. For Hallopeau-Siemens recessive DEB

with severe clinical symptoms, prenatal diagnosis is made by
fetal skin biopsy, amniocentesis and chorionic villis biopsy.
Treatment
Synthetic type VII collagen therapy has been attempted on
DEB patients in recent years. Friction is avoided and topical ther-
apies are applied. Fluid therapies, nutritional management and
genetic counseling are conducted for recessive DEB.
b. Other genetic blistering diseases
1. Skin fragility syndrome

Skin fragility syndrome, an autosomal recessive inherited dis-
ease, is caused by abnormality in the gene that codes for
plakophilin 1, a desmosomal structural protein. Epidermal fragili-
ty, painful hyperkeratosis in the hands and soles, and abnormali-
ties of hair, nails and perspiration are found.
2. Hailey-Hailey disease
Synonym: Familial benign chronic pemphigus
14
Outline
● Vesicles aggregate on an erythematous base in areas
hardcopy only. exposed to friction. The appearance resembles that of
impetigo.
● It is autosomal dominantly inherited and occurs in adults
in their 30s.
● It is caused by a mutation in the ATP2C1 gene that
g j
codes for a calcium pump in the Golgi p
apparatus
q
within
b c d e f h i k l m n o r
keratinocytes.
Fig. 14.17 Hailey-Hailey disease. ● The pathology is acantholysis and villi formation. It is
a, b: Vesicles, erosion, impetigo and pustules
form in the groin. c: Blisters may appear, somewhat similar to Darier’s disease.
although only rarely. ● Topical steroid application is the main treatment.
Clinical features
Hailey-Hailey disease is inherited. It tends to manifest in adults
in their 30s, appearing as aggregated erythema and blistering in
areas that are exposed to friction, such as the cervical regions,
axillary fossa, inguinal regions and anus. On an erythematous
blistering base there are crusts, pustule formation and pigmenta-
tion, and secondary infection produces impetigo-like lesions
(Fig. 14.17). Itching is usually present. Although it heals without
scarring, it leaves abnormal pigmentation and is recurrent. The
disease worsens in summer, and subsides in winter. It is wors-
ened by external friction, perspiration, infection and UV radiation.
Fig. 14.18 Histopathology of Hailey-Hailey Pathology
disease.
Intraepidermal acantholysis. Acantholysis of the epidermis leads to intradermal lacunae
Blistering diseases / B. Autoimmune blistering diseases 211
formation immediately above the basal layer. The dermal papil- Hailey-Hailey disease and MEMO
lae, which are covered by basal cells in the single layer that is left haploinsufficiency
in the lacunae, protrude and resemble villi. Dyskeratotic cells are Both Hailey-Hailey disease and Darier’s dis-
occasionally found. Acantholytic cells in the lacunae are connect- ease are autosomal dominantly inherited.
Mutation occurs in one of the allelic genes. In
ed loosely to each other by a few desmosomes (Fig. 14.18). most cases, cutaneous symptoms do not
Autoantibodies to the epidermis are not detected by immunofluo- appear until adulthood. Haploinsufficiency
rescence. has been proposed as the mechanism of onset
of these diseases. That is, the amount of pro-
tein produced by one allelic gene is sufficient
Diagnosis in childhood, but shortages that emerge with
Hailey-Hailey disease is diagnosed by the clinical symptoms age cause the later onset.
and pathological diagnosis. As it is autosomal dominantly inher-
ited and frequently occurs within a family, it is important to take
a thorough family history. Genetic diagnosis can identify the
mutation in the ATP2C1 gene.
Treatment
Topical application of steroids and antibiotics ointments is
useful. Oral etretinate (a vitamin A derivative) and surgical abla-
tion may be performed in intractable cases.
B. Autoimmune blistering diseases

14
a. Diseases with intra-epidermal blistering Adhesion of keratinocytes MEMO
(pemphigus group) Keratinocytes are firmly adhered by desmo-
somes. Transmembrane adhesion molecules
in the cadherin superfamily, such as
desmoglein 1 (Dsg1), desmoglein 3 (Dsg3),
Outline and desmocolin cadherin (DC), are important
● Middle-aged and elderly people are the most commonly to intercellular adhesion. In pemphigus,
autoantibodies are produced against Dsg1 and
affected. Intra-epidermal blistering with flaccid blisters Dsg3, some of whose molecular functions are
occurs. disturbed. This causes acantholysis.
● The two main pemphigus groups are the pemphigus vul-
keratin
garis group and the pemphigus foliaceus group. desmosome intermediate fiber
● They are an autoimmune diseases. Acantholytic intra-
epidermal blistering is produced by autoantibodies Ca2 ＋

against desmoglein (intercellular substances; MEMO). Dsg1 Dsg1
● Anti-desmoglein antibodies are detected by ELISA. In Ca2 ＋
Dsg3 Dsg3
vivo IgG deposition and IgG antibodies are observed by Ca2 ＋
immunofluorescence (IF). Nikolsky’s sign and Tzanck DC DC
test are positive (i.e., for acantholytic cells).

● Oral steroids and immunosuppressants are mainly keratinocytes mucous attachment
and desmosomes membrane plaque
administered.
Classification
Diseases with intra-epidermal blistering (pemphigus group)
are divided into two groups according to pathogenesis: pemphi-
gus vulgaris and pemphigus foliaceus. Pemphigus vegetans is a
type of pemphigus vulgaris; pemphigus erythematosus is a type
of pemphigus foliaceus. The characteristics of each type are sum-
marized in Table 14.2. Pemphigus vulgaris accounts for 60% of
Table 14.2 Types of pemphigus groups.

Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus
Age of onset Middle age to elderly Middle age to elderly Middle age Middle age to elderly
Frequent site Whole body skin, Intertriginous areas Whole body skin Oily areas of skin
of skin lesion oral mucosa (e.g., axillary fossae) (e.g., face)
Clinical Skin Blisters, erosion Blisters, erosion, Erosion, lamellar Erosion, butterfly rash,
finding papillary acanthosis, exfoliation, crusts seborrheic dermatitis-like
pustules skin lesion
Mucosal lesions ＋＋＋ − −
Nikolsky’s ＋＋＋＋
sign
Pathological Skin Intraepidermal blisters (acantholysis)
finding
Tzanck test ＋＋＋＋
Site of acantholysis Lower epidermal layer (directly on basal cells) Upper epidermal layer (granular cell layer)
Targeted antigen Only Dsg3, Dsg3 and Dsg1 Only Dsg1
ELISA Dsg1(＋/−), Dsg3(＋) Dsg1(＋), Dsg3(−)
Immunofluo- Direct (skin lesion) IgG(＋) in the epidermal intercellular space, C3(＋) positive
rescence
technique Indirect (serum) IgG (＋)
Treatment Steroids, immunosuppressants, plasmapheresis, human immunoglobulin therapy
14 horny cell layer

granular cell layer
suprabasal cell layer Dsg1 is distributed in all
epidermal layers.
basal cell layer
lamina densa
Dsg3 is predominant in
the lower epidermis.
damaged Dsg1 damaged Dsg3
Fig. 14.20 Direct immunofluorescence of

pemphigus vulgaris.
Intercellular deposition of IgG is observed in the
epidermis.
pemphigus foliaceus pemphigus vulgaris

Acantholysis and blistering occur Acantholysis and blistering
in the upper epidermal layer occur immediately above the
through lower horny cell layer. basal cells.
Fig. 14.19 Distribution of desmoglein 1 and desmoglein 3 in the

epidermis and pathomechanism of pemphigus.
Diseases with intra-epidermal blistering are classified according to the
desmoglein molecules that are impaired (see also Fig. 14.23).
all pemphigus cases.
Pathogenesis
In pemphigus vulgaris, autoantibodies against desmoglein 3
are produced. Because the basal cell layer is rich in desmoglein
3, the action of autoantibodies against desmoglein 3 causes ker-
atinocytes to lose adhesion: The basal cell layer erodes and blis- Clinical images are available in hardcopy only.
ters. In pemphigus foliaceus, however, autoantibodies against
desmoglein 1 (and not desmoglein 3) are produced. Acantholysis
occurs in the upper epidermal layer. Because the basal cell layer
is not rich in desmoglein 1, the action of autoantibodies against
desmoglein 1 has little adverse effect on basal cell adhesion: The
basal cell layer remains largely intact. (Fig. 14.19). a b c d e f g h
Pathology
Dissociation of intercellular connections in the epidermis is
called acantholysis. As dissociation progresses, epidermal cleav-
age and blistering occur. Keratinocytes deform to become spheri-
cal from loss of intercellular connection within the blisters
(acantholytic cells). Tzanck test is positive. In pemphigus vul-
garis, acantholytic blistering occurs immediately above epider-
mal basal cells; in pemphigus foliaceus and pemphigus
erythedermatosus, blistering occurs in the superficial epidermis,
such as at sites immediately below the horny cell layer. In pem-
14
phigus vegetans, besides the findings of pemphigus vulgaris,a b c d e f g h i
acanthosis and papillomatosis are found, and eosinophil-filled
pustules form in the epidermis.
Laboratory findings
Epidermal intercellular in-vivo-bound IgG in lesions are iden-
tified by direct immunofluorescence (IF). IgG anti-intercellular
antibodies in the serum of patients are detected by indirect IF and
ELISA (Fig. 14.20). Autoantibodies against desmoglein 1 and 3
are detected by ELISA. Tzanck test is also useful, in which the
bottom of the blister is smeared and labeled to investigate the
presence of acantholytic cells by Giemsa staining. Elevated lev-
els of eosinophils may be found in the peripheral blood or a in theb c d e f g h i j
blister contents. Fig. 14.21-1 Pemphigus vulgaris.
a: Edematous itching erythema and blister on the
trunk. b: Intractable erosion on the lips and in the
1. Pemphigus vulgaris oral cavity. c: Erosion on the membrane of the
genitalia (glans penis).
Outline
● Acantholytic blisters form immediately above epidermal
basal cells.
● The disease is caused by autoantibodies against
desmoglein 3, which is a desmosomal adhesion factor in

keratinocytes.
● The pathogenesis involves anti-desmoglein antibodies.
● When there is the involvement of autoantibodies against
desmoglein 1, pemphigus vulgaris becomes systemic.

● When anti-desmoglein 3 antibodies are exclusively

involved, an oral mucosa type of the disease develops.
● The disease most frequently occurs in the middle-aged
and elderly. It tends to manifest as oral enanthema.

● Nikolsky’s sign is positive.
● Oral steroids and immunosuppressants are the first-line
Clinical images are available in hardcopy only. treatment.
Clinical features
Pemphigus vulgaris most frequently affects the middle-aged
and elderly. Erosions and ulcers develop acutely in the oral
mucosa in 70% to 80% of cases. Subsequently, blisters of various
g j
sizes occur on normal skin (Figs. 14.21-1
p
and
q
14.21-2). This blis-
c d e f h i k l m n o r
tering may occur anywhere on the body; however, it tends to
appear at sites prone to pressure and friction, such as the back,
buttocks and feet.
The blisters easily rupture to form large erosions and crusts.
They are painful when touched. Blistering can be artificially pro-
duced by rubbing normal skin (Nikolsky’s sign). When the blis-
ters are pressed without breaking, the fluid contents extend to the
peripheral normal skin around the blisters (blister diffusion phe-
d e f g h i j k nomena,
l mor false
n Nikolsky’s
o sign).
p q r
Erosions form in the oral cavity and esophageal mucosa, caus-
14 Fig. 14.21-2 Pemphigus vulgaris.
ing dysphagia. When the eruptions are widespread, electrolyte
d: A mix of blisters, erosion and crusts is present
on the trunk. e: Blisters appear on normal skin. abnormalities resulting from loss of body fluid or hypoproteine-
mia are found; this can be fatal when there is secondary infection.
Complications include thymoma or myasthenia.

Acantholysis causes intra-epidermal blistering. Blisters often
form leaving one basal layer at the bottom; such blistering is
described as “tombstone-like” (Fig. 14.22). Highly eosinophilic
infiltration occurs in the blisters and the dermal upper layer.
Anti-desmoglein 3 antibodies are detected by ELISA.
Diagnosis
In diagnosis, it is necessary to identify intercellular in vivo IgG
Fig. 14.22 Histopathology of pemphigus vul- deposition by immunofluorescence (IF), and to detect anti-
garis.
Acantholysis is observed on the basement cells. desmoglein antibodies by ELISA. The quantity of antibodies in
Table 14.3 Autoantibody against desmoglein detected by ELISA,

and confirmed diagnosis
ELISA
Anti-Dsg1 IgG Anti-Dsg3 IgG Diagnostic name
antibody antibody
Pemphigus vulgaris (mucosa
− ＋ predominant type)
Pemphigus vulgaris
＋＋ (mucocutaneous type)
＋ − Pemphigus foliaceus
− − Normal or Non-pemphigus
Dsg1 Dsg3 Dsg1 Dsg3

horny cell layer
granular cell layer
suprabasal cell layer
basal cell layer

lamina densa
skin mucosa
Expression of desmoglein 1 and desmoglein 3 in skin and mucosa of a healthy
person. The differences in expression of Dsg1 and Dsg3 in the skin and
mucosa explain the pathogenesis of pemphigus.
Dsg1 Dsg3 Dsg1 Dsg3 Dsg1 Dsg3 Dsg1 Dsg3 Dsg1 Dsg3 Dsg1 Dsg3
skin mucosa skin mucosa skin mucosa

When only Dsg1 is inhibited, skin lesions When only Dsg3 is inhibited, mucosal When both Dsg1 and Dsg3 are inhibited,
occur only in the upper dermal layer. lesions occur. Skin lesion may also occur. both skin lesions and mucosal lesions 14
occur directly in the basal layer.
→ pemphigus foliaceus → pemphigus vulgaris → pemphigus vulgaris
(mucosa-predominant type) (mucocutaneous-predominant type)
Fig. 14.23 Mechanism of pemphigus, according to the expression of desmoglein 1 and desmoglein 3 (see also Fig.
14.19).
the serum is known to reflect the pemphigus condition. When

only desmoglein 3 is detected, the disease is membrane-dominant
pemphigus vulgaris, in which there is only minor blistering of the
skin. When both desmoglein 1 and 3 are detected, blistering is
often seen in the oral mucosa and systemic skin (Table 14.3, Fig.
14.23).
Differential diagnosis Clinical images are available in hardcopy only.
It is necessary to differentiate the disease from dermatitis her-

petiformis, bullous pemphigoid, impetigo, burns, bullous drug
eruptions, erythema multiforme and Stevens-Johnson syndrome.
Treatment
Systemic application of steroids is the first-line treatment. g
a b c d e f h
According to the severity, 0.5 mg to 1.0 mg prednisolone per 1
Fig. 14.24-1 Pemphigus foliaceus.
kg of body weight per day is administered. The dosage is tapered a: Erosion accompanied by scales and erythema
off to a maintenance dose or until it can be discontinued. on the back.
Immunosuppressants (mycophenolate mofetil, cyclophos-
phamide, azathioprine, methotrexate and cyclosporine) may be
used. In intractable cases, plasma exchange therapy and mega-
dose gamma-globulin therapy are also performed. Antibiotic
application, fluid replacement and nutrition management are con-

ducted supplementarily.
2. Pemphigus vegetans
Clinical features
Clinical images are available in hardcopy only. Pemphigus vegetans is a subtype of pemphigus vulgaris whose
onset is marked by the formation of vesicles and erosions that do
not re-epithelialize but gradually proliferate and elevate. Lesions
are often accompanied by vesicles and pustules. There is a strong
odor, and the disorder frequently occurs on areas exposed to fric-
tion, such as the axillary fossa, umbilical fossa, and the periphery
of the oculonasal and perioral regions. Pemphigus vegetans can
be of Neumann type or Hallopeau type. The onset of the Neu-
a b c d e f g h i
mann j is marked
type k lby blistering,
m p q
nand pemphigus-vulgaris-like
o r
blistered erosions form. Pustules mainly occur in the Hallopeau
type, which has a better prognosis.
Pemphigus vegetans should be differentiated from condyloma
latum, condyloma acuminatum, proliferative chronic pyoderma
and fungal granuloma.
Treatment
The treatment is the same as for pemphigus vulgaris.
3. Pemphigus foliaceus
Fig. 14.24-2 Pemphigus foliaceus. Outline
b: Erosion, erythema and pigmentation on the
chest. c: Exfoliation and erythema on the face.
● Autoantibodies are produced exclusively against
The blisters are thin and easily ruptured; tense desmoglein 1.
blisters are rarely seen. ● Acantholysis and blistering are seen in the superficial
epidermis (in the granular cell layer).

● Fragile blisters, scaling and erosion, accompanied by
crusts, occur systemically. Lesions are not produced in

the mucosa.
Clinical images are available in hardcopy only. ● Examinations and treatments are the same as for pem-
phigus vulgaris. The steroid dosage is usually less than

for pemphigus vulgaris.
Clinical features
Fig. 14.25 Pemphigus erythematosus. Pemphigus foliaceus most commonly affects the middle-aged
In addition to the skin lesion of the pemphigus
foliaceus, facial eruptions resembling the butter- and elderly. Extremely fragile flaccid vesicles are produced,
fly rash of systemic lupus erythematosus (SLE) some of which dry to become leafy and to exfoliate successively.
are present. The face, head, back and chest are most commonly affected.
When the disorder progresses and spreads over the whole body, it
resembles exfoliative erythroderma (Figs. 14.24-1 and 14.24-2).
Unlike pemphigus vulgaris, pemphigus foliaceus does not
involve the mucosa. Nikolsky’s sign is positive.

Transient acantholytic MEMO
Acantholytic blistering is found in and between the epidermal dermatosis
horny cell layer and the epidermal upper layer. This is also called Grover’s disease. Itching
Intercellular in vivo IgG deposition is observed by immunoflu- papules and blisters with acantholysis occur
on the trunk and extremities, subsiding within
orescence. Anti-desmoglein 1 antibodies can be detected by ELISA. three months. The pathogenesis is unknown.
Autoantibodies against skin are not present.
Treatment
Treatment is the same as for pemphigus vulgaris. The oral
steroid dosage may be less than that for pemphigus vulgaris.
Topical steroids are sufficient in some cases.
4. Pemphigus erythematosus
Synonym: Senear-Usher syndrome
Clinical features
Pemphigus erythematosus is a subtype of pemphigus foliaceus,
and it occurs most commonly in the middle-aged and elderly. It
frequently affects the seborrheic zones on the head, face, chest
and back. Systemic lupus erythematosus (SLE) like erythema or
seborrheic dermatitis-like eruptions occur on the face, and pem-
phigus foliaceus-like intra-epidermal blisters form on the trunk
(Fig. 14.25). The mucosa is not involved. Involvement of SLE is
seen in some cases.
14
Treatment
The treatment is the same as for pemphigus foliaceus.
5. Paraneoplastic pemphigus
Outline
● The disease accompanies malignant or benign neoplasm
(lymphoproliferative diseases in particular). Severe
mucosal lesions with erosion, and various cutaneous
lesions, appear.
● Autoantibodies against several epidermal proteins, such
as desmogleins and plakin family molecules, are found.
Clinical features
Erosions, ulceration and bloody crusts are widespread on
mucous membranes in the oral cavity, pharynx and lips.
Pseudomembranous conjunctivitis may lead to blepharosynechia.
Various cutaneous lesions occur. It is important to test for IgG
autoantibodies and to identify tumors accompanying paraneo-
plastic pemphigus.
Fig. 14.26 Pemphigus induced by D-penicil-
Treatment lamine.
The neoplasms underlying paraneoplastic pemphigus are treat- Erythema and vesicles are present. When
induced by D-penicillamine, the skin lesion tends
ed. Treatment is the same as for severe pemphigus vulgaris. to persist even after the medication is discontin-
ued.
intraepidermal blister ―― e.g., pemphigus

(flaccid bulla)
6. Drug-induced pemphigus
Drug-induced pemphigus is a catchall for diseases that cause
lesions that resemble pemphigoid clinically and immunological-
easily ruptures ly. It has various clinical symptoms and various histological and
subepidermal blister ―― e.g., bullous pemphigoid immunohistological findings (Fig. 14.26). Acantholysis is found
(tense bulla)
in the epidermis of the lesions. In vivo IgA deposition is found in
the epidermis of the lesions. Drug-induced pemphigus is most
frequently induced by drugs that contain SH residue, such as d-
Because a subepidermal
blister is caused with all penicillamine.
layers of the epidermis intact,
it does not easily rupture.
7. Neonatal pemphigus
Fig. 14.27 Difference between an intrader-
mal blister and a subepidermal blister. Neonatal pemphigus is seen in newborns of mothers with pem-
phigus. The mother’s IgG autoantibodies pass into the placenta,
affecting the newborn infant’s skin. The clinical symptoms, and
histological and immunohistological findings of pemphigus are
transiently observed in neonatal pemphigus.
8. Intercellular IgA dermatosis

Synonym: IgA pemphigus
14 Intercellular IgA dermatosis is a rare disease that causes epi-
dermal intercellular IgA deposition. Vesicles and pustules are
Table 14.4 Autoimmune blistering diseases that cause subepidermal blisters.

Herpes Cicatricial Epidermolysis Dermatitis Linear IgA bullous
Bullous pemphigoid
gestationis pemphigoid bullosa acquisita herpetiformis (Duhring) dermatosis (LAD)
Age of onset Elderly (youth in some 4-month- Adults and Adults and Middle age <10 or 40
cases) pregnant to elderly elderly
postpartum
women
Frequent site Whole body Abdomen, Oral cavity, Intertriginous areas Whole body Whole body
buttocks, ocular (e.g., elbows, knees,) (especially elbows,
extremities mucosa knees, buttocks)
Clinical Findings Tense blisters, Urticaria-like Blisters, Erosion, blisters, Itching, erythema, Erythema, tense
findings of skin edematous erythema, erosion, scarring urticaria-like wheal blisters, itching
erythema, itching itching scarring
Mucosal ＋ − ＋＋＋ − ＋
infiltration
Pathological Eosinophilic infiltration Eosinophilic Neutrophilic infiltration, Neutrophilic
findings infiltration microabscess infiltration
Autoantigen BP180, BP230 BP180 BP180, Type VII collagen 97kD (Degradation
laminin-332 products of BP180)
Immuno- Direct Linear deposition of Linear Linear deposition of Granular deposition of Linear deposition
fluorescence IgG and C3 in the deposition of IgG in BMZ IgA in the papillae of of IgG (sometimes
findings epidermal basement C3 in BMZ upper dermal layer C3) in BMZ
membrane zone (BMZ)
Indirect Detection of anti- Detection of Anti-autoantibody not Detection of anti-
(Serum) basement membrane autoantibody against detected IgA antibody in
antibody type VII BMZ
collagen (290kDa)
Treatment Oral steroids, immuno- Topical and Oral steroids, Oral DDS, DDS, oral steroids
suppressant, DDS oral steroids immunosuppressant, gluten-free diet
plasmapheresis
produced on the trunk and extremities, and they become chronic.

Some cases are not clinically differentiable from subcorneal pus-
tular dermatosis.
9. Fogo selvagem, Brazilian pemphigus Clinical images are available in hardcopy only.
foliaceus
Fogo selvagem (Brazilian pemphigus foliaceus) is endemic to
Brazil and certain other areas of South America. Autoantibodies
recognize desmoglein 1, which is the same as in pemphigus foli- a b c d e f g h
aceus. Transmission is thought to involve black flies of the fami-
ly Simuliidae.
b. Diseases with subepidermal blistering

(pemphigoid group)
Outline
● These are autoimmune blistering diseases in which
subepidermal blistering occurs as a result of autoanti-
body action against epidermal basement membranea b c d e f g h i
structural proteins.
● Unlike the flaccid intra-epidermal blisters of pemphigus,
these subepidermal blisters are tense and do not rupture

14
easily (Fig. 14.27).
● Bloody blisters and milium may occur together.
● The disease is divided into pemphigoid, linear IgA bullous
dermatosis, epidermolysis bullosa acquisita and other
(Table 14.4).
● Immunofluorescence is useful for diagnosis.
● Steroids and DDS (dapsone) are applied.
a b c d e f g h i j
1. Bullous pemphigoid (BP)
Outline
● Autoantibodies against hemidesmosomes in the epider-
mal basement membranes are found. Clinical images are available in hardcopy only.
● The major pathogenic antigen is Type XVII collagen
(COL17, BP180). The roof of the blister has the full thick-
ness of the epidermis.
● Elderly people account for the majority of cases.
● The disease is characterized by subepidermal blisters g j
a b c d e f h i k
that do not rupture easily, itching and enanthema. Fig. 14.28-1 Bullous pemphigoid.
● Oral steroids are administered. a: Itching, edematous erythema and tense bullae
on the extremities. This is a typical skin manifes-
Clinical features tation of bullous pemphigoid. b: Skin lesions on
the chest. c: Affected back. d: Comparatively
The elderly are more commonly affected by bullous pem- large erythema.
phigoid than are young people. Multiple relatively large and
severe subepidermal blisters form immediately below the epider-
mis. Bullous pemphigoid is often accompanied by edematous
erythema (Figs. 14.28-1 and 14.28-2) and is much less invasive

to the mucous membranes (about 20% of the mucous membrane
is involved) than is pemphigus vulgaris. The general condition of
the patient is favorable; however, it may be complicated by
Clinical images are available in hardcopy only. malignant tumors in the internal organs.
Pathogenesis
Autoantibodies are produced against hemidesmosome (HD)
d e f g h i j k l m proteins,
n o p q r
structural Type XVII collagen (COL17, BP180) and
BP230 (BPAG1) in the epidermal basement membranes, which
leads to blistering. Autoantibodies against the membrane-proxi-
mal NC16a domain of BP180 play a major role in pathogenesis.
e f g h i j k l m n o p q r
Differential diagnosis between bullous MEMO

pemphigoid and epidermolysis bullosa acquisita
using salt-split-skin analysis
Differentiating between bullous pemphigoid and epidermolysis bullosa
Clinical images are available in hardcopy only. acquisita is often difficult because of the similar clinical courses and
immunofluorescence (IF) findings. Normal human split skin processed
with 1M NaCl is used for differential diagnosis.
14 When normal human skin is soaked in 1M NaCl for 48 hours at 4 ˚C,
the epidermis and dermis separate in the lamina lucida and artificial
blistering occurs. The patient’s serum is reacted to skin with this epider-
g j mal-dermal separation
p as
q the matrix for IF: In the case of bullous pem-
f h i k l m n o r
phigoid, the serum reacts to hemidesmosomes on the epidermal side; in
the case of epidermolysis bullosa acquisita, the serum reacts to anchor-
ing fibrils on the dermal side. Using this split-skin method, it is possi-
ble to distinguish between the diseases by the location of the blisters.
basal cells 1M
NaCl
Clinical images are available in hardcopy only. hemidesmosomes
lamina lucida
lamina densa
anchoring fibril
② Epidermis and dermis
① normal skin are separated at the
g h i j k l m n o p q of a patient
serum r lamina lucida.
with bullous serum of a
pemphigoid patient with
epidermolysis
bullosa acquisita
③ Antibodies adhere to ③ Antibodies adhere to

the epidermal side. the dermal side.
h i j k l m n o p q r
Fig. 14.28-2 Bullous pemphigoid.
e, f, g: Tense bullae on the trunk. h, i: Tense bul-
lae on the palms, fingers and toes.

In bullous pemphigoid, subepidermal blistering is accompa-
nied by eosinophilic infiltration (Fig. 14.29). Linear IgG and C3
deposition in the basement membranes of the lesions is observed
by direct immunofluorescence (IF) (Fig. 14.30). Anti-epidermal
basement membrane antibodies in the serum of the patients are
detected by indirect IF; autoantibodies against Type XVII colla-
gen proteins are identified by ELISA. High IgE values and ele-
vated levels of eosinophils are found in peripheral blood in some
cases.
Diagnosis
Bullous pemphigoid is diagnosed by clinical and pathological
features and by IF and ELISA (Table 14.4). In vivo linear IgG
deposition on the epithelial basement membranes is seen in all
patients with bullous pemphigoid, which is a necessary criterion
for diagnosis. Indirect IF using normal human split skin
processed with 1M-NaCl is conducted to distinguish this disease
from other subepidermal blistering diseases such as epidermoly-
sis bullosa acquisita (MEMO).
Treatment Fig. 14.29 Histopathology of bullous pem-

Oral steroids (0.5 mg/kg/day) are administered; and then grad- phigoid.
ually reduced. Combination therapy of immunosuppressants such A distinct subepidermal blister. Inflammatory 14
cells including eosinophils are seen.
as cyclophosphamide, DDS, tetracyclines and nicotinic-acid
amide is also useful. Dehydration and secondary infections
should be carefully avoided, and nutrition management is impor-
tant for elderly patients. Topical steroid application may be suffi-
cient in cases with mild symptoms. Plasma exchange therapy
may also be performed in severe cases.
2. Herpes gestationis
Clinical features
Multiple urticarial erythema appears on the abdomen, buttocks
and extremities between the fourth month of pregnancy and
immediately following delivery, and vesicles form in the periph-
ery of the erythema. The mucosa is rarely involved. Intense itch-
ing is present. Although herpes gestationis disappears 2 to 3
months after delivery in most cases, it becomes more recurrent
and aggravated with each successive pregnancy.
Pathogenesis
It is thought to be a bullous pemphigoid that is specific to
pregnant women. Herpes gestationis occurs in 1 in 5,000 to 1 in
10,000 deliveries. Autoantibodies against Type XVII collagen
proteins are found in hemidesmosomes. Fig. 14.30 Direct immunofluorescence of
the skin of a patient with bullous pem-
Diagnosis phigoid.
Linear deposition of IgG is observed in the epi-
Itching is intense. Herpes gestationis resembles dermatitis dermal basement membrane.
herpetiformis; however, it is distinguished by the absence of IgA

deposition and the presence of linear C3 deposition (Table 14.4).
Treatment
Clinical images are available in hardcopy only. Topical steroids are mainly applied. In severe cases, oral
steroids are administered.
3. Cicatricial pemphigoid
Synonym: Benign mucous membrane pemphigoid
Fig. 14.31 Cicatricial pemphigoid.
Erosion in the eye and scarring occur.
Blistering and erosive lesions occur, mostly in the oral cavity
and conjunctiva, leaving scarring (Fig. 14.31). Lesions may
occur in the genitalia, perianal region, pharynx, esophagus and
nasal mucosa. Prompt treatment is required if there is ble-
pharosynechia or respiratory difficulty. Autoantibodies against
Type XVII collagen proteins and laminin 332 are found.
4. Epidermolysis bullosa acquisita

● Autoantibodies against type VII collagen, which is a
14 structural component of anchoring fibrils, are produced.
● Subepidermal blisters form. They leave milium when
they heal.
● Differential diagnosis from bullous pemphigoid is clinical-
ly difficult.
● Steroids are administered orally. The disease is
intractable.
Fig. 14.32-1 Epidermolysis bullosa acquisi-
ta. Clinical features
Blistering, erosion and ulceration occur, which
may be partially accompanied by scarring. In epidermolysis bullosa acquisita, friction erosions and blis-
ters appear on the knees, elbows, palms and soles. They may
leave scarring or progress in a course similar to bullous pem-
phigoid. Healing often leaves scarring and milium (Figs. 14.32-1
and 14.32-2).
Pathogenesis
Autoantibodies against type VII collagen, which is a structural
component of anchoring fibrils that connect the epidermis and
the dermis, are produced. Subepidermal blisters form as a result.
Laboratory findings
Linear IgG deposition is observed by direct immunofluores-
cence on the epidermal basement membrane of the lesions.
Autoantibodies against type VII collagen of 290kD are found by
immunoblot procedure using the patient’s serum.
Diagnosis
The absence of a hereditary history of blistering formation is
an important aid for diagnosis. The most reliable methods of

diagnosing epidermolysis bullosa acquisita are indirect immuno-
fluorescence using 1M-NaCl split skin as a substrate (MEMO),
and immunoblot procedure.
It is essential to differentiate this disease from other blistering
diseases such as bullous pemphigoid, pemphigus, porphiria,
drug-induced eruptions and amyloidosis. In progressive cases, Clinical images are available in hardcopy only.
cutaneous symptoms similar to dystrophic epidermal bullosa
(nail deformity, coalescence of fingers and toes) may be present.
Treatment
Epidermolysis bullosa acquisita is resistant to treatment. Oral
steroids, immunosuppressants (e.g., cyclosporine) and plasma
exchange are administered.
5. Dermatitis herpetiformis (Duhring)
Outline
● It is characterized by extremely intense itching and irrita-
tion, chronically recurrent erythema, and vesicles. The
vesicles tend to form circular patterns.
14
● HLA-B8, DR3 and DQ2 are involved. The disease is
rarely seen in ethnic Japanese. It is common in Cau-

casians.
● Granular IgA deposition is found in the dermal papillary.
● Gluten-induced enteropathy develops as a complication
in many cases.
● Oral DDS is effective.
Fig. 14.32-2 Epidermolysis bullosa acquisi-

Clinical features ta.
Extremely intense itching is present. Erythema and urticarial
wheals occur, with vesicles produced in a ring-shaped pattern at
the periphery (Fig. 14.33). The severe itching causes the patient
to scratch, resulting in crusts, including bloody crusts. The erup-
tions heal with abnormal pigmentation or depigmentation. Erup-
tions appear symmetrically on the entire body, especially on the
elbows, knees and buttocks. However, the palms, soles and
mucosa are hardly affected. Gluten-induced enteropathy is found
in more than 90% of cases. As in celiac disease, in which there is
hypersensitivity to gluten, atrophic changes in jejunal villi are
found in dermatitis herpetiformis.
Pathogenesis
In recent years, it has been discovered that patients with this
disease have IgA antibodies against tissue transglutaminase in the
serum. The granular IgA deposition in the skin is an immuno-
Fig. 14.33 Dermatitis herpetiformis (Duhring).
complex. Eczema and blisters accompanied by intense
itching are present.
Pathology
Subepidermal blistering is present. Micro-abscesses are caused
in dermal papillary by neutrophilic infiltration.
Laboratory findings
Granular IgA deposition is observed by direct immunofluores-
cence (IF) in the dermal papillary. Anti-cutaneous autoantibodies
are not seen in the patient’s serum by IF. The patient’s serum
does not contain IgA-class anti-transglutaminase antibodies.
Clinical images are available in hardcopy only. Involvement of HLA-B8 in dermatitis herpetiformis has been
found. There are elevated levels of eosinophils in the peripheral
blood.
Diagnosis
Dermatitis herpetiformis is diagnosed by the clinical features,
such as rashes, intense itching, subepidermal blistering, and gran-
ular IgA deposition in the papillary dermis. The symptoms are
reduced remarkably by DDS; this fact has diagnostic signifi-
cance. Dermatitis herpetiformis is rare in ethnic Japanese.
Fig. 14.34 Linear IgA bullous dermatosis.
Dermatitis herpetiformis should be distinguished from linear
IgA bullous dermatosis, bullous pemphigoid, herpes gestationis
14 and erythema multiforme.
Treatment
Sulfa drugs such as DDS are effective. A gluten-free diet and
antihistamines are also useful.
6. Linear IgA bullous dermatosis (LAD)
Clinical features
Linear IgA bullous dermatosis (LAD) is divided into child-
hood LAD, whose symptoms appear in children under age 10,
and adult LAD, which occurs in adults age 40 or older. Multiple
erythema and tense blisters accompanied by intense itching occur
over the entire body, as in dermatitis herpetiformis (Fig. 14.34).
Lesions may occur in the mucous membranes. The lesions tend
to aggregate on the genitalia and inner regions of the thighs in
childhood LAD and heal spontaneously in some cases.
LAD is caused by linear IgA deposition on the epidermal base-
ment membrane; the deposition pattern differs from that in gran-
ular dermatitis herpetiformis. In Japan, most cases of IgA
deposition on the epidermal basement membrane are LAD; der-
matitis herpetiformis is rare.
Pathology
Subepidermal blistering is found. Neutrophilic infiltration is
Pustular diseases / 1. Palmoplantar pustulosis (PPP) 225
seen. Linear IgA deposition is found in the epidermal basement

membranes. C3 may also deposit in some cases.

Linear IgA deposition on the epidermal basement membranes
can be identified by direct immunofluorescence (IF). Anti-epi-
dermal basement membrane IgA autoantibodies may be detected
in the patient’s serum by indirect IF.
LAD should be differentiated from dermatitis herpetiformis. In
LAD, ① there is a histopathological finding of linear patterns of
in vivo IgA deposition, ② there are anti-basement membrane
IgA auto-antibodies in serum in some cases, ③ there is no
involvement of HLA-B8, DR3, or DQ2, ④ there is involvement
of the mucosa, and ⑤ there is no sensitivity to gluten.
Treatment
DDS is effective, as are oral steroids.
Pustular diseases
14
1. Palmoplantar pustulosis (PPP)
Synonym: Pustulosis palmaris et pustulosis
Outline
● Multiple sterile pustules form symmetrically on the palms
and soles of the middle-aged and elderly, becoming
chronic.
● Smoking, bacterial infection (tonsillitis), dental caries and
dental metal allergy are associated with occurrence of

PPP.
● Sternocostoclavicular ossification and pain may develop
as complications.
● Topical steroid application, smoking cessation and tonsil-
lectomy are the main treatments.
Clinical features
Multiple vesicles occur on the thenar and antithenar regions of
the palms and arches of feet, and these become pustular. Erythe-
ma develops at the periphery of the lesions and fuses into plaques
(Fig. 14.35). Itching may be present. Punctate depressions and
thickening occur frequently in the nails. Pustules recur in 2- to 4-
week cycles and progress chronically. They may appear on the
knees, lower extremities and scalp. In 10% of palmoplantar pus-
tulosis (PPP) cases, sternocostoclavicular ossification accompa-
nied by chest pain develops as a complication.
Pathogenesis
PPP patients are mainly female and tend to have smoked at
least a pack a day for more than 20 years. If focal infections (e.g.,
tonsillitis, dental caries) are found and treated, PPP may improve.
Clinical images are available in hardcopy only. Cases induced by bacterial allergic reaction and metal allergy
have been reported. It is hypothesized that PPP is a localized type
of pustular psoriasis.
Pathology
Sterile pustules in the epidermis contain neutrophils and
degenerated epidermal cells. Mild cellular infiltration into the
dermis is seen.
Laboratory findings
To detect focal infections such as tonsillitis and dental caries,
the white blood cell count, antistreptolysin O, CRP and sedimen-
tation rate are examined by peripheral blood tests. In some cases,
skin lesions are aggravated by a tonsil provocation test. For con-
firmation of dental metal allergy in the mouth, metal patch tests
are conducted. Tests for detection of arthropathy and ossification
(sternocostoclavicular) are also conducted.
14 The disease should be distinguished from tinea manus, pustu-
lar psoriasis, contact dermatitis, pompholyx and Reiter disease.
Treatment
In most long-term smokers, the disorder disappears with cessa-
tion of smoking. Focal infectious diseases, if any, are treated.
Prevention of tonsillitis and otological and dental treatments are
important. Oral antibiotics are useful. Tonsillectomy may be per-
formed. For skin lesions, topical steroids are the first line of treat-
ment; additionally, vitamin D3 ointment and PUVA therapy are
applied. Methotrexate, colchicin and etretinate are administered
orally in severe cases.

2. Subcorneal pustular dermatosis
(Sneddon-Wilkinson disease)
Clinical features
Subcorneal pustular dermatosis occurs infrequently but most
commonly in women over age 40. Erythema and pustules appear
in a ring-shaped or serpigenous pattern on the trunk and on sites
Fig. 14.35 Palmoplantar pustulosis (PPP).
Multiple pustules aggregate on the hands and exposed to friction. Pustules quickly dry, leaving crusts and
feet. scales (frilly scales) (Fig. 14.36). Itching or systemic symptoms
are not present, and the mucosa is not involved. The disease
becomes chronic with recurrent aggravation and remission.
Pathogenesis, Pathology, Differential diagnosis

The etiology of subcorneal pustular dermatosis is unknown in
Pustular diseases / 3. Eosinophilic pustular folliculitis 227
many cases. In some cases, IgA myeloma or ulcerative colitis

exists as a complication. Sterile pustules mainly containing neu-
trophils are found histopathologically under the horny cell layer.
Spongiform pustules, seen in pustular psoriasis, are not found.
Subcorneal pustular dermatosis is distinguished from intracel-
lular IgA dermatosis by immunofluorescence. IgA class autoanti- Clinical images are available in hardcopy only.
bodies are not detected immunohistologically in the epidermal
intercellular space.
Treatment
DDS and oral steroids are effective. Etretinate (a vitamin A
derivative), and PUVA are effective in some cases.
3. Eosinophilic pustular folliculitis

Synonyms: Ofuji’s disease, Eosinophilic pustular dermatosis
Outline
● Itching papules and pustules are produced. They aggre-
gate, mainly in hair follicles.
● Male adults are the most commonly affected. Progress is
chronic, with recurrences and remissions. The etiology is

unknown.
● Multiple eosinophils are contained in the pustules.
14
● The disease may accompany HIV infection.
● Indomethacin is effective as a treatment.

Eosinophilic pustular folliculitis occurs most frequently in men
in their 20s or 30s. Sterile, follicular and itching papules or small
pustules occur and aggregate to form erythematous plaques that
spread centrifugally (Fig. 14.37). The face, upper body and
extensor surface of the upper arms are the most severely affected
regions; in some cases, however, the eruptions can occur in the Fig. 14.36 Subcorneal pustular dermatosis.
hands and soles, where hair follicles do not exist. They leave
abnormal pigmentation when they heal. Eosinophilic pustular
folliculitis recurs with remissions. The disease may accompany a
hematologic disorders or HIV infection. Most cases have been
reported from Japan. The cause is unknown.
Pathology, Laboratory findings, Differential diagnosis, Treatment

Eosinophils are found in large quantities in pustular compo-
nents. Eosinophilic infiltration into the hair follicles and hair
apparatuses results in destruction of hair follicles. Elevated levels
of eosinophils are seen in the peripheral blood. Eosinophilic pus-
tular folliculitis needs to be differentiated from tinea, candidiasis,
folliculitis, acne, rosacea and contact dermatitis. When it occurs
on the hands and soles, differentiation from pustulosis palmaris et
plantaris is difficult. Indomethacin is very effective.
4. Acute generalized pustular bacterid

The appearance of acute sterile pustules on the trunk and
extremities is followed by upper respiratory infection. Since the
pathogenetic mechanisms have not been clarified, there is a con-
troversy over whether acute generalized pustular bacterid is an
independent clinical entity.

5. Infantile acropustulosis
The extremities of infants are affected. Infantile acropustulosis
is a recurrent pustular disease that causes multiple sterile pustules
and vesicles with intense pustular psoriasis.
Refer to Chapter 15 for pustular psoriasis.
Fig. 14.37 Eosinophilic pustular folliculitis.

Follicular papules and pustules aggregate,
accompanied by itching.
14
Chapter
15 Disorders of Abnormal Keratinization
The mechanisms of keratinization have been clarified in recent years. The genes responsible for many heredi-
tary disorders of abnormal keratinization have been identified, but the pathogenesis of some disorders remain
unknown. It is expected that these will be elucidated in the near future.
Disorders of abnormal keratinization are classified as hereditary keratoses (e.g., ichthyosis, Darier’ s disease)
and acquired diseases. The acquired diseases are subclassified as inflammatory diseases, whose main symp-
tom is inflammation accompanied by itching (e.g., psoriasis, lichen planus), and non-inflammatory keratoses
(e.g., clavus, callus). This chapter discusses typical disorders of keratinization, based on that classification.
A. Hereditary keratoses
Table 15.1 Classification of ichthyosis.
a. Ichthyosis Congenital ichthyosis
Ichthyosis vulgaris
Ichthyosis is the clinical condition in which the whole body X-linked ichthyosis
skin dries and becomes coarse, resulting in scaling. It is caused Bullous congenital ichthyosiform erythroderma
by abnormality in keratinization and exfoliation of the horny cell (BCIE)
layer. The skin is covered with what appear to be fish-like scales. Nonbullous congenital ichthyosiform
erythroderma (NBCIE)
Patients with ichthyosis have a congenital abnormality in kera- 15
Lamellar ichthyosis
tinization and scaling, and most cases are classified as hereditary
Harlequin ichthyosis
keratoses. However, some may appear later in life as acquired
Ichthyosis accompanied by internal organ lesion
conditions; these cases often accompany malignant tumors.
(Ichthyosis syndrome)
Ichthyosis is classified by clinical features, inheritance pattern,
Sjögren-Larsson syndrome
and affected sites into more than ten subtypes (Table 15.1). This
Netherton syndrome
section introduces typical types of ichthyosis.
KID syndrome
Dorfman-Chanarin syndrome
1. Ichthyosis vulgaris Refsum syndrome
Rud syndrome
Outline Conradi syndrome
Acquired ichthyosis
● It is caused by mutation in the gene coding for filaggrin, a
key protein involved in skin barrier function. This is the Acquired ichthyosis
mildest form of ichthyosis. The main symptoms are dry-

ness and scaling of the skin.
● The onset is early childhood. Dryness, and scaling of the
skin are present, mostly on the extensor surfaces of

extremities and trunk. It subsides during summer.
● It is the common inherited disorder of keratinization.
● Inheritance is semidominant.
● Symptomatic therapies including application of moisturiz-
er are the main treatments.
Clinical features
The onset is early childhood. It is progressive until the patients
reach about the age of 10, the symptoms subsiding in adolescence
229
230 15 Disorders of Abnormal Keratinization
in most cases. The skin dries, appearing pityroid and lamellar.

The extensor surfaces of the legs and the back region are the
most commonly affected; the flexure of joints in the extremities,
axillary fossae genitals and thoraco-abdominal region are unaf-
fected (Fig. 15.1). Subjective symptoms and itching are rarely
observed. The symptoms subside during the summer and aggra-
vate during the winter, when the skin tends to dry. Filaggrin
Clinical images are available in hardcopy only. mutation is a major predisposing factor for atopic dermatitis, and
atopic disorders are strongly associated with ichthyosis vulgaris.
Pathogenesis
The causative gene has recently been identified as the filaggrin
gene (FLG). As a result of a decrease in the production of filag-
grin, which moisturizes the epidermis, there is abnormal exfolia-
tion of horny cells and dryness and scaling of the skin (Chapter
1). Ichthyosis vulgaris is semidominantly inherited (homozygous
patients have more severe symptoms than heterozygous patients)
and often runs in families.
Pathology
There is thickening of the horny cell layer and reduction or
loss of keratohyaline granules and granular cell layer because of
loss or reduction of filaggrins.
15
Ichthyosis vulgaris is diagnosed by the clinical and pathologi-
cal features, family history and filaggrin gene mutation.
In other hereditary ichthyoses, the onset is the time of birth,
and the flexures of the joints in the extremities are often involved
Fig. 15.1 Ichthyosis vulgaris. (Table 15.2). Acquired ichthyosis can be differentiated from
The skin dries, and pityriasis-like lamellar exfoli- ichthyosis vulgaris by the age of onset, the clinical course, and
ation occurs. the presence of malignant tumor in the case of the former.
Table 15.2 Comparison between types of ichthyosis.
Bullous congenital Nonbullous congenital
Harlequin
Ichthyosis vulgaris X-linked ichthyosis ichthyosiform ichthyosiform erythroderma
ichthyosis
erythroderma (BCIE) (NBCIE), lamellar ichthyosis
Frequency Common Uncommon Rare Rare Very rare
Inheritance pattern SD (semidominant) XR AD AR AR
Age of onset Babyhood, infancy At birth or early after birth At birth or early after At birth At birth
birth
Skin Site Extremities, trunk (back > Abdomen > back, Whole body Whole body Whole body
symptom abdomen), intertriginous intertriginous sites,
sites, extensor surface > extensor surface =
flexor surface flexor surface
Form Fine scales Large, dark brown scales Severe Flushing, fine or dark brown Markedly thick
hyperkeratosis (NBCIE) large scales hyperkeratosis,
(lamellar ichthyosis) deep fissures,
ectropion
Pathology Hyperkeratosis, thinned Hyperkeratosis, almost Degeneration of Hyperkeratosis (with or Severe
granular cell layer normal granular cell layer granular cell layer without parakeratosis) hyperkeratosis
Causative gene Filaggrin (FLG) Steroid sulfatase Keratin 1 or Transglutaminase 1 in some ABCA12
keratin 10 cases
(AD: autosomal dominantly inherited, AR: autosomal recessively inherited, XR: x-linked recessively inherited, SD: semidominantly inherited).
A. Hereditary keratoses 231
Treatments are symptomatic. Moisturizer, urea ointments, sali-
cylic acid petrolatum, and vitamin D3 ointments are applied. The
symptoms subside after adolescence.
2. X-linked ichthyosis
Outline
● Itis caused by loss or marked reduction of steroid sulfa-
tase, resulting in delayed exfoliation of the horny cell Clinical images are available in hardcopy only.
layer. It is X-linked recessively inherited.
● The symptoms are severer than those of ichthyosis vul-
garis. Eruptions also appear on the flexures of joints.
Clinical features
X-linked ichthyosis manifests shortly after birth and does not
improve with age. The cutaneous symptoms are severe; the
scales are large and dark brown (Fig. 15.2). The whole body of
newborns may be encased in a translucent covering (collodion
baby). Not only the extensor surfaces but also the flexures of
extremities are affected. The abdomen is most severely affected. Fig. 15.2 X-linked ichthyosis.
Corneal opacification may occur as a complication. As with Relatively large scales are present. The symp-
ichthyosis vulgaris, X-linked ichthyosis aggravates during the toms are severer than those of ichthyosis vul-
garis.
winter and subsides during the summer. 15
Pathogenesis
It is caused by mutation in the steroid sulfatase gene on X-
chromosome. Steroid sulfatase is the enzyme that breaks down
cholesterol sulfate, a substance which promotes intercellular
adhesion in the horny cell layer. The lack of steroid sulfatase
causes accumulation of cholesterol sulfate, leading to delayed
exfoliation of horny cells and hyperkeratosis (Chapter 1). X-
linked ichthyosis is recessively inherited and occurs in males. Clinical images are available in hardcopy only.

Thickening of the horny cell layer, and normal or mildly thick-
ened granular and suprabasal cell layers are present. Follicular
keratinization is rarely found. Absence or marked reduction of
steroid sulfatase is observed in the horny cell layer, peripheral
leukocytes, and fibroblasts. Estriol in the urine decreases in the
mothers (carriers) of children with X-linked ichthyosis.
Fig. 15.3-1 Bullous congenital ichthyosiform
Differential diagnosis, Treatment erythroderma.
Skin lesions accompanied by flushing and thick
Ichthyosis vulgaris is differentiated from X-linked ichthyosis keratinization occur on the whole body surface.
by the decrease of steroid sulfatase in the case of the latter. The
treatments are symptomatic and the same as those for ichthyosis
vulgaris.


15
Fig. 15.3-2 Bullous congenital ichthyosiform erythroderma.

Flushing appears on the whole body. Severe, dark keratinization with a dirty appearance occurs on the hands and feet (often in cases
of mutation in the keratin 10 gene).
3. Bullous congenital ichthyosiform

erythroderma (BCIE)
Clinical features
Patients with bullous congenital ichthyosiform erythroderma
(BCIE) are sometimes born as collodion babies. Diffuse flushing
and blistering recur for several weeks after birth. Scales gradually
thicken, leading to severe keratinization in later childhood (Figs.
15.3-1 and 15.3-2). The thickly keratinized plaques are accompa-
nied by flush and a characteristic odor. The whole body including
Fig. 15.4 Histopathology of bullous congeni- the flexures of joints and extremities appear erythrodermatic and
tal ichthyosiform erythroderma.
Granular degeneration occurs in the epidermis. dark rose in color. The prognosis is good.
Pathogenesis
The cytoskeleton (intermediate filament) of suprabasal cells is
composed of keratin 1 and keratin 10. Because of mutation in the

keratin 1 or keratin 10 gene, abnormal keratin fiber formation,
cytoskeleton distortion, and epidermal blistering occur, leading to
secondary thickening of the horny cell layer (Fig. 1.14). BCIE is
autosomal dominantly inherited.
Pathology
The horny and suprabasal cell layers thicken, keratin fibers
aggregate, and there are vacuolated cells containing large kerato-
hyaline granules in the granular and suprabasal cell layers (gran-
ular degeneration, Fig. 15.4).
Fig. 15.5 Ichthyosis bullosa of Siemens.
The clinical symptoms are milder than those of
Differential diagnosis, Treatment bullous congenital ichthyosiform erythroderma.
Blistering is marked, particularly in newborns. It is necessary Flushing and hyperkeratosis are present.
to differentiate BCIE from epidermolysis bullosa, incontinentia
pigmenti and impetigo contagiosa by the pathological findings.
The treatments are oral retinoid and application of moisturizer.
4. Ichthyosis bullosa of Siemens

It is caused by mutation in the keratin 2e gene. The clinical
features are similar to those of the mild type of bullous congeni- Clinical images are available in hardcopy only.
tal ichthyosiform erythroderma; nonetheless, erythroderma is not
present in ichthyosis bullosa of Siemens (Fig. 15.5). Localized
granular degeneration is histopathologically seen in part of the 15
uppermost prickle layer and granular layer where keratin 2e is
expressed in the epidermal granular layer.
5. Nonbullous congenital ichthyosiform

erythroderma (NBCIE)
Clinical features
Most of the patients are born as collodion babies. Two to three Clinical images are available in hardcopy only.
days after birth, the collodion covering exfoliates, leaving the
whole body surface with diffuse flushing and scaling (Figs. 15.6-
1 and 15.6-2). The affected sites include the flexures of joints.
Ectropion of eyelids may also occur. There are minor changes in
the symptoms with season. NBCIE progresses until the age of 10,
at which point it stops and subsides. The clinical manifestations Fig. 15.6-1 Nonbullous congenital
ichthyosiform erythroderma.
range from mild to severe. Erosive flushing and fine scales are seen on the
whole body. Blistering does not occur.
Pathogenesis
It is autosomal recessively inherited. The pathogeneses are
various. Six or more genes are thought to be associated with
occurrence of NBCIE. A certain mutation in the ABCA12 gene,
the causative gene for harlequin ichthyosis, also causes NBCIE.
The transglutaminase 1 gene, the causative gene for lamellar
ichthyosis, can also cause NBCIE. Complete absence of transglu-
taminase 1 activity causes typical lamellar ichthyosis; severe
reduction in such activity leads to NBCIE. The mechanism of
Clinical images are Clinical images are



Fig. 15.6-2 Nonbullous congenital ichthyosiform erythroderma.
loricrin
involucrin
cellular membrane
cornified cell
envelope
keratin pattern
magnification
cellular membrane
magnification
lamellar granule
keratohyaline
granule
nucleus
Cornified cell envelopes cover the horny cell membrane in the horny cell layer. They play an important role in increasing the
strength of the horny cell layer against physical and chemical stimuli.
Fig. 15.7 Cornified cell envelope.

NBCIE is known to be a marked decrease in physical and func-

tional strength of keratin (Figs. 15.7 and 1.16).
Treatment
Oral retinoid (a vitamin A derivative) is effective. The skin
should be kept clean to prevent secondary infection.
6. Lamellar ichthyosis
In approximately half of all cases of lamellar ichthyosis, the
cause is an absence of transglutaminase 1; however, its activity is
normal in some cases. Transglutaminase 1 is a calcium-depend-
ent enzyme that is necessary for the formation of cornified cell
envelopes in keratinocytes. The pathogeneses of lamellar
ichthyosis are various. The scales in lamellar ichthyosis are clini- Clinical images are available in hardcopy only.
cally rough and large in most cases, dark brown, and plate-like or
lamellar; these characteristics distinguish the scales from those in
nonbullous congenital ichthyosiform erythroderma (NBCIE)
(Fig. 15.8).
7. Harlequin ichthyosis Fig. 15.8 Lamellar ichthyosis.

Large, dark brown scales are characteristic of
Synonym: Harlequin fetus lamellar ichthyosis.
The patient is covered with an extremely thick stratum 15

corneum at birth. Cracks in the skin, ectropion of eyelids, protru-
sion of lips, and difficulty of opening the mouth are so severe
that most patients die within 2 weeks after birth (Fig. 15.9). In
2005, a Japanese dermatologist identified ABCA12 as the
causative gene. ABCA12 is a lipid transporter in the lamellar
granule, and the lack of ABCA12 leads to marked reduction of
lipid content in the horny layer. There is abnormality of the Clinical images are available in hardcopy only.
lamellar granules in harlequin ichthyosis. It is autosomal reces-
sively inherited, and DNA-based prenatal diagnosis is clinically
applied.
8. Ichthyosis syndrome
Ichthyosis syndrome is a general term for congenital
ichthyosis accompanied by involvement of certain organs. Most
of the cutaneous symptoms resemble those of nonbullous con-
genital ichthyosiform erythroderma (NBCIE). The most frequent-
ly occurring types of ichthyosis syndrome are listed in Table Clinical images are available in hardcopy only.
15.3.
①Sjögren-Larsson syndrome
It is autosomal recessively inherited. The main characteristics
are congenital ichthyosiform erythroderma, spasmodic acroparal-
ysis, and mild to moderate mental retardation (Fig. 15.12). There Fig. 15.9 Harlequin ichthyosis.
is abnormality in the gene that codes for fatty aldehyde dehydro- There is marked hyperkeratosis on the whole
body surface. Ectropion of the eyelids results in
genase (FALDH/ALD). The condition is caused by absence of reddening over the eyes. Normal eyeballs are
FALDH. present underneath.
Table 15.3 Major ichthyosis syndromes.

Disease Inheritance pattern Eruptions Other symptoms
Sjögren-Larsson syndrome AR Nonbullous congenital ichthyosiform erythroderma Mental retardation, spastic quadriplegia
Netherton syndrome AR Atopic dermatitis-like eruption, bamboo hair Atopic diathesis
KID syndrome AD Spiny hyperkeratosis in the extremities and face Hearing impairment, keratitis
Dorfman-Chanarin AR Nonbullous congenital ichthyosiform erythroderma Lipid droplets in leukocytes, hepatic
syndrome steatosis, cataract, neurologic manifestation
Refsum syndrome AR Lamellar ichthyosis-like skin Retinitis pigmentosa, polyneuropathy,
cerebellar ataxia, inner-ear deafness
Rud syndrome AR Nonbullous congenital ichthyosiform erythroderma Seizure, mental retardation, low height,
gonadal hypofunction
Conradi syndrome AD or AR Nonbullous congenital ichthyosiform erythroderma Skeletal defects, cataract, punctate shadow
at bone ends, quadriplegia

Clinical images are
hardcopy only. Clinical images are available in
available in
hardcopy only.
hardcopy only.
15
Fig. 15.12 Sjögren-Larsson syndrome.
Nonbullous congenital ichthyosiform erythroderma-like eruptions occur.

hardcopy only. ②Netherton syndrome
Autosomal recessively inherited, it is caused by a mutation in
the SPINK5 gene, which codes for serine protease inhibitor. The
eruptions resemble atopic dermatitis or nonbullous congenital
ichthyosiform erythroderma (Fig. 15.10). Scalp hair becomes
a b c d e f g h i j k easily
l broken
m (bamboo
n o p q r
knotted, short and hair).
Fig. 15.10 Netherton syndrome. ③Keratitis, ichthyosis and deafness (KID) syndrome
a: It is accompanied by atopic dermatitis-like
eruptions and nonbullous congenital ichthyosi- It is autosomal dominantly inherited. The main symptoms are
form erythroderma-like eruptions. b: The scalp keratitis, ichthyosis and deafness. Papillomatous or prickle kera-
hair becomes knotted and easily breaks at the totic lesions occur mainly on the face and extremities (Fig.
knots, resulting in short hair (bamboo hair).
15.11).
④Dorfman-Chanarin syndrome
It is an autosomal recessively inherited metabolic disorder of
neutral lipids, caused by mutation in the CGI-58 gene, which
codes for an enzyme that regulates metabolism of phospholipids.
Triacylglycerol accumulates in the cytoplasma of various cells to
form lipid droplets. The disorder may be accompanied by
ichthyosis, liver disorder, hearing loss, mental retardation,
cataract and nystagmus (Figs. 15.13 and 15.14).
⑤Refsum syndrome
Fig. 15.11 KID syndrome. It is autosomal recessively inherited. In addition to lamellar-
Prickle keratotic macules on the scalp. ichthyosis-like eruptions, there is night blindness caused by
Clinical images are

Clinical images are available Clinical images are available Clinical images are available in
available in
in hardcopy only. in hardcopy only. hardcopy only.
hardcopy only.
Fig. 15.13 Dorfman-Chanarin syndrome.
retinitis pigmentosa. Cerebellar ataxia, multiple neuritis

polyneuritis, and sensorineural deafness are present. Levels of
phytanic acid in the blood increase from congenital metabolic
disorder.
⑥Rud syndrome
It is known to be autosomal recessively inherited; boys are
more commonly affected than girls, and most cases are sporadic.
Congenital ichthyosiform erytheoderma-like skin manifestations,
epilepsy, mental retardation, gonadal hypofunction and short 15
stature may occur as complications.
⑦Conradi syndrome (Conradi-Hünermann-Happle syn-
drome)
The symptoms of nonbullous congenital ichthyosiform ery- Fig. 15.14 Histopathology of Dorfman-Cha-
narin syndrome.
throderma, abnormal formation of bones, cataract, and paralysis
in all extremities occur. Conradi syndrome is X-linked dominant-
ly inherited. Males die prenatally. The cause is mutation in the
emopamil binding protein (EBP) gene at Xp11.22-p11.23.
b. Palmoplantar keratoderma
Palmoplantar keratoderma is a generic term for diseases that
hereditarily cause hyperkeratosis in the palms and soles. It is sub-
classified by clinical features and patterns of inheritance (Figs.
15.15-1 and 15.15-2; Table 15.4). Genetic mutation is identified
in some cases. Further clarification is necessary for exact classifi-
cation of palmoplantar keratoderma. The main types of palmo-
plantar keratoderma are shown below.
Treatment
There is no effective treatment for any types. Oral retinoid (a
vitamin A derivative) and topical application of petrolatum sali-
cylate or moisturizer are the main treatments.
1. Thost-Unna palmoplantar keratoderma

Thost-Unna palmoplantar keratoderma is autosomal dominant-
ly inherited. Localized diffuse lesions with a red halo form on the
palms and soles of infants. Thickening of the horny cell layer and
Clinical images are available epidermis is seen. In recent years, cases with mutation in the ker-
in hardcopy only.
atin 1 gene have been reported. The palms and soles of patients
with Thost-Unna palmoplantar are usually hyperhidrotic.
2. Vörner palmoplantar keratoderma

It is autosomal dominantly inherited. Differentiation from
Thost-Unna palmoplantar keratoderma can be made by
histopathological detection of granular degeneration; such differ-
entiation is impossible from clinical findings. Mutation in the
keratin 9 gene is found in half of all patients with Vörner palmo-
plantar keratoderma.
in hardcopy only.
3. Mal de Meleda
Synonym: Meleda disease
This autosomal recessively inherited disease is often seen in

offspring of consanguineous marriages. It hardly ever occurs in
15 Asians. Hyperkeratosis accompanied by flush appears immedi-
ately after birth. Keratinization progresses and extends as the
patient ages. In many cases, not only are the palms and soles
affected, but so are the dorsal hands and feet, arms and legs. It is
hardcopy only. progressive until the patients become elderly. Mental retardation
may occur.
4. Dominant Meleda palmoplantar keratoder-

ma
Fig. 15.15-1 Palmoplantar keratoderma.
Keratinization of varying severity is present on Relatively mild reddening and keratinization affect the dorsal
the hands. It is often difficult to determine the hands and feet.
subtype only by clinical findings.
Table 15.4 Major types of palmoplantar keratoderma.

Disease Inheritance pattern Age of onset Eruptions Other symptoms
Thost-Unna keratoderma AD Babyhood, infancy Diffuse keratotic eruption with a red-halo in the Hyperhidrosis on the palms and
periphery localized on the palms and soles soles
Vörner keratoderma AD Babyhood, infancy Thost-Unna keratoderma-like eruption Granular degeneration (histologically)
Mal de Meleda AR Babyhood Hyperkeratosis accompanied by flushing, spreading Mental retardation
to the dorsum of hands and feet with age
Dominant Mal de Meleda AD Infancy, early Resembles eruption in Mal de Meleda; however,
keratoderma childhood keratosis and flushing are milder
Keratosis palmoplantaris AR Babyhood, infancy Mild keratosis on the dorsum of hands and feet
transgrediens Nagashima
Keratosis palmoplantaris AD Infancy, early Linear, band-like, or round hyperkeratosis on the
linearis/striata childhood palms and soles
Punctate palmoplantar AD Early childhood to Multiple, firm, punctate keratotic papules on the May be accompanied by nail
keratoderma elderly palms and soles deformity resulted from malnutrition

Fig. 15.15-2 Palmoplantar keratoderma.
5. Keratosis palmoplantaris transgrediens

Nagashima
The symptoms are relatively mild, similar to those of Mal de
Meleda. Keratinization is mild. It is autosomal recessively inher- 15
ited. The pathogenesis has not been identified.
6. Keratosis palmoplantaris linearis/striata
It is autosomal dominantly inherited. Linear, band-like or round
hyperkeratosis is present in the palms and soles. Mutations in the
desmoglein 1 and desmoplakin genes are found in some families.
7. Punctate palmoplantar keratoderma

Fig. 15.16 Keratosis palmoplantaris muti-
It is autosomal dominant inherited. Punctuate keratinization is lans (Vohwinkel).
seen in the palms and soles.
8. Keratosis palmoplantaris mutilans

(Vohwinkel)
Keratosis occurs in the palms and soles, which leads to stran-
gulation obstruction in fingers and toes (Fig. 15.16). Star-shaped Clinical images are available
keratinized plaques develop on the dorsal surfaces of the hands in hardcopy only.
and feet and on the kneecaps. Mutation in the loricrin gene has
been reported.
9. Papillon-Lefévre syndrome
Flush and hyperkeratosis occur on the palms, soles, the dorsal Fig. 15.17-1 Papillon-Lefévre syndrome.
surfaces of hands and feet, and the extremities. The syndrome is Flushing and the hyperkeratosis are present.
characterized by periodontal disease (Figs. 15.17-1 and 15.17-2).

It is autosomal recessively inherited.

10. Richner-Hanhart syndrome
The three major characteristics are painful palmoplantar ker-
atosis, photophobia, and mental retardation. It is autosomal reces-
Fig. 15.17-2 Papillon-Lefévre syndrome. sively inherited. The pathogenesis is a reduced activity of
tyrosine aminotransferase.
11. Náxos disease

Keratosis, cardiac myopathy of the right ventricle, cardiac
enlargement, and palmoplantar keratosis are present. Cases with
mutation in the plakoglobin gene have been reported.
c. Other hereditary keratoses
1. Darier’s disease
Synonym: Keratosis follicularis
Outline
● Keratotic papules of 2 mm to 5 mm in diameter appear,
15 mainly on seborrheic and intertriginous areas. The condi-
tion is aggravated by perspiration in summer.
● The pathogenesis is genetic mutation in SERCA2, the
calcium pump of keratinocytes. It is autosomal dominant-
ly inherited.
● The characteristic pathological findings are acantholysis,
lacunae, corps ronds, and grains.

Clinical features
Darier’s disease first occurs in infancy and continues through
adolescence. Multiple dark brown keratotic papules of 2 mm to 5
mm in diameter covered by thick crusts occur in the seborrheic
and intertriginous areas such as the neck, axillary fossae, sternal
region, inframammary region, abdomen and groin (Figs. 15.18-1
and 15.18-2). The papules may be moist and give off a bad odor.
On the perspiratory intertriginous areas, papules coalesce and
condyloma-like proliferation occurs. The following occur: ker-
atosis in the palms and soles, verrucous keratosis in the dorsal
surfaces of hands and feet, punctuate depression in the palms,
enanthema, deformity of nails, and sometimes nervous symptoms
such as mental retardation and epilepsy. Bacterial or viral infection
(e.g., Kaposi’s varicelliform eruption) may occur secondarily.
g j
Pathogenesis p q
b c d e f h i k l m n o r
Darier’s disease is caused by mutation in the ATP2A2 gene,
Fig. 15.18-1 Darier’s disease.
a, b: Dark brown, keratotic papules on the whole which codes for the SERCA2 calcium pump. That pump controls
body. c: Verrucous keratinization on the palm. the calcium concentration in the cytoplasm of keratinocytes.
Since calcium regulates intercellular adhesion and differentiation

of keratinocytes, the genetic mutation promotes keratinization
and abnormal formation of desmosomes and keratin fiber com-
plex, leading to abnormal dyskeratosis and acantholysis.
Pathology Clinical images are available in hardcopy only.
Darier’s disease is characterized by dyskeratosis. Therefore,

corps ronds (large round cells with a basophilic pyknotic nucleus
and bright cytoplasm) and grains (long, thin cells that resemble
parakeratotic cells and stain dark) are found in the granular layer.
g j
There is acantholysis, its accompanying lacunae aformation,b andc d e f h i k
villi formation in which dermal papillae extend upwards into the Fig. 15.18-2 Darier’s disease.
d: Changes of nail plates.
lacunae (Fig. 15.19).
Darier’s disease should be differentiated from acanthosis nigri-
cans, Hailey-Hailey disease and seborrheic dermatitis.
Treatment
The symptoms are improved temporarily by oral retinoid. Urea
ointments are also useful. Secondary infections and sun exposure
should be avoided.
2. Erythrokeratodermia
15
Localized keratotic lesions accompanied by flush may be pro-
duced in infancy; erythrokeratodermia is the generic term for
these clinical conditions. There are various clinical features and Fig. 15.19 Histopathology of Darier’s disease.
There are dyskeratotic cells, acantholysis, fis-
causative genes (Fig. 15.20). The following are the major types sures and villi in the epidermis.
of erythrokeratodermia.
①Progressive symmetric erythrokeratodermia
It is autosomal dominantly inherited. In some cases, mutation
in the gene coding for loricrin has been identified. Localized,
sharply circumscribed flushing and keratotic lesions are present.
The extremities are most commonly affected. It often appears
symmetrically. The lesions extend with time. The main treatment
is oral retinoid.
②Erythrokeratodermia variabilis
It is autosomal dominantly inherited. In some cases, mutation
in the gene coding for connexin has been identified. Localized,
sharply circumscribed flushing and keratotic lesions appear in
infants under 1 year old. The lesions occur symmetrically on the
face, trunk and extremities, and tend to extend and coalesce.
They disappear in several days to several weeks, recurring on dif- Clinical images are available in hardcopy only.
ferent sites. Scaling is marked and gives the skin an unwashed
appearance, but there are no subjective symptoms. The main
treatment is oral retinoid.
Skin fragility syndrome→See Chapter 14.

Fig. 15.20 Erythrokeratodermia variabilis.
Sharply demarcated keratotic erythema.
B. Acquired keratoses
a. Inflammatory keratoses
1. Psoriasis (Fig. 15.21)

● It most frequently occurs in young and middle-aged men
and women. Erythema and papules are accompanied by
thick silvery-white scales. Inflammation in the epidermis
and accelerated turnover of epidermal cells are found.
● It is classified by clinical features into five types: psoriasis
vulgaris, guttate psoriasis, pustular psoriasis, psoriatic

Fig. 15.21 Psoriasis vulgaris on the back.
erythroderma and psoriatic arthritis.
● Auspitz phenomenon and Köbner phenomenon are the
characteristic features.
● The pathological findings are thickening of the epidermis,
hyperkeratosis associated with parakeratosis, vasodila-

tion in the papillary dermis, and neutrophilic infiltration
directly under the horny cell layer (Munro’s microab-
scess).
● The main treatments are topical vitamin D3 ointments,
15
topical steroids, PUVA therapies and narrow-band UVB.
Immunosuppressants (methotrexate and cyclosporin)
and retinoids are also useful, and biological therapies are
also used for severe cases.
Classification
Psoriasis occurs in 1% to 2% of Caucasians and about 0.1% of
ethnic Japanese. Men outnumber women by 2 to 1. Psoriasis is
classified by symptoms into five types: psoriasis vulgaris (mainly
keratotic erythema accompanied by scaling), guttate psoriasis
(scattered small lesions with a diameter of 1 cm or less), pustular
psoriasis (mainly pustular eruptions), psoriatic erythroderma and
psoriatic arthritis (Table 15.5). Some cases change from one type
to another. Psoriasis vulgaris accounts for an overwhelming
majority of all cases.
Clinical features
The onset of psoriasis is mostly in adolescence through middle
age. Remissions and exacerbations recur through life. Some
cases have complete remission. Each type is described below.
Pathogenesis
The essential pathogenesis is unknown. The turnover from
basal cell to horny cell to exfoliation, which normally takes 28
days, takes only 4 to 7 days, because of enhanced proliferation of
epidermal cells. Psoriasis is strongly familial, especially in
B. Acquired keratoses 243
Table 15.5 Types and findings of psoriasis.

Clinical findings Pathological findings
Psoriasis Red papules become Munro’s microabscess,
vulgaris sharply demarcated erythema that club-shaped epidermal
is accompanied by silver-white rete ridges, capillary
scales. Scratching generates vasodilation
silvery-opaque scale. Auspitz
phenomenon, Köbner phenomenon
Guttate The same severity of psoriasis Munro’s microabscess,
psoriasis vulgaris. The size of erythema is club-shaped epidermal
about 1 cm in diameter. rete ridges, capillary
vasodilation
Pustular Sterile pustules on erythema, fever, Kogoj’s spongiform
psoriasis malaise pustules Fig. 15.22 Histopathology of psoriasis.
There is hyperkeratosis and club-shaped exten-
Psoriatic Diffuse flushing, fine scales on the sion of the epidermis (regular acanthosis).
erythroderma whole body
Psoriatic Seronegative arthritis accompanied Munro’s microabscess,
arthritis by psoriasis, in DIP joints and club-shaped epidermal
vertebra rete ridges, capillary
vasodilation
Caucasians. For this reason, multiple genes are certainly

involved. When one identical twin has psoriasis, the other is
reported to have a 65% chance of also having the disorder. HLA-
Cw6 is associated with the occurrence. Recent study suggests
that dysfunction of T cells is the primary event and that dysker-
atosis of the epidermis occurs secondarily. Additional inductive 15
factors include irritants, injury, sunlight, infection (hemolytic Fig. 15.23 Histopathology of pustular psori-
asis (Kogoj’s spongiform pustule).
streptococcus, in particular), and drugs (e.g., lithium, βblockers, The dermis projects to the bottom of the horny
calcium antagonists). cell layer. Sterile abscess (Munro’s microab-
scess) caused by neutrophils is seen directly
Pathology beneath the horny cell layer.
Inflammation occurs, most severely in the upper epidermal
layer (Fig. 15.22). As the epidermal turnover is abnormally
enhanced, epidermal cells forming the horny layer retain their
nuclei (parakeratosis). Hyperkeratosis is present. Munro’s
microabscesses caused by infiltration of neutrophils are found
directly below the horny cell layer. Because epidermal cells
move to the horny cell layer before they produce keratohyaline
granules, the granular layer thins and disappears, resulting in
thickening of the suprabasal cell layer. Because the epidermal
rete ridges become club-shaped and extend toward the dermis,
the dermis protrudes directly below the horny cell layer in some
areas. In pustular psoriasis, multiple neutrophils infiltrate into the
upper suprabasal cell layer, and epidermal cells are destroyed to
form spongiosis called Kogoj’s spongiform pustule (Fig. 15.23).
Laboratory findings
Köbner phenomenon and Auspitz phenomenon are present.
Inflammatory findings such as elevated erythrocyte sedimenta-
tion rate, leukocytosis and hyperproteinemia may be caused in
pustular psoriasis and psoriatic erythroderma. In psoriatic arthri-
tis, rheumatoid factors are usually negative. Fig. 15.24-1 Psoriasis vulgaris.
Diagnosis
Psoriasis is diagnosed by the characteristic clinical findings;
however, a biopsy may be conducted for differential diagnosis. In
Clinical images are available in hardcopy only. pustular psoriasis, pustules are sterile.
Diseases to be differentiated from psoriasis

See Table 15.6.
Treatment
The main treatments are topical active forms of vitamin D3
ointments and steroids, PUVA therapies, and narrowband UVB
therapies. In severe cases, retinoids or immunosuppressants (e.g.,
methotrexate, cyclosporine A) are orally administered. Oral
Clinical images are available in hardcopy only. steroids tend not to be used because they may induce pustular
psoriasis. The combination of tar with UV light (Goeckerman
regimen) is no longer widely used due to its oncogenicity. Biolog-
ical therapy has come to be used.
Types of psoriasis
1) Psoriasis vulgaris
Rose pink papules appear and extend to coalesce gradually
into sharply circumscribed erythematous plaques with thick sil-
very scales on the surface (Figs. 15.24-1 to 15.24-4). The erup-
15 tions are usually asymptomatic; however, itching is present in some
cases. Areas that are subjected to external stimulation, such as the
elbows, patellae, scalp and buttocks are most commonly
involved. The disorder may also occur in the intertriginous areas
of obese people.
2) Guttate psoriasis
Fig. 15.24-2 Psoriasis vulgaris.
Sharply demarcated, thick, silver-gray scales Multiple keratotic erythema of up to 1 cm in diameter occurs
adhere to the surface of the erythematous
plaques. on the trunk and proximal sides of the extremities with a relative-
ly acute course (Figs. 15.25-1 and 15.25-2). Individual eruptions
are the same as those of psoriasis vulgaris. It is often seen in chil-
dren. Streptococcal infection or drugs can be the causative fac-
tors.
Laboratory findings on psoriasis: Wax- MEMO

fragment phenomenon, Auspitz phenom-
enon
When psoriatic eruptions are scraped with a finger- scraped
nail, white scales that resemble wax flakes are seen. scraped more
With the peeling off of the scales, petechia is easily
caused; this is called Auspitz phenomenon. It is
caused by the intrusion of dermal papillae directly
into the horny cell layer. Stimulation such as injury Waxy silver- Petechia is caused by
may induce eruptions at normal sites of skin in gray flakes and reduction in the
patients with psoriasis (Köbner phenomenon). lamellar scales granular layer and
occur. telangiectasia (Auspitz
phenomenon).
Table 15.6 Differential diagnosis of psoriasis.

Disease Differential points
Seborrheic The clinical findings resemble those of psoriasis, but the
dermatitis affected sites are relatively localized at seborrheic areas.
Chronic Various, localized skin lesions including erythema, scales,
eczema papules, and blisters. Intense itching. The lesions are less
clearly margined than in psoriasis.
Parapsoriasis Pigmentation and atrophy are often present.
Histopathological differentiation may be necessary.
Pityriasis rosea Psoriasis-like lesion appears after manifestation of the
(Gibert) first eruption, and disappears in 1 or 2 months.
Mycosis Clinical findings may resemble those of psoriasis.
fungoides Histopathological infiltration of atypical lymphocytes to the
epidermis (Pautrier's microabscess).
Syphilitic Psoriasis-like eruptions on the palms and soles. History-
psoriasis taking and serologic test for syphilis are important.
Drug eruption History-taking on drugs and tolerance test are conducted.
Ankylosing Psoriasis-like eruption in some cases; differentiation from
spondylitis psoriatic arthritis is important.
3) Pustular psoriasis
Pustules are the main clinical feature. The disorder is
subdivided into a generalized type and a localized type (Table
15.7). In the generalized type, fever, systemic fatigue and bodily
chills accompany erythema on which multiple sterile pustules 15
occur and coalesce. The pustules rupture spontaneously to form
erosions. Exudative fluid may cause hypoproteinemia, leading to
marked systemic aggravation in some cases. It may occur in the
course of psoriasis vulgaris, or it may develop suddenly without
any history of psoriasis (Fig. 15.26).
4) Psoriatic erythroderma
Psoriatic skin lesions appear all over the body and become ery-
throderma. Proteins are consumed in large amounts in the Clinical images are available in hardcopy only.
lesions. The horny cell layer forms incompletely, bringing
hypoproteinemia, dehydration and electrolyte abnormality.
5) Psoriatic arthritis
Arthritis symptoms may accompany psoriasis. The majority of
cases are the peripheral type, which affects distal interphalangeal Fig. 15.24-3 Psoriasis vulgaris on the arm
and buttocks.
(DIP) joints. There is a type in which vertebra and sacroilitis are
involved. Arthritis proceeds without psoriatic skin lesions in
many cases. There is association with the HLA-Cw6 gene.
2. Pityriasis rubra pilaris
Clinical features
Follicular inflammatory papules of 2 mm to 3 mm in diameter
Clinical images are available in Clinical images are available Clinical images are Clinical images are
hardcopy only. in hardcopy only. available in hardcopy only. available in hardcopy only.
Clinical images are

available in Clinical images are available in hardcopy only. Clinical images are available in hardcopy only.
hardcopy only.
15
Clinical images are available in Clinical images are available in Clinical images are available in
hardcopy only. hardcopy only. hardcopy only.
Fig. 15.24-4 Psoriasis vulgaris on the extremities and nails.
occur on the fingers, extensor surfaces of the extremities, and

upper abdomen. The papules are flushed and have a white kera-
totic acuminate plug (keratotic plug) in the center (Fig. 15.27).
When produced on the elbows and back of the knees, these erup-
tions coalesce to present sharply circumscribed orange psoriatic
plaques to which scales are attached. Multiple white keratotic
papules also occur with a coarse, grater-like appearance. Highly
Clinical images are available in hardcopy only. diffuse keratosis is seen on the palms and soles. It is usually
asymptomatic.
There are cases in which the eruptions may spread and become
erythroderma, and cases with reduced dark adaptation resulting
from lack of vitamin A.
The etiology is unknown. There are peaks of occurrence at
Fig. 15.25-1 Guttate psoriasis on the trunk.
Multiple keratotic erythema of 1 cm in diameter infancy and in the fifth decade of life; pityriasis rubra pilaris is
occur. divided into a juvenile type and an adult type. Most of the juvenile
Table 15.7 Classification of pustular psoriasis.

Classification Clinical findings
Localized Localized Pustules are localized
type pustular around the plaques of
psoriasis psoriasis vulgaris.
Pustular psoriasis Palmoplantar Pustules are localized
with generalized pustulosis (PPP) bilaterally on the thenar
skin lesion and arch of the foot.
Acrodermatitis Often occurs secondarily
continua of after an external injury.
Hallopeau Pustules and nail
deformity occur on the
tips of fingers or toes on
one side of the body.
Generalized Generalized Acute generalized Psoriasis vulgaris
type pustular pustular psoriasis progresses to be
psoriasis (GPP) (von Zumbusch accompanied by
psoriasis) systemic symptoms.
Fig. 15.25-2 Guttate psoriasis on the buttocks.
Poor prognosis.
Subacute, circular The systemic symptoms
pustular psoriasis are milder than those of
von Zumbusch psoriasis.
Impetigo Pustules are generalized
herpetiformis during the middle and last
stages of pregnancy.
cases are familial and autosomal dominantly inherited. A subtype

caused by HIV has been reported in recent years. 15
Pathology
The follicles are dilated and filled with keratin. The peripheral
epidermis is thickened and there is parakeratosis in some parts.
Complete keratinization alternates with incomplete keratiniza-
tion. Polymorphonuclear cells do not infiltrate into the epidermis,
which is useful for differentiation from psoriasis. Vasodilation
and lymphocytic infiltrate are observed in the upper dermis.
Pityriasis rubra pilaris should be differentiated from psoriasis,
cutaneous T-cell lymphoma, seborrheic dermatitis, drug eruption,
ichthyosis and contralateral progressive erythrokeratoderma.
Both types heal spontaneously, within a year in the juvenile
type and within 2 to 3 years in the adult type. The symptomatic
therapies are application of urea ointments, salicylic acid petrola-
tum ointments, and active forms of vitamin D3 ointments. Oral
retinoid is also useful.
3. Parapsoriasis en plaque
It is a generic term for diseases that produce multiple psoriasis-
like keratotic erythema. The pathogenesis is unknown, but it is
thought to be different from that of psoriasis. Some large-plaque
Clinical
images are
available in
hardcopy
only.
Fig. 15.26 Pustular psoriasis.

The main skin lesions are sterile pustules.

15
Fig. 15.27 Pityriasis rubra pilaris.

There are follicular papules, diffuse keratinization on the hands and soles, and orange psoriatic plaques.
parapsoriasis may be prodromes of mycosis fungoides. However,

there are many cases in which small-plaque and large-plaque
parapsoriasis occur at the same time.
1) Small-plaque parapsoriasis
Parapsoriasis MEMO
Monomorphic round to oval erythematous plaques of 2 to 5
The definition, concept and diagnostic name
for parapsoriasis have not been clarified. In cm in diameter appear mainly on the trunk. Lesions are asympto-
the 1970s, it became widely accepted that matic, and histopathologically findings are non-specific. Emol-
large-plaque parapsoriasis and small-plaque lients and UVB are helpful.
parapsoriasis are two distinct disorders. In
recent years, large-plaque parapsoriasis has
come to be regarded as the early patch stage 2) Large-plaque parapsoriasis
of mycosis fungoides. Pityriasis lichenoides is
known to be a parapsoriatic disease, and it is
classified into pityriasis lichenoides chronica
Large erythematous or yellowish atrophic plaques occur on the
(PLC; formerly called guttate parapsoriasis) trunk and extremities. The lesions persist for many years, and
and pityriasis lichenoides et varioliformis gradually increase in number and affected area. They occur most
acuta (PLEVA; also called Mucha-Haber- frequently in middle-aged and elderly men (Fig. 15.28). Subjec-
mann disease).
tive symptoms such as itching are not present. The eruptions are
usually more than 5 cm in diameter and accompanied by poikilo-

derma. Some but not all patients may develop mycosis fungoides
(Fig. 22.35). Careful check up of the disease course is necessary.
PUVA therapy is effective.
4. Pityriasis lichenoides
This disorder is difficult to classify. This entity is sometimes
regarded as cutaneous vasuculitis, rather than as a keratotic disor-
der. Pityriasis lichenoides tends to be limited to the trunk, thighs Clinical images are available in hardcopy only.
and upper arms. It rarely occurs on the face, palms or soles. The
eruption progresses slowly over the course of many years. Adult
men are most commonly affected. Erythema or rose pink papules
of several millimeters to 1 cm in diameter, to which white scales
are attached, appear. The eruptions are continuously produced,
and a distinguishing characteristic of the disorder is the presence
of new eruptions together with older ones (Figs. 15.29-1 and
15.29-2). It is asymptomatic. It heals with pigmentation or depig-
mentation. Pityriasis lichenoides is divided into two main forms,
Pityriasis lichenoides chronica (PLC) and Pityriasis lichenoides Fig. 15.28 Large-plaque parapsoriasis.
Relatively sharply demarcated slight erythema is
et varioliformis acuta (PLEVA), but intermediate forms or present.
patients with both forms are often seen.
① Pityriasis lichenoides chronica (PLC)
Synonym: guttate parapsoriasis
This is a chronic form. This individual eruption is a rose pink 15
plaque. Young adults are usually affected.
Table 15.8 Classification and features of parapsoriasis.

Parapsoriasis en plaque and pityriasis lichenoides
Clinical findings Pityroid scales and erythema appear. Itching is not
present.
Pathological Lymphocytic infiltration in the dermo-dermal
findings junctions
Large-plaque The eruption is 5 cm or more in diameter,
parapsoriasis accompanied by atrophy, and may be a precursor of
mycosis fungoides in some cases.
Small-plaque The eruption is less than 5 cm in diameter.
parapsoriasis
Pityriasis lichenoides (guttate parapsoriasis)
Clinical findings Fine white scales, erythema of 1 cm or less in
diameter, polymorphic skin lesion with old and new
eruptions
Pathological Lymphocytic infiltration to the epidermis
findings
Pityriasis lichenoides The main symptom is erythematous plaque.
chronica (PLC)
(previous guttate
parapsoriasis)
Fig. 15.29-1 Pityriasis lichenoides chronica.
Pityriasis lichenoides The main symptoms are severe inflammatory Old eruptions are rarely seen simultaneously with
et varioliformis acuta symptoms and ulceration. new ones on the lesion. Ulceration does not occur.
(PLEVA)
② Pityriasis lichenoides et varioliformis acuta (PLEVA)

Synonym: Mucha-Habermann disease
This is more acute form and less common. Intense acute
Clinical images are available in hardcopy only. inflammatory symptoms are present. Multiple papules are
accompanied by ulceration. Some patients with lymphomatoid
papulois show similar clinical appearance to PLEVA (Figs.
15.30 and 15.31).
Fig. 15.29-2 Pityriasis lichenoides chronica.
5. Lichen planus
Outline
● Flat-topped, elevated, grayish-blue to purplish-rose
plaques form on the flexures of the extremities and in the
Clinical images are available in hardcopy only. oral cavity. It progresses slowly.
● It is often induced by drugs. However, the cause is het-
erogeneous.
● Köbner phenomenon is positive. Delicate white lines
known as Wickham striae are seen on the surface.

● Vacuolar degeneration is pathologically found. Band-like
infiltration of lymphocytes occurs in the superficial der-

mis.
● Use of the causative drug is discontinued. Steroid oint-
15 ments and tacrolimus ointments are useful.
Clinical features
Clinical images are available in hardcopy only. Lichen planus occurs in male and female adults. Polygonal or
map-like, grayish-blue to purplish-red papules or flatly elevated,
purplish-red erythema of coin size or smaller appear, often with
central concavity. The erythema surface is either characteristical-
ly glossy, or it has thick whitish scales attached. The eruptions
may coalesce to form plaques (Figs. 15.32-1 and 15.32-2). The
Fig. 15.30 Pityriasis lichenoides et vario-
flexures of the extremities, and the trunk and genitalia are the
liformis acuta. most frequently affected sites, with itching in some cases. In the
There are intense acute inflammatory symptoms, oral mucosa, irregularly shaped infiltrative leukoderma, Wick-
and old and new eruptions are present. These are ham striae, or erosive plaques are found. Intense pain may be
accompanied by diffuse ulcers.
present in such cases. Deformity and thinning of nails are seen in
about 10% of all cases (Fig. 15.33).
Pathogenesis
Lichen planus is induced by drugs in many cases. When the
cause is not identified, the disorder is classified as idiopathic.
Inflammation caused by CD4+T cells in the dermo-epidermal
junctions leads to dyskeratosis accompanied by impairment of
basal keratinocytes, resulting in formation of flatly elevated pur-
plish-rose erythema or papules. It may be caused by drugs (anti-
hypertensive agents such as thiazide, cerebral excitometabolic
agents, antitubercular agents) or by chemicals (photographic
Fig. 15.31 Histopathology of pityriasis developing solution, dental metals). Association with hepatitis C
lichenoides et varioliformis acuta. and bone marrow transplantation (MEMO) has been suggested.
Pathology
The pathological findings are hyperkeratosis that is not accom-
panied by parakeratosis, and thickening of the granular layer, ser-
rated extension of epidermal rete ridges, Vacuolar degeneration
of the basal layer, and band-like lymphocytic infiltration in the
papillae and lower papillary layer (Fig. 15.34). Dyskeratotic ker-
atinocytes that have undergone vacuolar degeneration are called
Civatte bodies. Clinical images are available in
hardcopy only.
Köbner phenomenon is present (i.e., rubbing normal skin or
exposing it to UVB produces lichen planus eruptions). Delicate
white lines known as Wickham striae typically cross the slightly
scaly surface and form a network on the coalesced plaques.
Lichen planus is easily diagnosed by the clinical and pathological
findings. History-taking on drugs and dental treatments is con- a b c d e f g
ducted to determine whether lichen planus is induced by drugs or Fig. 15.32-1 Lichen planus.
dental metal. A drug-induced test may be performed when a drug a: A typical case.

in hardcopy only.
15
Clinical images are available Clinical images are
in hardcopy only. Clinical images are available in Clinical images are available
available in
hardcopy only. in hardcopy only.
hardcopy only.

in hardcopy only.
b c a
d b
e cf ga
d hb
e fic a gjd b hke c jg e
ilf d m knh f ol i g m
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n i orl j pm k qn l

hardcopy only.
f g h i j k l m n images
Clinical p
o are available inq r Clinical images are available in

hardcopy only.
g d h e i a f j b g kc h l d i me j n f k og l phm q i n r j o k p l q m r n o p q
Fig. 15.32-2 Clinical features of lichen planus.
b, c: Lichen planus annularis. It is important to differentiate this from porokeratosis. Erythema at the periphery of the lesion is char-
acteristic of lichen planus. d: Lichen planus pigmentosus. e: A typical case of lichen planus on the lower leg. f: It is necessary to dif-
ferentiate this from lichen sclerosus et atrophicus. g: Multiple lichen planus on the foreskin and glans penis. h, i: Affected lips. j:
Linear, white lichen planus near the molar teeth in the buccal mucous membrane. k: Typical lichen planus on the wrist.
Clinical images are

available in
hardcopy only.
Fig. 15.33 Nail deformities in lichen planus.

Atrophic changes to the nails.
is suspected of being the cause. It takes several days to induce an

eruption.
Treatment
Lichen planus progresses chronically but responds to treatment
in most cases. The causative drug or other agent is determined
and its use is discontinued. It takes several weeks or drug-
induced eruptions to disappear after such discontinuation of use.
Steroid ointments (ODT) and anti-histamines are applied.
Tacrolimus ointments are effective against lichen planus in the
15 mucous membranes.
6. Lichen striatus

Eruptions arrange in linear arrays or along cleavage lines, most
frequently on the extremities (Fig. 15.35). The condition is
asymptomatic. Lichen striatus begins as several solitary, polygo-
nal to round, sometimes scaly, light pink to dark rose papules of
2 mm to 4 mm in diameter. The papules tend to coalesce and
Fig. 15.34 Histopathology of lichen planus.
Hyperkeratosis and hypergranulosis without
become 1- to 2-cm-wide, linear or band-like, light pink to dark
parakeratosis are characteristic of the disorder. red eruptions. The etiology is unknown.
Sawtoothed acanthosis, band-like lymphatic infil-
tration in the upper dermal layer, and vacuolar Differential diagnosis
degeneration in the basal layer are also seen.
Lichen striatus should be differentiated from inflammatory lin-
ear epidermal nevus, incontinentia pigmenti (second-stage), lin-
ear warts and lichen planus.
Graft-versus-host-disease MEMO Treatment, Prognosis
(GVHD) after bone marrow
transplantation and lichen planus Topical steroids are the main treatment. Lichen striatus heals
Lichen planus often occurs as a symptom of spontaneously in most cases, particularly in infants.
chronic GVHD after bone marrow transplan-
tation (100 days after transplantation). GVHD
results from destruction of host tissue caused
by immunologic response of T cells. The
same mechanism is thought to be associated
with lichen planus.
7. Lichen nitidus

Small papules of uniform size, with a smooth flat glossy sur-
face and a diameter of 1 mm to 2 mm occur. They can be scat-
tered or aggregated (Fig. 15.36). The eruptions do not coalesce or
cause erythema; they are normal skin color to yellowish white. Clinical images are available in hardcopy only.
Subjective symptoms such as itching are not present. Lichen
nitidus most commonly occurs in the genitalia and extremities of
young men, especially the glans penis and penis shaft. Köbner
phenomenon is observed in about 50% of all cases.
Pathology
Directly under the epidermal rete ridges that slightly extend
from small papules, there are epithelioid cells, lymphocytes, and
a small spherical infiltrative nest consisting of Langerhans giant
cells. Vacuolar degeneration is seen.
Prognosis
Lichen nitidus progresses slowly in cycle of several months. Clinical images are available in hardcopy only.
Most cases heal spontaneously.
8. Pityriasis rosea (Gibert)

15
Outline
Fig. 15.35 Lichen striatus.
● It is transitory, inflammatory keratotic erythema of
unknown etiology. It most commonly occurs in young
men.
● Oval eruptions scatter mainly on the trunk, presenting as
erythematous plaques with peripheral collarettes of

scales. The long axes of eruptions run parallel to the
cleavage lines. Clinical images are available in hardcopy only.
● The first eruption is called a herald patch.
● It heals spontaneously in 1 to 3 months. Topical steroids
are the first-line treatment.
Clinical features
Pityriasis rosea occurs frequently in men and women from the Fig. 15.36 Lichen nitidus.
ages of about 10 to 40, especially in spring and autumn. Two Small, scattered, mulitple papules of a few mil-
thirds of all cases begin as an eruption called a herald patch (Fig. limeters in diameter and normal skin color or yel-
lowish white.
15.37). An oval erythematous scaling plaque with a diameter of 2
cm to 5 cm occurs on the trunk. The light pink plaque is accom-
panied by scaling at the rim and slightly yellowish central discol-
oration (collarette of the herald patch). Seven to ten days after
onset, multiple oval erythema of 1 cm to 2 cm in diameter with
peripheral scaling occur suddenly. These eruptions vary in size,
and the long axes run along the Langer cleavage lines of the skin;
a Christmas-tree appearance is seen on the back. The eruptions
spread from the trunk to distal areas; however, the palms, soles,
and head (sun-exposed areas) are not involved. There are no

severe systemic symptoms, except mild itching sometimes. The
condition usually heals naturally in 1 to 3 months and does not
recur.
Pathogenesis
The cause is unknown. In recent years, association with viral
infections including HHV-6 and HHV-7 has been pointed out.
Clinical images are available in hardcopy only. Pityriasis rosea may occur as a drug eruption.
Pathology
Thickening of the epidermis, spongiosis, parakeratosis, and
intraepidermal filtration of mononuclear cells are found. These
findings are similar to those of eczema and are nonspecific.
a b c d e f g h Pityriasis
i j should
rosea k be differentiated
l m n
from p list-q
theo diseases r
ed in Table 15.9.
Treatment
Clinical images are available in hardcopy only. Topical steroids and oral histamines are the main treatments.
Petrolatum, UVB and anti-inflammatory analgesics are also use-
ful. Since these drugs may induce eruptions, history-taking is
important.
15
9. Acquired ichthyosis

● Itoccurs secondarily to a malignant disorder (e.g., lym-
phoma), sarcoidosis or drug eruption.
● The skin clinical features similar to that of hereditary
ichthyosis; however, both the extensor surfaces and flex-
Fig. 15.37 Pityriasis rosea (Gibert). ures of joints are affected.
a: The eruptions are distributed in a Christmas-
tree pattern. b: Pityriasis caused by pityriasis
rosea (Gibert). c: The first rash, called a herald
patch.
Table 15.9 Diseases that are differentiated

from pityriasis rosea.
Disease Differential points
Pityriasis Flushing does not occur.
versicolor Malasezia furfur is detected.
Seborrheic Seborrheic areas such as the head
dermatitis and face are most commonly
involved.
Roseola Fewer scales are present.
syphilitica Eruptions also appear on the
palms and soles. Serologic test for
syphilis is positive.
Psoriasis Silver-gray scales are present.
Auspitz phenomenon and Köbner
phenomenon are positive.
Drug eruption History-taking on drugs
Clinical features
Various symptoms of ichthyosis are present. Both the extensor
surfaces and flexures of the extremities are affected (Fig. 15.38).
Pathogenesis
Patients have the primary diseases listed below. The symptoms Clinical images are Clinical images are
of ichthyosis appear thereafter. available in available in
( i ) malignant tumor (e.g., malignant lymphoma (Hodgkin’s dis-
ease in particular), leukemia, carcinoma, Kaposi’s sarcoma).
( ii ) systemic disease (e.g., sarcoidosis, hypothyroidism,
Hansen’s disease, tuberculosis, systemic lupus erythemato-
sus)
(iii) drug eruption (e.g., from nicotinic acid) a b ca db ec fd ge hf
Fig. 15.38 Acquired ichthyosis
Pathology a: Accompanying Hodgkin’s disease. b: Accom-
panying mycosis fungoides.
The pathology of acquired ichthyosis is similar to that of
ichthyosis vulgaris.

Acquired ichthyosis cannot be distinguished from ichthyosis
vulgaris only by cutaneous symptoms and histopathology. The
clinical course and detection of a malignant tumor are important Clinical images are available in hardcopy only.
for diagnosis.
b. Noninflammatory keratoses 15
1. Clavus
Fig. 15.39 Clavus.
Clinical features, Pathogenesis horny cell layer

Clavus, commonly called a “corn,” is localized thickening of
the horny cell layer, usually caused by mechanical stimulation epidermis
(Fig. 15.39). It tends to occur in the feet from the friction of
dermis
shoes. The center of the thickened horny cell layer sinks deep core
into the dermis (core), resembling the eye of a chicken or fish. clavus callus
Tenderness is present (Fig. 15.40).
Fig. 15.40 Diagram of clavus and callus.
Clavus is distinguished from plantar warts, which are caused
by human papilloma virus and tend to occur multiply. Plantar
warts also occur in areas that are not subjected to friction, and
minor bleeding may be seen; differentiation between planter
warts and clavus is easy by scraping the horny cell layer with a
razor blade. In clavus, pressure causes pain (tenderness). In plan-
tar wart, pinching causes pain.
Treatment
Friction should be avoided. Cushioned footpads are helpful.
The horny cell layer is removed, and salicylic acid is applied.
2. Callus
Synonym: Tylosis

Callus (tylosis) is also caused by friction. Sites that are repeat-
Clinical images are available in edly subjected to mechanical stimulation, including pressure and
hardcopy only.
friction, and bony sites are involved. The most common site in
Japan is between the second and third distal phalanxes (from
pen-holding) and the dorsal region of the ankles (from sitting on
the floor). The horny cell layer is even in thickness, and there is
almost no tenderness (Figs. 15.40 and 15.41).
Treatment
Fig. 15.41 Callus, tylosis. The treatments are the same as those for clavus.
3. Lichen pilaris
Synonym: Keratosis pilaris
Clinical features, Pathogenesis, Pathology

Multiple follicular keratotic papules of 1 mm to 3 mm in diam-
eter and normal or light pink in color occur on the extensor sur-
Clinical images are available in faces of the upper arms and thighs (Fig. 15.42). Lichen pilaris
hardcopy only. occurs most commonly in adolescent females. In most cases, the
15
onset is in early childhood, and the clinical features become dis-
tinct in adolescence. The papules have a coarse surface and no
tendency to coalesce or enlarge. The condition is usually asymp-
tomatic. Pathologically, the hair follicles are dilated and filled
with keratin plugs and there is pili torti. Lichen pilaris tends to be
hereditary and is assumed to be autosomal dominantly inherited.
There are cases associated with ichthyosis vulgaris.
Fig. 15.42 Lichen pilaris.
Lichen pilaris occurs with high frequency; however, it heals
naturally after adolescence. The symptomatic therapy is topical
application of moisturizer or keratolytic agents such as salicylic
acid petrolatum.

hardcopy only. 4. Erythromelanosis follicularis faciei (Kita-
mura)
Erythematous plaques occur symmetrically on the preauricular
region and cheeks. Follicular keratotic papules form on the ery-
thematous plaques (Fig. 15.43). Lichen pilaris often occurs on
other sites as a complication. It is frequently seen in young men
Fig. 15.43 Erythromelanosis follicularis faciei and women. It is thought to be a facial type of lichen pilaris.
on the face of a teenage female.
Erythematous plaques caused by follicular kera- Moisturizer is applied topically.
totic papules are observed on the preauricular area
and cheek.
5. Lichen spinulosus
In this type of lichen pilaris, follicular papules with prickle-
like projections aggregate. The disorder is mostly seen in infants,
on the neck.
6. Acanthosis nigricans (AN)
Outline
● Plaques with coarse dark-brown surface occur on the Clinical images are available in hardcopy only.
neck and axillary fossae.
● It is divided into three types: malignant AN, accompany-
ing a malignant tumor (stomach cancer in particular);

benign AN, accompanying endocrinopathy; and pseudo-
AN, accompanying obesity.
● The pathological findings are papillomatosis, thickening
of the horny cell layer, and pigmentation. Thickening of

the epidermis (acanthosis) does not usually occur.
Clinical features
Dark brown papillary elevations with a coarse surface occur on
the neck, axillary fossae, umbilical fossa and groin. They have a
velvety or rough-textured appearance (Fig. 15.44). Malignant
AN tends to have severe symptoms, and often itching is present. 15
In pseudo-AN, pigmentation and coarse surface are found in
intertriginous areas.
Pathogenesis
The cause is unknown. Some cases are induced by a malignant
tumor.
Pathology
The main symptoms are papillomatosis, hyperkeratosis and
hyper-pigmentation. Despite the name, thickening of the epider-
mis is not present in most cases.
Diagnosis
Diagnosis of acanthosis nigricans can be confirmed by the Clinical images are available in hardcopy only.
clinical features. An eruption precedes or coincides with an inter-
nal organ cancer, stomach cancer in particular, in more than 70%
of cases of malignant acanthosis nigricans; diagnosis of acantho-
sis nigricans may lead to early discovery of a cancer.
Treatment Fig. 15.44 Acanthosis nigricans.

In malignant acanthosis nigricans, the malignant tumors are
detected and treated. Eruptions subside with treatment. In benign
AN, endocrine abnormality is investigated and treated. Weight loss
is advisable for patients with pseudo-AN.
7. Confluent and reticulated papillomatosis

Grayish pigmented macules and keratotic papules occur on the
trunk (intermammary region and upper abdomen, in particular),
and coalesce to form a network of plaques (Fig. 15.45). The dis-
order occurs most frequently in men and women from adoles-
cence to adulthood. It progresses slowly and is asymptomatic.
Clinical images are available in hardcopy only. Differentiation from pityriasis versicolor is important. Treatment
is application of topical keratolytic agents, such as salicylic acid
petrolatum, and oral administration of mimocycline and
retinoids.
8. Bazex syndrome
Several months after psoriatic erythematous keratotic lesions
appear symmetrically on the extremities, nasal apex and auricle,
Fig. 15.45 Confluent and reticulated papil- a malignant tumor becomes apparent. The syndrome occurs most
lomatosis. commonly in men over age 40. The main malignant tumors
caused by Bazex syndrome are squamous cell carcinomas in the
upper gastrointestinal tract, upper respiratory tract and liver. The
keratotic lesions aggravate according to the progression of the
malignant tumor.
Clinical images are available in hardcopy only. 9. Keratosis follicularis squamosa (Dohi)
15
Small black follicular keratotic spots occur symmetrically on
the trunk, particularly the hips, abdomen, and buttocks. Round or
lamellar, grayish-white scales varying in size from 3 mm to 1 cm
attach mainly to follicular comedo-like black spots (Fig. 15.46).
10. Pityriasis circinata (Toyama)

This is an acquired dyskeratosis in which round, sharply cir-
cumscribed lesions occur on the hips, abdomen and buttocks.
Scaling, crêpe-surfaced, brown to grayish-white plaques form.
11. Hyperkeratosis lenticularis perstans

Synonym: Flegel’s disease
It occurs in middle-aged men and women, most frequently on

the extremities, especially on the dorsal surfaces of feet and
hands. Prickle-like, flatly elevated papules with red to dark
brown keratotic scales of 1 mm to 5 mm in diameter are attached.
a b c d e f g h i
They j
appear k l
symmetrically. m n o p q r
Fig. 15.46 Keratosis follicularis squamosa
(Dohi).
a: Clinical features. b: Histopathological features.
Chapter
16 Disorders of Skin Color
Human skin color is mainly determined by melanin pigments, carotene and hemoglobin. Of these, melanins
contribute the most. Racial differences in skin color result from differences in the kinds and amounts of melanin.
Most diseases of abnormal pigmentation are caused by elevated or reduced melanin content; the disorders
involving skin color tend to be congenital or to be caused by autoimmune reaction or sun exposure.
When carotene, a precursor of vitamin A, is taken into the body, it accumulates in the horny cell layer and sub-
cutaneous fat layer, resulting in yellowish skin color (carotinoid pigmentation). This chapter also discusses der-
mal deposition of extrinsic substances caused by tattooing or injury. Although abnormalities of the blood vessels
and hemoglobin may also cause changes in skin color, they are not included here.
A. Diseases of depigmentation
Table 16.1 Major types of oculocutaneous
1. Oculocutaneous albinism (OCA) albinism (OCA).
OCA type 1 Tyrosine-related
Synonym: Congenital albinism
1A Complete lack of synthesis of
Outline tyrosinase (formerly tyrosinase-
negative type)
● There is congenital abnormality in melanin synthesis
1B Dysfunction of tyrosinase synthesis
(Fig. 1.18). Pigment in skin, hair and eyes is reduced or (formerly yellow mutant type)
absent from birth. 1mp Minimal-pigment albinism 16
● All types are autosomal recessive.
1ts Temperature-sensitive
● Patients tend to be prone to skin cancer, from high pho-
OCA type 2 P protein-related type (formerly
tosensitivity to sunlight. tyrosinase-positive type)
● Sunscreen is essential.
OCA type 3 TRP-1 related
Classification OCA type 4 MATP-gene type

HPS type Hermansky-Pudlak syndrome
Oculocutaneous albinism (OCA) is classified by the causative
genes into OCA1, OCA2, OCA3 and OCA4 (Table 16.1). It is CHS type Chédiak-Higashi syndrome
also seen as a symptom of hereditary diseases including Herman-
sky-Pudlak syndrome and Chédiak-Higashi syndrome.
Pathology
Melanocytes are normal in number and size; however, imma-
ture melanosomes (stage I, II and III) are observed by electron
microscopy (Fig. 16.1). In Chédiak-Higashi syndrome, giant
lysosomes are detected in the skin, leukocytes and other organs.
The maturity of melanosomes in melanocytes should be
observed by electron microscopy. In the severest OCA1 cases,
there are only immature melanosomes that lack melanin deposi-
tion (stage I or II). In OCA in which some pigment production
remains, stage III melanosomes are seen and there may also be a
few stage IV melanosomes. Prenatal diagnosis may be conducted
259
260 16 Disorders of Skin Color
for the severest OCA1A cases. Identification of the affected gene

is necessary for determination of subtype.
Mel
Treatment
Use of sunscreen is essential from birth, in order to protect the
skin from UV-related cancer and skin aging. The eyes are pro-
tected by tinted contact lenses or sunglasses.
Types of oculocutaneous albinism (OCA)
g
1) OCA1 j p q
This is caused by tyrosinase gene mutation. OCA1 is classified
into subtypes including OCA1A, in which tyrosinase activity is
completely lost from such mutation (this type used to be classi-
fied as tyrosinase negative OCA), and OCA1B, in which some
tyrosinase activity remains. All OCA1 subtypes are autosomal
Mel
recessively inherited.
When melanin is not synthesized, as is the case in OCA1A, the
skin appears white to pink, and the hair is white from birth (Fig.
16.2). The skin is easily sunburned, and sun-exposed areas of the
body are easily injured by UVR and are prone to malignant
a b c d e f g h tumor
i (e.g.,
j basal
k cell
l carcinoma,
m nsquamous
o cell
p carcinoma,
q r
Fig. 16.1 Electron microscopic image of a malignant melanoma). The iris and choroid membrane are blue,
melanocyte (Mel) from a healthy person and the ocular fundus is pink; the eyes appear blue when lit edge-
(a) and from a patient with oculocuta- on, and pink when lit head-on (pink-eye). Patients have a charac-
neous albinism (b).
a: In a melanocyte from a healthy person, the teristic facial expression of squinting and looking out of the
16 cytoplasm contains large amounts of mature, corner of the eyes, from photophobia and impaired eyesight that
blackish, stage IV melanosomes (arrows). The cannot be corrected. Horizontal nystagmus may be present.
melanocytes transport melanosomes to neighbor-
ing keratinocytes. b: In oculocutaneous albinism,
When melanin is scant but present, pigment may gradually
most melanosomes are immature, not progressing appear in hair and skin as the patient grows, although it is impos-
beyond stage II. Mature melanosomes are not sible to distinguish these cases from OCA1A at birth.
seen in the cytoplasm.
2) OCA2
OCA2 is caused by mutation in the P protein gene on chromo-
some 15. It is autosomal recessive. In mice, the P protein works
to convey tyrosine to melanosomes; however, the functions of
human P protein have not been clarified.
Pigment may be largely or completely absent at birth; it is
impossible to distinguish OCA2 from OCA1 only by the clinical
symptoms. In OCA2 the eye color is bluish gray and the hair is
pale yellow to blonde; both come to contain more pigment as the
patient ages.
3) OCA3
OCA3 is caused by genetic mutation in TRP-1 (tyrosinase-
related protein 1), which controls melanin synthesis. It tends to
Fig. 16.2 Oculocutaneous albinism (OCA1A) in occur in patients of African descent. The skin color is reddish
a girl.
The hair will be white throughout her lifetime, brown, and the hair is light reddish brown to red. Eye symptoms
from lack of melanin production. do not usually occur.
A. Diseases of depigmentation 261
4) OCA4
OCA4 is caused by abnormality in the membrane-associated
transporter protein (MATP). OCA4 is mainly seen in patients of
African or Japanese ancestry. In Japan, it occurs with the second-
most frequency, after OCA1. Pigment is present in the skin in
small amounts. The hair is light yellow in many cases; however,
there are some cases in which the hair is brown (Fig. 16.3). The
eyes are blue, gray or reddish brown. Nystagmus is found in
about half of all cases.
5) Hermansky-Pudlak syndrome (HPS)

Some causative genes that are thought to be associated with
intracellular protein transport have been identified in Hermansky-
Pudlak syndrome (HPS). HPS is classified by the causative genes
into four subtypes: HPS1, HPS2, HPS3 and HPS4. It is autoso-
mal recessive. Pigment appears in the skin and hair to some Fig. 16.3 Oculocutaneous albinism (OCA4).
This patient had white hair at birth; however, pig-
extent (Fig. 16.4). Pulmonary fibrosis or granulomatous colitis mentation gradually appeared in the hair with
may occur as a complication by deposition of ceroid-lipofuscin. age. Her hair is now blonde.
There is a hemorrhagic tendency in HPS, which manifests as sus-
ceptibility to bruising and nasal or gingival hemorrhaging.
6) Chédiak-Higashi syndrome (CHS)

Abnormality of the LYST gene on chromosome 1 (1q42) dis-
turbs the normal function of microtubules. It is autosomal reces- 16
sive. The main symptoms are partial albinism from melanocyte
trafficking failure and photosensitive disorder. The hair is red and
the skin color is cream, although sun-exposed areas such as the
face sunburn to a dark red. Neutrophilic immune compromise
often leads to bacterial infection. Histopathologically, giant lyso-
some granules (peroxidase-positive) are found in the peripheral
leukocytes. During exacerbation, lymphatic and histiocytic infil-
trate is found in the systemic organs, and acute symptoms of pan-
cytopenia occur. Symptomatic therapies are performed for
infection. Bone marrow transplantation may also be conducted.
The prognosis is poor; most patients with CHS die young in the
Fig. 16.4 Hermansky-Pudlak syndrome
so-called “accelerated phase,” which is a lymphoproliferation (HPS).
into various organs resulting in hemophagocytosis, infection and This patient had blond hair and a fair complex-
bleeding. ion; however, more pigment gradually appeared
as she grew. There was hemorrhagic tendency in
this case. Symptoms such as pulmonary fibrosis
and intestinal catarrhs often appear after the
2. Vitiligo vulgaris patient reaches a certain age.
Outline
● Because melanocytes are reduced or lost, hypopigment-
ed patches (leukoderma) occur.
● Autoimmunity against melanocytes or melanin is thought
to cause vitiligo vulgaris; however, the pathogenesis is

unknown.
● Topical steroids and PUVA are useful treatments.
Classification
Vitiligo vulgaris is classified into focal, segmental, generalized
and universal types. Vitiligo vulgaris in which leukoderma distri-
bution is not associated with cutaneous innervation is called gen-
eralized vitiligo vulgaris. When unilateral leukoderma runs
parallel to cutaneous nerves, it is called segmental vitiligo vul-
garis.
Vitiligo vulgaris often occurs in men and women about age 20.
The incidence has been calculated as between 1% and 2% of the
population. Familial cases account for 1% to 2% of all cases.
Sharply circumscribed complete leukoderma occurs. There is a
Clinical images are available in hardcopy only. slight increase in pigmentation at the periphery of the eruptions.
The lesions are irregular in shape and size, and they often coa-
lesce (Figs 16.5-1 and 16.5-2). Gray hair is seen around the
leukoderma. It is asymptomatic.
Generalized vitiligo vulgaris occurs most frequently on areas
a b c d e f g h prone
i toj mechanical
k stimulation,
l m such n as theo seborrheic
p areas
q andr
the extremities, lumbar region, abdomen, intertriginous areas,
face and neck.
Segmental vitiligo vulgaris occurs unilaterally on certain
innervated areas. Young people are most commonly affected.
Pernicious anemia, hyperthyroidism, and autoimmune diseases
16 such as Addison’s disease may develop as complications.
Pathogenesis
The cause has not been identified. Autoimmunity against
melanocytes and melanins and abnormal peripheral nerve func-
tion are thought to be involved.
Pathology
In the early stages, there is melanocyte degeneration with
reduced or lost dopa response and lymphocytic and histiocytic
infiltration into in the dermal upper layer. In the final stages,
melanocytes are lost and melanin granules are absent in the basal
layer.
Clinical images are available in hardcopy only. Differential diagnosis

The disease should be differentiated from piebaldism, nevus
depigmentosus, senile leukoderma, Vogt-Koyanagi-Harada dis-
ease, melanoleukoderma, pityriasis versicolor and Hansen’s dis-
ease.
Treatment
c d e f g h i j k l p q
Topical andmoral PUVA
n o
therapies r
and topical steroids are the
Fig. 16.5-1 Vitiligo vulgaris on various sites. first-line treatments. Leukoderma on the face and fingers can be
a: Chest. b: Back. c: Lips. d: Sharply demarcated
depigmented macules occur on the dorsum of the concealed by special cosmetics to alleviate psychological
hands. distress. Steroids and sedatives are given in small doses, and
surgical intervention (Fig. 16.6) and narrowband UVB exposure

are also conducted.
3. Piebaldism
Synonym: Partial albinism Clinical images are available in hardcopy only.
Definition
Piebaldism is characterized by localized leukoderma with
leukotrichia on the forehead and frontal region of the head. Few
melanocytes are found around the areas of aleukoderma
b c whited
and e f g h i j k l
hair; albinism develops locally. A congenital, autosomal domi- Fig. 16.5-2 Vitiligo vulgaris on various sites.
nant disease, it occurs with a frequency of 1 in 200,000. e: On the forehead.
Clinical features
Triangular or diamond-shaped leukotrichia and leukoderma
are seen on the forehead and frontal region of the head (white
forelock) at the time of birth. These do not enlarge or shrink with
age. Contralateral geographic vitiligo occurs on the extremities
and trunk. Small pigmented patches often occur within the leuko-
derma.
Pathogenesis, Pathology
Piebaldism is caused by abnormality in the c-kit gene. In fetal
development, melanoblasts migrate from the neural crest to the
epidermis to anchor and differentiate into melanocytes. The c-kit
gene on chromosome 4 (4q12) encodes a receptor that is associ- 16
ated with the migration and anchoring of melanoblasts. Because
piebaldism is autosomal dominant, abnormality occurs in half of a b c d e f g h
each receptor, leaving an area on which melanoblasts do not
anchor, and resulting in leukoderma. Histopathologically,
melanocytes are lacking at the sites with leukotrichia and leuko-
derma.
Diagnosis, Treatment
Diagnosis is made by history-taking of autosomal dominant
expression, and white forelock and small pigmented patches on Clinical images are available in hardcopy only.
leukoderma. Waadenburg-Klein syndrome, whose symptoms are
similar to those of piebaldism, is accompanied by facial displasia
and deaf-mutism. Skin graft and cultured pigmented cell trans-
plantation have been reported to be effective.
a b c d e f g h i
Fig. 16.6 Suction blister treatment of vitiligo
vulgaris.
a: Vacuum aspiration is applied on normal skin
to artificially produce a suction blister. b: Vacu-
um aspiration is applied on skin with vitiligo vul-
garis to produce a suction blister. The covering of
the vitiligo vulgaris blister is removed and
replaced with the covering of the normal skin
blister.
4. Sutton nevus
Synonym: Halo nevus

Clinical images are available in hardcopy only. Sutton nevus has nevocellular nevus (lentigo) in the center,
surrounded by oval leukoderma (Fig. 16.7). It tends to occur in
children and young men and women, on the trunk, face and neck.
Autoimmunization occurs against melanin at the center of the
lentigo, and immunoreaction occurs against melanin at the
periphery of the lentigo; this is thought to be the mechanism of
Sutton nevus. Leukoderma may also be produced at the periphery
of a malignant melanoma, angioma, blue nevus, soft fibroma, and
seborrheic keratosis; it is called Sutton’s phenomenon.
Pathology
Degenerated or destroyed nevus cells and melanocytes, with
dense lymphocytic and macrophagic infiltration, are found at the
periphery.
Treatment
The treatments for vitiligo vulgaris are applied. The central
Fig. 16.7 Sutton nevus. nevus may be removed. It may heal spontaneously.
Sharply demarcated leukoderma appears around
the nevus cells.
Prognosis
Leukoderma enlarges centrifugally. At the same time, the cen-
16 tral nevus discolors, flattens and eventually disappears. As the
nevus disappears, the leukoderma heals spontaneously. Excision
of the central nevus induces spontaneous healing and prevents
vitiligo vulgaris, a complication.
5. Vogt-Koyanagi-Harada disease
Outline
● Vogt-Koyanagi-Harada disease is caused by autoimmu-
nization against melanocytes.
● Uveitis, leukoderma, leukotrichia and alopecia occur.
● The treatments for the skin lesions are oral and local
steroids and PUVA therapies.
Clinical features
Vogt-Koyanagi-Harada disease progresses rapidly, and the
main symptom is eye lesion. Cutaneous lesions appear during
recovery after remission of inflammation (about 2 months after
onset) (Fig. 16.8). Melanocytes are destroyed, leading to irregu-
lar-shaped diffuse cutaneous leukoderma, symmetrically around
the eyes in particular. The eyebrows, eyelashes and hair become
white from pigment loss. Alopecia may be present.
There are three stages: prodromal, eye disease and recovery. In
the prodromal stage, there are persistent headaches, slight fever,
dizziness, and pain in the eyes for 5 to 7 days. In the eye disease
stage, acute bilateral uveitis develops. Sensorineural deafness and
disequilibrium frequently occur. These symptoms persist for 1 to
2 months and then gradually subside. The main symptoms of the
recovery stage are those of the prodrome stage and eye disease
stage. Loss of uveal melanocytes results in light red color of the
entire fundus oculi.
Pathogenesis
Vogt-Koyanagi-Harada disease is thought to be caused by Clinical images are available in hardcopy only.
allergy or viral infection. It should be grouped with autoimmune
diseases because of the autoimmune reaction against
melanocytes. HLA-DR4 is highly associated with the occurrence
of Vogt-Koyanagi-Harada disease.

Diagnosis is made by the characteristic clinical features.
Treatment
The main treatment is systemic steroids. Steroid pulse thera-
Fig. 16.8 Vogt-Koyanagi-Harada disease.
pies (1,000 mg methylprednisolone administered intravenously Irregularly shaped leukoderma is sporadically
for 3 consecutive days) and immunosuppressants (e.g., seen.
cyclosporine) are also used for eye involvement. Steroids and
PUVA therapies are applied to the cutaneous lesions.
6. Senile leukoderma
16
Sharply circumscribed, round or irregular-shaped leukoderma
of 4 mm to 10 mm in diameter appear diffusely on the trunk and
extremities of men and women in their 30s, increasing in number
with age. Senile leukoderma is essentially identified with idio-
pathic guttate hypomelanosis. Pathological findings show a
reduction in the number of activated melanocytes and
melanosomes and dysfunction in melanocytes and melanosomes
from melanocytic senescence.
7. Nevus depigmentosus
Nevus depigmentosus is a common nevoid abnormality pres-
ent in about 1 in 125 neonates. Because of the congenital Clinical images are available in hardcopy only.
melanocytic dysfunction in skin, incomplete hypopigmented
patches are seen at birth or shortly thereafter (Fig. 16.9). The
patches vary in shape and distribution from solitary and irregular
to multiple and band-like. Size, distribution and number of nevus
depigmentosus patches remain the same over the course of a life-
time. Fig. 16.9 Nevus depigmentosus.
8. Leukoderma pseudosyphiliticum
Leukoderma pseudosyphiliticum most commonly occurs on
the lumbar regions and buttocks of men in their 20s and 30s
whose skin is naturally dark, in Asians in particular. Multiple,

sharply circumscribed, incomplete hypopigmented patches of 1
cm to 2 cm in diameter occur, often coalescing to become reticu-
lar. It is asymptomatic. The reticular leukoderma resembles
syphilitic leukoderma; nevertheless, the two can be differentiat-
ed: Syphilitic leukoderma tends to occur on exposed sites, and
the standard serologic test for syphilis is positive.
B. Disorders of hyperpigmentation
1. Ephelides
Clinical features
Multiple round smooth-surfaced brown patches about 3 mm in
Clinical images are available in hardcopy only. diameter occur on the sun-exposed areas of the face, neck and
forearms (Fig. 16.10). Ephelides darkens with sun exposure
(especially exposure to UVR) in summer and tends to fade in
winter. It worsens with age and is most remarkable at puberty; it
lightens thereafter.
Ephelides tends to run in families; it is thought to be autosomal
dominant. However, it can be autosomal recessive in severe
16 cases. Melanocytes are activated by hereditary factors, and
melanosomes markedly increase in the basal keratinocytes.
Melanocytes in patients with ephelides have well-developed den-
Clinical images are available in hardcopy only. dritic spines and enhanced functions; however, the number of
melanocytes does not change.
Differentiation from lentigo, Peutz-Jeghers syndrome, xeroder-
ma pigmentosum, and progeria is necessary. Sunscreen is useful
for blocking UVR.
Fig. 16.10 Ephelides.
2. Melasma
Synonym: Chloasma
Clinical features
Melasma tends to occur in women in their 30s or older. It is
rare in men. Sharply demarcated light brown patches occur on
the face (forehead, cheeks, and around the mouth, in particular),
usually symmetrically. Melasma patches are irregular in size and
shape. The disorder is aggravated by UVR in summer, and it sub-
sides in winter (Fig. 16.11). Pregnancy may trigger the onset
(chloasma gravidarum).
B. Disorders of hyperpigmentation 267
Pathogenesis
Abnormalities in sex hormones and adrenocortical hormones
that activate melanocytes are known to cause melasma.

Riehl’s melanosis should be distinguished from melasma.
Unlike Riehl’s melanosis, melasma is asymptomatic and is not
preceded by dermatitis-like symptoms. Histologically, there is an Clinical images are available in hardcopy only.
increase in the content of melanin throughout the epidermis and
an increase in the number of epidermal melanocytes. Differentia-
tion from nevus of Ota is also important; the periphery of the
eyes is affected by nevus of Ota but not by melasma.
Treatment
The causal factors, such as artificial sex hormones, are discon-
tinued. Chloasma gravidarum occurs during pregnancy and sub-
sides several months after delivery. Protection from UVR is
useful. Today topical hydroquinone and tretinoin are used for
bleaching treatment.
3. Riehl’s melanosis
A diffuse, vaguely circumscribed grayish-purplish-brown net-
work of pigment deposition appears, most commonly on the face
of middle-aged women. Riehl’s melanosis may be accompanied
by follicular keratotic papules. In most cases, inflammatory
symptoms such as flush and itching precede pigmentation. 16
The cause is recurrent contact dermatitis on the face. The anti-
gens in most cases are cosmetic products containing tar pigment.
Most of such products are no longer produced, because of restric-
tions on components used in cosmetics. Histopathologically,
macrophages that have phagocytosed melanosomes are observed
in the dermal upper layer.
4. Friction melanosis
Synonym: Towel melanosis
Definition, Clinical features
Prolonged and vigorous use of nylon towels or brushes may
stimulate the skin mechanically, resulting in pigmentation. Fric-
tion melanosis occurs frequently in persons in their 20s and 30s.
A network pattern or diffuse brown pigmentation is seen in the
skin above the clavicular region, neck, ribs and vertebral region
(Fig. 16.12). Subjective symptoms such as itching are not pres-
ent. Fig. 16.11 Melasma, Chloasma.
Brown spots on the cheeks.
Melanosomes sink into the dermis from mechanical stimula-
tion and inflammation. As a result of histological pigmentary
incontinence, increase of melanophages in the upper dermis leads
to friction melanosis. Histopathologically, multiple migrant

melanosomes and melanophages are seen. Amyloid deposition is
found in some cases.

Treatment
The skin color gradually returns to normal by discontinuation
of the mechanical irritation, such as discontinuation of vigorous
rubbing with nylon towels.
5. Dyschromatosis symmetrica hereditaria

Multiple brown patches and hypopigmented patches of 3 mm
to 8 mm in diameter occur on the extremities, including the dorsa
of hands and feet, coalescing into reticular forms (Fig. 16.13).
Generally, the more distally the pigmentation occurs, the severer
are the symptoms. The patches are flat and smooth. The onset is
age 6 or younger in most cases. It is autosomal dominant, which
Clinical images are available in hardcopy only. runs in families, and is caused by mutation in the RNA-specific
adenosine deaminase gene (DSRAD). It progresses with age,
until adulthood. It most commonly occurs in Asians.
Diagnosis
Dyschromatosis symmetrica hereditaria can be diagnosed by
the characteristic cutaneous features and familial incidence. It
16 should be differentiated from acropigmentatio reticularis (Kita-
mura), a similar autosomal dominant disease with reticular pig-
mentation in the distal extremities. Acropigmentatio reticularis is
Fig. 16.12 Friction melanosis.
distinguished by the fact that the pigmented patches are concave
Diffuse, reticular, brown pigmentation occurs on and there are no hypopigmented patches.
the trunk, particularly on the back. The eruptions
are blackish papules of several millimeters in Treatment
diameter. Histopathologically, amyloid deposi-
tion is observed. Special concealing cosmetics are useful. Dermabrasion may be
conducted for pigmented patches.
6. Senile lentigo
Synonym: Solar lentigo
Clinical images are available in hardcopy only. Definition, Clinical features

Senile lentigo appears in almost all men and women middle-
aged and older. Round brown patches of various sizes occur on
sun-exposed areas of the face, dorsa of hands, and extensor sur-
faces of the arms. The patches are relatively clearly circum-
scribed. Mild scaling may be present (Fig. 16.14).
Fig. 16.13 Dyschromatosis symmetrica
hereditaria. Treatment
Multiple brownish macules of 2 mm to 10 mm in Alexandrite lasers and cryotherapies are conducted.
diameter occur on the dorsum of hands. They
coalesce to present a reticular pattern. Depigmen-
tation is also seen.
B. Disorders of hyperpigmentation 269
7. Addison’s disease
Secretion of ACTH and MSH from the anterior lobe of the
hypophysis is enhanced by reduced secretion of adrenocortical
hormones, and this causes pigmentation by stimulating Clinical images are available in hardcopy only.
melanocytes. Pigmentation is seen on the entire body. The face,
genitalia, axillary fossae and umbilical region are most severely
affected. The pigmentation is also found on areas that normally
contain less pigmentation than skin, such as the tongue, gingiva
and oral mucosa; this is helpful for diagnosis.
8. Pigmentatio petaloides actinica

Multiple, sharply circumscribed, brown, petal-shaped or spiny
patches of several millimeters to 1 cm in diameter occur on the
shoulders and upper back (Fig. 16.15). Multiple patches often Clinical images are available in hardcopy only.
occur in persons with light complexion, 1 to 3 months after
intense sunburn such as from a beach outing.
9. Erythema dyschromicum perstans

Synonym: Ashy dermatosis
Fig. 16.14 Senile lentigo.
Multiple, small erythematous lesions occur on the trunk and Sharply demarcated brown patches appear. They
extremities of non-Caucasians, and these soon turn into grayish- may partially elevate and progress to seborrheic
keratosis in some cases.
white to grayish-blue patches of 1 cm to 3 cm in diameter. Ery-
thematous elevation is seen at the periphery in many cases (Fig. 16
16.16). Itching may be present; however, it is asymptomatic in
most cases and develops slowly. Drug eruption or lichen planus
resembling erythema dyschromicum perstans may appear.
Fig. 16.15 Pigmentatio petaloides actinica

This skin lesion occurred after PUVA therapy for
vitiligo vulgaris (center of photo).
Fig. 16.16 Erythema dyschromicum per-

stans, ashy dermatosis.
Grayish-blue patches and erythematous eruptions
are seen around the patches.
C. Diseases caused by extrinsic deposition
1. Carotenemia
Synonym: Aurantiasis cutis

Carotene concentration increases in the blood, resulting in
carotene deposition in the epidermal horny cell layer and subcu-
Clinical images are available in hardcopy only. taneous fat tissues. This yellows the skin (Fig. 16.17). The col-
oration is marked in the palms and soles, whose horny cell layer
is thick. The color may appear in the face (e.g., forehead, ala
nasi, nasolabial groove); however, it does not occur in the sclera
or other mucous membranes, and it rarely becomes generalized.
It is asymptomatic. Coloration tends to appear when the carotene
concentration in the blood reaches 0.5 mg/dl. Carotenemia is
caused by high intake of carotene-containing foods (citrus fruits,
pumpkins, carrots, spinach, seaweeds, corn, egg yolks, butter), by
Fig. 16.17 Carotenemia. liver dysfunction (carotene concentration in the blood increases
when carotene fails to be metabolized into vitamin A), or by
hyperlipidemia (carotene concentration tends to increase by
hyperlipidemia because of its liposolublility).
16 Jaundice is differentiated from aurantiasis cutis by yellowed
sclera, itching and bilirubin level. Aurantiasis cutis heals sponta-
neously when intake of the causative food is restricted.
2. Argyria
Clinical images are available in hardcopy only. Definition, Pathogenesis, Clinical features
Argyria results from deposition of silver in the skin. This
occurs from the use of silver medical supplies (silver needles,
sutures, dental fillings) or prolonged intake of silver-containing
foods. Cases caused by silver-containing health food products in
Europe and the United States have been reported. Silver com-
pounds deposit in collagen in the sweat glands, seborrheic
glands, connective tissues and basal keratinocytes, giving the
skin a bluish-gray hue. The condition tends to occur in exposed
areas such as the face, neck and forearms.
Fig. 16.18-1 Tattoo.
Pigments of various colors have been injected. Diagnosis, Treatment, Prognosis
Fine brown granular masses are found histopathologically. Sil-
ver can be observed by X-ray microprobe analysis. There is no
effective treatment for argyria, except to refrain from intake of
silver. Systemic complications of argyria include pulmonary
fibrosis, pneumonitis, hepatotoxicity and myopathy.
C. Diseases caused by extrinsic deposition 271
3. Tattoos
Tattoos are images or text artificially created in the skin by
injection of pigment or ink (Figs. 16.18-1 and 16.18-2). Pigment-
ed granules tend to remain in the dermal upper layer; however,
some are phagocytosed by macrophages and carried in the lymph
flow to deposit in the lymph nodes. Allergic reaction against the
injected pigment or photosensitivity may occur as complications.
Laser therapies are useful in removing tattoos of certain colors.
Fig. 16.18-2 Tattooed skin.
16
Chapter
17 Metabolic Disorders
Congenital or acquired abnormality in biosynthesis and metabolic pathways can cause qualitative and quantita-
tive abnormalities in bodily substances. Diseases caused by such abnormalities are called “metabolic disor-
ders.” Metabolic abnormalities in amyloids, mucins, lipids, nucleic acids, porphyrins, vitamins and electrolytes,
for example, cause various diseases.
A. Amyloidoses
Table 17.1 Classification of cutaneous amy-
Outline
loidoses.
● These disorders are caused by deposition or accumula-
Localized cutaneous amyloidoses
tion of amorphous glycoproteins, called amyloids, in the
Primary localized cutaneous amyloidosis
tissue or intercellular spaces.
Lichen amyloidosis ● Amyloids consist of various precursor substances whose
Macular amyloidosis compositions differ according to the type of disease.
Nodular localized cutaneous amyloidosis ● Localized cutaneous amyloidosis occurs only in the skin;
Poikiloderma-like cutaneous amyloidosis systemic amyloidosis affects systemic internal organs
Anosacral cutaneous amyloidosis (Table 17.1).
Secondary localized cutaneous amyloidosis
Systemic amyloidoses
AL amyloidosis
Amyloids deposit and accumulate in the tissue and intercellu-
lar spaces, inducing dysfunction in the whole body or specific
AA amyloidosis
17 Familial systemic amyloidosis
organs. Amyloids are glycoproteins that have a fibrous structure.
They are not seen in normal metabolism. They consist of various
Hemodialysis-related amyloidosis precursors, such as immunoglobulin L-chains, abnormal prealbu-
min, and serum proteins. In each disease, the amyloids have a
different composition. Cutaneous amyloidoses are classified as
shown in Table 17.1.

Amyloids stain light red with PAS and orange-red with Congo
red, and appear green to fluorescent yellow in polarizing
microscopy. Localized cutaneous amyloidosis does not readily
stain with Congo red; methyl violet (purple), thioflavine (fluores-
cent yellow), and dylon staining (reddish brown) are used instead
(Fig. 17.1). Detection of Bence Jones proteins in the urine and
detection of M proteins by electrophoresis of the serum has diag-
nostic value for systemic amyloidosis.
Fig. 17.1 Histopathology of amyloidosis.
Amyloids stain reddish brown in dylon staining. Treatment, Prognosis
Topical steroids are effective against localized cutaneous amy-
loidosis, which has a good prognosis. Systemic amyloidosis
accompanied by myeloma has a poor prognosis. Most patients
die from renal dysfunction or heart failure within several years
after onset.
272
A. Amyloidoses 273
a. Localized cutaneous amyloidoses
1. Lichen amyloidosis
Lichen amyloidosis frequently occurs on the extensor surfaces
of the lower legs, and on the forearms and back. Multiple, flat-
surfaced, smooth, light-brown papules appear and may aggregate
(Fig. 17.2). Intense itching is present in most cases. Histopatho-
logically, the horny cell layer and epidermis thicken diffusely,
melanin granules increase in the basal layer, and amyloid accu-
mulates in the dermal papillae. Topical steroids and oral hista-
mines are effective.
2. Macular amyloidosis
Punctuate or reticular pigmentation occurs, most commonly on
the scapular region and back of middle-aged women. Chronic
rubbing of the skin with nylon towels causes ripple pigmentation
(friction melanosis; Chapter 16). Amyloids may deposit in the
skin. Friction melanosis is thought to be strongly associated with
macular amyloidosis.

3. Nodular localized cutaneous amyloidosis
Synonym: Amyloidosis cutis nodularis atrophicans
It most frequently occurs in women middle-aged and older.

Tan nodules appear on the lower abdomen. Atrophy of the der- 17
mis occurs. Diffuse amyloid deposition is found directly below
the epidermis and fat tissue (Fig. 17.3).
4. Poikiloderma-like cutaneous amyloidosis

Amyloid deposition is found in skin with poikiloderma.
5. Anosacral cutaneous amyloidosis

This occurs in the anus and sacral region of the elderly. It is
clinically characterized by pigmentation accompanied by hyperk-
eratosis. Amyloid deposition is seen pathologically.
6. Secondary localized cutaneous amyloidosis Fig. 17.2 Lichen amyloidosis.

Deposition of amyloids is observed histologically in the der- Multiple, light brown papules appear and aggre-
gate, accompanied by intense itching.
mal papilla in association with various skin disorders. Lesions
including those of seborrheic keratosis, actinic keratosis, basal
cell carcinoma, Bowen’s disease, cylindroma, calcified epithe-
lioma, nevus sebaceus, verruca vulgaris, malignant lentigo,
mycosis fungoides, psoriasis, discoid lupus erythematosus, lichen
simplex chronicus, and solar dermatitis occur.
b. Systemic amyloidoses
1. AL amyloidosis
AL amyloidosis occurs frequently in men and women in their
60s. The cause is known to be plasma cell dyscrasia (such as
multiple myeloma), in which abnormal immunoglobulin-related
amyloid light chain (AL) was produced. Shiny yellowish-white
papules occur, most frequently in the eyelids and often accompa-
nied by purpura. Amyloid deposition is found among the colla-
gen fibers in the epidermis and outer membranes of the blood
Fig. 17.3 Histopathology of nodular localized vessels at the sites around the eruptions. Such deposition is also
cutaneous amyloidosis. seen in the systemic organs, such as the gastrointestinal tract, car-
Abundant amyloid deposition (arrows) is
observed in the upper dermal layer. diac muscles and skeletal muscles, where it causes various symp-
toms (Fig 17.4a). Lesions develop in the oral cavity and
laryngeal mucosa, resulting in macroglossia and hoarseness.
Generalized scleroderma-like stiffness in the fingers and nail
deformity are present (Figs. 17.4b and 17.4c). Bence Jones pro-
teins are excreted in the urine in some cases (a finding of myelo-
Clinical images are available in hardcopy only. ma). Treatments are mainly made for plasma cell dyscrasia. It
has a poor prognosis as a result of the complication of cardiac
insufficiency; most patients die within 2 years after onset.
a b c d e f g h 2. AAi amyloidosis
j k l m n o p q r
The precursor protein of AA amyloidosis is serum amyloid A
(AA) protein. The disorder is caused secondarily by a chronic
17 inflammatory disease or an infectious disease, such as rheuma-
toid arthritis, tuberculosis or leprosy. Skin lesions rarely form.
3. Familial systemic amyloidosis

This disorder is autosomal dominantly inherited. Amyloid dep-
a b c d e f g h osition
i jin various
k organs,
l including
m n the nerves,
o pstomach
q andr
heart, causes dysfunction.
4. Hemodialysis-related amyloidosis

Synonym: b 2-microglobulin amyloidosis
This occurs in those who have a prolonged hemodialysis. b 2-

microglobulin, which is not readily removed by hemodialysis,
deposits as amyloids. The intercarpal synovial membranes,
b c d e f g h i j k l m n p
otract and q
joints, heart, blood vessels, digestive kidneys areraffect-
Fig. 17.4 AL amyloidosis. ed. Erythema, papules, purpura and subcutaneous nodules are the
a: Macroglossia. The tongue is markedly firm
and swollen from amyloid deposition. b: Amy- main cutaneous symptoms.
loid deposition in the fingers results in hardening
of the skin that resembles systemic scleroderma.
c: Nail deformity is caused by amyloid deposi-
tion in the nail matrix and nail beds.
B. Mucinoses
Definition, Pathogenesis Table 17.2 Classification of major cuta-
neous mucinoses.
Mucinosis is a general term for diseases in which acid
Generalized mucinoses
mucopolysaccharide (mucin) deposits in the skin. The mucin,
produced by fibroblasts, consists of complex of mucopolysaccha- Scleredema
rides (glycosaminoglycans) and proteins. The main types of gly- Diffuse myxedema
cosaminoglycan are hyaluronic acid (hyaluronan), dermatan Pretibial myxedema
sulfate, chondroitin sulfate and keratan sulfate. The mucin stains Lichen myxedematosus
positive with Alcian blue and colloidal iron, and metachromatic Reticular erythematous mucinoses
with toluidine blue. Localized mucinoses
Abnormal deposition of mucin among collagen fibers results Follicular mucinosis
in swelling and separation of those fibers and the edematous skin.
Cutaneous focal mucinosis
Mucin deposition is often induced by collagen disease, thyroid
dysfunction or tumor; however, the precise mechanism is
unknown. Mucinosis is classified by the location of deposition
and clinical features (Table 17.2).
1. Scleredema
Synonym: Scleredema adultorum Clinical images are available in hardcopy only.
Stiffness occurs in the skin, especially of the face, neck, shoul-

ders, upper back, and in some cases the upper extremities and
trunk (Fig. 17.5). The distal portions of the extremities are not
involved. The induration is non-pitting and hard. It is asympto-
matic at the early stages; however, mild mobility impairment 17
appears gradually. Scleredema is often induced by acute infec-
tious disease. The epidermis of the lesions thickens. Hyaluronic
acid and dermatan sulfate deposit among the dermal collagen
fibers (Fig. 17.6). Differentiation from diabetic scleredema
(described later) is important; when scleredema is suspected, dia-
betes should be tested for. Scleredema heals spontaneously in
several months to several years.
2. Diffuse myxedema
Fig. 17.5 Scleredema.
It is mucoid edema (myxedema) on the entire body skin, Marked hardening of the skin on the neck and
which often occurs when there is decreased thyroid activity. The upper back.
skin is cold, dry and white. When pinched, the skin is soft and no
marks are left (non-pitting edema). The disorder is characterized
by the facial features: the entire face is swollen, the nose widens,
and macroglossia and lip swelling are present. The scalp hair and
the hairs in the lateral one-third of each eyebrow become thin and
fragile.
3. Pretibial myxedema
The frontal tibiae and the dorsa of feet are most commonly
276 17 Metabolic Disorders
involved. Light pink to brownish plaques, subcutaneous indura-

tion, and nodules occur. Dilated follicles and hirsutism are pres-
ent. The etiology is unknown. It occurs in 1% to 10 % of all
hyperthyroid cases. Ophthalmopathy is seen in almost all
patients.
4. Lichen myxedematosus
Synonyms: Scleromyxedema, Papular mucinosis
Soft, yellowish papules aggregate and coalesce on the axillary

Fig. 17.6 Histopathology of scleredema. fossae, dorsal hands and fingers, and extensor surfaces of fore-
arms, presenting an orange-peel-like appearance. Hyalunic acid
deposition is present in the lesions. Endocrine function is usually
normal. Myeloma, diabetes, and liver dysfunction may occur.
5. Reticular erythematous mucinosis

Clinical images are available in hardcopy only. Reticular erythema occurs on sun-exposed areas of the trunk
(Fig. 17.7). It is characterized by glycosaminoglycan deposition
in the dermal upper layer.
6. Follicular mucinosis
Papules of normal skin color to rose pink aggregate, coalesc-
Fig. 17.7 Reticular erythematous mucinosis.
ing mainly on the scalp and face and becoming elevated plaques
(Fig. 17.8). Alopecia often accompanies this. Pathologically,
edema and mucin deposition are seen in the outer root sheaths
17 and sebaceous glands. Vacuolization of follicles and lymphatic
infiltration also occur. Follicular mucinosis may occur primarily
or secondarily. Mycosis fungoides may develop as complica-
tions.
Fig. 17.8 Follicular mucinosis.

The skin lesion is accompanied by relatively
sharply demarcated, reddish infiltration of 3 cm
to 4 cm in diameter, and alopecia.
C. Xanthomas
Definition
Lipid-laden foamy histiocytes aggregate on the skin or mucous
membranes to form yellowish lesions. This condition usually
accompanies a systemic abnormality of lipid metabolism; howev-
er, lipid abnormality is not found in all cases. Xanthoma is divid-
ed by clinical features into several subtypes described below.
Pathology
Xanthoma presents histologically as aggregation of foam cells
in the dermis (Fig. 17.9). Touton giant cells may be found.
Fig. 17.9 Histopathology of xanthoma.
Treatment Foamy histiocytes that have phagocytosed fat
Hyperlipemia should be treated first. Eruptive xanthoma may droplets are observed in the dermis.
disappear when the triglyceride level falls. However, cases with
nodules do not readily respond to oral drugs.
1. Tuberous xanthoma
Embossed, firm, pinkish-yellow tumors of 5 mm to several
centimeters in diameter occur, mostly on the extensor surfaces of
the elbows and knees and on the joints of the hands and feet (Fig.
17.10). The condition accompanies hyperlipoproteinemia (type
IIa, type III, type V).
2. Tendon xanthoma 17
This is a type of tuberous xanthoma. The Achilles tendons and
the tendons of hands, legs and knees become tumorous. It accom-
panies hyperlipoproteinemia (type IIa).
Fig. 17.10 Tuberous xanthoma on the metacar-
pophalangeal joints and proximal inter-
3. Plane xanthoma pharangeal joints.
Redness is seen in some of the affected sites.
Almost flat or slightly elevated, yellowish lesions occur. They
may be accompanied by hyperlipoproteinemia (Fig. 17.11).
4. Xanthelasma palpebrarum
The inner canthus of the upper eyelids becomes flatly elevated.
This disorder often accompanies hypercholesterolemia (type IIa,
type III). About half of all cases are not accompanied by hyper-
lipoproteinemia (Fig. 17.12).
5. Eruptive xanthoma
Multiple, small, yellowish papules of 5 mm in diameter or Fig. 17.11 Plane xanthoma that occurred
secondarily after chronic lymphedema on
smaller occur on the entire body. Eruptive xanthoma accompa- the upper arm.
nies hypertriglyceridemia (Fig. 17.13). There are vaguely demarcated yellow plaques.

Fig. 17.12 Xanthelasma palpebrarum.

Flatly elevated yellow plaques occur on the inner canthus of the upper
and lower eyelids, accompanied by mild infiltration. Fig. 17.13 Eruptive xanthoma.
D. Electrolytic disorders
1. Acrodermatitis enteropathica
Synonym: Zinc deficiency syndrome
Outline
● This is a zinc deficiency whose main symptoms are der-
matitis, alopecia and diarrhea.
● The main types are a congenital type (autosomal reces-
sively inherited) and an acquired type that is caused by

administration of parenteral central venous nutrition or
excision of the digestive tract.
17 ● Erythema and erosion form on the distal portions of the
extremities, and on the genitalia and orifices (the periph-

ery of the eyes and mouth, nares, and auditory meatus),
presenting clinical features similar to psoriasis, seborrhe-
Clinical images are available in hardcopy only. ic dermatitis and cutaneous candidiasis.
Clinical features
Dermatitis tends to occur on sites that have mechanical pres-
sure, such as the distal portions of the extremities, the genitalia,
and the facial orifices (the periphery of the eyes and mouth, nares,
and auditory meatus; Fig. 17.14). Acrodermatitis enteropathica
begins with papules, small blisters, or erythema accompanied by
pustules, and progresses to erosion and crusts. Annular scaling is
clinically observed, resembling psoriasis, impetigo, seborrheic
dermatitis and cutaneous candidiasis. Nail deformity and peri-
onychia occur.
Alopecia occurs in almost all cases, appearing on the occipital
and temporal region of the head first and then spreading to the
entire scalp and eyebrows. Diarrhea and vomiting recur.
Pathogenesis
Fig. 17.14 Acrodermatitis enteropathica.
The congenital type of acrodermatitis enteropathica is autoso-
mal recessively inherited. It is caused by a mutation in the
D. Electrolytic disorders 279
SLC39A4 gene on chromosome 8. SLC39A4 is a specific protein

for transporting zinc and iron. Acquired zinc deficiency is caused
mainly by prolonged parenteral central venous nutrition, excision
of the digestive tract, or severe diarrhea or vomiting. It may be
induced by the anti-rheumatoid drug oral penicillamine, or by
deficiency of zinc in breast milk. Clinical images are available in hardcopy only.

Zinc levels are low in patients. In normal people, zinc levels
are 60 to 130 mg/dl in serum, and 300 to 600 mg/day in urine.
The alkaline phosphatase level in the blood is also low, because
of the low zinc level.
The eruptions resemble psoriasis, impetigo, seborrheic der-
matitis and cutaneous candidiasis. Acrodermatitis enteropathica
is a rare metabolic disease; however, dermatitis, diarrhea, and
alopecia may also occur in congenital biotin metabolic disorder
and essential fatty acid deficiency.
Treatment
Sufficient supply of zinc is essential.
2. Hemochromatosis
Synonym: Bronze diabetes
Outline
● Excessive accumulation of iron in the body leads to Fig. 17.15 Hemochromatosis. 17
organ failure from deposition of hemosiderin (an iron-
binding protein) in various organs. It is caused hereditari-
ly or by anemia, liver dysfunction, excessive intake of
iron preparations, or excessive transfusions.
● Diffuse, brownish-blue-gray pigmentation occurs on sun-
exposed areas and genitalia. Diabetes may occur as a

complication. Abnormality is not seen in the central nerv-
ous system.
● Iron and increased ferritin are found in the serum by a
blood test.
● Phlebotomy and iron chelator administration are the
main treatments.
Clinical features
Diffuse, brownish-blue-gray pigmentation occurs in the skin as
a result of marked deposition of hemosiderin, ferritin or melanin
(Fig. 17.15). The sun-exposed areas of the body such as the face,
dorsal hands, extensor surfaces of forearms, and genitalia are
most severely affected. Atrophy and dryness are present. The
axillary and pubic hair may become sparse. The symptoms
progress gradually.
Liver dysfunction almost always accompanies the cutaneous
symptoms. Impaired hepatic function and hepatomegaly are

found. Atrophy and dryness of the skin are present. Without
proper treatment, liver cirrhosis may progress to hepatocellular
carcinoma.
Classification
Hemochromatosis is divided into genetic hemochromatosis
a b c d e f g (autosomal
h i recessively
j k inherited)
l and
m secondary
n hemochromato-
o p q r
sis (from excessive intake of iron).
Pathogenesis
In genetic hemochromatosis there is overabsorption of iron
from the intestinal tract and of iron metabolic dysfunction in the
endothelial system.
Secondary hemochromatosis may be caused by ① anemia
a b c d e f g h accompanied
i j by
k ineffective
l merythropoiesis
n o (e.g.,p sideroblastic
q r
anemia, hemolytic anemia), ② liver disease (e.g., alcoholic cir-
Fig. 17.16 Histopathology of hemochromato-
sis. rhosis), ③ excessive oral intake of iron (e.g., high intake of red
a: Melanin deposition is observed in the epider- wine, excessive intake of iron preparations), or ④ blood transfu-
mal basal keratinocytes. b: There is iron deposi- sion in large volumes.
tion in the dermis (the portions stained blue).
Pathology
Hyperpigmentation of the skin is caused by increased dermal
melanin and dermal hemosiderin within macrophages, seen as
melanophages and siderophages. Iron deposits in the deep der-
mis. Dermal atrophy and pigmentation are present. Marked iron
deposition can be found at the periphery of the sebaceous glands
(Fig. 17.16).
17
Serum iron, transferrin saturation and serum ferritin values
increase from iron excess. UIBC is decreased. A liver biopsy is
conducted for differential diagnosis.
Treatment
An iron chelator (deferoxamine) is administered. Symptomatic
therapies are performed for organ failure. Alcohol intake is
restricted.
3. Menkes disease
Synonym: Menkes kinky-hair disease
Outline
● This disease is an X-linked recessive disorder of copper
metabolism.
● It is characterized by kinky hair and reduced skin pig-
mentation.
Clinical features
Congenital lack of a copper-dependent enzyme that is essential
E. Vitamin deficiencies 281
for synthesis of melanin and keratin leads to reduced skin pig-

mentation. Hair is whitish and fragile (kinky hair). Babies with
Menkes disease are born underweight and demonstrate convul-
sions and other neurological symptoms shortly after birth. Psy-
chomotor retardation, muscular hypotonia, poor sucking, low
body temperature, abnormality in the blood vessels in the whole
body, and osteoporosis are present. Without proper treatment,
most patients die before age 3.
Pathogenesis Fig. 17.17 Calcinosis cutis on the extensor

surface of an infant’s forearm.
Mutation in the gene that codes for copper-transporting Multiple papules of several millimeters in diame-
ATPase (ATP7A) causes malabsorption of copper in the intestin- ter are caused by calcium deposition. Some rup-
al tract, resulting in copper insufficiency in the body. This leads ture and coalesce, discharging their contents.
to various symptoms. It is an X-linked recessive disorder; boys
are most commonly affected.
Treatment
Parenteral copper salt is effective in mild cases. The gene
responsible for Menkes disease has been identified; this may be
useful for gene therapies.
hardcopy only.
4. Calcinosis cutis
Calcinosis cutis is a condition in which calcium deposits in
large amounts to form firm, yellow to white papules or nodules.
When the deposition is in the stomach, kidneys, lungs muscles,
or is in/under the skin and hypercalcemia is present, the cause is
parathyroid tumor, excessive intake of vitamin D, or bone Fig. 17.18 Calcinosis cutis on the scrotum.
destruction caused by a tumor. Calcinosis cutis may appear as a 17
symptom in systemic sclerosis and dermatomyositis, even in
cases with normal serum calcium level (Fig. 17.17). There are
also idiopathic cases: e.g. scrotal carcinosis cutis (Fig. 17.18).
E. Vitamin deficiencies
1. Pellagra
Outline
● It is caused by lack of B vitamins, especially niacin.
● The main symptoms are dermatitis, diarrhea and demen-
tia.
● It most frequently occurs in recipients of isoniazid (INH),
and in alcoholics and those who have had a gastrectomy

or who have poor eating habits.
● Supplementation of niacin is the main treatment.
Clinical features
Symptoms of pellagra are characterized by the “3D’s”:
dermatitis, diarrhea and dementia; however, there now tend to be

few cases with all three symptoms together. The cutaneous
symptoms are burning sensation and itchy photosensitive der-
matosis. Sunburn-like eruptions appear on sun-exposed areas of
the body, which develop into red-brown erythema, blistering and
erosion. The skin coarsens. Sharply circumscribed, dark-brown
pigmentation and atrophy are present (Fig. 17.19). Eruptions on
hardcopy only. the frontal neck region (the so-called V-neck zone) are called
Casal’s necklace. Angular chelitis at the early stages and typhus-
like intense diarrhea are characteristic gastrointestinal symptoms.
Stomatitis, esophagitis, and nausea and vomiting occur. Psy-
choneurotic symptoms including depression, epileptic seizure,
dementia, and peripheral neuropathy may occur.
Pathogenesis
Fig. 17.19 Pellagra caused by poor diet. Pellagra is caused by niacin deficiency. Although the mecha-
Blackish-brown pigmentation is present. nism of eruptions is unknown, it is associated with cellular defi-
ciency of niacin that results from an inadequate dietary supply of
niacin.

The amount of N1-methyl nicotinamide, a metabolic product
of niacin, quantitated in the urine for 24 hours is low. Pellagra
should be carefully differentiated from other photosensitive der-
matoses.
Administration of nicotinic-acid amide, dietary improvement,
17 and avoidance of exposure to light are useful.
2. Biotin deficiency
Biotin deficiency is caused by a lack of this water-soluble vita-
min, which is associated with biosynthesis of fatty acids (Fig.
17.20). Cutaneous symptoms that resemble zinc deficiency syn-
drome occur, and alopecia and exfoliative dermatitis-like lesions
are produced at sites that come into contact with diapers and in
the intertriginous areas. Ichthyosis and erythroderma appear on
the whole body in severe cases. Anemia accompanied by atrophy
in the lingual papillae, loss of appetite, fatigue, and muscular
pain are present.
3. Vitamin C deficiency

Synonym: Scurvy
Vitamin C (ascorbic acid) is essential for hydroxyproline pro-

duction, which in turn is necessary for collagen synthesis. Defi-
ciency leads to fragility of the blood vessels and the peripheral
supporting structures, resulting in easy bleeding, follicular ker-
Fig. 17.20 Biotin deficiency. atosis, purpura and bleeding in the gums. There may be systemic
F. Porphyrias 283
symptoms, such as fatigue and bone fracture. However, these are

promptly improved by vitamin C supplementation.
F. Porphyrias
Outline
● Porphyria is a general term for diseases caused by dep-
osition of intermediate products such as porphyrins in the
liver or skin, as a result of congenital or acquired impair-
ment of an enzyme essential for heme synthesis.
● It is divided into hepatogenous porphyrias and myeloge-
nous ones.
● The main cutaneous symptom is photosensitivity accom-
panied by blistering.
Porphyrin is a general term for molecules that have a por-
phyrin ring, which is an intermediate metabolite synthesized in
the process of heme biosynthesis from glycine and succinyl-CoA.
This biosynthesis occurs in various cells, particularly in the liver
and bone marrow. Metabolic enzymes such as P450 occur as
glycine + succinyl CoA

ALA synthase
d -aminolevulinic acid (ALA) 17

ALA dehydrase
porphobilinogen (PBG)
deficient in acute
deficient in congenital PBG deaminase intermittent
erythropoietic porphyria (AIP)
porphyria (CEP) hydroxymethyl bilane
uroporphyrinogen III uroporphyrinogen I
synthase synthase
uroporphyrin III uroporphyrinogen III uroporphyrinogen I uroporphyrin I

deficient in deficient in
uroporphyrinogen III porphyria uroporphyrinogen I porphyria cutanea
decarboxylase cutanea tarda decarboxylase tarda (PCT)
(PCT)
coproporphyrin III coproporphyrinogen III coproporphyrinogen I coproporphyrin I
coporphyrinogen
oxidase
protoporphyrinogen IX
deficient in
protoporphyrinogen variegate
oxidase porphyria (VP)
protoporphyrin IX
deficient in erythropoietic
Fe2＋ ferrochelatase protoporphyria
(EPP)
heme
Fig. 17.21 Metabolic pathway of porphyrin and functional enzymes (arrows).
Table 17.3 Major types of porphyria.

Porphyrin Inheritance
Porphyria Photosensitivity Enzyme deficiency
accumulates in... pattern
Erythropoietic Congenital erythropoietic porphyria + Urine, feces, Uroporphyrinogen III AR
porphyrias (CEP) erythrocytes synthase
Erythropoietic protoporphyria (EPP) + Feces, erythrocytes Ferrochelatase AD
Hepatic Acute intermittent porphyria (AIP) - - Porphobilinogen deaminase AD
porphyrias
Variegate porphyria (VP) + Urine, feces Protoporphyrinogen oxidase AD
Porphyria cutanea tarda (PTC) + Urine, feces Uroporphyrinogen AD in
decarboxylase familial PCT
hemeproteins in the liver and are synthesized into the heme of

hemoglobin. That is, there are hepatogenous porphyrias and ery-
thropoietic (myelogenous) porphyrias. These are subclassified by
the affected enzyme (Fig. 17.21). The major subtypes are shown
in Table 17.3.
Porphyrins induce cutaneous and neurological symptoms.
They become activated by light energy, which produces reactive
oxygen that causes cytotoxicity and results in the cutaneous
symptoms of photosensitive diseases. d -aminolevulinic acid (d -
ALA) passes through the blood-brain barrier and acts neurotoxi-
cally.
1. Congenital erythropoietic porphyria (CEP)
Clinical features
Congenital erythropoietic porphyria (CEP) appears shortly after
17 birth, first as photosensitivity (blistering, pustule formation, ulcera-
tion) and later as scarring. Wine-colored urine and purplish-black
feces result from excretion of intermediate products. The intermedi-
ate products deposit in erythrocytes, teeth and bones. They fluoresce
red under Wood’s lamp. Hemolytic anemia causes splenomegaly.
Pathogenesis
Large amounts of uroporphyrin I and coproporphyrin I are pro-
duced in the hematopoietic tissue as a result of congenital
absence of uroporphyrinogen III synthase (Fig. 17.21). Uropor-
phyrin I and coproporphyin I deposit in the skin and hemoglobin,
where they absorb light energy and destroy cellular membranes.
CEP is a rare, autosomal recessively inherited disease.
2. Erythropoietic protoporphyria (EPP)
Clinical features
Mild photosensitivity, heat sensation, pain, flash, edema or
urticaria manifests in children age 10 or younger. Moderate
hemolytic anemia occurs. Protoporphyrin deposited in the liver is
crystallized and excreted in the bile; mild liver dysfunction and
gallstones are present.
F. Porphyrias 285
Pathogenesis
Erythropoietic protoporphyria (EPP) is caused by congenital
abnormality in the ferrochelatase (FECH) gene, the last gene in
the heme synthesis pathway. Protoporphyrin IX is not trans-
formed into heme and deposits in the body, particularly in the
erythron of the bone marrow, causing EPP (Fig. 17.21). Proto-
porphyrin increases in the serum, bile and feces. EPP is the sec-
ond most frequent porphyria subtype after PCT (described later).
It is autosomal dominantly inherited. Clinical images are available in hardcopy only.
Differential diagnosis of EPP can be made by photosensitivity
in adolescents and increased protoporphyrin in the blood and
feces. Administration of b-carotene and the protection from radi-
ation afforded by tanning are effective treatments.
a b c d e f g h
3. Acute intermittent porphyria (AIP)
Acute intermittent porphyria (AIP) is induced by drugs, sex
hormones and stress, for example, and the symptoms appear
acutely. It is autosomal dominantly inherited and most frequently
occurs in women of adolescent age or older. Reduced activity of
porphobilinogen deaminase (PBGD) leads to deposition of d -ALA
and porphobilinogen, precursors of porphyrins. Cutaneous symp-
toms are not seen; however, neurological symptoms, peripheral Clinical images are available in hardcopy only.
nervous symptoms and abdominal symptoms are present.
4. Variegate porphyria (VP)

17
Variegate porphyria (VP) is autosomal dominantly inherited
hepatic porphyria caused by abnormality in protoporphyrinogen
oxidase. It is clinically similar to PCT (described later), and thea b c d e f g h i
symptoms are less severe than those of hereditary coproporphyria.
5. Porphyria cutanea tarda (PCT)
Clinical features
Blistering is caused by injury and sun exposure on the face and Clinical images are available in hardcopy only.
dorsal hands during the spring and summer. It resolves with mod-
erate scarring, atrophy and pigmentation; the course recurs (Fig.
17.22). Reddening of urine from excretion of uroporphyrin,
abdominal symptoms resembling those of AIP, hypertrichosis of
the face, and liver dysfunction may occur.
Pathogenesis a b c d e f g h i j
Uroporphrinogen decarboxylase activity decreases. Intermedi- Fig. 17.22 Porphyria cutanea tarda (PCT) on
ate products such as uroporphyrin deposit in the liver and skin various sites.
(Fig. 17.21). The condition is induced by chronic alcohol con- a: Face. b: Dorsum of hands. c: Forearm. Blister-
ing, mild scarring, atrophy and pigmentation
sumption, hepatitis, hepatocellular carcinoma, hemodialysis, or occurred at all these sites. The symptoms
drugs such as estrogen, hexachlorobenzene, iron preparations or recurred when the sites were exposed to the sun.
sulfonylurea drugs. Familial cases have been reported; these are

autosomal dominantly inherited. Men in their middle ages and
older and those who have habitually drunk alcohol for a long
period of time are most commonly affected.
Pathology
Subcutaneous blistering is found. Endothelial cells are injured.
PAS-positive substances are detected in the peripheral blood ves-
sels.
Laboratory findings
Red fluorescence of porphyrins is observed by liver biopsy.
There are elevated levels of uroporphyrins in the urine.
Treatment
Abstinence from alcohol consumption, shading from light,
phlebotomy (300 ml to 500 ml of blood drawn over the course of
2 to 3 weeks), administration of an iron chelating agent, liver
support therapy, and oral sodium hydrogen carbonate are effec-
tive.
G. Skin manifestations associated with diabetes

Various cutaneous lesions are induced by diabetes.
1. Diabetic gangrene
17 Gangrene occurs on the toes, soles, and fingers. It is associated
with underlying diseases such as microangiopathy and arterial
sclerosis. External factors such as injury, burn or secondary
infection induce ulceration. Sharply circumscribed necrotic foci
occur secondarily to ulceration, and these become intractable
(Fig. 17.23). Circulatory stimulants, antibiotics, and surgical
treatments including débridement, ablation and revascularization
are conducted in combination with treatments for diabetes. Arte-
riosclerosis obliterans in the main artery is surgically treated.
2. Diabetic scleredema
Scleredema occurs in the nuchal region (Fig. 17.24). Although
it is clinically similar to scleredema adultorum, acute infection
does not occur in diabetic scleredema as a prodrome nor is there
spontaneous healing.
3. Diabetic xanthoma
Eruptive xanthoma occurs commonly on the extensor surfaces
of the extremities and buttocks. When hyperlipemia is resolved
by diabetic treatment such as administration of insulin, xanthoma
also subsides.
G. Skin manifestations associated with diabetes 287
4. Necrobiosis lipoidica
The frontal tibiae of women age 40 or older are most common-
ly affected. Irregularly shaped, vaguely circumscribed, atrophic,
and yellow to tan plaques of 5 cm to 10 cm in diameter occur. Clinical images are available in hardcopy only.
The periphery is purplish-brown, accompanied by telangiectasia
(Fig. 17.25). Histological findings are similar to those for granu-
loma annulare. It may also occur on the thighs and hands.
a b c d e f g h
5. Diabetic bulla
Tense bullae like those seen in burns are produced by minor
trauma. Microangiopathy is thought to be the cause of diabetic
bulla. Because the reduced sensory perception of diabetic Clinical images are available in hardcopy only.
patients tends to make them less sensitive to high temperatures,
differentiation from second-degree burn is necessary.
a b c d e f g h i
6. Dupuytren contracture
Painful subcutaneous core-like induration occurs on the palms
and soles. As it progresses, flexion contracture occurs in the fin-
gers and toes. It often accompanies diabetes.
7. Pretibial pigmented patches

Atrophic brown patches are caused by microvessel abnormali- Clinical images are available in hardcopy only.
ty in the frontal areas of the lower extremities.
8. Disseminated granuloma annulare 17

Aggregated, solid, light-pink papules or infiltrating erythema
occurs (Chapter 18). Glucose intolerance is frequently seen.
a b c d e f g h i j
9. Eczema, Pruritus
The seborrheic and intertriginous areas are the most commonly
affected areas. If diabetes is not treated appropriately, the der-
matitis recurs, and photosensitivity and purpura occur as compli-
cations. Sebum reduction, xeroderma and pruritus are also
present. Topical steroids tend to induce mycotic infection. Clinical images are available in hardcopy only.
a b c d e f g h i j k
Can necrobiosis lipoidica occur without MEMO
Fig. 17.23 Diabetic gangrene.
diabetes? a: Ulceration occurring secondarily after tinea
Necrobiosis lipoidica used to be understood as a skin lesion caused by pedis. b, c: Ulceration resulting from shoe sores.
diabetes, hence the name “diabetic necrobiosis lipoidica.” However, d: Progressed diabetic gangrene in a foot. The
some cases without diabetes have recently been described. Even so, aponeurosis is exposed by the deep ulcer.
reports have found a close association between the two. This textbook
includes it in the diabetes section.
10. Opportunistic infection

Cutaneous infectious diseases, including various opportunistic
infections, occur. These include folliculitis, subcutaneous
abscess, cellulitis, perionychia, necrotizing fasciitis, erythrasma,
non-Clostridium gas gangrene, mycosis and viral infections.
Fig. 17.24 Diabetic scleredema in the nucha.

This is a markedly firm, large, plate-like plaque.
17
Fig. 17.25 Necrobiosis lipoidica.

Sharply demarcated, irregularly shaped, atrophic
plate-like plaques on the tibial anterior regions.
H. Other metabolic disorders

Cer − Glc − Gal − Gal
1. Fabry’s disease
a-galactosidase A
Synonym: Angiokeratoma corporis diffusum (Fabry)
Cer − Glc − Gal
This is an X-linked recessive lysosomal storage disorder. The
pathogenesis is absence or marked reduction of a-galactosidase
activity caused by genetic mutation (Figs. 17.26 and 17.27). Tri- Cer − Glc
hexosylceramide fails to be degraded because of a lack of this
enzyme, resulting in deposition in the blood vessels, causing dys-
function (Fig. 17.28). Multiple angiokeratoma, small papules of Cer ceramide
2 mm to 3 mm in diameter accompanied by telangiectasia, occur,
Fig. 17.26 Mechanism of Fabry’s disease.
mostly on the abdominal and lumbar regions (“bathing trunk” Trihexosylceramide (Cer-Glc-Gal-Gal) deposits
distribution). Renal failure, cerebrovascular disorder, heart fail- in the kidneys and vascular tissue from lack of a-
ure and breathing difficulty occur, with most patients dying at trihexosylceramide activation.
about age 40. Clinical features of Fabry’s disease differ greatly
from case to case. Enzyme replacement therapies have been
attempted in recent years.
2. Kanzaki disease
Synonym: Angiokeratoma corporis diffusum (Kanzaki) Clinical images are available in hardcopy only.
This is a lysosomal storage disorder. Enzyme deficiency

results from mutation in the N-acetyl-a-d-galactosaminidase
gene on chromosome 22. This disorder of glycoprotein metabo- 17
lism is autosomal recessively inherited. The cutaneous symptoms
resemble those of Fabry’s disease: Small multiple angiokeratomas
occur on the whole body, particularly on the lumbar region (Fig.
17.29). Oligohidrosis, sensory nerve failure, and hearing impair-
ment are present. The prognosis is good.
3. Gouty tophus Clinical images are available in hardcopy only.

Multiple nodules of 5 mm to 30 mm in diameter occur on the
auriculae, finger and toe joints, elbows, knees and Achilles ten-
dons. The skin becomes tense and thin, with yellowish-white
tone in subcutaneous areas. When the skin is broken, a chalk-like
substance containing uric acid crystals is excreted. Gouty tophus Fig. 17.27 Fabry’s disease in a male in his
heals with scarring after ulceration. 20s.
Gout is caused by hyperuricemia; uric acid is hyperproduced Multiple red papules of 2 mm to 3 mm in diame-
and/or underexcreted. Acute gouty arthritis tends to present as ter are present on the face and trunk, accompa-
nied by telangiectasia (angiokeratoma).
intense pain in the great toe that gradually spreads to the other
joints. Joint swelling and tenderness are present. Peripheral areas
swell and become dark red, and these changes are accompanied
by burning sensation, fever, leukocytosis, and elevated erythro-
cyte sedimentation rate.
a b c d e f g h i j
Fig. 17.28 Electron microscopic view of the
dermis in Fabry’s disease.
B a: Low-power magnification. Arrows indicate the
C following: A. Vascular endothelial cell. B. Macrophage.
C. Neurocyte.
b: High-power magnification. Trihexosylceramide is
a b c d e f g h i j observed
k asl black deposition
m n with high p den-q
o electron r
sity in various cytoplasms.
4. Lipoid proteinosis
Synonym: Hyalinosis cutis et mucosae
17 Clinical images are available in hardcopy only. Hyaline-like substances deposit in cutaneous membranes to
form wart-like nodules and papules on the eyelids and eyelash
regions, and white nodules in the oral cavity. Nodules in the glot-
tis cause hoarseness. Cases caused by autosomal recessively
inherited mutation in the extracellular matrix protein 1 (ECM1)
gene on chromosome 1q21 have been reported in recent years.
5. Phenylketonuria
This autosomal recessively inherited disorder is caused by
mutation of the phenylalanine hydroxylase (PAH) gene, which
Clinical images are available in hardcopy only. codes for an enzyme that metabolizes phenylalanine into tyro-
sine. Reduced skin pigmentation, brownish hair color, and mental
developmental delay result from the atic dysfunction. In Japan,
Guthrie newborn mass screening is conducted for phenylke-
tonuria. The incidence is 1 in 60,000 to 1 in 80,000. Maintaining
a phenylalanine-restricted diet until about age 3 prevents cerebral
disorder. The skin and hair color returns to normal by dietary
Fig. 17.29 Kanzaki disease in a female in
her 40s. supplementation of tyrosine.
Multiple angiokeratoma of 2 mm to 3 mm in
diameter occurred on the chest and abdominal
region. It is impossible to differentiate Kanzaki
disease from Fabry’s disease only by the clinical
features of the eruptions.
Chapter
18 Disorders of the Dermis and
Subcutaneous Fat
The dermis and subcutaneous tissue hold and support the epidermis. If the tissue is injured, the entire structure
of the skin may be greatly affected, even though the surface of the skin itself might show only minor changes.
This chapter discusses diseases that predominantly affect the dermis and subcutaneous tissue.
Disorders of the dermis
A. Cutaneous atrophy
1. Striae
Synonyms: Striae distensae, Striae atrophicae
Outline
● Slightly concave, linear cutaneous atrophy follows the
lines of cleavage (skin tension lines). Clinical images are available in hardcopy only.
● The thighs and lower abdomen are most commonly
affected.
● Oral steroids may be the inductive factor. Striae occur
when skin undergoes rapid growth or stretching, espe-

cially in pregnancy (striae gravidarum) and adolescence.
18 Clinical features 18
Striae are slightly concave, several millimeters wide, and Fig. 18.1 Striae atrophicae (“stretch marks”).
10 cm or more long. They run roughly parallel each other. The
color is rose pink in the early stages, becoming grayish white
later on (Fig. 18.1). The long axis of the striae follows the lines
of cleavage (skin tension lines) in most cases. The buttocks, lum-
bar region, thighs and popliteal fossae are often involved.
Striae gravidarum is seen in more than 90% of all pregnancies.
It occurs on the abdomen, breasts and groin from the 6 month of
pregnancy to after delivery. Adolescent striae occur in the but-
tocks, lateral thighs, back and breasts.
Pathogenesis
Glucocorticoid inhibits fibroblast activity (collagen produc-
tion), leading to reduction of connective tissue. Wound healing is Fig. 18.2 Solar elastosis.
The epidermis is atrophic. The elastic fibers and
impaired. If skin in this condition is subjected to external pres- collagen fibers in the upper dermis tear in a club
sure or excessive extension, the connective tissue is destroyed, shape.
resulting in striae and atrophy in the skin. Striae tend to occur
when glucocorticoid levels are elevated, such as in conditions
that require oral administration of steroids, Cushing syndrome,
severe infection and diabetes. It may occur in those who are preg-
291
292 18 Disorders of the Dermis and Subcutaneous Fat
nant or obese, or those in adolescence.
Pathology
Striae (distensae) are basically scars.
No specific treatment is necessary. The disorder subsides with
age; nonetheless, it is irreversible and does not disappear com-
pletely.
2. Solar elastosis
Synonyms: Actinic elastosis, Senile skin atrophy
Outline
● Itis dermal degeneration caused by excessive exposure
to sunlight.
● This is an aging change and atrophy of the skin.
● Cutis rhomboidalis nuchae, a specific subtype of this
condition, is deep rhombus striae that occur in the nuchal

region.
Clinical features
The onset of solar elastosis is in the fourth decade of life. The
skin becomes thin and yellowish, and degeneration of dermal
Clinical images are available in hardcopy only. elastic fibers is observed histologically. The skin slackens on the
whole body. Large folds of skin form on the face, neck and
joints. Because of the functional reduction of sweat glands and
seborrheic glands, the whole body skin becomes dry and rough,
leading to scaling, a characteristically atopic gloss, and brownish
18 color.
Solar elastosis is remarkable on sun-exposed areas. Outdoor
Fig. 18.3 White fibrous papulosis of the neck. workers show marked changes caused by solar elastosis. Deep
Small, multiple, white papules of 2 mm to 4 mm
in diameter appear on the neck. cleavages are seen, particularly in the nuchal region (cutis rhom-
boidalis nuchae).
Pathology
Atrophy and thinning of the dermis occur. Reduction of colla-
gen fibers is marked (Fig. 18.2). The elastic fibers are ruptured,
and solar elastosis is observed by Elastica-Van Gieson method.
The sweat glands and seborrheic glands decrease in size and
number, and subcutaneous fat tissue decreases.
3. White fibrous papulosis of the neck

(Shimizu)
Fig. 18.4 Histopathology of white fibrous
papulosis of the neck.
Fibrosis in the upper dermis (arrows). Clinical features
Small round or oval papules 2 mm to 4 mm in diameter and
white to light yellow occur on the neck region of the elderly (Fig.
18.3). Sharply circumscribed eruptions occur on follicular and
Disorders of the dermis / A. Cutaneous atrophy 293
non-follicular sites. They do not coalesce. Thickening of the col-

lagen fibers is histopathologically observed in the upper dermal
layer (Fig. 18.4). The pathogenesis is age-related dermal
degeneration.
Epidemiology
White fibrous papulosis of the neck may occur in any race.
4. Lichen sclerosus et atrophicus (LSA)
Clinical features
White, flat-topped papules of 2 mm to 3 mm in diameter
appear and aggregate, forming firm white plaques. Later, the
plaques shrink and take on a crepe-like appearance (Fig. 18.5).
Inflammation may occur, accompanied by itching and pain.
Lichen sclerosus et atrophicus (LSA) is a chronic disorder with a
predilection for the anogenital lesion and trunk of middle-aged Fig. 18.5 Lichen sclerosus et atrophicus
(LSA) on the labia majora (white) of an
and elderly women. In postmenopausal women, when the vulva elderly woman.
is involved the condition may be accompanied by atrophy in the The lesion has partially progressed to squamous
labia majora and clitoris (kraurosis vulvae). LSA in the male gen- cell carcinoma (elevated red).
italia is called kraurosis penis or balanitis xerotica obliterans.
Atrophy may result in urethral stricture in male patients.
Pathogenesis
The pathogenesis is unknown; however, hereditary factors,
endocrine abnormality or immunological mechanisms may be
involved. Autoantibodies against extracellular matrix 1 (ECM1)
have been found in the patient’s serum.
Pathology 18
Hyperkeratosis epidermal atrophy and vacuolar degeneration
are present. In the dermal upper layer, collagen fibers are homo-
geneous and edematous, leading to reduction of cellular compo-
nents. As it progresses, band-like lymphatic infiltration is seen in
the dermis. There is keratin proliferation and the formation of
follicular keratin plugs in some cases (Fig. 18.6).
Prognosis
LSA progresses slowly and tends to be intractable; however, it
may resolve spontaneously. When the genitalia are affected, it
progresses to squamous cell carcinoma in several percent of all
cases, after a long course. Topical steroids and tacrolimus oint-
ment are applied.
Fig. 18.6 Histopathology of lichen sclerosus

et atrophicus (LSA).
Hyperkeratosis, loss of epidermal rete ridges,
homogenization of collagen fibers in the upper
dermis, edema, and lymphocytic infiltration
occur.
5. Werner’s syndrome
Synonym: Adult progeria
Outline
● It typifies diseases of premature aging. Aging occurs in
systemic tissue at adolescence.
● It is caused by mutation in RecQ DNA helicase gene,
RECQL2. It is autosomal recessively inherited.
Clinical features
Premature aging begins in systemic organs around adoles-
cence. Subcutaneous fat and muscle markedly atrophy and
adhere to the subcutaneous layer. Scleroderma-like articular con-
tracture and atrophic hardening of the skin occur. The nose
a b c d e f g h j
i thin and k froml atrophy,
m giving
n the face p
o a bird-like q r
becomes pointy
appearance. Keratinization and ulceration on the soles, pigmenta-
tion on the whole body, telangiectasia, and subcutaneous calci-
nosis occur. Gray hair and alopecia often accompany these
Clinical images are available in hardcopy only. symptoms (Fig. 18.7). In organs other than the skin, osteoporo-
sis, arterial sclerosis, cataracts, insulin-resistant diabetes and
gonadal hypofunction are caused by premature aging. High-
pitched voice and loss of hircus and pubes are present.
Fig. 18.7 Werner’s syndrome. Pathogenesis
a: Thin and sparse scalp hair. b: Ulcer on the Werner’s syndrome is caused by mutation in RECQL2 encod-
foot.
ing the DNA helicase on chromosome 8. The product of the
RECQL2 gene is thought to repair genes that are damaged during
DNA replication. The mechanism of premature aging is
unknown; nonetheless, it is thought that chromosomal instability
18 is increased by incapacitation of the repairing gene, resulting in
the onset of Werner’s syndrome.
Differential diagnosis from other premature aging syndromes
(progeria and acrogeria), scleroderma, and Rothmund-Thomson
syndrome must be made.
Prognosis
Clinical images are available in hardcopy only. Most patients are short-lived, with an average age of 46 years,
as a result of myocardial infarction, cerebral apoplexy and aggra-
vated diabetes. The incidence of malignancy is high.
6. Rothmund-Thomson syndrome
It is autosomal recessive. The cause is genetic mutation. One
of the causative genes is RECQL4 encoding the DNA helicase,
on chromosome 8. In infancy and childhood, the skin atrophies,
reticular or diffuse erythema occurs on the face, and juvenile
Fig. 18.8-1 Rothmund-Thomson syndrome. cataract appears (Figs. 18.8-1 and 18.8-2). Photosensitivity is
Reticular erythema on the cheek. present in one third of cases. In adulthood, head and body hair
Disorders of the dermis / B. Dysplasia 295
becomes sparse, and keratinization occurs on sun-exposed areas.

There is impaired development of nails. Internal malignant tumor
accompanies roughly 30% of cases; tibial osteosarcoma and mul-
ticentric osteosarcoma have been reported. The prognosis is good
in the absence of malignancy. Like Werner’s syndrome, Roth-
mund-Thomson syndrome may be categorized as a type of prog-
eria.
7. Progeria
Synonym: Hutchinson-Gilford syndrome
This is a premature aging syndrome. Abnormality in the lamin

A gene has been reported. The main symptoms are growth
impairment, evidenced by short stature, low body weight and
skin atrophy. Patients are characterized by bird-like facial fea-
tures. Basic treatments for progeria have not been found; sympto-
matic therapies including administration of growth hormones and
a high-calorie diet are performed.
8. Acrogeria
Synonym: Gottron’s syndrome Fig. 18.8-2 Rothmund-Thomson syndrome.
Thin and sparse body hair. Reticular, diffuse ery-
Onset is thought to have a genetic contribution; however, the thema on the buttocks.
details are unknown. Skin atrophy and loss of subcutaneous fat
are observed in the fingers, toes, nasal apex and auriculae.
Acrogeria is a premature aging syndrome. It occurs most com-
monly in women. Atrophy, shortening and thickening of the nail
plates occur. There are no systemic symptoms, and the prognosis
is good; there are no basic treatments for acrogeria. 18
B. Dysplasia
1. Congenital ectodermal dysplasia

This term is a catchall for congenital diseases of the hair, teeth,
nails and sweat glands that cause abnormal formation of ectoder-
mal tissue. It is classified into more than 100 subtypes according
to the combinations of dysplastic components. Mutation in p63
has been found and reported. The main diseases caused by con-
genital ectodermal dysplasia are listed below.
1) Anhidrotic (hypohidrotic) ectodermal dysplasia

The main symptoms are thinning of hair, anhidrosis and abnor-
mality in dental formation (Fig. 18.9). It is autosomal recessively
inherited or X-linked, and is caused by mutation in the ectodys-
plasin anhidrotic receptor gene (EDAR) or the ectodysplasin-A
gene (EDA), respectively. The whole body skin is thin and dry
from the absence or marked reduction of sweat gland complex.
The patient is prone to heatstroke. Decreased lacrimation and
dryness of the oral and nasal membranes lead to conjunctivitis,
stomatitis, purulent rhinitis and hoarseness. It is possible for
patients to have a normal life as long as they avoid living envi-
ronments with high temperatures.
2) Hidrotic ectodermal dysplasia

a b c d e f g h (Clouston
i j syndrome)
k l m n o p q r
Deformity of nail plates, thinning of hair, and palmoplantar

keratoderma are the three major symptoms. However, 30% of
cases demonstrate only deformity of nail plates. Linear patterns
form in the nail plates, which thicken and suffer from growth
retardation. It is an autosomal dominant disease caused by muta-
tion of the GJB6 gene, which codes for connexin 30 (Chapter 1).
The prognosis is good.
2. Cutis verticis gyrata
Fig. 18.9 Anhidrotic (hypohidrotic) ectoder-
mal dysplasia. Hyperplasia of the scalp results in skin folds at the top of the
a: Thin and sparse scalp hair. b: Dental dysplasia. head. It occurs most commonly in boys. The folds are 1 cm to
2 cm wide, highly elastic and mobile. Normal hair growth is
present in the groove portions, but not in the elevated portions
(Fig. 18.10). Cutis verticis gyrata is classified into a primary
form and a secondary form that accompanies nevoid abnormali-
ties (e.g., nevus-cell nevus, connective tissue nevus) or systemic
diseases (e.g., acromegaly). Plastic surgical repair may be con-
ducted.
18 Clinical images are available in hardcopy only. Pachydermoperiostosis (MIM, 167100) is a hereditary disease
in which cutis verticis gyrata can be seen with clubbed fingers,
osteohypertrophy and brawny skin change. It is autosomal domi-
nant.
3. Chondrodermatitis nodularis chronica helicis

Painful keratotic nodules of 1 cm in diameter occur in the
Fig. 18.10 Cutis verticis gyrata. helices, particularly their upper parts (Fig. 18.11). These nodules
result from chronic inflammatory reaction against collagen fibers
that are degenerated by extrinsic stimulation such as of sunlight,
injury or the cold. They occur most frequently in men of middle
age and older. This disorder should be differentiated from sebor-
rheic keratosis, basal cell carcinoma and squamous cell carcino-
Clinical images are available in hardcopy only. ma. The main treatments are topical and local injection of
steroids and surgical excision.
Fig. 18.11 Chondrodermatitis nodularis

chronica helices.
A painful nodule.
C. Perforating dermatosis
Elastosis perforans serpiginosa
Clinical features
Small, bilaterally symmetrical, reddish-brown keratotic
papules with an atrophic and umbilicated center are produced in
linear or circular arrangement on the neck region, extremities and
upper trunk, giving the skin a serpentine appearance (Fig. 18.12).
Köbner phenomenon tends to be positive.
Pathogenesis
Transepidermal elimination results from elimination of degen-
erated elastic fibers in the upper dermal layer through the epider-
mis. It may appear idiopathically in young men. In up to a third
of cases, there is an associated systemic condition or connective
tissue disorder. It tends to accompany abnormality of the dermis,
such as Marfan syndrome, Ehlers-Danlos syndrome, pseudoxan-
thoma elasticum or dysosteogenesis. It may be caused by pro-
longed intake of D-penicillamine. Clinical images are available in hardcopy only.
Pathology
Degenerated elastic fibers accumulate in the dermal upper
layer, on which the epidermis proliferates to enwrap the abnor-
mal fibers into the dermis. Thickening of the epidermis and for- Fig. 18.12 Elastosis perforans serpiginosa
eign-body granuloma in the dermis occur. in a patient with Wilson disease who was
taking D-penicillamine.
18
D. Granulomatous disorders
1. Sarcoidosis
What is perforating MEMO
Outline dermatosis?
Perforating dermatosis is a general term for
● Itis a systemic granuloma of unknown pathogenesis. skin lesions resulting from epidermal excre-
● The skin symptoms are granulomatous lesion (cuta- tion of decomposed skin components. Dis-
neous sarcoidosis) and inflammatory reactive lesion eases that cause perforating dermatosis are
elastosis perforans serpiginosa (elastic fibers
(e.g., erythema nodosum). are excreted), Kyrle’s disease (keratin fibers
● Extracutaneous lesions such as those of bilateral hilar are excreted), perforating folliculitis (follicu-
lymphadenopathy (BHL) and uveitis occur. lar components are excreted), and reactive
● Angiotensin converting enzyme (ACE) activity is elevat-
perforating collagenosis (collagen fibers are
excreted). These diseases tend to occur in
ed, and hypercalcemia is present. patients with chronic renal failure. Epidermal
● Topical and oral steroids are the first-line treatments. excretion of decomposed skin components
may be seen in some cases of granuloma
annulare.
Pathogenesis
It is unknown.
Clinical images are available in hardcopy only. Cutaneous symptoms
Skin lesions are seen in 20% to 35% of cases of systemic sar-
g coidosis. Somej cases demonstrate only skin lesions. The p cuta-q
neous symptoms of sarcoidosis vary widely depending on the
location and severity of the infiltration of epithelioid cell granu-
loma (Figs. 18.13-1 and 18.13-2). The disease tends to be asymp-
tomatic and is often classified into nodular, plaque, diffuse,
Clinical images are available in hardcopy only. infiltrative and subcutaneous types. More than one type of cuta-
neous symptom may be seen in one patient.
Nodular sarcoidosis: This is the most frequent type. The face,
particularly around the nose, and the extremities and the center of
a b c d e f g h i trunkj are most
the k commonly
l maffected.n Multiple,
o p
slightly q
elevatedr
infiltrative erythema range in color from light pink to dark red
and in diameter from 3 mm to 30 mm. There may be scaling.
Small papules are often produced in the lower legs.
Plaque sarcoidosis: Relatively large, flat-topped infiltrative
plaques with an elevated rim and an atrophic center occur, most
frequently on the face (forehead, cheeks and nose in particular).
Clinical images are available in hardcopy only. Diffuse infiltrative sarcoidosis: Dark red, diffuse, infiltrative
plaques occur symmetrically, mainly on the nose, cheeks, fingers
and toes. It is asymptomatic. Areas that are prone to frostbite are
frequently involved (lupus pernio).
Subcutaneous sarcoidosis: It most commonly appears in the
extremities, as palpable, elastic, subcutaneous induration of 1 cm
to several centimeters in diameter.
b c d e f g h i j
Scarring k infiltrative
l m n
sarcoidosis: p occurq on areas
Itotends to r that
are prone to injury, such as knees and elbows. Epithelioid cell
18 granuloma occurs on a preexisting scar that was caused by injury,
for example. This is specific to sarcoidosis and has diagnostic
value.
Clinical images are available in hardcopy only. Other cutaneous sarcoidoses: ① Erythema nodosum-like
eruptions resemble erythema nodosum, except that epithelioid
cell granuloma is found histopathologically. They heal sponta-
neously in many cases. ② Lichenoid sarcoidosis is multiple,
asymptomatic small papules on the trunk and extremities.
c d e f g h i j k Otherl typesmof sarcoidosis
n p q
o are ichthyosis-like r
eruptions, and
Fig. 18.13-1 Sarcoidosis. ulcerative, leukodermal, verrucous, psoriatic and erythematous
a, b: Nodular sarcoidosis. c, d: Plaque sarcoidosis.
types.
Besides the granulomatous lesions (cutaneous sarcoidoses)
Sarcoidosis and erythema MEMO listed above, erythema nodosum may also occur as a nonspecific
nodosum
Erythema nodosum may occur as a result of eruption (MEMO).
reactive inflammation of fat tissue in patients
with sarcoidosis. Or sarcoidal granuloma may Systemic symptoms
form in subcutaneous tissue, usually on the
extensor surfaces of the extremities. This Subjective symptoms are rarely present. Although various
cutaneous sarcoidosis is also called “erythema organs may be involved, the bilateral hilar lymph node (BHL),
nodosum-like eruption.” There is no clinical lungs (e.g., pulmonary fibrosis) and eyes (uveitis) are most fre-
difference between erythema nodosum and
erythema nodosum-like cutaneous sarcoidosis.
quently affected.
Pulmonary lesion: This is the most frequent sarcoidosis lesion.
Disorders of the dermis / D. Granulomatous disorders 299
Patients with chronic sarcoidosis are characterized by bilateral

hilar lymphadenopathy (BHL). Subjective symptoms are rarely
present. Emphysema and pulmonary heart disease may occur in
the final stages.
Eye lesion: Uveitis and iridocyclitis occur. Clinical images are available in hardcopy only.
Cardiac lesion: The condition is known as cardiac sarcoidosis.
Heart block, arrhythmia and Adams-Stokes syndrome may cause
unexpected death.
Bone lesion: Sausage-like swelling of occurs a
in the
b
finger
c
joints.d e f g h i j k l
Bone cysts are observed by osteal X-ray.
Neural lesion: The central nervous system and the peripheral
nervous system are affected. Paralysis occurs in the facial nerve,
glossopharyngeal nerve and vagus nerve.
Additionally, Sjögren syndrome may occur. When facial nerve
paralysis, uveitis and parotid bubo are caused, it is called Heer-
fordt syndrome. Clinical images are available in
hardcopy only.
Pathology
Noncaseating epithelioid cell granuloma is characteristically
observed (Fig. 18.14). Slight lymphocytic filtration is seen at the
periphery of granulomas (naked granuloma). There are inclusion
bodies such as Schaumann bodies and a asteroid
b bodies
c in the
d giante f g h i j k l m
cells of granuloma, but these are not specific for sarcoidosis and
they may occur in other granulomation reactions. The Schau-
mann bodies have a basophilic round lamellar structure that is
positive for alkaline phosphatase and calcium deposition. The
asteroid bodies have a radiated, acicular structure with a central
core. In addition to granulomatous lesion, foreign substances
such as silica are found in scarring infiltration.
Sarcoidosis is diagnosed mainly from clinical and
a b c d e f g h i j k l m n
a b c d e f g h i j k l m n o
Fig. 18.13-2 Sarcoidosis.
e, f: Diffuse infiltrative sarcoidosis (lupus pernio).
Fig. 18.14 Histopathology of sarcoidosis. g, h: Scarring infiltrative sarcoidosis.
Noncaseating granuloma is characteristically observed.
histopathological findings. Tuberculin test is negative and levels

of angiotensin-converting enzyme (ACE) and calcium are elevat-
ed. Accumulation of 67Ga is observed by 67Ga scintigraphy. BHL
revealed by chest X-ray or CT scan has diagnostic value.
Clinical images are available in hardcopy only. Treatment

Oral steroids are effective; however, they are not usually
necessary in the early stages because sarcoidosis tends to heal
spontaneously and has a good prognosis. Oral steroids are used
when sarcoidosis is progressive and extensive pulmonary lesions
a b c d e f g h causing
are i j
clinical k
symptomsl suchm as breathing
n p
o difficulty, orq r
when lesions occur in the heart, eyes or nervous system. Topical
steroids are applied for cutaneous lesions.
2. Granuloma annulare (GA)
Clinical images are available in Outline

hardcopy only. ● Itis a doughnut-shaped eruption with an elevated rim.
● Histopathologically,
there is the formation of a palisading
granuloma.
● When GA generalizes to the whole body, diabetes melli-
tus may be involved.
a b c d e f g h j
i Classification
k l m n o p q r
Granuloma annulare (GA) is classified by the clinical features
into four subtypes: localized, generalized, perforating and subcu-
taneous (Figs. 18.15-1 and 18.15-2; MEMO).
Clinical features, Pathology

18 Small, firm, doughnut-shaped nodules with a concave center
Clinical images are available in hardcopy only. appear and spread centrifugally. Firm, small papules 2 mm to
Granuloma annulare classified by clinical MEMO

features
1) Localized granuloma annulare
g It occurs most commonly in young women and p tends to be localized to
b c d e f h i j k hands
the dorsal l and m n
finger joints. o half of casesq heal sponta-
About r
Fig. 18.15-1 Granuloma annulare. neously within 2 years after onset.
a, b: Localized granuloma annulare. c: General- 2) Generalized granuloma annulare
ized granuloma annulare. Small contralateral or dispersed granuloma annulare occurs multiply,
most frequently on the trunk and distal extremities of middle-aged
women. In about half of cases, the disease is associated with diabetes
mellitus. When generalized granuloma annulare is suspected, examina-
tion for diabetes mellitus is highly recommended.
3) Perforating granuloma annulare
It is a papule with a centralized concavity that may ulcerate and crust.
Dermal excretion of degenerated collagen fibers occurs. It often arises
secondarily after localized granuloma annulare.
4) Subcutaneous granuloma annulare
A palpable, subcutaneous nodule of normal skin color, it commonly
occurs in early childhood. Bony sites that tend to be subject to pres-
sure, such as the elbows, are easily affected.
Disorders of the dermis / D. Granulomatous disorders 301
4 mm in diameter form in circular arrangement. The papules are

normal skin color to light pink and are asymptomatic.
Histopathologically, degenerated collagen fibers at the center are
radially surrounded by histiocytes, lymphocytes and giant cells
(palisading granuloma) (Fig. 18.16). Acid mucopolysaccharides
deposit in the lesion in the central area of incomplete necrosis. Clinical images are available in hardcopy only.
Pathogenesis
The mechanism of GA has not been fully clarified. Impaired
peripheral circulation, diabetes, insect bites, UV radiation and
injury may induce GA. a b c d e f g h i j k
Treatment
GA tends to heal spontaneously. After a skin biopsy, the biop-
sy lesion often disappears. As local therapies, topical steroids,
PUVA therapy and cryotherapy are conducted. If diabetes melli-
tus is involved, it is treated.
3. Annular elastolytic giant cell granuloma

(AEGCG) g j
a b c d e f h i k l
Synonyms: Actinic granuloma, Elastophagic giant cell gran- Fig. 18.15-2 Granuloma annulare.
uloma d: Perforating granuloma annulare. e: Granuloma
annulare in a diabetic patient.
A granulomatous lesion whose main components are elastic
fiber-phagocytosing giant cells occurs, most frequently in mid-
dle-aged women. A large, circular erythematous eruption with an
elevated rim and central depigmentation occurs on exposed areas,
such as the face, neck region and extremities (Fig. 18.17). It may
resemble annular erythema. The lesion heals spontaneously in
many cases. AEGCG is widely known as a subtype of GA. It 18
often accompanies diabetes mellitus.
4. Cheilitis granulomatosa
Synonym: Melkersson-Rosenthal syndrome
Clinical features
Men and women in their 20s are most frequently affected.
When all three main symptoms are present together – swelling of
the lips, fissured tongue (scrotal tongue, lingua plicata) and facial
nerve palsy – it is called Melkersson-Rosenthal syndrome. ★
Swelling of lips: Swelling occurs suddenly in the lips (particular-
ly the upper lip) as the earliest symptom in most cases of cheilitis
granulomatosa. The buccal mucosa may also be involved.
Although subjective symptoms such as pain are not present, the
swelling persists for several hours to several days. It recurs, lead- Fig. 18.16 Histopathology of granuloma
ing to rubber-like stiffness. annulare.
Lingua plicata: Swelling occurs in the tongue at the same time Collagen fiber degeneration and the mucin depo-
sition are observed at the center (★). Palisading
as the lips are affected. The folds in the surface of the tongue epithelioid cell granuloma forms at the periphery.
become marked.
Facial paralysis: At the same time or earlier than swelling of the

cheeks, peripheral facial paralysis suddenly occurs on one cheek.
Recurrences and remissions are repeated.
Other symptoms: Migraine, autonomic failure and mental dete-
rioration may occur.
The cause is unknown; however, dental metal allergy and sar-
coidosis reaction are suspected. Lymphatic edema in the dermis,
and lymphoid and histiocytic infiltration are pathologically found
in the early stages. As it progresses, inflammatory granulomatous
Fig. 18.17 Annular elastolytic giant cell gran- lesions consisting of lymphocytes, epithelioid cells and Langhans
uloma.
giant cells occur.
Treatment
Oral antihistamines and oral or locally injected steroids are
useful as symptomatic therapies.
E. Hereditary connective tissue disease
1. Ehlers-Danlos syndrome (EDS)
Outline
● Itis a congenital disease of the connective tissue. In
most cases, it is autosomal dominant.
● Hyperextensible skin, fragility of the skin and blood ves-
sels, and excessive mobility of joints are the main symp-

18 toms.
Clinical features
Ehlers-Danlos syndrome (EDS) is a common inherited disor-
der; the incidence is on the order of 1:5000 of the population.
The skin is soft and stretches excessively, despite appearing nor-
mal; when stretched and released, the skin immediately returns to
its former appearance. The skin is easily torn by extrinsic force or
injury. Because injuries do not heal promptly, parchment-like
scars form. At the terminal stages, the skin hangs saclike from
the body. In areas subjected to strong extrinsic forces, such as the
heels, subcutaneous fat enters the torn connective tissue and
develops into lump tumors. The joints of the digits, elbows and
knees hyperextend, exceeding 180 degrees of bending in the
direction opposite the flexure direction. They become valgus
(Fig. 18.18). Deformity and dislocation of the joints often occur.
Congenital dislocation of the hip joints and gait disorder are pres-
ent. Bleeding under the skin and in the ocular fundus, cardiac
anomaly and valvular involvement, aneurysm, lens deviation and
severe myopic astigmatism occur in the later stages of life, from
fragility of the blood vessels.
Disorders of the dermis / E. Hereditary connective tissue disease 303
Table 18.1 Types of Ehlers-Danlos syndrome (EDS).

Newly established Traditional Causative molecule Inheritance pattern
Classical Gravis (EDS type I) Type V collagen AD
Mitis (EDS type II) Type V collagen AD
Hypermobility EDS type III AD
Vascular Arterial-ecchymotic (EDS type IV) Type III collagen AD
Kyphoscioliosis Ocular-Scoliotic (EDS type VI) Procollagen lysine hydroxylase AR
Arthrochalasia Arthrochalasis multiplex congenita (EDS type VII A, VII B) Type I collagen AD
Dermatosparaxis Human dermatosparaxis (EDS type VII C) ADAMTS2 AR
Other X-linked EDS (EDS type V) XR
Periodontitis (EDS type VIII) AD
Progeroid EDS XGPT1
Tenascin X Tenascin X AR
AD: autosomal dominant, AR: autosomal recessive, XR: X-linked recessive
(Adapted from: Beighton P, et al. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31-37).
Pathogenesis
The causative genes vary according to disease type. Abnormal-
ity is found in collagen types I, III and V; the genetic mutations
have been identified. EDS is classified by the clinical features,
pattern of inheritance, causative gene and biochemical abnormal-
ity into more than ten subtypes (Table 18.1). The patterns of
inheritance are various; however, EDS is autosomal dominant in
many cases. Clinical images are available in hardcopy only.

The skin fibroblasts are cultured for detection of collagen
abnormality. Genetic mutation is identified.
18
Treatment
There are no ultimate treatments for EDS, only symptomatic
therapies. Pregnancy and delivery of the patients with EDS may
cause uterine rupture or massive bleeding.
2. Marfan syndrome

● It is a congenital disease of the connective tissue. Skele-
tal abnormality, eye symptoms and cardiovascular
impairment are the main symptoms.
● It is autosomal dominant, caused by mutation in the fib-
rillin-1 gene.
● Striae occur in the chest as a cutaneous symptom.
Fig. 18.18 Ehlers-Danlos syndrome.
Abnormal elastic fibers are eliminated from the epider- Overextension of the skin occurs.
mis.
● The major symptoms are arachnodactyly, skeletal defor-
mity of the chest, annuloaortic ectasia and lens devia-

tion.
Clinical features
Striae distens appear in the chest and thighs. Abnormal elastic
fibers produced in the patient’s upper dermal layer are eliminated
(elastosis perforans serpiginosa, described previously) in some
cases. When this phenomenon occurs, small, keratotic, reddish-
brown papules appear in a serpentine or circular pattern with an
atrophic center. The patients are abnormally tall, with a markedly
elongated lower body relative to the upper body. The extremities
and digits are thin and long (arachnodactyly). Deformities occur
in the chest (funnel chest or pigeon breast) and spine, and hyper-
tension and dislocation of the joints occur. Mitral valve prolapse
often occurs, as a result of reduced elasticity of the cardiovascu-
lar system. Incompetence of the aortal valve and dissecting aortic
aneurysm are easily caused by annulo-aortic ectasia. Death may
result.
Since Marfan syndrome is caused by abnormality in the fib-
rillin-1 gene, deviation occurs in the crystalline lens, because the
zonules of Zinn, which support that lens, are composed of fib-
rillin. Severe myopia may be caused by elongation of the eyeball
in the anteroposterior direction.
Pathogenesis
Marfan syndrome is caused by mutation in the fibrillin-1 gene
on chromosome 15. Fibrillin-1, a protein component of the extra-
cellular matrix, is essential to elastic fiber synthesis. The condi-
tion is autosomal dominant; however, it is caused by sporadic
mutation in about 30% of cases.
Diagnosis, Differential diagnosis, Treatment

Marfan syndrome can be diagnosed easily by the clinical fea-
18 tures. Genetic examination is necessary for differential diagnosis.
3. Pseudoxanthoma elasticum (PXE)
Outline
● It is a hereditary disease caused by mutation in the
ABCC6 gene. This gene encodes the multidrug-resistant
protein MRP6. Abnormality occurs in the elastic fibers.
● Yellow or orange papules aggregate on the neck region
and flexor surfaces of joints. Dermal laxity progresses

with age. It is asymptomatic.
● Eye symptoms and vasoconstriction occur.
Clinical features
Slightly yellowish papules aggregate and form reticular
plaques with an orange-peel-like appearance, most frequently on
the lateral region of the neck, axillary fossae and flexor surfaces
of joints. The skin is soft and saggy. Skin wrinkling becomes
Fig. 18.19 Pseudoxanthoma elasticum.
The skin of the axillary fossae becomes soft and marked with age (Fig. 18.19). It is asymptomatic.
saggy, resembling orange peel. Visual impairment or blindness results from formation of
Disorders of subcutaneous fat / A. Panniculitis 305
angioid streaks caused by degeneration of the Bruch’s mem-

brane, which exists between the retina and choroids and contains
abundant elastic fibers. It is at this point that many patients with
pseudoxanthoma elasticum (PXE) first see a doctor. Fibrosis and
calcinosis occur in the aortic tunica media, leading to constriction
of the blood vessels and bleeding. This results in high blood pres-
sure in renal arteries, claudication in the lower legs, cardiac
attack, cardiac infarction, coldness of the limbs and gastrointesti-
nal bleeding. Women outnumber men by two to one, but male
cases tend to be more severe.
Pathogenesis
Mutation in ABCC6 on chromosome 16, a member of the ATP
binding cassette (ABC), has been associated with the occurrence
of PXE. This gene encodes multidrug-resistant protein MRP6.
Although both dominant and recessive inheritance patterns are
known, recent studies support the leading theory that PXE is
autosomal recessive.
Pathology
Swelling and disruption occur in the elastic fibers in the mid-
dle-dermal to deeper-dermal layers, accompanied by calcium
deposition and changes in the vascular walls (Fig. 18.20). Fig. 18.20 Histopathology of pseudoxan-
thoma elasticum (von Kossa stain).
Treatment, Prognosis Calcium deposition stains brownish-black with
Kossa.
The prognosis is good, as long as the cardiovascular symptoms
are not severe. Eye symptoms should be treated.
Disorders of subcutaneous fat

18
A. Panniculitis
Inflammatory lesions of the subcutaneous fat can be classified
into three distinct categories.
① Septal panniculitis
② Lobular panniculitis
③ Panniculitis associated with vasculitis
1. Erythema nodosum (EN)
Outline
● Red nodules accompanied by tenderness occur, most
commonly on the extensor surfaces of the lower extremi-
ties. They do not ulcerate.
● It is an inflammatory reaction whose inductive factors
include upper respiratory infection, drug eruption, Behçet’s

disease and sarcoidosis.
● Inflammation is histopathologically found in the subcuta-
neous fat tissue septum.

● Itshould be differentiated from erythema induratum.
● Conservative therapies such as bed rest and cooling are
the first-line treatments. When induced by an infection,

antibiotics are administered. NSAIDs and potassium iodide
are also useful. Steroids may be used for severe cases.
Clinical features
Adult women are most commonly affected. After a precursor
of upper respiratory infection, a few symmetrical, vaguely mar-
gined, light pink erythema occur, sometimes accompanied by a
fever. There is arthralgia. The erythema occur predominantly on
the extensor surfaces of the lower legs (Fig. 18.21). The erythe-
mata vary in size from 1 cm to 10 cm. The eruptions are slightly
elevated indurations that are accompanied by heat sensation.
Tenderness and spontaneous pain are present. Ulceration does
not occur. In progressive cases, the same type of eruptions may
develop on the arms and hands. The eruptions change color from
dark red to yellow to blue in 2 to 4 weeks, and heal without scar-
ring.
Pathogenesis
Erythema nodosum (EN) is induced by infectious allergy to
bacteria, fungi or viruses. It often appears secondarily after upper
respiratory or enteric infection caused by hemolytic streptococ-
cus. Hansen’s disease, tuberculosis, toxoplasmosis and chlamy-
diosis may also cause EN. When the cause is infectious disease,
the condition is called acute EN, because it progresses rapidly
Fig. 18.21 Erythema nodosum (EN). and resolves in several weeks. Drugs such as sulfa drugs and oral
Multiple erythema accompanied by severe ten-
derness on the extensor of the lower legs. contraceptives can also be causes. Additionally, EN may accom-
18 pany Behçet’s disease, ulcerative colitis, Crohn’s disease, sar-
coidosis or leukemia. However, it may occur sporadically
without any underlying diseases.
Pathology
In the early stages of EN, lymphoid cells and neutrophils infil-
trate the dermis and subcutaneous fat tissue (fatty septum in par-
ticular); the condition is septal panniculitis. There are no findings
of vasculitis or degeneration of fat cells. Granulomas that contain
giant cells develop in the later stages.
Diagnosis
Clinical features of tenderness, histopathological findings and
precursory infectious disease are diagnostic. EN often occurs as a
symptom of various diseases (Table 18.2); the primary disease
should be identified.
It is differentiated from erythema induratum, cellulitis, throm-
bophlebitis, Weber-Christian disease, lupus erythematous profun-
dus and polyarteritis nodosa.
Treatment Table 18.2 Primary diseases that cause ery-

thema nodosum (EN).
Bed rest is required. The lower extremities are kept cool and
elevated. In cases with intense inflammation, oral NSAIDs, Disease Findings and check points
potassium iodide and steroids are administered. Any primary dis- Allergy caused Symptoms of various infectious
by bacterial, diseases
eases are treated. If bacterial infection is identified, antibiotics are fungal or viral
used. infection
Behçet’s Findings of other diseases (oral
Prognosis disease aphtha, uveitis, genital ulcers),
When induced by drugs or infection, EN does not recur as long needle reaction test positivity
as it is appropriately treated. When the cause is any of the chron- Tuberculosis Tuberculin skin test positive,
tuberculous granuloma in
ic underlying diseases listed above or is unknown, there may be tissue, nodules by chest X-ray
recurrence.
Sarcoidosis Bilateral hilar lymphadenopathy
(BHL) by chest X-ray, uveitis,
high concentration in serum of
2. Erythema induratum Ca2+/ACE/lysozyme, negative
tuberculin skin test
Synonyms: Erythema induratum Bazin, Nodular vasculitis
Drug eruption History-taking and investigation
Outline of oral drugs is needed.
● Painless
Ulcerative Occult blood in stool,
subcutaneous nodules occur most frequently on colitis, Crohn’s gastrointestinal endoscopy
the lower legs of women. The primary disease is lobular disease
cellulitis. Myelodysplastic Atypical hemocytes in bone
● It is clinically similar to EN; however, acute inflammatory syndrome marrow and peripheral blood,
findings are not present. The nodules are firm and often chromosomal abnormality
accompanied by ulceration with scarring. Leprosy Histological findings, lepromin
● When tubercle bacillus allergy (tuberculid) is identified, test positive, neurological
findings
therapy for tuberculosis should be given.
Clinical features
Symmetrical, diffuse, elevated, dark red infiltrative erythema
and subcutaneous induration occur on both the extensor and flex-
or surfaces of the lower legs of middle-aged and elderly adults 18
(Fig. 18.22). Women are more commonly affected than men. The
induration disappears in 1 to 2 months; however, it may ulcerate
or coalesce to become plate-like, and scarring may be present.
The skin lesion may occur singly or multiply. When multiple,
eruptions from each stage are present at the same time. Nodular
vasculitis is a subtype of erythema induratum.
Pathogenesis
Erythema induratum used to be regarded as tuberculid, i.e., an
allergic reaction to tubercle bacilli or to metabolites of such
bacilli. Nevertheless, there were cases in which tuberculosis did
not present, and steroids were effective as a treatment. Therefore,
erythema induratum has come to be thought of as lobular panni-
culitis that occurs with circulatory failure as the underlying dis-
ease. Even so, the tubercle bacillus was recently reported to have
been detected by PCR assay of skin biopsy in about 80% of
cases. In recent years, the theory of tubercle bacillus allergy as
the causative factor has reemerged.
Fig. 18.22 Erythema induratum.
Ulceration and erythema accompanied by indura-
tion occurred.
Pathology
Necrosis of fat lobular tissue and granuloma are accompanied
by giant cells and epithelioid cellular infiltration. In typical cases
caused by tuberculosis, there are tuberculoid granulomas with
caseous necrotic centers surrounded by epithelioid cells, Langer-
hans giant cells and lymphocytes. Vasculitis of subcutaneous fat
tissue (most frequently in veins) is present (Fig. 18.23).
Diagnosis, Examination
Tuberculin skin test and chest X-ray are conducted to deter-
mine whether there is a tubercle bacillus allergy. Tubercle bacil-
lus DNA is identified by PCR assay of biopsy tissue.
Fig. 18.23 Histopathology of erythema indura- The disorder should be differentiated from EN, throm-
tum. bophlebitis migrans, cutaneous polyarteritis nodosa and other
vasculitis, and ulceration in the lower extremities. EN is differen-
tiated by its tenderness, its acute, intense inflammatory reaction,
and lesions that do not rupture spontaneously and whose main
pathological component is fat tissue septum.
Treatment
Therapy for tuberculosis should be given. Tubercular lesions
subside with treatment in a few months in most cases. Erythma
induratum that is not caused by tuberculosis is intractable and
progresses slowly. Bed rest for the lower extremities and preven-
tion of stasis are effective. NSAIDs are administered orally.
Steroids are used in severe cases.
3. Weber-Christian disease
18
Synonyms: Systemic nodular panniculitis, Relapsing febrile
nonsuppurative nodular panniculitis
Weber-Christian disease is subcutaneous inflammation with

unknown cause. Internationally, recent theories have described
Weber-Christian disease as a subtype of EN or T-cell lymphoma
rather than as an independent disease. Weber-Christian disease
was defined in the past as a rare disorder with recurrent subcuta-
neous nodules and plaques, typically or extremities and buttocks,
and commonly associated with fever. Young and middle-aged
Weber-Christian disease MEMO women are most commonly affected. After systemic symptoms
as a distinct disorder such as fever, fatigue and arthralgia, there are multiple, painful,
Weber-Christian disease may display almost
the same clinical course and pathology as the subcutaneous nodules or splenial induration of 1 cm to several
panniculitis (lupus profundus) that accompa- centimeters in diameter. The eruptions most frequently occur in
nies collagen diseases. Some studies have the extremities and trunk. They are light pink and edematous at
questioned whether Weber-Christian disease
is a distinct disorder. While cases of Weber- the beginning, gradually becoming dark purplish-red and stiff,
Christian disease with poor prognosis have with high elasticity. The eruptions chronically recur to cause con-
been reported, it is likely that those cases are cavities and pigmentation in the sites.
actually misdiagnosed subcutaneous panni-
culitis-like T-cell lymphoma (SPTCL).
Systemic symptoms are characterized by the markedly high
fever. Myocarditis and pericarditis are caused by inflammation of
pericardial fat tissue. There is also anemia, neurological symp- Panniculitis caused by MEMO
toms from meningitis, and liver enlargement from hyperlipemia absence of enzyme
resulting from fat tissue degradation. a1-antitrypsin deficiency, a1-antichymotrypsin
Degeneration and necrosis occur in the lobular fat tissue. As deficiency: These are rare diseases. Enhanced
decomposition and Weber-Christian-disease-
time passes, foamy and other histiocytes are found in the neu- like panniculitis may be caused by decrease
trophilic infiltration, giving the appearance of lipid granuloma. of proteolytic enzyme inhibiting substances.
The foamy histiocytes become fibrotic. Blood test shows elevat- Enzymic panniculitis: Increase of lipase and
amylase in serum may lead to panniculitis in
ed erythrocyte sedimentation rate, leucopenia and abnormality in patients with pancreatitis. Pancreatitis is an
the coagulation-fibrinolytic system. Primary diseases and com- important underlying disease in patients with
pounding factors, if found, are treated or removed. As sympto- panniculitis.
matic therapies, systemic steroids and immunosuppressants are
administered.
4. Poststeroid panniculitis
It occurs a few days after large doses of steroids are reduced or
stopped. Multiple subcutaneous nodules 5 mm to 50 mm in
diameter suddenly occur on the whole body. They are sometimes
accompanied by tenderness, spontaneous pain and itching. They
are normal skin color or light pink. The pathological findings are
necrosis and degradation of the fat tissue, fat cells and foreign-
body giant cells. They subside spontaneously; however, re-
administration of steroids may be necessary in severe cases.
5. Cold panniculitis
Subcutaneous nodules accompanied by erythema occur on
skin (mainly the cheeks and extremities) that is exposed to the
cold, such as ice and cold air. Newborns and infants are most
commonly affected. The skin lesion heals spontaneously in a few
days to a few weeks. 18
6. Traumatic panniculitis
It is an inflammatory reaction caused by damage to fat cells
after injury. A painful erythematous plaque or nodule accompa-
nied by palpable infiltration forms, most frequently in the breasts
or lower legs of obese women.
B. Lipodystrophy
Fat tissue is markedly reduced or lost. It is classified by
whether the atrophy primarily occurs systemically or locally, and
whether the causative agent is congenital or acquired. Atrophy is
often accompanied by dysbolism and internal organ failure.
1. Generalized lipodystrophy
1) Congenital generalized dystrophy

Several genes are involved in the occurrence of this rare auto-
somal recessive disease. With absent or reduced fat in the whole
body from the time of birth or early infancy, muscles appear
sharply defined. Hyperlipemia, hyperinsulinemia, enlargement of
internal organs and insulin-resistant diabetes occur as complica-
tions.
2) Acquired generalized lipodystrophy

It manifests several days to several weeks after infectious pre-
cursors such as measles and varicella. Fat disappears in several
months to several years, sometimes in several weeks. Girls are
more commonly affected than boys. The cause is thought to be
autoimmune abnormality.
2. Localized lipodystrophy
It is divided into congenital and acquired. Fatty atrophy occurs
18 locally in the body. Atrophy occurs locally in fat tissue after pan-
niculitis or in sites subjected to external stimulation. It may occur
at the injection site of insulin, steroids, iron preparations or vac-
cines (post-injectional panniculitis). Panniculitis accompanying a
collagen disease often causes lipodystrophy, such as in lupus ery-
thematosus profundus, dermatomyositis, and scleroderma.
3. HIV-associated lipodystrophy
A lipodystrophy can be seen in patients with acquired immun-
odeficiency syndrome (AIDS). There are some variants. The
most common type can develop following the use of protease
inhibitor therapy. This type is characterized by the presence of
peripheral lipoatrophy and central adiposity.
4. Lipodystrophia centrifugalis abdominalis

infantilis
It is localized lipodystrophy produced most frequently on the
groin or axillary fossae of infants. The etiology is unknown;
however, genetic involvement is suspected because there are
Disorders of subcutaneous fat / C. Localized atrophy of fat tissue caused by various injurious stimuli 311
familial cases. This is a rare disease, and most patients are

Asians. Girls outnumber boys by 1.5 to 1. Painless erythema
becomes sharply circumscribed and concave, with a swollen
lymph node at the periphery. Within 7 years after onset, the
depression stops expanding. It subsides in the two thirds of all
cases.
C. Localized atrophy of fat tissue caused by various injurious stimuli
Subcutaneous fat necrosis of the newborn

Several days to 1 month after birth, plate-like subcutaneous
indurations of various sizes occur on the buttocks and thighs,
where fat is distributed. This is known to be a localized hypoxic
condition in tissue. It may be accompanied by hypercalcemia.
The induration heals spontaneously without scarring in 1 to 2
months.
18
Chapter
19 Disorders of the Skin Appendages
This chapter discusses disorders of the skin appendages: sweat glands, sebaceous glands, hair follicles and
nails. When these are affected by intrinsic or extrinsic factors, cosmetic appearance and the ability to regulate
the body temperature are affected. The diseases whose main lesions occur in the skin appendages are intro-
duced in this chapter (see Chapter 1 for the functions of skin appendages).
A. Disorders of the sweat glands
1. Miliaria
Synonym: Sweat retention syndrome
Outline
● Commonly called heat rash, it is caused by obstruction to
the eccrine sweat ducts.
● Skin care is the main treatment.

Miliaria is classified by the location of the obstructed sweat
ducts into miliaria crystallina, miliaria rubra and miliaria profun-
da (Fig. 19.1).
① Miliaria crystallina
The sweat ducts are obstructed in or directly under the horny
cell layer, producing superficial transparent vesicles. Flushing is
19
sweat accumulation at the level of occlusion of sweat duct
horny cell layer
occlusion
of sweat
duct
intraepidermal
sweat
accumulation
intradermal
sweat
accumulation
miliaria crystallina miliaria rubra miliaria profunda
Fig. 19.1 Classification of miliaria, and obstructed portion of the sweat duct.
312
A. Disorders of the sweat glands 313
not present. The vesicles soon dry and become thin, white scales.
They heal in one to several days without itching or inflammation.
They commonly occur on the face of infants; however, they may
appear accompanying fever in adults.
② Miliaria rubra
It frequently occurs in an environment with high temperature Clinical images are available in hardcopy only.
and humidity, or in infants, the obese and persons with hidrosis
(Fig. 19.2). Inflammation occurs from obstruction of the sweat
ducts in the granular cell layer region, and rose pink papules of 1
mm to 2 mm in diameter are produced. It is accompanied by
flushing and itching. The trunk, extensor surfaces of the extremi-
ties, neck region and axillary fossae are most commonly affected. Fig. 19.2 Miliaria rubra after fever.
It often becomes eczematous (miliaria eczematosa) or pustular
(miliaria pustulosa).
③ Miliaria profunda
The sweat ducts are destroyed at the dermo-epidermal junc-
tion. Flat-surfaced, white papules without itching occur secondar-
ily after miliaria rubra.
Pathogenesis
The pathogenesis of miliaria is poorly understood. It is thought
that the sweat ducts are obstructed by eccrine perspiration, affect- Clinical images are available in hardcopy only.
ing the sweat flow. Retained sweat leaks into the peripheral tis-
sue of the sweat ducts, causing eruptions. Miliaria is easily
caused when hyperhidrosis is present from physical exercise in a
hot, humid environment. It tends to occur in those who have a
febrile disease or who wear dressings, casts, medical tape, or
clothing that does not breathe.
Treatment Fig. 19.3 Pompholyx.

High temperature and humidity should be avoided. Careful Multiple vesicles on the palm.
washing of the body is necessary. When the eruptions are
eczematous, the treatments are the same as those for eczema. 19
Secondary infections should be carefully avoided.
2. Pompholyx
Synonym: Dyshidrosis
Pompholyx is a form of eczema of the palms and soles in

which edema fluid accumulates to form visible vesicles or bullae. Clinical images are available in hardcopy only.
Small blisters 1 mm to 5 mm in diameter occur multiply on the
palms and soles. The contents of the blister disappear in a few
days, resulting in scaling (Fig. 19.3). The blisters may become
eczematous and itchy in some cases; the condition is called
dyshidrotic eczema (Fig. 19.4).
Previously, pompholyx was thought to be a phenomenon
caused by sweat retention, because it most frequently occurs dur-
ing the summer, and hidrosis accompanies many cases. Never-
theless, the pathology is subcutaneous blistering accompanied by
epidermal spongiosis, which is not always associated with sweat Fig. 19.4 Dyshidrotic eczema.
314 19 Disorders of the Skin Appendages
ducts or sweat glands. Further, the blister contents differ from

those of sweat.
Any exacerbating factors such as allergenic drugs should be
removed. Antiperspirant and keratolytic agents are used. Steroids
are applied topically on eczematous lesions.
3. Bromhidrosis
Synonym: Osmidrosis
Definition, Classification, Clinical features

Bromhidrosis (osmidrosis) is a general term for abnormal body
odor arising from sweat glands. Eccrine bromhidrosis and apoc-
rine bromhidrosis are the main types.
① Eccrine bromhidrosis
Eccrine sweat may have a distinct odor, from intake of drugs
and foods such as garlic and spices. Bromhidrosis in feet is
caused by the bacterial action on keratin softened by sweat.
② Apocrine bromhidrosis
Osmidrosis axillae, commonly called body odor, is the well-
known type. Bromhidrosis of the genitalia is also caused by
apocrine sweat. The sweat itself is odorless; however, fatty acids
are decomposed by superficial bacteria, resulting in the odor. The
apocrine glands begin to develop at puberty. Perspiration increas-
es with mental excitement and physical exercise.
Treatment
The skin should be kept clean to reduce bacterial flora and
apocrine sweat of the axilla. Application of antiperspirants,
deodorants or antibiotics, and shaving are effective. Systemic
antibiotics are most helpful. Laser, surgical or electrolysis depila-
tion may be performed as permanent cure. Reduction of eccrine
19 sweating using aluminum chloride may help decreases the local
bacterial flora, but will not reduce apocrine sweat production.
However, many patients who complain of offensive odor do not
actually have the odor; the complaints may represent paranoia
and phobia (osmidrophobia).
4. Fox-Fordyce disease
Synonym: Apocrine miliaria
Definition
Chronic, itchy papules occur, mainly on areas distributed with
apocrine sweat glands, such as the axillae and the pubic area.
Clinical features
The disease is uncommon and most of the reported cases have
occurred in young or middle-aged women. Follicular, solid, nor-
mal skin color or rose pink papules 2 mm to 3 mm in diameter
aggregate on the axillary fossae, areola of nipples, and genitalia.
A. Disorders of the sweat glands 315
They are accompanied by intense itching.
Pathogenesis
When the sweat ducts of apocrine sweat glands are obstructed,
apocrine sweat exudes into the epidermis. The pathogenesis of
sweat gland obstruction is unknown; however, there is possible
involvement of hormones.
Treatment
The treatment of Fox-Fordyce disease is difficult. Laser thera-
py and topical application or local injection of steroids are the
first-line treatments. Clindamycin solution and tretinoin cream
are occasionally effective.
Prognosis
It is chronic and intractable.
5. Hyperhidrosis
Synonym: Hyperidorosis
Hyperhidrosis, caused by enhanced perspiration from the

eccrine glands, is classified into the subtypes described below.
① Generalized hyperhidrosis
This occurs physiologically in hot, humid environments, dur-
ing exercise, or from sympathetic hypertonia. It also occurs in
patients with hyperthyroidism, diabetes, hypoglycemia, dumping
syndrome, gout, neurologic disease, spinal cord injury, malignan-
cies (especially, in Hodgkin’s disease), or other primary disease,
or it may be induced by drugs (e.g., antipyretics, anti-
cholinesterase agents), pregnancy or obesity.
② Localized hyperhidrosis
This occurs in the palms, soles, axillary fossae, face and else- Table 19.1 Diseases thought to cause 19
where. Most cases are from emotional perspiration. The condition anhidrosis.
is associated with constitutional factors and mental stress. Ion- Cause of
Disease producing that cause
tophoresis using tap water is effective as a treatment in some cases. anhidrosis
Hyperhidrosis palmaris et plantaris may accompany atopic Congenital Hypohidrotic ectodermal dysplaisia
condition or palmoplantar keratosis. absence of
sweat gland
Hemihyperhidrosis is seen in patients with partial paralysis or
function
Parkinson’s disease. The hyperhidrosis occurs on one side of the
Metabolic Hypothyroidism, dehydration,
body from impairment of the peripheral nerves on that side. disorder thermic fever, Fabry’s disease
Neurological Disorder of the hypothalamus and
6. Anhidrosis disorder spinal cord, alcoholic neuritis, lep-
rosy, diabetic neuropathy
Synonym: Hypohidrosis Obstruction Ichthyosis, seborrheic dermatitis,
of sweat atopic dermatitis, erythroderma,
pores and psoriasis
This is a condition with scant or absent perspiration. The skin ducts
is dry and coarse. Scaling and mild itching occur, and fever may
Atrophy or Scleroderma, systemic sclerosis,
be produced by exercise because of lack of perspiration. Diseases damage of Sjögren syndrome, systemic lupus
suspected of causing anhidrosis are shown in Table 19.1. sweat erythematosus, solar elastosis, and
glands the like
B. Disorders of sebaceous glands
1. Acne vulgaris
Outline
● Itmost frequently occurs on the face of adolescent men
and women. Comedones, folliculitis, papules and pus-
Clinical images are available in hardcopy only. tules are produced.
● Agents and factors such as Propionibacterium acnes, the
Demodex folliculorum mite, endocrine secretion and

stress are associated with the occurrence.
● Lifestyle guidance and administration of sulfa drugs and
antibiotics are effective.
Clinical features
Multiple follicular inflammatory papules occur, most com-
monly on the seborrheic areas of the face, precordial region, and
back of men and women from the ages of about 10 to 40 (Fig.
19.5). The papules worsen at puberty. The initial eruption, called
a comedo, is classified as an open comedo (the follicles are open,
also called “blackheads”) or a closed comedo (small yellowish-
white nodules in the skin: “white heads”). Closed comedos often
Clinical images are available in hardcopy only. progress to erythematous papules or pustules. Subjective symp-
toms such as itching are not usually present; however, the come-
dos become painful as they develop further. Acne vulgaris is
characterized by intermingled eruptions of different stages.
Pathogenesis
The main pathogenesis involves hormonal imbalance, abnor-
19 mal keratinization and bacterial infection (Fig. 19.6). Along with
keratinization dirt

increase of free P. acnes
fat mechanical
stimuli
increase of
sebum inflammation
comedo
Fig. 19.5 Acne vulgaris.

Multiple, follicular, inflammatory papules occur
on oily areas of the face, such as the cheeks and DHT receptors
forehead. The hair follicles are obstructed and
appear as yellowish-white nodules (closed come-
androgen increase, especially in adolescents
dos).
endogenous factors
Fig. 19.6 Mechanism of acne vulgaris.

B. Disorders of sebaceous glands 317
these main factors, hereditary factors, the patient’s age, diet,

stress and extrinsic factors such as cosmetics are complicatedly
associated with the onset. Acne caused by Demodex folliculorum
is called acne demodecica, and it occurs most frequently in
women after puberty.
Hormonal imbalance: Androgen in the blood increases accord- Clinical images are available in hardcopy only.
ing to pubertal endocrine changes, and the function of the seba-
ceous glands is enhanced by adrenogenic dihydrotestosterone
(DHT). Accordingly, sebum retention and bacterial proliferation
readily occur.
Follicular hyperkeratinization: The infundibulum is obstructed
by keratin as a result of poor hygiene or hereditary factors. When a b c d e f g h
sebum components are decomposed by bacteria, free fatty acid is
produced; stimulated by this phenomenon, the infundibulum
induces keratinization. Sebum retention is accelerated by these
causative factors to produce an initial comedo.
Bacterial infection: Propionibacterium acnes resident in the
infundibulum break down triglycerides in the sebum, producing
free fatty acids that destroy the hair follicles and lead to inflam- Clinical images are available in hardcopy only.
mation. The bacteria themselves also cause destruction of folli-
cles and inflammation, especially when there is infestation by the
Demodex folliculorum mite.
Pathology
Acne vulgaris is characterized by enlargement of the seba-a b c d e f g h i
ceous glands and follicular keratinization. Cystic dilation occurs
in follicles, and destruction of the follicular walls causes inflam-
matory reaction.
Acne vulgaris must be differentiated from steroid acne, a side
effect of oral or topical steroid use, and from lupus miliaris dis- Clinical images are available in hardcopy only.
seminatus faciei, and verruca plana. Acne-like eruptions are 19
caused by immunosuppressants in the same mechanism as that in
steroid acne; these eruptions must also be differentiated from
acne vulgaris. Thorough history-taking is important.
Treatment a b c d e f g h i j
Lifestyle guidance is primary. Observance of a regular sched- Fig. 19.7 Rosacea erythematosa on the tip
ule of sleeping and eating, and avoidance of cosmetics (oily of the nose.
a: A male patient in his 20’s. b: A female patient
creams and foundation, in particular) are helpful. Washing the in her 30s. c. A male patient in his 30s. Telang-
face and maintaining regular bowel movements are important. iectasia is remarkable.
Topical application of retinoids (tretinoin or adapalene cream),
sulfa drugs, and antibiotic ointments and oral antibiotics such as
tetracyclines and roxithromycin are effective. Chemical peeling
or extraction of comedos may be useful in some cases. Unless
treated appropriately, acne vulgaris heals with scarring, leaving a
cosmetic problem.
2. Rosacea
Rosacea is a chronic inflammatory disease that causes diffuse
reddening and vascular dilation on the face of middle-aged and
older men and women. Acne-like papules and pustules may be
produced.
Clinical features
Rosacea is classified by severity into three stages. The first
stage (rosacea erythematosa) and second stage (acne rosacea)
occur frequently in middle-aged and older women. Progression to
Fig. 19.8 Acne rosacea in a male patient in the third stage (rhinophyma) is more common in men. In addition
his 50s.
A red skin lesion is present on the nose and to the cutaneous symptoms listed below, eye symptoms (e.g.,
cheeks. ketatitis and conjunctivitis) may occur.
① First stage (rosacea erythematosa): Transient reddening
appears on the tip of the nose and on the cheeks, glabella and chin.
It progresses gradually to become persistent and accompanied by
telangiectasia and seborrhea (Fig. 19.7). Cold and warm weather,
sunlight and alcohol consumption aggravate it. Subjective symp-
Clinical images are available in hardcopy only. toms such as itching, hot flashes and irritability are present.
② Second stage (acne rosacea): In addition to the symptoms of
the first stage, follicular papules and pustules occur. Seborrhea is
intense (Fig. 19.8). The lesions spread to cover the face.
③ Third stage (rhinophyma): The papules aggregate and coa-
lesce to become tumorous. The surface of the nose becomes
Fig. 19.9 Rhinophyma in a male patient in rough and reddish purple. The skin appears orange-peel-like with
his 60s.
The skin lesion becomes tumor-like and the hair open follicles (Fig. 19.9). Rosacea keratitis, conjunctivitis, and
follicles dilate. The skin takes on the appearance blepharitis occur as complications.
of orange peel.
Pathogenesis
19 Involvement of sunlight, mental stress, intake of alcohol or
spicy food, liver dysfunction, and infection by Demodex follicu-
lorum is suspected; however, the pathogenesis is unknown.
Rosacea progresses gradually and tends to be intractable.
Spicy foods, excessive sun exposure, and stress should be avoid-
Clinical images are available in hardcopy only. ed. Laser irradiation is performed on the telangiectasia. The treat-
ments for acne rosacea are the same as those for acne vulgaris.
Topical metrohidazole, imidazoles and tretinoin may bring
improvement. Steroid should never be used. Laser therapy, cryother-
apy and surgical treatment are conducted for rhinophyma.
3. Rosacea-like dermatitis
Fig. 19.10-1 Rosacea-like dermatitis.

Synonym: Steroid-induced dermatitis
Eruptions occurred after continuous application
of topical steroid for 1 month. Diffuse flushing, Outline
exfoliation, itching and burning sensation ● Prolonged application of steroids to the faces induces
occurred.
B. Disorders of sebaceous glands 319
rosacea-like erythematous papules, diffuse flushing, and

acne.
● Perioral dermatitis is also known to be caused by topical
steroid therapy.
● After discontinuation of steroids, the treatments for acne
vulgaris are given.
Clinical features Clinical images are available in hardcopy only.
Erythema, telangiectasia, papules, pustules, diffuse flushing,

and scaling occur on sites where steroids have been applied.
These symptoms are accompanied by itching and burning sensa-
tion (Figs. 19.10-1 and 19.10-2). Localized rosacea-like dermati-
tis around the mouth is called perioral dermatitis.
a b c d e f g h
Pathogenesis
Rosacea-like dermatitis most commonly occurs in middle-aged
women. Rosacea-like dermatitis is a typical side effect of topical
steroids.
Treatment
Steroids are immediately discontinued. After that discontinua-
tion, rebound phenomenon occurs. Reddening and swelling
aggravate, and erosion may persist for several weeks to several
months. The same treatments as for acne vulgaris are performed. Clinical images are available in hardcopy only.
Topical steroids are tapered off only when rebound is severe.
4. Lupus miliaris disseminatus faciei (LMDF)

Synonym: Acne agminata
Outline
● Multiple small papules of 2 mm to 5 mm in diameter the
g 19i
color of normal skin or redder occur on the face, particu-a b c d e f h
larly the lower eyelids. They are asymptomatic. Fig. 19.10-2 Rosacea-like dermatitis as a side
effect of topical steroids.
● The histology is epithelioid cell granuloma with central
a: Eruption at the early stage. b: Eruption that has
necrosis. progressed.
● Tetracyclines are administrated in small doses.
Clinical features
Lupus miliaris disseminatus faciei (LMDF) occurs in both
sexes equally, most patients being in their 20s and 30s. Multiple
small papules with central necrosis of 2 mm to 5 mm in diameter Clinical images are available in hardcopy only.
the color of normal skin or redder occur symmetrically on the
face, especially on the lower eyelids, cheeks and sides of the
nose, accompanied by pustules (Figs. 19.11-1 and 19.11-2). The
disorder is asymptomatic. Small yellowish-white nodules are observed
by diascopy. These heal with concave scarring one to several years
after onset. The scars become indistinct in about 1 year. Fig. 19.11-1 Lupus miliaris disseminatus
faciei (LMDF).
Pathogenesis Small multiple papules of normal skin color or
red and 2 mm to 5 mm in diameter occur sym-
LMDF is first thought to be a form of tuberculid, but an metrically on the face. Some heal with scarring.
association with tuberculosis has been excluded. Tuberculin reac-

tion test is negative in most cases. The mechanism is predomi-
nantly thought to be reaction against the hair follicle tissues or
their contents.
Pathology
A biopsy from a well established lision shows that epithelioid
granuloma with central necrosis is present.
Syringoma, milium, rosacea and acne vulgaris should be dif-
ferentiated from LMDF.
Treatment
Clinical images are available in hardcopy only. Tetracyclines are administered in small doses. Topical steroids
may be the inductive factor in some cases. After a period of
months or up to 2 years, the condition resolves spontaneously.
5. Xerosis, Asteatosis
Fig. 19.11-2 Lupus miliaris disseminatus Dehydration of the horny cell layer and decrease of sebum
faciei.
cutaneum lead to dryness and coarseness of skin, resulting in
pityroid scaling. These symptoms tend to aggravate during the
winter. Xerosis is often caused by excessive washing and rubbing
during bathing. It may be observed as a change in the aging
process. It may also be caused by specific climates and environ-
ments. It appears as a symptom of nutritional deficiency or atopic
dermatitis in some cases. It may progress to pruritus, nummular
eczema or asteatotic eczema (Chapter 7).
C. Disorders of the hair

19
1. Alopecia areata
Outline
● Round, sharply margined hair loss suddenly occurs.
● Hair regrows spontaneously in several months in most
cases. Cases with multiple alopecia areata may progress
Clinical images are available in hardcopy only. to alopecia totalis or alopecia universalis.
● Topical steroids and PUVA are applied.
Clinical features
Alopecia areata is quite common, affecting up to 1% of the
population. Sharply margined hair loss occurs suddenly without
prodromes or subjective symptoms (Figs. 19.12-1 and 19.12-2).
Fig. 19.12-1 Alopecia areata. Alopecia areata is usually a round or oval, single but sometimes
Sharply demarcated hair loss occurs. In active
alopecia areata, the hairs around the lesion easily multiple, alopecia of 2 cm to 3 cm in diameter. The alopecia patches
come out. may coalesce, progressing to complete scalp hair loss (alopecia
C. Disorders of the hair 321
totalis) in some cases (Fig. 19.13).

Besides occurring in the scalp, alopecia areata may occur in
the eyebrows, beard areas and the extremities; cases in which
hair on the whole body is affected are called alopecia universalis,
which is intractable. In nails, desquamation, coarseness,
cloudiness and slight depression occur.
Pathogenesis
Hair matrix cells are impaired temporarily for unknown rea-
son. Theories include nutritional failure, heredity and mental
stress; however, the pathogenesis is unknown. Some cases are
accompanied by autoimmune thyroid deficiency and atopic der-
matitis. Autoimmune involvement is suspected.
Fig. 19.12-2 Alopecia areata.
Pathology Formation of hairs is observed at the center of the
skin lesion.
In the lesion, there is infiltration of CD4+T cells and the
appearance of Langerhans cells in the hair follicles at the anagen
stage. Expression of MHC class II in hair bulb epitheliocytes, and
deposition of C3, IgG and IgM in the hair follicular basement
membrane are observed. There is possible involvement of autoim-
munity. The affected hair follicles form abnormal atrophic hair
that falls out.
Diagnosis
Alopecia areata is easily diagnosed by the clinical features.
The hairs around the lesion easily fall out at the early stages of Clinical images are available in hardcopy only.
the lesion. The hairs are characteristically thin and atrophic at the
end of the hair root, giving them the appearance of exclamation
marks (“exclamation-point hair”). The hairs stop falling out and
newly grown hairs are seen during the healing period.
Trichotillomania and traumatic alopecia are distinguished from 19
alopecia areata. Trichotillomania, which produces short, break-
able, hard hair in the lesion, occurs most commonly in children; a b c d e f g h
however, there is no diseased hair in trichotillomania, and the
hair around the lesion does not come out easily. In traumatic
alopecia, the lesion is not round, and it is caused by extrinsic fac-
tors such as scarring. Fibrosis and pigmentation are also found.
Alopecia areata also should be distinguished from systemic lupus
erythematosus (SLE) and alopecia caused by syphilis.
Treatment
Alopecia areata resolves spontaneously in several months, although
in some cases it may be intractable or recurrent. It is important to
address the patient’s distress about hair loss. Sedatives may be used
if necessary. Steroids, immunosuppressants and hair-growth lotionsa b c d e f g h i
are topically applied. In severe cases, PUVA therapy, steroid Fig. 19.13 Alopecia totalis.
injection, cryotherapy, and application of squaric acid dibutylester a. Complete alopecia on the head. b. Multiple,
(SADBE) are performed. Steroids and immunosuppressants are small concavities in the nails.
administered orally in alopecia totalis or universalis.
2. Androgenetic alopecia
Synonyms: Male-pattern baldness, Alopecia prematura
Clinical features
Androgenetic alopecia also called male pattern baldness, is
hair loss in adolescent and adult men. Androgenetic alopecia is a
very common disorder, affecting at least 50% of men by the age
Clinical images are available in hardcopy only. of 50. The hairline recedes to form an M shape (with vellus hair
at the frontal region of the head) or an O shape (with vellus hair
on the top of the head). These patterns may appear separately or
simultaneously. The diameter of the vellus hair is smaller than
that of normal hair. The density (hairs per unit area), also
decreases. It progresses to complete hair loss.
Pathogenesis
Patients usually have a familial history of baldness. Elevated
sensitivity of hair follicles to androgen (dihydrotestosterone, in
particular) begins at some point. The anagen period is shortened,
hairs at telogen decrease in number, hair follicles contract, and
vellus transformation occurs. The thin, sparse vellus hair pro-
duced in androgenetic alopecia becomes less densely distributed,
eventually progressing to alopecia.
Treatment
Topical minoxidil and anti-androgenetic drugs such as 5a -
reductase inhibitor fenasteride are effective in some cases. Stimu-
lating the affected site, stimulating the local circulation of the
scalp by massaging, and using hair growth lotions containing
female hormones are helpful.
19 3. Congenital alopecia
Congenital atrichia, alopecia and oligotrichia are observed in
various conditions, including those listed below.
Fig. 19.14 Congenital hypotrichosis in a ① Atrichia congenita
girl. It is autosomal recessive. Hair may be present at birth; howev-
This patient has thin, sparse hair (oligotrichia).
She has never had a haircut, but the hair does not er, it falls out between several months after birth and puberty,
grow beyond this length. until no hair remains on the body. Involvement of the hairless
(hr) gene has been identified as a cause in some cases of certain
subtypes.
② Hypotrichosis congenita
Normal hair is present at birth; however, alopecia gradually
leads to thin, sparse hair (Fig. 19.14).
③ Arrichia and alopecia associated with hereditary syn-
drome
Arrichia and congenital alopecia are associated with congenital
ectodermal defect (aplasia cutis congenita (Fig. 19.15)), derma-
tothlasia, Werner’s syndrome, poikiloderma congenital and Nether-
ton syndrome. Odontogenesis imperfecta, abnormal nail plates,
palmoplantar keratosis and anhidrosis often occur as complications.
D. Disorders of nails 323
4. Alopecia pityrodes
Pityriasis capitis (“dandruff”) occurs in combination with
alopecia most frequently in men after puberty. Fine, dispersed,
grayish-white scaling occurs constantly on the scalp. The hair is
thin and the natural gloss is not present. Itching and reddening of Clinical images are available in hardcopy only.
the scalp often occur. The treatments are the same as for sebor-
rheic dermatitis.
5. Trichotillomania
Patients with trichotillomania, who tend to be in their late Fig. 19.15 Aplasia cutis congenita.
childhood, have an uncontrollable compulsion to pull out their Hair loss on the top of the head is seen. It is
own hair. The patients may deny this hair-pulling behavior. caused by skin loss in the fetus.
Vaguely circumscribed, irregular-shaped, incomplete alopecia is
present. Both short and broken remaining hairs and newly pro-
duced hairs are observed in the same alopecia, which is within
reach of the hand, often on the frontal and temporal region of the
head on the right side. The patient’s psychological background,
personality and domestic environment may trigger trichotilloma-
nia; cooperation with a psychiatrist is necessary for treatment.
6. Scarring alopecia
As a result of scarring caused by injury, burn, or discoid lupus
erythematosus. The hair follicles are irreversibly destroyed, lead-
ing to alopecia. Surgical treatment is necessary.
D. Disorders of nails
a. Color change of nail plates 19
1. Melanonychia
Melanonychia may be caused by increased number of nail
matrix melanocytes (e.g., from nevocellular nevus, inflammation,
melanocytes activated by pressure), fungal infections, malignant
melanoma, Behçet’s disease, subungual hemorrhage, Addison’s
disease or drugs (e.g., 5-FU, bleomycin, hydroxyurea). When the
skin of the nail fold region is also affected, it is called Hutchin-
son’s sign and has a high likelihood of indicating a malignant
melanoma (Fig. 19.16).
Approximately 20% of ethinic Japanese and up to 96% of ethnic
Africans have pigmented streaks.
2. Yellow nail
It is caused by nutritional deficiency or infection of nails, or by
aurantiasis cutis, or jaundice. When yellowing of the nails occurs
in patients with lymphoma and chronic pulmonary disease, it is

called yellow nail syndrome, which may be induced by
D-penicillamine or tetracyclines.
Clinical images are Clinical images are 3. Green nail

hardcopy only. hardcopy only. This opportunistic infection is caused by Pseudomonas aerugi-
nosa infection and tends to accompany tinea unguium and candi-
da onychomycosis (Fig. 19.17).
a b c a d b e c f d g e h 4. i g
f White j h k i l j mk n l om p n q o r p
nail
Fig. 19.16 Melanonychia.
a: The nail is partially pigmented. Deformity is Synonym: Leukonychia
seen at the tip. Melanoma is suspected in this
case. b: The fingernail of a 25-year-old woman.
The symptoms rapidly progressed in the previous
These white punctate patches may be caused in nails by local-
6 months, presenting melanoma in situ histologi- ized incomplete keratinization from injury (Fig. 19.18). They are
cally. harmless. White nail accompanies hypoalbuminemia as in
nephrosis and cirrhosis, diabetes, anemia, systemic sclerosis,
arsenic poisoning, onychomycosis and onycholysis.
5. Subungual purpura
Clinical images are available in Punctate or linear purpura results from bleeding caused by
hardcopy only. injury, Osler’s disease, or subacute endocarditis.
b. Abnormal formation of nail
1. Clubbing
Fig. 19.17 Green nail. This disorder is also called clubbed finger or hippocratic nail.
The entire nail plate bulges like the glass face of a watch. The
distal fingers and toes enlarge in drumstick shape (Fig. 19.19).
19 Clubbing is caused by mucopolysaccharide deposition in the soft
tissue of the distal fingers and toes. It occurs in chronic car-
diopulmonary diseases (pneumonectasia, lung cancer, bronchiec-
Clinical images are available in hardcopy only. tasis, congenital heart disease), hyperthyrea, ulcerative colitis and
Crohn’s disease. It may appear as a symptom of pachydermope-
riostosis running in families (Chapter 18).
2. Spoon nail
Fig. 19.18 White nail. Synonym: Koilonychia
Spoon nail is associated with iron-deficiency anemia, lichen

planus, psoriasis, fungal infection, extrinsic injury and chemical
substances. The nail plates become thin, with spoon-like concavi-
ty with raised edges. Fingers are more severely affected than
toes. It may be seen in otherwise normal infants.
D. Disorders of nails 325
3. Onycholysis
The nail plate detaches from the nail bed at the periungual area.
Desquamation occurs, but nails do not fall out. The causes may
be injury, nail polish, or inflammation in the periungual skin of
the nail plate region caused by detergent, localized diseases includ- Clinical images are available in hardcopy only.
ing candida onychomycosis, systemic diseases such as

hyperthyroidism, peripheral circulatory failure, or drug-induced
disease.
4. Onychomadesis, Nail shedding

The nail plate detaches at proximal sites of the nail root, which
is the end opposite that in onycholysis desquamation, and the nail
exfoliates. It may occur sporadically or be caused by injury, peri-
onychia, psoriasis, lichen planus, syphilis or erythroderma. Clinical images are available in hardcopy only.
5. Pachyonychia
The nail plate thickens, or hyperkeratosis occurs under it.
Thickening of the nail is also caused by hindered growth.
6. Longitudinal groove Clinical images are available in hardcopy only.

Linear grooves run vertically in the nail plate. It is seen as a
senile change. It may progress to onychorrhexis, a condition in
which nails tend to split longitudinally. Longitudinal grooves are
caused by injury, eczema, systemic scleroderma, and anemia. When
the nail is thickened and curved, it is called onychogryphosis.
7. Transverse groove
Grooves cross in the nail as a result of impaired growth of nail 19
caused by failure in the nail matrix. The width of the grooves
shows the period of a disease, and the depth shows the degree of
impairment. By measuring the position of the transverse grooves,
it is possible to date previous illness. It occurs in infectious dis-
eases including typhus and hemolytic streptococcal infection
Fig. 19.19 Clubbing.
(scarlet fever), diabetes, severe blood loss, drug-induced diseases, The entire nail plate bulges like the glass face of
zinc deficiency and cases of periungual injury or infection. Trans- a watch. The distal fingers enlarge in drumstick
verse grooves caused by an intrinsic factor are called Beau’s lines. shape.
8. Nail pits
Multiple, small, needle-like indentations occur on the nail
plate. It is caused by psoriasis and alopecia areata, or it may
occur under normal conditions.
9. Onychoschisis
Fine, scaly, lamellar separation occurs at the tip of the nail, caus-
ing fragility. It is most frequently caused by nail polish applica-
tion; however, it may be induced by systemic diseases such as SLE.
10. Ingrown nail

The sides of the nail grow into the nail fold, leading to
a b c d e f g swelling,
h i reddening
j and
k inflammation
l m with
n a granuloma-like
o p q r
appearance. The condition is accompanied by tenderness (Fig.
19.20a). In severe cases, a secondary infection such as parony-
chia occurs, causing formation of reactive granuloma (Fig.
19.20b). It is commonly caused in the great toes by pressure from
wearing shoes or by clipping the toenail too short. When it
occurs secondarily after nail deformity caused by fungi of the
Clinical images are available in hardcopy only. genus Trichophyton, the primary disease is treated. Avoidance of
extrinsic pressure and maintenance of cleanness are the first-line
treatments; however, surgery may be necessary for intractable
cases (Fig. 19.20c).
19
Fig. 19.20 Ingrown nail.
a: On the great toe. The sides of the nail grow
into the nail fold, causing sharp pain. b: Reactive
formation of granulation. c: Part of the nail,
including the nail matrix, was removed.
Chapter
20 Nevus and Neurocutaneous Syndrome
“Nevus” is Latin for “maternal impression” or “birthmark.” It denotes a circumscribed, non-neoplastic skin or
mucosal lesion. The term is qualified according to the cell or tissue of origin. Nevi may be caused by hereditary
or embryologic factors and may appear at any time in life (Unna, 1894). They progress extremely slowly.
Neurocutaneous syndrome includes nevi formed in the skin and nevoid lesions produced in the systemic organs
that cause central nervous symptoms. Neurocutaneous syndrome is often categorized as a phacomatosis; how-
ever, that term has fallen out of use internationally in recent years. This chapter introduces the most common
nevi. Angiomas are described in Chapter 21.
Nevus
A. Melanocytic nevi (Fig. 20.1)

a. Nevocellular nevus
Synonyms: Pigmented nevus, Nevus pigmentosus
Outline
● Nevocellular
nevus is caused by proliferation of nevus cells.
A small nevocellular nevus is commonly called a mole.
● A hairy, giant, pigmented nevocellular nevus of 20 cm or
more in diameter is called a giant congenital melanocytic

nevus. It tends to progress to malignant melanoma.
● Dermoscopic findings are important for diagnosis.
● “Pigmented nevus” may be used as a synonym; howev-
er, non pigmented lesions are often seen.

20
Pathological Junctional nevus

classification Intradermal nevus
Compound nevus
Nevocellular Clinical images are available in hardcopy only.
nevus Giant congenital
melanocytic nevus
Divided nevus
Specific
Nevus striatus unguis
Melanocytic diagnosis Sutton nevus
nevus Spitz nevus
Dysplastic nevus
Blue nevus Spotted grouped nevus
Dermal Nevus of Ota Balloon-cell nevus
melanocytic Nevus of Ito
nevus Acquired dermal melanocytosis Fig. 20.2-1 Nevocellular nevus.
Mongolian spot
Fig. 20.1 Classification of melanocytic nevi.
327
328 20 Nevus and Neurocutaneous Syndrome
Clinical features
A nevocellular nevus is a flat-surfaced or verrucous macule or
tumor that is brown, black, or sometimes normal skin color (Figs.
20.2-1 to 20.2-3). It may be accompanied by terminal hair. Nevo-
cellular nevi are classified by size into three types. Small nevo-
cellular nevus is commonly called mole or lentigo and varies in
size from several millimeters to 1 cm in diameter. It is not pres-
ent at birth but first appears between the ages of 3 and 4 and
gradually increases in number and size to peak at puberty. After
puberty, the color often fades and the nevus is replaced by fat tis-
sue or fibrotic tissue. When the diameter exceeds 20 cm, the
nevus is called a giant congenital melanocytic nevus.
Pathogenesis
Clinical images are available in hardcopy only. Nevus cells are derived from neural crests and proliferate
abnormally, resulting in blackish-brown pigmented macules.
Melanocytes and Schwann cells are derived from neural crests;
however, nevus cells do not differentiate into either of these (Fig.
20.3).
Pathology
Nevocellular nevi are classified by location of proliferation
into junctional nevus, intradermal nevus and compound nevus
(Fig. 20.3).

Nevocellular nevus should be differentiated from freckles,
lentigines, non-melanocytic lesions such as seborrheic keratosis,
dermatofibroma, and most importantly early malignant
melanoma (Chapter 22). Any pigmented lesion in adults that is
growing or changing in any way should be examined carefully.
When pigmentation spreads beyond the nail in the nail plate
(Hutchinson’s sign), there is a high likelihood that a malignant
Clinical images are Clinical images are melanoma is involved. Dermoscopic findings are important for
20 available in
hardcopy only.
available in
hardcopy only. diagnosis.
Treatment
Even when the dermoscopic findings are benign, follow-up is
necessary. Surgical removal is the basic treatment for cases in the
palms and soles, which tend to have a high likelihood of malig-
nancy, and in cases with a relatively large congenital nevocellular
Clinical images are available in hardcopy only. nevus. Laser therapy may be conducted if there are cosmetic con-
cerns. Excision, ablation or skin grafting may be performed on a
giant congenital melanocytic nevus. When it is too large for
removal, long-term follow-up may be chosen to observe for any
signs of malignant melanoma.
Fig. 20.2-2 Nevocellular nevus.

Nevus / A. Melanocytic nevi 329
neural cleft cell

⋮differentiation
⋮

A B C
melanocyte nevus cell Schwann cell
pathological
distribution
of nevus
cells
A：junctional B：compound C：dermal
Fig. 20.3 Origin of nevus cells and histological classification of

nevocellular nevi.
Common types of nevocellular nevi
1. Junctional nevus
Nevus cells are localized in the dermo-epidermal junction.
Junctional nevus is a compound of nevus cells that function simi-
larly to melanocytes and resemble nevus cells morphologically. It
is formed by large cubical cells that are able to produce melanin
in great quantities.
2. Compound nevus
This is a combination of junctional nevus and intradermal
nevus. The nevi tend to be small and hyperpigmented.
3. Intradermal nevus Fig. 20.2-3 Nevocellular nevus.

20
Nevus cells are localized in relatively deep areas of the dermis
(Fig. 20.4). Melanin production is markedly low in cells of intra-
dermal nevus. The cells appear spindled, resembling Schwann
cells.
Specific types of nevocellular nevi
1. Giant congenital melanocytic nevus

Giant congenital melanocytic nevus is seen at birth, sometimes
accompanied by black bristles (giant hairy nevus). It may be larg-
er than 20 cm in diameter (Fig. 20.5). In several percent of cases,
malignant melanoma may develop, sometimes accompanied by
central nervous symptoms (neurocutaneous melatosis, described Fig. 20.4 Histopathology of nevocellular
later). Surgical treatment is difficult. nevus.
2. Divided nevus
Divided nevi distribute predominantly on the upper and lower
eyelids. With the eye closed, they appear to be a single lesion.
The color is blackish-brown. They are found at birth in most
Clinical images are available in hardcopy only. cases. When occurring in the penis, it is a pigmented lesion that
is separated by the coronal sulcus into the glans and the penis
(Fig. 20.6).
3. Melanonychia due to nevocellular nevus

Fig. 20.5 Giant congenital melanocytic nevus. Black lines appear on the nail plate because of the presence of
nevus cells in the nail bed (Fig. 20.7). Most cases are benign;
however, there is a possibility of malignant melanoma.
4. Sutton nevus
Clinical images are available in hardcopy only. It is nevus pigmentosus that is surrounded by leukodermas
(Chapter 16).
5. Spitz nevus
Synonyms: Juvenile melanoma, Spindle and epithelioid cell
Fig. 20.6 Divided nevus. nevus
Outline
● This specific subtype of nevocellular nevus frequently
occurs in young adults.
Clinical images are Clinical images are ● It appears suddenly on the face in most cases and
hardcopy only. hardcopy only. enlarges quickly to about 1 cm in diameter. The periph-
ery may become reddish.
● It may have clinically and histopathologically similar fea-
tures to malignant melanoma; nevertheless, Spitz nevus

is benign and may resolve spontaneously.
20 Fig. 20.7 Melanonychia due to nevocellular ● Differential diagnosis from malignant melanoma is
nevus. essential. Surgical removal is the first-line treatment.
Clinical features
A small, dome-shaped nodule, usually solitary and ranging in
color from light pink to reddish-brown or black and ranging in
size from several millimeters to 2 cm occurs, most commonly in
children but also in adult men and women. It suddenly appears,
Clinical images are available in hardcopy only. mainly on the face but also elsewhere, and enlarges to about 1 cm
in diameter (Fig. 20.8). Because it may be accompanied by dark
brown pigmentation, Spitz nevus is sometimes difficult to differ-
entiate from malignant melanoma. Spitz nevus is benign and
does not enlarge beyond a certain size, nor does infiltration
occur.
Pathology, Diagnosis
Fig. 20.8 Spitz nevus. Spitz nevus is a compound nevus containing various cells,
including spindle cells, epithelioid-like cells and multinuclear

cells. Dermal edema, telangiectasia, and inflammatory cell infil-
tration may occur. These findings resemble those of malignant
melanoma; differentiation between Spitz nevus and malignant
melanoma is often difficult. The basic structural pattern of nevo-
cellular nevi is preserved in Spitz nevus: the lack of cellular atyp-
ism in the cells is important in distinguishing Spitz nevus from
malignant melanoma. Homogenous nonstructural eosinophilic
substances called Kamino bodies are found in the nevus cell nest
in 60% of cases (Fig. 20.9). Dermoscopy shows sharply circum-
scribed pigmented lesions with a characteristic starburst pattern a b c d e f g h
at the periphery.
Treatment
Excision is conducted. Spitz nevus does not aggravate; howev-
er, careful differentiation from malignant melanoma is necessary.
6. Dysplastic nevus
Synonym: Clark nevus
Dysplastic nevus occurs around puberty. A slightly elevated,a b c d e f g h i

flat-topped patch or a pigmented nevus larger than 6 mm in Fig. 20.9 Histopathology of Spitz nevus.
diameter occurs. A light brown or black, sometimes light pink, a: Spitz nevus at low magnification. b: Spitz
nevus at high magnification. Kamino bodies
lesion with roughly margined pigmentation forms. Dysplastic (arrows) are stained by eosin.
nevus is basically a benign nevocellular nevus. When multiple
familial atypical nevi and malignant melanoma occur it is called
dysplastic nevus syndrome. Dysplastic nevus syndrome is auto-
somal dominantly inherited, and it frequently develops into
malignant melanoma. Most patients are Caucasians, and there are
few Asian cases. Histopathologically, many cases show com-
pound nevi. Atypism is not usually found in the cells. Dermo-
scopic differentiation from superficial spreading melanoma is
necessary.
20
7. Spotted grouped nevus
Small blackish-brown pigmented macules or nodules densely
aggregate in brown to light-brown patches. This nevocellular
nevus occurs frequently on the trunk and less frequently at other MEMO
Lentigo
sites. Most cases of the pigmentation that is com-
monly called lentigo are small nevocellular
nevus. Lentigo simplex, a dermatological
8. Balloon-cell nevus term, is a flat blackish-brown lesion of several
millimeters in diameter caused by localized
This nevus consists of balloon cells that contain clear, large proliferation of epidermal melanocytes in
cytoplasm. The cells are thought to be degenerated nevus cells. which the nevus cells do not increase in num-
ber over time. Lentigo simplex is not usually
Nevertheless, balloon-cell nevus cannot be distinguished clinical- present at birth, but it may appear around 3
ly from ordinary nevocellular nevus. years of age. It accompanies systemic dis-
eases (neurocutaneous syndrome) including
Peutz-Jeghers syndrome, Cronkhite-Canada
syndrome, and LEOPARD syndrome.
b. Dermal melanocytic nevus

Dermal melanocytes are produced in dermal melanocytic
Clinical images are available in hardcopy only. nevus, blue nevus, Mongolian spot and nevus of Ota. The distri-
bution of cells varies according to the disease. Distributions of
dermal melanocytes in blue nevus and other melanocytic nevi
such as nevus of Ota and Mongolian spot are compared in Fig.
20.12.
Fig. 20.10 Blue nevus.
1. Blue nevus
Outline
●A flat or slightly elevated blue nodule results from prolif-
eration of melanocytes in the dermis (dermal melanocytes).
● It appears between the time of birth and infancy in most
cases. The head, extremities and buttocks are most

commonly involved.
Clinical features
A firm, blue or blackish small nodule of 1 cm or less in diame-
ter appears. It may be flat or tumorous (Fig. 20.10). Blue nevus
tends to appear singly and to progress gradually. The head, face,
hands, legs, back and buttocks are most commonly affected.
Pathogenesis
Dermal melanocytes that have the ability to produce melanin
and originate from neural crests become tumorous, causing blue
nevus. The dermal melanocytes are filled with melanin granules
that appear blue to brown on the skin.
There is tumorous proliferation of dermal melanocytes (Fig.
20 Fig. 20.11 Histopathology of blue nevus.
20.11). In nevocellular blue nevus, the dermal Schwann-cell-like
cells lacking melanin production are seen. Blue nevus should be
blue nevus nevus of Ota acquired Mongolian spot

dermis epidermis
nevus of Ito dermal

melanocytosis
subcutaneous
tissue
Deep dermis to Superficial to Superficial Mid to deep

Dermal melanocytosis MEMO subcutaneous mid-epidermis dermis dermis
Dermal melanocytosis is the term used in tissue
Japan; dermal melanocytic nevus is the term
used internationally. Fig. 20.12 Classification of dermal melanocytic nevi by the dis-
tribution of melanocytes.
differentiated from malignant melanoma: blue nevus is character-

ized by its double-layered structure, and atypism and irregularity
of size are not seen in the cell nuclei.
The entire lesion is usually removed for cosmetic purposes.
Careful clinical follow-up is necessary, because blue nevus may Clinical images are available in
hardcopy only.
become malignant.
2. Nevus of Ota
Synonym: Nevus fuscocaeruleus ophthalmomaxillaris Ota
Outline
● Adolescent Asian women are most commonly affected. A
light blue macule appears unilaterally on the skin at the
first and second divisions of the trigeminal nerve.
Melanosis of bulbar conjunctiva occurs.
● This nevus is caused by proliferation of dermal
melanocytes.
● It is not malignant, nor does it heal spontaneously. Laser
therapy is effective.
hardcopy only.
Clinical features
A light blue nevus occurs unilaterally on the skin over the first
and second divisions of the trigeminal nerve (eyelids, zygomatic
region, lateral forehead, cheek). The nevus is light blue and punc-
tatedly dispersed with various other colors, including brown, red
and dark blue (Figs. 20.13-1 and 20.13-2). It may be bilateral in
some cases. Nevus of Ota with pigmentation in the sclera, iris
and fundus is called oculodermal melanosis and is found in about
half of cases. Pigmentation may also occur in the tympanic mem-
branes, nasal membranes, pharynx and palate. A nevus with the
same pigmentation as nevus of Ota but in the acrominon and del-
toid region is called nevus of Ito or nevus fuscocaeruleus 20
acromiodeltoideus Ito. It often causes great mental distress and
cosmetic concern.
Classification hardcopy only.
Nevus of Ota is classified into an early-onset type, in which
pigmentation is present at birth and the color darkens as the
patient grows, and a later-onset type, which occurs after puberty.
Both types occur most frequently in Asian women and tend not
to disappear spontaneously.
Pathology
Fig. 20.13-1 Nevus of Ota.
Melanocytes are dispersed in the dermis. Pigmentation is pres-
ent in the epidermal basal cell layer (Fig. 20.12).
Treatment
Laser therapy is extremely effective.
3. Acquired dermal melanocytosis

Acquired dermal melanocytosis used to be classified as a sub-
type of bilateral nevus of Ota; however, the two are now regard-
ed as distinct diseases. Multiple, punctate, grayish-brown
pigmentation of 1 mm to 3 mm in diameter occurs on both sides
of the forehead and zygomatic region. The bulbar conjunctiva
and palate are not involved (Fig. 20.14). Women between adoles-
Clinical images are available in hardcopy only. cence and middle age, particularly those of Japanese and Chinese
descent, are most commonly affected. Histologically, there are
dermal melanocytes in the upper dermal layer and pigmentation
in the epidermal basal cell layer.
4. Mongolian spot
Clinical features, Differentiation

Fig. 20.13-2 Nevus of Ota. Mongolian spot occurs in the lumbosacral regions and but-
tocks of newborns. Nearly 100% of Asians, 80% to 90% of
Africans (in whom the blue color tends to be invisible), and 1%
to 20% of Caucasians are affected. It remains until adulthood in
3% to 4% of all cases. The blue hue intensifies until the age of 2
years and then gradually fades, disappearing by age 10. The
Mongolian spot is differentiated from nevus of Ota by its lack of
brownish tone. Mongolian spot on sites other than the lum-
Clinical images are available in hardcopy only. bosacral regions and buttocks is called aberrant or ectopic Mon-
golian spot (Figs. 20.15-1 and 20.15-2), and the color tends not
to fade spontaneously.
Pathogenesis
Mongolian spot is dermal melanosis in which dermal
melanocytes from the embryonic period partially remain.
Fig. 20.14 Acquired dermal melanocytosis.
Treatment
20 Treatment is not necessary in most cases. Laser therapy may
be conducted on large spots or ectopic Mongolian spots by the
age of 2 or 3 years (Fig. 20.16).
Fig. 20.15-1 Aberrant or ectopic Mongolian

spot.
Nevus / B. Epithelial nevi 335

a b c d e a f b g c h d i e j f ak g bl h cm i dn j eo k fp l gq m hr
Fig. 20.15-2 Ectopic Mongolian spot.
a: Forehead. b: Back. c: Lumbar region.

a b c d e a f b g c h d ia e jb f kc g ld h me i nf j og k ph l qi m rj
Fig. 20.16 Laser treatment of aberrant Mongolian spot.
a: Mongolian spot on the shoulder and the right arm (pre-treatment). b: Mongolian spot after one session of alexandrite laser therapy.
c: This portion (arrows) has improved significantly by alexandrite laser application.
20
B. Epithelial nevi
1. Epidermal nevus
Clinical features
Rough-surfaced, yellow to dark-brown papules or nodules are
present at birth or in early childhood. They spread gradually,
aggregate and form plaques of various sizes (Fig. 20.17).
Although they may be localized, in most cases they are unilateral
and arranged systematically along the Blaschko lines (Fig. 1.2).
A generalized type spreads on the whole body.
Although epidermal nevus tends to be asymptomatic, it may be

accompanied by itching and eczematous changes. In inflammato-
ry linear verrucous epidermal nevus (ILVEN), multiple, intensely
itchy, light pink verrucous papules occur, most commonly on the
lower legs of girls. They coalesce, become lichenified and
arrange in linear pattern (Fig. 20.18).
Central nervous symptoms and skeletal abnormality are seen
in rare cases; this is called epidermal nevus syndrome.
Pathogenesis
Hyperplasia of epidermal keratinocytes results in localized or
systematized verrucous nevus that enlarges gradually and
becomes distinct.
Pathology
Papilloma-like proliferation occurs in the epidermis. Granular
degeneration also occurs in some cases. When ILVEN is accom-
panied by severer itching than usual, there is also inflammation,
thickening of the epidermis, and parakeratosis.
Treatment
Epidermal nevus can be left untreated, because changes and
tumor formation rarely occur. Surgical excision, cryotherapy or
laser therapy may be conducted for cosmetic improvement.
Fig. 20.17 Epidermal nevus.

2. Nevus sebaceus
Synonym: Organoid nevus
Outline
● It is caused by abnormal proliferation of various cells that
originate in the epidermis, dermal appendages and con-
nective tissue.
● It is present at birth. The scalp and face are most com-
20 monly affected. Nevus sebaceus on the scalp leads to
alopecia.
Clinical images are available in hardcopy only. ● Removal is preferable, because malignant tumor such as
basal cell carcinoma may develop.
Clinical features
Nevus sebaceus occurs most frequently on the head and face
(Fig. 20.20). The symptoms progress though three stages: first, at
birth white to yellowish alopecia-areata-like plaques are present;
second, with age the plaques elevate flatly, and gradually become
verrucous and brownish; third, at puberty the lesions of the sec-
ond stage worsen and additional epithelial tumors appear. Epithe-
Fig. 20.18 Inflammatory linear verrucous lial tumors such as dermal appendage tumors (e.g.,
epidermal nevus.
syringocystadenoma papilliferum, trichoblastoma, outer root
sheath tumor) and basal cell carcinomas may occur secondarily.
Nevus / B. Epithelial nevi 337
normal 1st stage (at birth) 2nd stage (infancy) 3rd stage (adolescence ∼ )
epithelial tumor
Fig. 20.19 Histopathology of nevus sebaceus classified into

three stages.
The pathological and clinical features of the sebaceous glands gradually
change with age.
Pathology
The histology differs for each of the three stages (Fig. 20.21).
In the first stage, premature pilosebaceous tissue proliferates. In Clinical images are available in hardcopy only.
the second stage, there is maturation of the tissue, papilloma-like
proliferation of the epidermis, ectopic proliferation of apocrine
glands, and abnormality of dermal connective tissue. In the third
stage, the histological changes of the second stage accelerate,
with additional epithelial tumorous proliferation (Fig. 20.19).
Fig. 20.20 Nevus sebaceous.
Treatment Nevus sebaceus and hair loss on the scalp.
Surgical excision is conducted when secondary tumor is sus-
pected or there are cosmetic concerns.
3. Accessory mamma
The primordia of the mammary glands, which exist along the
line of the embryonic mammary ridge, normally disappear except
for one pair in the chest. Accessory mamma is a condition in
which more than one pair of primordia remains, usually on or
around the axillary fossae. A brown patch or a palpable nodule of
1 cm to 2 cm in diameter appears on the axillary fossae or the 20
anterior margin in most cases, accompanied by terminal hair.
Swelling, pain and galactopoiesis may occur during pregnancy.
Breast cancer may occur in rare cases.
4. Nevus comedonicus
Dilated hair follicles with a black keratin plug aggregate or
form a cord-like pattern (Fig. 20.22). They often occur between
the time of birth and age 10. The face, neck, precordial region,
abdomen and scalp are frequently affected.
5. Hair follicle nevus

Fig. 20.21 Nevus sebaceous.
Dome-shaped or polyp-like papules or nodules of normal skin
color are present at birth. The face is most frequently affected.
Hair follicles in various stages of differentiation proliferate in all
dermal layers. The disorder may be accompanied by nevus

sebaceus.
6. Eccrine nevus
Congenital localized hamartoma occurs in the eccrine sweat
glands. A hyperhidrotic nodule and a plaque form. They occur
between birth and infancy, most frequently on the extremities.
When accompanied by angioma, it is called eccrine angiomatous
hamartoma.
Fig. 20.22 Nevus comedonicus.
7. Apocrine nevus
Congenital localized hamartoma occurs in the apocrine sweat
glands. The apocrine nevus is a papule or a small nodule, often
accompanied by nevus sebaceous, which occurs on the scalp or
axillary fossae.
C. Mesenchymal-cell nevi
1. Connective tissue nevus

Proliferation of dermal collagen fibers, elastic fibers or
Clinical images are available in mucopolysaccharides results in eruptions of normal skin color
hardcopy only. that are called connective tissue nevi (Fig. 20.23). They may
aggregate in patches.
2. Nevus lipomatosus cutaneous superficialis

Ectopic proliferation of fat cells in the dermis results in soft
yellow nodules of several centimeters in diameter.
20
Clinical images are available in 3. Nevus cartilagineus
hardcopy only.
Dome-shaped, cartilage-containing papules of normal skin
color appear. Nevus cartilagineus in the ear region, called acces-
sory ear, accompanies embryonic developmental failure of the
branchial arch.
Fig. 20.23 Connective tissue nevus.
4. Smooth muscle hamartoma

This is a hamartoma in the arrector pili (Fig. 20.24). The lum-
bar and sacral regions are most commonly involved. The onset in
hardcopy only.
most cases is within 6 months after birth. Slightly vaguely mar-
gined light brown patches appear. They may be hairy in some
cases.
Fig. 20.24 Smooth muscle hamartoma.
D. Other nevi accompanied by skin pigmentation
1. Nevus spilus
Synonym: Speckled and lentiginous nevus
Nevus spilus is a sharply margined brown macule that can be

of various sizes and shapes (Table 20.1). There is a congenital
type and a late-onset type whose onset is infancy or later. A late-
onset nevus spilus called Becker’s nevus occurs most commonly
on the chest and scapular region of adolescent boys (Section 2,
below). Melanocytic nevocellular nevus cells do not proliferate.
Enhanced localized melanin pigmentation in the epidermal basal
layer is the main finding. When multiple nevus spilus occurs in
infancy, there is the possibility of café-au-lait spots of neurofi-
bromatosis type 1 and McCune-Albright syndrome. Laser thera-
py and concealing cosmetics are useful.
2. Becker’s nevus Fig. 20.25 Becker’s nevus.
Synonym: Nevus spilus tardivus
This is histopathologically similar to nevus spilus. Irregularly

shaped, patchy, light brown pigmentation first appears. It coa-
lesces with newly produced macules at the periphery and
enlarges to a diameter of several centimeters to 20 cm (Fig.
20.25). Hypertrichosis is present in about half of all cases. Prolif-
eration of smooth muscle fibers is found in the dermis: Some Nevus spilus MEMO
The term is sometimes used to describe the
regard Becker’s nevus as a type of smooth muscle hamartoma. small, dark patches in the nevus as well as the
Q-switched laser therapy is more effective on Becker’s nevus nevus itself, but in the United States and
than on nevus spilus. Europe, those patches are called speckled and
lentiginous nevus. Nests of nevus cells are
observed in the dark small patches. Café-au- 20
3. Nevus depigmentosus lait spots produced in neurofibromatosis type
1 are individually indistinguishable from
Leukodermas of various sizes appear. They become more dis- nevus spilus. The name nevus spilus may be
diagnostically ambiguous.
tinct several months to 1 year after birth (Chapter 16).
Table 20.1 Comparison between congenital nevus spilus and nevus spilus tardivus.
Congenital nevus spilus Nevus spilus tardivus (Becker’s nevus)
Age of onset Present at birth Shortly before and after adolescence
Commonly affected sites Whole body Shoulders, lumbar area
Complications Neurofibromatosis in some cases None
Hypertrichosis No Yes, in some cases
Color tone Light brown to blackish-brown Darker than that of congenital nevus spilus
Size of eruption Various Usually large
Histopathological findings Elevated levels of melanin in basal Increased melanin in basal keratinocytes, possibly changes in the
keratinocytes epidermis and increased arrector pili muscle
4. Nevus anemicus
A sharply circumscribed white patch occurs, often on the
upper chest, when the skin is flushed by bathing or rubbing.
Known to be capillary dysfunction (catecholamine sensitivity), it
may accompany neurofibromatosis type 1 (NF1) or nodular scle-
Clinical images are available in hardcopy only. rosis.
Fig. 20.26 Nevus anemicus.
Neurocutaneous syndrome
1. Neurofibromatosis type 1 (NF1)

Synonym: Von Recklinghausen disease
Outline
● It is a neurocutaneous syndrome caused by proliferation
Clinical images are available in hardcopy only. of cells that originate from neural crests. Neurofibroma,
pigmentation and nervous tumor in multiple organs are
the main symptoms.
● It is autosomal dominantly inherited, characterized by
multiple pigmentation (café-au-lait spots) at birth and soft

tumors (neurofibromas) after infancy.
● Surgical removal and laser therapy are conducted.
Fig. 20.27-1 Café-au-lait spot caused by Clinical features

neurofibromatosis type 1 (NF1).
20 ① Café-au-lait spot
This is a flat, oval eruption of the color of coffee with cream or
darker brown. It varies in size and appears on the trunk and
extremities. A café-au-lait spot with a diameter of about 10 cm is
called a large Recklinghausen spot; one with a diameter of 1 cm
or less is called a small Recklinghausen spot. Individual erup-
tions cannot be distinguished from nevus spilus. A café-au-lait
spot on the axillary fossae, called axillary freckling, is thought to
be a specific symptom of NF1. The pigmentation of the spot is
solid (Figs. 20.27-1 and 20.27-2). Café-au-lait spots are present
in 70% of all newborns. After infancy, the number of spots does
not increase.
② Neurofibroma
A neurofibroma is a soft tumor of normal skin color or light
brownish-pink of various sizes (Figs. 20.28-1 and 20.28-2). It
may be produced on any site of skin. It may be elevated and
dome-shaped or papillary, or flat and palpable. Valvular or hanging
Neurocutaneous syndrome / 1. Neurofibromatosis type 1 (NF1) 341
neurofibroma is called diffuse plexiform neurofibroma or pachy-

dermatocele (Fig. 20.29). Neurofibroma first appears between
childhood and puberty, after which it gradually enlarges and
increases in number. It may increase rapidly during pregnancy
and after delivery.
Nodular plexiform neurofibroma, neurofibroma in the periph-
eral nerves, is a slightly palpable, spindle-shaped tumor that
appears on the skin over the subcutaneous nerves. It may appear
in a beaded linear pattern and be accompanied by tenderness or
radiating pain.
③ Other skin lesions caused by NF1
Nevus anemicus may occur in some cases with NF1. Small
yellow tumors may appear on the face and scalp of infants and
disappear spontaneously in several years (juvenile xanthoen-
dothelioma).
④ Other symptoms of NF1
Central nervous symptoms include neurofibroma in the brain
and spiral nerves, gliacytic tumor, meningioma, convulsive
seizure, and mental retardation or learning impairment. Bone
abnormality, including scoliosis, deformity or bone defect in the
thorax, occurs in about half of all cases. Ocular symptoms of NF1
Fig. 20.27-2 Café-au-lait spot caused by NF 1.
are irridic nodules, called Lisch nodules, and orbital neurofibro- Many small café-au-lait spots are present on the
ma in which ophthalmocele may occur. Congenital glaucoma and axilla.
retinal tumor may occur.
Classification
Neurofibromatosis (NF) is pathologically classified into 8
types: NF1 through NF8. NF1 is the most common and occurs in
1 in 3,000 births. It is autosomal dominantly inherited, and 60%
to 70% of NF1 cases are sporadic and caused by genetic muta-
tion. Occurrence of NF3 through NF8 is extremely rare. Clinical images are available in hardcopy only.
Pathogenesis
The gene involved in NF1 is on chromosome 17 (17q11.2). It
produces neurofibromin, a tumor suppressor. In NF1, gene muta- 20
tion in 17q11.2 is thought to increase proliferation of cells (the
penetration rate of NF1 is 100%).
Pathology
Neurofibroma is formed by Schwann cells and intraneural
fibroblasts, with thin undulating collagen fibers in the middle
(Fig. 20.30). Schwann cells test positive for S-100 protein anti- Clinical images are available in hardcopy only.
bodies.
Diagnosis
NF1 is easily diagnosed by café-au-lait spots and neurofibro-
ma. Although NF1 in childhood is difficult to diagnose because a
few café-au-lait spots are the only symptom, the likelihood of Fig. 20.28-1 Neurofibroma caused by NF 1.
NF1 is high when there are six or more café-au-lait spots (the 6-
spot criterion) or when there is a Recklinghausen patch on the
axillary fossae. The criteria for NF1 established by the National
Fig. 20.28-2 Neurofibromatosis type 1 (NF1).
Institutes of Health are shown in Table 20.2. Even areas that are
not sun-exposed may be involved in NF1, which distinguishes
the condition from freckles.
Treatment
Clinical images are available in hardcopy only. Symptomatic therapy is the main treatment. Café-au-lait spots
are treated by laser therapy and dermabrasion; nevertheless, they
tend to recur. Neurofibromas on highly visible areas such as the
face or extremities are surgically removed. When a diffuse plexi-
form neurofibroma is excised, there is a risk of massive
perioperative hemorrhage.
Prognosis
As NF1 is a progressive disease, numerous neurofibromas may
20 occur on the whole body after middle age. The prognosis tends to
be good. The central nervous lesion and neurofibroma may wors-
en and develop a malignant peripheral nerve sheath tumor in rare
cases.

hardcopy only. 2. Neurofibromatosis type 2 (NF2)
Clinical features
An elastic, firm, sharply margined subcutaneous neurilemmo-
ma is the main cutaneous symptom. The café-au-lait spots seen
with NF1 are not observed. Lesions in the central nervous sys-
a b c d e f g h tem,
i such
j as acoustic
k schwannoma
l m (vestibular
n o sheath
p tumor),
q arer
Fig. 20.29 Diffuse plexiform neurofibroma, the main symptoms of neurofibromatosis type 2 (NF2). Hearing
pachydermatocele. impairment and dizziness are present. Paralysis in the extremities
a: Affected breast. b: Side of the body. The lesion and reduced sensory perception are induced by enlargement of
has been partially removed by excision and
suturing. the tumor.
Neurocutaneous syndrome / 3. Tuberous sclerosis 343
NF2 is autosomal dominantly inherited. It occurs in 1 in
50,000 to 1 in 100,000 persons. About half of the cases are spo-
radic. The related gene on chromosome 22 (22q12) codes for a
protein called merlin (a moesin-ezrin-radxin-like protein), whose
structure is similar to that of cytoskeleton proteins. NF2 is caused
by mutation of this gene; however, the mechanism is unknown.
Pathology
Verocay bodies, which are characteristic to neurilemmoma, are
found in NF2. Neurofibromas, which develop in NF1, are not
found in NF2.
Total resection of the neurotumor is the basic treatment.
Removal may impair hearing. Because tumors enlarge unexpect-
edly, it is difficult to determine the policy of treatment consider-
ing the prognosis for cases with NF2. NF2 has a worse prognosis
than NF1.
3. Tuberous sclerosis
Synonym: Bourneville-Pringle’s phacomatosis
Outline Fig. 20.30 Histopathology of neurofibroma.

● The main symptoms are multiple facial angiofibroma, Table 20.2 Diagnostic criteria of neurofibro-
intelligence impairment and convulsive seizure. matosis type 1 and type 2 (NIH).
● It is autosomal dominantly inherited.
Neurofibromatosis-1 (NF1)
● It is characterized by white leaf-shaped macules in infan-
At least 2 of the following
cy and multiple papules (angiofibroma) that occur around 1. Six or more café-au-lait spots of 5 mm or
the nose after early childhood. Shagreen patch and Koe- more in diameter (before adolescence)
nen’s tumor are also important findings. Six or more café-au-lait spots of 15 mm or
more in diameter (after adolescence)
2. Two or more neurofibroma, or at least 1
Clinical features neurofibroma in the peripheral nerves
① Facial angiofibroma 3. Pigmented macules in the axillary fossae or 20
the groin
Multiple firm papules of normal skin color or light pink and 2 4. Neurofibroma in the eye socket
mm to 10 mm in diameter appear symmetrically on the nasolabi- 5. Two or more Lisch nodules
al sulcus, cheeks, and the area around the nose (Fig. 20.31). The 6. Bone abnormality
7. Family history of NF1
papules occur in about 90% of cases with tuberous sclerosis; the
papules and their high specificity are useful for diagnosis of Neurofibromatosis-2 (NF2)
facial angioma. Facial angiofibromas do not appear until the ages At least 1 of the following
1. Tumors in the acoustic nerves on the both
of 3 to 4 in most cases, and they become more numerous with
sides observed by CT or MRI
age. As the patient grows, the eruptions coalesce to take on a 2. Family history of NF2 and the patient has a
tumorous or plaque-like appearance. Facial angiofibroma used to unilateral acoustic tumor, or at least 2 of the
be called adenoma sebaceum but now is called angiofibroma, following: neurofibroma, meningioma, glioma,
neurilemmoma, juvenile cataract
because the main pathological condition is degeneration of the
blood vessels and connective tissue.
② Shagreen patch
Shagreen patch is a special subtype of connective tissue nevus.
Shagreen refers to rough, untanned leather. Firm, flatly elevated
lesions of about 3 cm in diameter occur mainly on the lumbar
region and buttocks and coalesce in an arabesque pattern. They

often become marked after puberty. Shagreen patch is thought to
be a connective-tissue nevus of the sacral region.
③ White leaf-shaped macules
White leaf-shaped macules are oblong depigmentations caused
by reduced production of melanin, most frequently on the trunk
and lower legs. They are seen in about half of all cases with
tuberous sclerosis. The onset is usually infancy, and prompt
Clinical images are available in hardcopy only. discovery is important. However, they may occur in adults in rare
cases. Careful inspection is required for diagnosis. Wood’s lamp
is helpful for observation. The white leaf-shaped macules do not
become more numerous over time.
④ Koenen’s tumor
Angiofibroma appears on the edge or surface of the nail plate
(Fig. 20.32). Small spindle-shaped nodules with a diameter of 2
mm to 10 mm and a color range of light pink to brown appear.
The nodules are as firm as cartilage.
⑤ Central nervous symptoms
Convulsive seizure and intelligence impairment are the main
symptoms. Convulsive seizure occurs in about half of all patients
with tuberous sclerosis; it subsides within one year after birth.
Various symptoms including epilepsia nutans, Lennox-Gastaut
syndrome, and tonic-clonic epilepsy are present. Mental retarda-
tion may also occur.
⑥ Other symptoms of tuberous fibroma
Translucent tumor (astrocytic hamartoma) in the retina and
Clinical images are available in hardcopy only. lamellar leukoderma in the iris may occur. Honeycomb lung may
be caused in rare cases. Rhabdomyoma may occur in the heart as
a complication. Many cases are asymptomatic. Angiomyolipoma
and renal failure from hydronephrosis and renal cyst often occur.
Pathogenesis
The genes responsible for tuberous sclerosis are TSC1 (tuber-
ous sclerosis complex 1) on chromosome 9 (9q34) and TSC2 on
20 chromosome 16 (16p13.3). Both are thought to play a role in
Fig. 20.31 Tuberous sclerosis. tumor suppression. Although tuberous sclerosis is autosomal
Angiofibroma on the face. dominantly inherited, 60% to 70% of all cases are sporadic and
there are relatively few familial cases.
Laboratory findings
Nodule-like calcium deposition on the lateral ventricular walls
and basal nuclei and enlargement of the lateral ventricle are
found by head CT scan. A nodule-like tumor is observed by MRI
in the cerebral cortex. The pathology is that of an anastrocytic
hamartoma.
Diagnosis
Tuberous sclerosis is easily diagnosed by the cutaneous symp-
toms, which include multiple angiofibroma of the face. Calcium
Fig. 20.32 Koenen’s tumor. deposition and nodules observed by CT scan and MRI are diag-
nostic, as is ocular fundus tumor. Electroencephalogram and
Neurocutaneous syndrome / 4. Peutz-Jeghers syndrome 345
renal angiography are also helpful for diagnosis.
Dermabrasion, excision, cryotherapy and laser therapy are
conducted on the cutaneous lesions for cosmetic reasons, which
nevertheless tend to recur. Drug therapy is useful for convulsive
seizure. There is no treatment for the progressive mental retarda-
tion. The prognosis depends on the severity of cerebral tumorous
lesions and renal leisions.
4. Peutz-Jeghers syndrome
Outline
● Autosomal dominantly inherited, it is characterized by
pigmentation on the lips, oral mucosa and distal extremi-
ties, and gastrointestinal polyposis.
● Careful observation is required, because intussusception Clinical images are available in hardcopy only.
and cancer may develop as a result of gastrointestinal

polyps.
● Laser therapy, dermabrasion and polypectomy are con-
ducted.
Clinical features
① Skin pigmentation
Flat, asymptomatic, sharply margined, blackish-brown mac-
ules of 2 mm to 10 mm in diameter occur symmetrically on the
lips, oral mucosa, palms and soles (distal extremities in particu-
lar) (Fig. 20.33). The longitudinal axis of the macule runs paral-
lel to the dermatoglyphic lines. Pigmentation is darkest in the
crista cutis and lightest in the sulcus cutis. Pigmentation appears
between the time of birth and infancy, and tends to increase in
number and size with age; it fades in adulthood.
② Gastrointestinal polyposis
Gastrointestinal polyposis may occur in any part of the gas- 20
trointestinal tract, especially the jejunum. A single lesion or more
than ten may be produced. They tend to cause intussusception
leading to intense abdominal pain and melena. Most cases of gas-
trointestinal polyposis are histologically hamartoma; the tissue
structure of the lesion is normal and malignant transformation
rarely occurs (Table 20.3). Adenoma occurs in about 10% of
cases and may become cancerous.
Pathogenesis Fig. 20.33 Peutz-Jeghers syndrome.

Pigmentation occurred on the lips and hand.
Peutz-Jeghers syndrome is autosomal dominantly inherited;
however, about half of all cases occur sporadically. It is caused
by mutation in the LKB1 gene on chromosome 19 (19p13.3).
The LKB1 gene codes for a serine-threonine kinase whose activi-
ty is lost in many patients with Peutz-Jeghers syndrome. The
mechanism is unknown.
Table 20.3 Major cutaneous symptoms accompanying gastrointestinal polyposis.

Sites where polyps likely Canceration
Disease Inheritance pattern Cutaneous symptoms
form of polyp?
Peutz-Jeghers Autosomal dominant Jejunum in many cases Sometimes Pigmented macules on the lips, oral
syndrome mucosa and palms
Cronkhite-Canada Not inherited Entire digestive tract No Alopecia, nail plate abnormality, pigmented
syndrome macules on the dorsum of hands
Gardner syndrome Autosomal dominant Large intestine in most cases Yes Neurofibromatosis, lipoma, dental dysplasia
Turcot syndrome Autosomal recessive Large intestine Sometimes Nervous system tumors
Pathology
Melanocytes and melanin pigment increase in the epidermal
basal layer. There is hyperpigmentation in the crista profunda
intermedia, which is the thick portion of the epidermis. The cuta-
Clinical images are available in hardcopy only. neous lesions do not show malignancy.
As with Peutz-Jeghers syndrome, Cronkhite-Canada syndrome
is characterized by gastrointestinal polyposis and pigmentation
Fig. 20.34 Incontinentia pigmenti. (especially on the dorsal hands). However, the onset of
Cronkhite-Canada syndrome is at middle age or later and the
condition is not inherited. Alopecia and abnormality of nail plate
also occur in Cronkhite-Canada syndrome.
Alexandrite laser therapy and dermabrasion are effective in
reducing pigmentation when there are cosmetic concerns. Endo-
scopic or surgical excision is conducted on gastrointestinal
polyps.
5. Incontinentia pigmenti (Fig. 20.34)

Synonym: Bloch-Sulzberger syndrome
20
Outline
● Characteristic pigmentation occurs on the skin. The
symptoms are clinically classified into 4 stages.
● Blistering and erythema occur at birth. The disease
Clinical images are available in hardcopy only. course begins with papules that progress to pigmentation
and disappear.
● It is X-chromosome dominantly inherited; female patients
greatly outnumber male patients.

● The prognosis is good. Ocular symptoms and deformity
are treated.
Clinical features
Incontinentia pigmenti is classified by the clinical features.
① Cutaneous symptoms
Fig. 20.35-1 Incontinentia pigmenti at the Inflammatory stage: Vesicles accompanied by erythema appear,
inflammatory stage. most commonly on the trunk (Figs. 21.35-1 and 21.35-2). The
Neurocutaneous syndrome / 5. Incontinentia pigmenti 347
onset is within a week after birth. They become pustules or ero-

sion, persisting for several weeks to several months before heal-
ing gradually. Eruptions resembling alopecia plaques may occur
on the scalp.
Verrucous and lichenoid stage: After the blisters subside (6 to
12 weeks after birth), multiple hyperkeratotic verrucous papules
occur, mainly on the distal extremities. Most cases resolve in sev-
eral months, but some persist until adulthood (Fig. 20.36).
Pigmented stage: Grayish-brown or purplish-brown pigmenta- Clinical images are available in hardcopy only.
tion becomes distinct around 6 months after birth at sites where
eruptions were. The pigmentation often appears in linear, droplet-
like, marbled and reticular patterns (Fig. 20.37).
Regression stage: Pigmentation begins to disappear at age 4 or
5. It disappears completely at puberty in most cases.
② Symptoms of incontinentia pigmenti in sites other than skin
Ocular symptoms: Ocular symptoms develop in about one third
of incontinentia pigmenti cases. Strabismus is the most common
such symptom, followed in frequency by cataract, glioma and
microphthalmos. There are findings similar to those of retinopa-
thy of prematurity.
Central symptoms: Epilepsy and intelligence impairment may
be caused in rare cases. Abnormality may occur in teeth (e.g.,
deficiency, developmental retardation, odontoparallaxis) and Clinical images are available in hardcopy only.
bones (e.g., dwarfism, hyperdactylia).
Incontinentia pigmenti is caused by mutation in NEMO (NF-
k B essential modulator), which is mapped on Xq28. It is an X-
linked dominant trait that is usually lethal in males; most male
fetuses with the genetic abnormality are not carried to term,
which is why more than 95% of all patients are females. More
than 700 cases have been reported. About half of all cases occur
sporadically.
Pathology, Laboratory findings 20

There is eosinophilic infiltration in the intraepidermal blisters
of the first stage (Fig. 20.31). Eosinophil levels in the peripheral
blood are elevated in 30% of cases. Verrucous papules of the sec-
ond stage are structurally similar to epidermal nevus.
Melanophages are observed in large numbers in the upper dermal Fig. 20.35-2 Incontinentia pigmenti at the
layer of pigmentation at the third stage. In the fourth stage, inflammatory stage.
bottom: Eosinophilic infiltration in the epidermis
melanophages in the upper layer decrease. is characteristically seen.

It is easy to diagnose incontinentia pigmenti by the characteris-
tic clinical features. The condition is sometimes misdiagnosed as
epidermolysis bullosa because of blistering at birth; however,
incontinentia pigmenti can be distinguished by its eosinophilic
infiltration. Ocular examination is essential, because blindness
and amblyopia may occur.

a b c d e f ag bh ci dj a ek b f l c gm d h n e io f jp g kq h lr i
Fig. 20.36 Incontinentia pigmenti at the verrucous and lichenoid stage.
a: Eruptions on the scalp. Alopecia also occurred. b: Reticular pigmentation. c: Verrucous eruptions accompanied by severe hyperk-
eratosis, which resembles epidermal nevus.

20
Fig. 20.37 Incontinentia pigmenti at the pigmented stage.
Pigmentation appears in various degrees.
Complications associated with incontinentia pigmenti and
deformities should be promptly treated. As the skin lesion heals
spontaneously in many cases, symptomatic therapy may be per-
formed if necessary. The prognosis is good. About half of all
male fetuses whose mothers have incontinentia pigmenti do not
survive to term. Half of all girls whose mothers have incontinen-
tia pigmenti also have the disease.
Neurocutaneous syndrome / 6. Sturge-Weber syndrome 349
6. Sturge-Weber syndrome
Outline
● Hemifacial hemangioma simplex, choroidal hemangioma
and hemangioma of the leptomeninx are the main symp-
toms.
● The disease is nonhereditary.
● The distribution of facial hemangioma is unilateral on the Clinical images are available in hardcopy only.
area over the first division of the trigeminal nerve.
● Glaucoma is caused by hemangioma, leading to buph-
thalmia.
● Laser therapy, resection of the brain and ocular
treatments are conducted.
Clinical features
Sturge-Weber syndrome is characterized by hemifacial heman-
gioma simplex, choroidal hemangioma, and hemangioma of the Fig. 20.38 Sturge-Weber syndrome.
leptomeninx; however, most cases are incomplete, with only
hemifacial hemangioma simplex and hemangioma of the lep-
tomeninx.
Cutaneous symptoms: Unilateral, or bilateral in rare cases, flat
hemangioma simplex is present at birth on the skin over the first
or second division of the trigeminal nerve of the face (Fig.
20.38).
Central nervous symptoms: Hemangioma of the leptomeninx
occurs on the side with semi-facial angioma, especially on the
occipital lobe. Contralateral hemiplegia may occur in some cases.
Convulsive seizure appears in infancy in about 80% of cases.
Atrophy and calcinosis of the cerebral hemisphere and intelli-
gence impairment may also occur.
Ocular symptoms: Choroidal angioma may occur on the side
with semi-facial angioma, leading to abnormal formation of the
anterior chamber of eyes. High fluid pressure is present in the
eyes (glaucoma) in early childhood as a result. The cornea is 20
hyperextended by increased fluid pressure of the eyes, and the
corneal diameter enlarges accordingly, a condition called buph-
thalmia. The result is blindness in most cases.
Pathogenesis
Abnormal development of blood vessels caused by embryonic
impairment of the sympathetic nerve is thought to cause Sturge-
Weber syndrome; however, the details are unknown. It is con-
genital; nevertheless, it is known to be nonhereditary in general.
It occurs in about 1 in 100,000 people.
Laboratory findings
The double-contoured calcification observed along the cere-
bral convolution by skull X-ray is called tramline calcification.
Head CT scan and MRI are able to find angioma before calcifica-
tion occurs; this is useful for early diagnosis.
Treatment
Laser therapy is performed on facial hemangioma. When drug
therapy is ineffective on convulsive seizure, resection of the brain
hemangioma is conducted. For ocular symptoms, early diagnosis
and adjustment of ocular pressure are important.
7. Klippel-Trenaunay-Weber syndrome
Synonyms: Klippel-Trenaunay syndrome, Klippel-Weber
syndrome
Outline
Clinical images are available in hardcopy only. ● Hemangioma simplex in the extremities and enlargement
and extension of the affected limb are observed.
● Spinal curvature is caused by the different length of the
extremities, and there is the risk of ulceration and heart

failure caused by arteriovenous fistula.
● Symptomatic therapy is the main treatment.

The cause of Klippel-Trenaunay-Weber syndrome is
unknown; however, there is fragility of mesodermal tissue in the
vascular walls. Cutaneous hemangioma simplex is present at
birth in many cases. Usually one arm or leg, but sometimes both
arms or legs, is involved. It may spread beyond the extremities
Fig. 20.39 Klippel-Trenaunay-Weber syn- (Fig. 20.39). Lymphangioma, congenital venectasia, angioker-
drome.
The right arm, which is affected by hemangioma, atoma and congenital arteriovenous fistula may also occur and
is longer than the left arm. become distinct with age. These vascular lesions may cause
edema, ulceration and varix secondarily. Klippel-Trenaunay-
Weber syndrome is also characterized by enlargement and over-
growth of the bone and soft tissue: The extremities may become
different in length and the difference becomes more distinct with
age. The bone abnormality usually occurs in the leg on the same
side of the body as the skin lesion, or rarely, on the opposing
20 side. The different length of the legs results in claudication and
compensatory scoliosis. Angioma in internal organs, syn-
dactylism or other dysplasia of fingers and toes, and heart failure
(if the arteriovenous fistula is severe) may occur. Abnormality of
coagulation may be caused in vascular channels. Severe clotting
abnormality called Kasabach-Merritt syndrome may occur in
some cases.
Klippel-Trenaunay-Weber syndrome is easily diagnosed by
the characteristic clinical features. Diagnosis can be confirmed
by bone radiography and systemic CT scan. Arteriovenous fistula
is examined by thermography, blood gas analysis and angiogra-
phy. Symptomatic therapy is the main treatment. Laser therapy is
conducted when the hemangioma simplex raises cosmetic con-
cerns. Ligation or excision is performed on arteriovenous fistu-
lae, because they may cause heart failure. For prevention of
Neurocutaneous syndrome / 9. LEOPARD syndrome 351
arthropathy and curvature caused by the different length of the

extremities, orthopedic shoes and osteotomy are helpful.
8. Neurocutaneous melanosis Clinical images are available in hardcopy only.
Synonym: Mélanoses neurocutanées
Clinical features a b c d e f g h
Neurocutaneous melanosis is nonfamilial and occurs in both
men and women. Large congenital melanocytic nevus, in most
cases a giant hairy pigmented nevus, is present on nearly half the
trunk (Figs. 20.40-1 and 20.40-2) or multiple congenital small
melanocytic nevi disperse over the whole body. These nevi can
be a serious burden cosmetically. Clinical images are available in hardcopy only.
Cerebral nervous symptoms such as increased intracranial
pressure and secondary hydrocephalia occur. These are accompa-
nied by headache, vomiting, epileptic seizure and intelligence
impairment. Malignant melanoma often develops on the site of
the body with giant hairy nevus and leptomeninx. a b c d e f g h i
Pathogenesis
Neurocutaneous melanosis is caused by proliferation of
melanoblasts that originate from neural crests in the skin and cen-
tral nervous system (e.g., leptomeninx). Congenital, extensive or
disseminated melanocytic nevi occur. In the brain, perivascular
proliferation of melanocytes impairs reabsorption of cere-
brospinal fluid, leading to hydrocephalia.
Diagnosis
Neurocutaneous melanosis is characterized by giant hairy pig-
mented nevus and multiple small melanocytic nevi. MRI head
scan, lumbar puncture and ventriculography are necessary for
diagnosis. Increased levels of proteins and reduced sugar levels
are often found in the cerebral fluid. Melanin-containing cells
may be detected. 20
a b c d e f g h i j
Treatment
Fig. 20.40-1 Neurocutaneous melanosis.
Giant pigmented nevus is removed as completely as possible. a: On the whole body. b: It is often accompanied
The sooner curettage is performed after birth, the better is the by nodules (arrows). c: The affected site (b) was
result cosmetically (Fig. 20.40-1). Symptomatic therapy such as removed.
shunting for hydrocephalia and anti-epilepsy drugs are useful for
central nervous symptoms. There is no effective treatment for
melanoma of the leptomeninges.
Origin of the term MEMO

9. LEOPARD syndrome LEOPARD syndrome
LEOPARD is an initialism for the following
Synonym: Multiple lentigines syndrome systemic symptoms: L (multiple lentigines), E
(electrocardiographic conduction defects), O
The main symptoms are multiple lentigines, café-au-lait spots, (ocular hypertelorism), P (pulmonary steno-
sis), A (abnormalities of genitalia), R (retar-
systemic symptoms including abnormality in cardiac transmitter dation of growth), D (sensorineural deafness).
function (detected by electrocardiogram), ocular hypertelorism,
genital abnormality, stunted stature, hearing loss and mental

retardation. LEOPARD syndrome is caused by mutation in the
PTPN11 gene (protein-tyrosine phosphatase, nonreceptor type
11). It is thought to be autosomal dominantly inherited; neverthe-
less, many cases occur sporadically. Multiple lentigines are pres-
ent at birth and gradually increase in number until puberty. They
are comparatively small, 5 mm or less in diameter, and appear on
the whole body skin. The mucous membranes are not involved.
Various skin lesions, including nail malformation and skin hyper-
elasticity may occur. Among all lesions caused by LEOPARD
syndrome, heart lesions affect the prognosis most severely.
10. Basal cell nevus syndrome

Synonym: Nevoid basal cell carcinoma syndrome
Multiple basal cell nevi and small depression in the palms and
soles occur (Fig. 20.41), accompanied by multiple maxillary
Clinical images are available in hardcopy only. cysts, skeletal defects and central nervous symptoms (e.g., calci-
fication of the cerebral dura mater, hydrocephalia, mental retar-
dation). It is autosomal dominantly inherited. The causative gene
is PTCH on chromosome 9 (9q22.3). Small multiple brown nod-
ules of 1 mm to 2 mm in diameter are present on the whole body
Fig. 20.40-2 Neurocutaneous melanosis. until the age 10. The tissue of the nodules is the same as that of
basal cell carcinoma. Infiltrating lesions may form. When basal
cell carcinoma is seen in young patients, basal cell nevus syn-
drome is suspected.
11. Von Hippel-Lindau syndrome

Von Hippel-Lindau syndrome is autosomal dominantly inher-
ited, caused by a mutation in the VHL tumor-suppressor gene on
chromosome 3 (3q25). Angioma and café-au-lait spots may
appear in rare cases. Multiple tumors occur throughout the body,
20 such as renal cell carcinoma, angioblastoma in the central nerves,
retinal hemangioma, pancreatic tumor and pheochromocytoma.
12. Phakomatosis pigmentovascularis

This is a comorbid disease of cutaneous hemangioma simplex
and nevus pigmentosus. It affects the eyes, skin and central nerv-
ous system (Fig. 20.42). Phacomatosis pigmentovascularis,
which is known to be nonhereditary, is classified into four types:
port-wine stain and linear epidermal nevus (type 1), port-wine
stain and dermal melanocytosis (type 2), port-wine stain and
nevus spilus (type 3), and port-wine stain, dermal melanocytosis,
and nevus spilus (type 4). Type 2 phacomatosis pigmentovascu-
a b c d e f g h i j k p q
laris accounts for 80%l of allmcases. nAlthough
o
phacomatosis pig-r
Fig. 20.41 Nevoid basal cell carcinoma syn- mentovascularis causes only cutaneous lesions, it is classified as
drome.
a: Small concavities (pitting) in the palm. b: Mul- a neurocutaneous syndrome because it is accompanied by Sturge-
tiple basal cell nevi on the eyelid. Weber syndrome and Klippel-Trenaunay-Weber syndrome in
Neurocutaneous syndrome / 16. Dyskeratosis congenita 353
about 20% of cases. Laser therapy and concealing cosmetics are

useful.
13. Osler’s disease

Synonyms: Hereditary hemorrhagic telangiectasia, Osler-
Rendu-Weber disease
Absence of elastic fibers and smooth muscles leads to telang-
iectasia in the arteriovenous anastomotic region. Osler’s disease
is autosomal dominantly inherited. Multiple papules appear on
the chest, tongue, lips and palms after puberty. The papules are
red at the center and are accompanied by peripheral papillary
telangiectasia (Figs. 20.43-1, 20.43-2 and 20.44). Mucosal bleed-
ing, especially recurrent epistaxis, first occurs at the onset; it has
diagnostic value. Broken pulmonary arteriovenous fistula may
result in hemoptysis, hematothorax, gastrointestinal hemorrhage
Fig. 20.42 Phacomatosis pigmentovascu-
and hepatic cirrhosis. laris.
14. Blue rubber bleb nevus syndrome

Multiple, elastic, rubber-ball-like blue cavernous angiomas
occur in the skin and gastrointestinal tract. It is a rare autosomal
dominantly inherited disease that occurs between birth and infan-
cy, and the appearance does not change over the course of the
patient’s life. The angiomas vary in diameter from 2 mm to 10
cm, or sometimes larger. Gastrointestinal angioma spreads to the
oral cavity, tongue and colon, leading to iron-deficiency anemia
and intussusception from bleeding. Angiomas may be produced
in the liver, brain, lungs, spleen, gallbladder, skeletal muscles or
kidneys.
15. Maffucci syndrome

Congenital abnormality of mesoblasts causes angioma in the 20
skin and internal organs, and ossification in the epiphyseal carti-
lage. Angioma is cavernous in many cases. It may be accompa-
nied by hemangioma simplex and lymphangioma. Condroma and
imperfect osteogenesis lead to bone deformity and fracture from
impaired ossification of the epiphyseal cartilage.
16. Dyskeratosis congenita Fig. 20.43-1 Osler’s disease.
Synonym: Zinsser-Cole-Engman syndrome
The onset of dyskeratosis congenita is between early child-

hood and puberty. More men are affected than women. The main
symptoms are cutaneous reticulated pigmentation, atrophy and
thinning of the nail plate, and oral leucoplakia. The onset is in
late childhood. Deformity of the nail plate occurs first, followed
by reticular pigmentation on the neck region spreading to the
trunk and extremities. Leukoderma keratosis-like change appears

most frequently on the tongue, buccal mucous membranes and
genitalia, and it tends to become malignant. It is accompanied by
progressive aplastic anemia, splenomegaly and esophageal block-
age. The main treatments are excision for leukoplakia and symp-
Clinical images are available in hardcopy only. tomatic therapy for anemia.
17. Epidermal nevus syndrome

Epidermal nevus syndrome is unilateral epidermal nevus
accompanied by central nervous abnormalities such as mental
Fig. 20.43-2 Osler’s disease. deficiency and epilepsy, nystagmus and strabismus, bone defor-
mity and angioma. Malignant tumor may occur as a complica-
tion.
18. Cutis marmorata telangiectasia congenita

Livedo reticularis appears at the time of birth or shortly there-
after. Telangiectasia usually accompanies it. Deformity occurs in
the central nerves, heart, blood vessels, muscles, skeleton and
eyes in nearly half of cases. Reticularis disappears with age, and
most cases resolve within 2 years after birth. There is no differ-
ence in occurrence between sexes and races. Although it usually
occurs sporadically, there are rare familial cases.
Fig. 20.44 Histopathology of Osler’s disease.
20
Chapter
21 Benign Skin Tumors
Examination of a skin tumor is for determination not only of malignancy or benignancy but also of the skin com-
ponent from which the tumor derives. A tumor may originate from epidermal keratinocytes, from cells of
appendages such as those in sweat glands, or from neural crest cells or mesenchymal cells including dermal
fibroblasts. The epidemiology, pathology and course of tumors vary depending on the origin of the cells. This
chapter classifies benign skin tumors into the subtypes below.
A: Epidermal tumor B: Follicular tumor C: Sebaceous tumor D: Sweat gland tumor E: Cyst
F: Neural tumor G: Hemangiomas/vascular malformations H: Fibrous tumor I: Histiocytic tumor
J: Adipocellular tumor K: Myogenic tumor L: Osteogenic tumor M: Hematopoietic tumor
A. Epidermal tumors
Epithelial tumors originate mainly from epidermal keratinocytes.
1. Seborrheic keratosis (SK)

Synonyms: Senile warts, Senile verruca
Outline
●A benign verrucous tumor occurs, most frequently on the
face, head or trunk of men and women middle aged and
older. It derives from keratinocytes in the epidermis or
infundibular hair follicle.
● Elevated, sharply demarcated, grayish-brown to black-
ish-brown nodules of 1 cm to 2 cm in diameter occur.

● Cryotherapy, laser therapy and excision are the main
treatments.
● When multiple, itchy, SK rapidly occurs on the whole
body within 6 months after the onset of SK, it is called

Leser-Trélat syndrome. It may be accompanied by inter-
nal malignancy. 21
Clinical features
Seborrheic keratosis (SK) appears in people in their 20s and is
seen in nearly everyone in their 80s or older. Flat-topped papules Clinical images are available in hardcopy only.
of 1 cm to 2 cm in diameter, varying in color from brown to
blackish brown occur on the face, head and trunk (Figs. 21.1-1
and 21.1-2). The palms and soles are unaffected. The surface of
the papules is keratotic and often papillary or granular, resem-
bling clay adhered to the skin. Itching and pain are not usually
present. As the synonym “senile warts” suggests, SK occurs as a
skin aging change. Senile freckles often elevate to form SK.
Fig. 21.1-1 Seborrheic keratosis (SK).
Pathology Multiple, flatly elevated, brown or blackish-
brown keratotic papules of 1 cm to 2 cm in diam-
There is upward intraepidermal proliferation of basal cells and eter on the back of an elderly man.
355
356 21 Benign Skin Tumors
suprabasal cells (exophytic lesion). The ratio of proliferative cells

to normal cells varies. Dysplasia is not present, but melanin pig-
mentation occurs in each proliferative cell to a varying degree
(Fig. 21.2). Pseudohorn cyst formation presents as milia-like cyst
by dermoscopy.
The disease should be differentiated from actinic keratosis,
Bowen’s disease (papular type), basal cell carcinoma, squamous
cell carcinoma, keratoacanthoma, follicular tumor, syringoma,
flat warts, verruca vulgaris and lentigo simplex.
Treatment
Treatment is not necessary except when there are cosmetic
concerns or suspected malignancy. The lesions do not disappear
Clinical images are available in hardcopy only. spontaneously but increase in number with age. If necessary,
cryotherapy, laser therapy or surgical removal is conducted.
2. Clear cell acanthoma

Clear cell acanthoma is usually a solitary, elastic, firm, dome-
Fig. 21.1-2 Seborrheic keratosis (SK). shaped or flatly elevated small tumor whose diameter is up to 2
The skin lesion resembles clay adhered to the cm. It may be pedunculated, fungiform or papillomatous. The
skin. The surface of the lesion is keratotic and surface is smooth, granular or velvety. The color is usually rose
papillary.
pink, but it may be brown to blackish brown in some cases. The
pathogenesis is unknown. There is a question of whether clear
cell acanthoma is a genuine tumorous lesion or a reactive lesion
that accompanies inflammation. Histologically, epidermal cells
containing clear cytoplasm (clear cells) proliferate.
3. Warty dyskeratoma
In warty dyskeratoma there are verrucous or flatly elevated
tumors of 1 cm to 2 cm in diameter that tend to keratinize at the
center. The condition is largely asymptomatic, although tender-
ness and pain are present in some cases. Basaloid cells proliferate
21 pathologically toward the dermis directly above which cleavage
appears. Warty dyskeratoma clinically resembles Darier’s disease
but is a different disease.
Leser-Trélat sign MEMO

Fig. 21.2 Histopathology of seborrheic ker- Sudden development of numerous seborrheic keratosis lesions, usually,
atosis (SK). with pruritus, is called Leser-Trélat sign. This sign implies the presence
The epidermis proliferates and elevates above the of internal malignancy. Therefore, systemic investigation must be
normal skin surface. Pseudohorn cysts form made for such malignancies when dermatologists see this phenomenon.
(arrows).
A. Epidermal tumors 357
4. Porokeratosis
Outline
● Scattered, round, brown keratotic lesions with elevated Clinical images are available in hardcopy only.
rims occur on the extremities, trunk and face.
● The disorder is asymptomatic. There is transformation to
squamous cell carcinoma in rare cases.

● Characteristic pathological features called cornoid lamel- a b c d e f g h
la are observed.
● Excision and cryotherapy are the main treatments.
Clinical features
An elevated keratotic eruption, round or oval in shape, occurs Clinical images are available in hardcopy only.
on the extensor surfaces of extremities and on the trunk and face
(Fig. 21.3). Atrophy occurs at the center of the lesion, which
becomes slightly concave. Porokeratosis begins as a blackish-
brown papule, gradually enlarging centrifugally. It is asympto-
g
matic, it progresses slowly, and it does not subside. It maya b c d e f h i
aggravate and progress to Bowen’s disease or squamous cell car-
cinoma. Despite the disease name, the eruptions are not associat-
ed with the sweat pores. Porokeratosis is divided by morphology
into the six subtypes below. Pathologically, the most frequently
seen type is disseminated superficial porokeratosis, which occurs Clinical images are available in hardcopy only.
on sun-exposed areas of the body.
Porokeratosis of Mibelli: This is the classic porokeratosis, in
which small multiple eruptions up to 2 cm in diameter occur
symmetrically on the extremities and face. a b c d e f g h i j
Linear porokeratosis: The onset is between birth and early
infancy. The eruptions are arranged in band-like or linear pattern.
Localized porokeratosis: A large, solitary, localized eruption
occurs.
Disseminated superficial porokeratosis: Multiple, disseminat-
ed, small eruptions coalesce.
Disseminated superficial actinic porokeratosis: Multiple erup-
tions occur on sun-exposed areas of the body, particularly the
extensor surfaces of extremities in adults. 21
Porokeratosis palmaris et plantaris disseminata: a Small b kera-c d e f g h i j k
totic papules occur multiply on the palms and soles.
Pathogenesis
Porokeratosis is induced by epidermal clones that cause local-
ized dyskeratosis. It may be triggered by sunlight, external injury
or aging. Some cases are autosomal dominant.
Fig. 21.3 Porokeratosis.
Pathology a, b: Porokeratosis of Mibelli. The eruption is
Acanthosis and hyperkeratosis are found at the periphery of keratotic, with an elevated rim and a diameter of
porokeratosis. The rim of the lesion is elevated, and there is about 2 cm. c: Disseminated superficial actinic
porokeratosis. d, e: Disseminated superficial
cornoid lamella, a column of incompletely keratinized cells that porokeratosis. The eruptions are 5 mm in diame-
stain more brightly than the peripheral horny cell layer. Under- ter and slightly elevated at the edge.
neath the cornoid lamella, the granular cell layer is absent (Fig.
21.4). Thinning of the epidermis accompanied by parakeratosis is

lesion normal area
present in the concave center of the lesion.
Treatment
Excision, electrical coagulation, cryotherapy, dermabrasion,
and administration of retinoids are the main treatments. Poroker-
atosis is chronic and intractable.
Fig. 21.4 Histopathology of porokeratosis.

The cornoid lamella (arrow) around the lesions
can be observed by the naked eye as an elevated
rim of the skin lesion.
B. Follicular tumors
1. Trichofolliculoma
Small, smooth-surfaced, dome-shaped tumors or papules
5 mm to 10 mm in diameter occur, most commonly in the nasal
region and its peripheries (Fig. 21.5). Trichofolliculoma is char-
acterized by small keratotic cavities with several immature woolly
Clinical images are available in hardcopy only. hairs at the center. The pathogenesis is unknown. Trichofolliculo-
ma is considered a benign tumor in which the entire follicle –
including the inner root sheath, outer root sheath, and dermal hair
papilla – differentiates.
2. Trichoadenoma
A firm, solitary, elastic nodule 1.5 cm or less in diameter
Fig. 21.5 Trichofolliculoma.
There is a small keratotic concavity at the center appears, most frequently on the face. It is thought to be a tumor
of the lesion. Many fragile young hairs are pres- whose morphological differentiation falls between that of tri-
ent. chofolliculoma and that of trichoepithelioma. The border
21 between the normal dermis and trichoadenoma is clear. There are
Hyperplasia, Adenoma, MEMO multiple keratin-containing cyst(s) and solid masses of cells in
Epithelioma the dermis.
Benign tumors in skin appendages are classi-
fied by the degree of cellular differentiation.
In order of least abnormal (most differentiat- 3. Solitary trichoepithelioma
ed) to most abnormal (least differentiated),
they are hyperplasia, adenoma and epithe- This is a benign tumor derived from hair germs that differenti-
lioma. When the degree of cellular differenti-
ation is lower than that of epithelioma, the ate into various hair components, such as hair follicles, outer root
tumor becomes a blastoma or malignant sheaths, and hairs. Small, firm but elastic tumors of 2 mm to 5
tumor. A tumor that has components of all mm in diameter and normal skin color occur around the nose,
three germ layers (ectoderm, mesoblast,
endoblast) is called a teratoma. The diagnos- eyebrows, upper lip, and chin. It is nonhereditary. Solitary tri-
tic name epithelioma may also be used for choepithelioma histopathologically consists of a small keratin-
malignant tumors such as basal cell epithe- containing cyst(s) and basaloid cells, and there is proliferation of
liomas, which are synonymous with basal cell
carcinomas.
dermal stroma. It may be difficult to distinguish from basal cell
carcinoma; however, in most cases of solitary trichoepithelioma,
B. Follicular tumors 359
there are well-differentiated keratinous cysts and formation,

although incomplete, of hair follicles. Foreign body granuloma
and calcium deposition may be present.
4. Trichoepithelioma papulosum multiplex

Multiple, dome-shaped, firm papules of several millimeters to
1 cm in diameter and normal skin color occur symmetrically on Clinical images are available in hardcopy only.
the midline facial region, scalp, nuchal and neck region, and
trunk (Fig. 21.6). The onset is puberty, and the lesions gradually
increase in number. Women are slightly more likely to be affect-
ed than men. It is autosomal dominant and may be familial. In
recent years, abnormality in the cylindromatosis (CYLD1) gene
has been identified as the cause.
Pathology
Trichoepithelioma papulosum multiplex is a tumor mass con-
sisting of basaloid cells that resemble basal cell carcinoma cells.
Fig. 21.6 Trichoepithelioma papulosum mul-
A keratinous cyst forms in the tumor. tiplex.
Multiple, dome-shaped, firm, normal skin color
Differential diagnosis papules of 5 mm in diameter occur on the face.
The papules produced on the midline facial region are similar
to facial angiofibroma seen in tuberous disease (Chapter 20). In
tuberous sclerosis, other symptoms such as leukoderma and sha-
green patch are present.
Treatment
As malignant transformation is not present in trichoepithe-
lioma papulosum multiplex, treatment and follow-up are unnec-
essary, except when there are cosmetic concerns. Clinical images are available in hardcopy only.
5. Desmoplastic trichoepithelioma
Circular nodules or plaques of several millimeters to 1 cm in
diameter and normal skin color or light yellow occur, most fre- 21
quently on the cheeks, forehead and nasal region of relatively
young adult women. The lesions are characterized by elevated
edges and concave centers (Fig. 21.7). Miliary, papular lesions Fig. 21.7 Desmoplastic trichoepithelioma.
may occur at the periphery of the lesion. Histopathologically, The skin lesion is 5 mm in diameter, with an ele-
vated-rim and small surrounding circular nod-
cordlike proliferation of basaloid tumor cells, multiple keratinous ules.
cysts and hyalinized collagen fibrils are present. Differentiation
from basal cell carcinoma may be difficult.
6. Trichoblastoma
A dome-shaped nodule occurs, most frequently on the face or
scalp. It consists of fibrous interstitium and tumor cells that
resemble follicular germinative cells. It may arise on sebaceous
nevi. Differentiation from basal cell carcinoma may be difficult.
7. Pilomatricoma
Synonyms: Calcifying epithelioma, Pilomatrixoma
Clinical images are available in hardcopy only. Clinical features

A firm, intradermal or subcutaneous tumor 3 cm to 4 cm in
diameter occurs on the face, neck or upper arms of infants, usual-
ly solitarily. The tumor surface is rough and the color is of nor-
mal skin or translucent bluish white. It is the firmness of bone
Fig. 21.8 Calcifying epithelioma.
(Fig. 21.8). Although it is usually asymptomatic, mild tenderness
This is a subcutaneous nodule of 15 mm in diam- may be present. Myotonic dystrophy may induce multiple calci-
eter. It is accompanied by tenderness and light fying epithelioma. Malignant formation rarely occurs (pilomatrix
pink erythema. carcinoma).
Pathogenesis
Calcifying epithelioma is a teratoma that originates from the
hair follicle bulge. Some cases are caused by genetic abnormality
in b-catenin.
Pathology
A sharply margined, irregularly shaped tumor mass appears in
the lower dermal layer or subcutaneous tissue. The mass is not
covered by a distinct membrane but is surrounded by fibrous
connective tissue (Fig. 21.9). The tumor contains basaloid cells
(originating from the hair matrix and staining basophilic) and
shadow cells. Shadow cells are enucleated cells that stain
eosinophilic. Foreign body granuloma and calcification are seen.
Treatment
The treatment is surgical removal.
8. Trichilemmoma
A tumor of 3 mm to 8 mm in diameter and normal skin color
to light brown occurs, usually solitarily and most commonly on
the face. Histopathologically, there are columnar cells arranged
21 Fig. 21.9 Histopathology of calcifying
in a palisading pattern and a mass of clear cells that resemble
epithelioma.
outer root sheath cells. Malignant trichilemmoma occurs in rare
cases.
9. Proliferating trichilemmal tumor

A subcutaneous nodule or tumor 1 cm to 10 cm in diameter
occurs, most frequently on the scalp. It is pathologically similar
to epidermal cyst and trichilemmal cyst (described later). Erosion
and ulceration may be present on the surface. Trichilemmal kera-
tinization is observed histopathologically. Overproliferation of
cell components is also seen. Malignant proliferating trichilem-
mal tumor accompanied by atypism is pathologically differentiat-
ed from proliferating trichilemmal tumor.
C. Sebaceous tumors
1. Sebaceous hyperplasia
Synonym: Senile sebaceous hyperplasia
Flat, yellowish-white papules or small nodules with a diameter Clinical images are available in hardcopy only.
of 3 mm to 8 mm occur on the face (forehead, cheeks, nose), fre-
quently in the elderly (Fig. 21.10). Several eruptions occur in
most cases. They are centrally umbilicated and may discharge
sebum from the center.
Fig. 21.10 Sebaceous hyperplasia.
2. Sebaceous adenoma
A yellowish nodule or tumor occurs, most frequently on the
face or scalp of middle-aged persons. Histopathologically, the
tumor differentiates into sebaceous glands that contain a normal
sebaceous lobular structure.
3. Sebaceoma Clinical images are available in hardcopy only.
Synonym: Sebaceous epithelioma
This is a dome-shaped or pediculate nodule that occurs on the

face or scalp (Fig. 21.11). It may be yellowish. Histopathologi-
cally, there is proliferation of tumor cells that resemble basal
cells. Some of the tumor cells are anaplastic and some spread to Fig. 21.11 Sebaceoma.
Dome-shaped yellowish nodule is seen.
the sebaceous ducts.
21
Fordyce’s condition MEMO

Small, multiple, aggregated yellow papules of 1 mm to 2 mm in diame-
ter occur in the lips, buccal membrane, foreskin, or labia majora and
minora. They are caused by proliferation of sebaceous glands. The con-
dition is seen in the oral mucosa of about 80% of those middle aged
and older. Fordyce’s condition is not related to Fox-Fordyce disease
(Chapter 19), a condition of chronic inflammation in the apocrine
sweat glands.
Muir-Torre syndrome (also see Chapter 22) MEMO

This is a hereditary disease in which sebaceoma, sebaceous adenoma
or sebaceous gland cancers occur multiply, in addition to malignant
gastrointestinal tumors such as stomach cancer and colon cancer. Kera-
toacanthoma may also occur.
D. Sweat gland tumors
1. Eccrine hidrocystoma
A small, translucent-bluish papule 2 mm to 3 mm in diameter
Clinical images are available in occurs on the face, usually solitarily but sometimes multiply
hardcopy only. (Fig. 21.12). When there are multiple papules, the number tends
to increase in summer and decrease in winter. The skin lesion is
thought to be a cystic intradermal channel enlarged by sweat dep-
osition; it is known to be a stagnating cyst that accompanies
deformity of the eccrine sweat ducts (Fig. 21.13). Sweat deposi-
Fig. 21.12 Eccrine hidrocystoma. tion can be identified by puncture with a needle.
2. Syringoma
Clinical features
Small, multiple, flatly elevated papules with a diameter of
1 mm to 3 mm and normal skin color result from localized prolif-
eration of intradermal sweat ducts. The eyelids are the most com-
monly affected. The papules may disseminate on the trunk and
coalesce (Fig. 21.14). The incidence is higher among women than
men, and the disease is seen most often in puberty, when sweat
Fig. 21.13 Histopathology of eccrine hidro-
cytstoma. secretion increases. It is asymptomatic and rarely heals sponta-
neously.
Pathology
Clinical images are available in Strands of epithelia form luminal structures of various sizes in
hardcopy only.
the upper and middle dermal layers. The strands form cystic
g
luminal structures
j
with a tadpole-like shape. The lumen is p
com-q
posed of double-layered mural cells with peripheral proliferation
of connective tissue (Fig. 21.15).
21 Differentiation from lupus miliaris disseminatus faciei
(LMDF), milium and angiofibroma is easy by histopathological
imaging.
hardcopy only.
Treatment
Treatment is usually unnecessary, as syringoma is asympto-
matic and there is no malignant transformation. Carbon dioxide
gas laser therapy and cryotherapy may be conducted for cosmetic
purposes.
Fig. 21.14 Syringoma. 3. Eccrine poroma
a: Multiple, small, flatly-elevated papules of 2
mm to 5 mm in diameter on the eyelids. b: Multi-
ple eruptions of syringoma on the axillary fossa. Definition, Clinical features
They coalesce into a large plaque.
Outer cells of eccrine sweat ducts proliferate in eccrine sweat
D. Sweat gland tumors 363
glands. Some of the cells differentiate into sweat duct luminal

cells and further into sweat duct excretion cells. A small, dome-
shaped or pedunculated nodule occurs on any site of the body,
particularly on the soles and palms. The nodules are character-
ized by dark red color and easy bleeding (Fig. 21.16).
Pathology
There is a proliferating nest of poroid cells in the epidermis
and the dermis. Eosinophilic cells form small lumens in the focus
(cuticular cells, Fig. 21.17). The tumor cells contain large quanti-
ties of glycogen.
Treatment
Eccrine poroma may become malignant in rare cases (eccrine
porocarcinoma). The skin lesion should be surgically removed. Fig. 21.15 Histopathology of syringoma.
The eruptions contain the tadpole-like or comma-
tail-like tumor cells that are characteristic of
4. Eccrine spiradenoma syringoma.
A firm, solitary, sharply margined, intradermal or subcuta-

neous nodule 1 cm to 2 cm in diameter occurs on the face, neck,
trunk or upper arm. The nodule is normal skin color or bluish. It
is accompanied by spontaneous pain and tenderness. Large light
cells and small dark cells are pathologically observed to prolifer-
ate in a palisading pattern or in clusters, forming a tubular struc-
ture.
5. Papillary eccrine adenoma

Fig. 21.16 Eccrine poroma.
Small solitary nodules of 1 cm to 3 cm in diameter occur on A pedunculated, dark-red nodule is noted.
the extremities. Histopathologically, cystic structures of several
sizes, and columnar strands of epithelium are found. Papillary
eccrine adenoma is thought to be a benign tumor that differenti-
ates into the eccrine sweat ducts; however, it is not known
whether it originates from eccrine sweat gland cells or apocrine
sweat gland cells.
21
6. Nodular hidradenoma
This is a solitary intradermal nodule. The tumor cells are Fig. 21.17 Histopathology of eccrine poro-
ma.
Classification and subtypes of eccrine MEMO

poroma
Hidracanthoma simplex: Tumor cells proliferate within the epider-
mis. The lower legs are most commonly involved. The surface of the
lesion is slightly keratinized.
Eccrine poroepithelioma: Tumor cells proliferate in the direction of
the dermis. Atypism is slight.
Dermal duct tumor: Tumor cells proliferate only in the dermis, with-
out connection to the epidermis.
Eccrine porocarcinoma: Eccrine poroma often progresses to eccrine
porocarcinoma. High atypism and infiltrative proliferation result in
canceration.
polygonal cells containing eosinophilic cell bodies. Histopatho-

logically, there are spindle-shaped cells containing long, thin
nuclei, and round cells containing round nuclei. Nodular hidrade-
noma is a benign tumor that differentiates into eccrine sweat
glands. There may be malignant formation (malignant nodular
Clinical images are available in hardcopy only. hidradenoma) in some cases.
7. Mixed tumor of the skin

Synonym: Chondroid syringoma
Relatively firm intradermal nodules of 3 cm or less in diameter

occur, most frequently on the face, head and scalp of young and
middle-aged persons (Fig. 21.18). Mobility is present at the bot-
tom of the nodules on the skin surface. There are luminal struc-
tures of several sizes in the skin lesion, which are surrounded by
single- or double-layered cell walls. Epithelial adenomatous tis-
sue is interspersed with luminal structures and mucus-like or car-
tilage-like fibrotic stroma. Mixed tumor of the skin is thought to
be a benign tumor that differentiates into sweat ducts in the
secretory part of the eccrine and apocrine sweat organs. It may be
cancerous in rare cases.
Fig. 21.18 Mixed tumor of the skin.
8. Apocrine hidrocystoma
This is a tumor of the apocrine organs. A small, solitary,
dome-shaped nodule with a diameter of several millimeters to 2
cm occurs around the eye or elsewhere on the face, or on the ear
or scalp, of persons middle aged or older. The nodule is transpar-
ent or bluish. A large cystic structure is found in the dermis. The
nodule is composed of single-layered pillar cells that show apoc-
rine secretion, and myoepithelial cells that are located on the
outer side of the pillar cells. It is asymptomatic. Excision may be
conducted at the patient’s request.
Fig. 21.19 Cylindroma.
21 9. Cylindroma
Hidradenomas MEMO Multiple dome-shaped or slightly pedunculated tumors of 1 cm
Benign tumors that originate from sweat to 10 cm in diameter and normal to brown skin color occur, most
glands in the skin or that differentiate into commonly on the scalp of adolescent boys and girls (Fig. 21.19).
sweat glands are collectively called hidrade-
nomas. An apocrine hidradenoma divides in When the entire scalp is affected, the head has the appearance of
the direction of the apocrine glands. An being wrapped by a turban (turban tumor). The condition seldom
eccrine hidradenoma divides in the direction occurs in ethnic Japanese. Cylindroma may occur solitarily in
of the eccrine glands. Hidradenomas are sub-
classified by the location of the main prolifer- rare cases. Multiple cylindroma is an autosomal dominant disor-
ation into poromas (proliferation is mainly in der in which abnormality of the cylindromatosis gene (CYLD1
the epidermal portion of sweat glands), der- gene) has been identified, and multiple papular trichoepithelioma
mal duct tumors (in the dermal sweat duct),
and spiradenomas (in the secretory portion). is seen. Cylindroma is thought to be a tumor of the sweat organs.
Clear cell poromas, mixed tumors of the skin, There may be malignant formation in rare cases (malignant cylin-
cylindromas, hidradenoma papilliferum, and droma).
cystadenomas are distinguished by the histo-
logical findings of proliferative cells.
E. Cysts 365
10. Hidradenoma papilliferum

A small, dome-shaped tumor occurs, often accompanied by
erosion and bleeding. It most frequently appears on the female
genitalia. The tumor resembles granulation tissue. Pathologically,
there is dense papillary proliferation of glandular epithelial cells
of apocrine-type secretion. Hidradenoma papilliferum is the typi-
cal type of apocrine neoplasm.
11. Syringocystadenoma papilliferum

Fig. 21.20 Syriogocystadenoma papilliferum.
An erosive rose-pink-surfaced verrucous nodule occurs, most Verrucous nodule on the nipple. Syringocystadeno-
commonly on the scalp or face of infants (Fig. 21.20). It is an ma papilliferum on the chest is rare.
apocrine organic hamartoma and often occurs secondarily after
sebaceous nevus. Histopathologically, there is a double-layered
luminal structure with long cylindrical cells on the inner side,
cubical cells on the outer side, and marked plasmacytic intersti-
tial infiltration in the nodule (Fig. 21.21). Basal cell carcinoma
occurs secondarily in 10% of cases.
12. Tubular apocrine adenoma

A nodule of 1 cm to 2 cm in diameter and normal skin color or
brown occurs, usually on the scalp. Histopathologically, prolifer-
ation of small, multiple cyst-like lumens is seen.
13. Erosive adenomatosis of the nipple

A benign tumor occurs in the nipple, often accompanied by
erosion and exudation. Differentiation from mammary Paget’s
disease and breast cancer is necessary. A dense concave structure
and a luminal structure are histopathologically observed. Erosive
adenomatosis of the nipple is a benign tumor that differentiates
into the apocrine sweat glands. The only treatment is total exci-
sion; unless it is complete, there is recurrence.
Fig. 21.21 Histopathology of syriogocys- 21

tadenoma papilliferum.
E. Cysts
1. Epidermal cyst
Clinical features
A dome-shaped, intradermal or subcutaneous tumor with a
diameter of 1 cm to 2 cm (or more than 10 cm in rare cases)
occurs, most frequently on the head or neck, upper trunk, or lum-
bar region (Fig. 21.22). The tumor adheres to the skin surface;
however, the sides and bottom of the tumor mass do not firmly
adhere to the peripheral tissue. It tends to occur on haired sites.
Cysts are elastic but firm, with a surface color of normal skin or
light blue and a black punctate opening at the center. They are
Clinical images are available in hardcopy only. asymptomatic. When pressed after excision, the cyst exudes a
putrid-smelling, white, gruel-like discharge. Most cases clinically
diagnosed as “atheroma” are epidermal cyst. Reddening, swelling
and tenderness may be caused by secondary infection and rupture
a b c d e f g i wallsj (inflammatory
h the cyst
of k l epidermal
m n
cyst). o p q r
Pathogenesis
The epidermis or infundibulum-derived epithelial components
invaginate into the dermis and proliferate to form a cyst that con-
Clinical images are available in hardcopy only. tains keratinous substances. Invagination of the epidermis or
epithelial components into dermis that is caused by injury or by
infection of HPV-57 or HPV-60 is thought to be associated with
epidermal cysts in some cases, in which cases the cysts occur in
a b c d e f g h the
i palmsj and soles
k (Table
l 23.1).
m n o p q r
Fig. 21.22 Epidermal cyst.
a: There is a black opening at the center of the Pathology
eruption. b: Secondary infection resulted in red-
dening and swelling at the periphery.
The wall of the cyst has the same structure as normal epider-
mis: basal layer, suprabasal cell layer and granular cell layer
(Fig. 21.23). However, instead of the horny cell layer, there are
Atheroma in Japan MEMO gruel-like, layered keratinous contents. When the keratinous sub-
In Japan, epidermal cysts are also called
“atheromas.” Sometimes atheroma refers to a
stance is released into the dermis by rupture of the cystic wall,
cystic nodule that is similar to an epidermal immunological reaction against foreign substance occurs, and a
cyst, such as a trichilemmal cyst, giant come- foreign body granuloma containing multiple polynuclear giant cells
do or even pilomatricoma. may be produced.
Treatment
The cyst and its walls are excised.
2. Milium
Clinical features
21 A small, firm, white to yellowish-white papule of 1 mm to 2
mm in diameter occurs immediately below the epidermis (Fig.
21.24). White keratinous contents are discharged by incision. Pri-
mary milium occurs most frequently on the eyelids, followed by
the cheeks, penis and labia. Plaques may form. The histological
Fig. 21.23 Histopathology of epidermal cyst. findings are nearly the same as those of epidermal cyst.
The pathogenesis of primary milium is thought to be keratotic
cyst formation resulting from abnormality of embryonic epithe-
lial buds. Secondary milium occurs after a blistering disease
(e.g., dystrophic epidermolysis bullosa, epidermolysis bullosa
acquisita), burn scarring or radiodermatitis. The skin appendages
and epidermal cells are damaged by these diseases and proliferate
Fig. 21.24 Milium. in cyst-like shape under the epidermis.
E. Cysts 367
Treatment
A small incision using a scalpel, or a puncture with a hypoder-
mic needle, is conducted to remove the spherical white sub-
stance.
3. Dermoid cyst
A dome-shaped subcutaneous cyst with a diameter of 1 cm to
4 cm appears, most frequently on the head. It is present at birth. It
a b c d e f g h
is often misdiagnosed as an epidermal cyst. Histopathologically,
sebaceous glands and sweat glands are found in the cyst walls
that are produced by the epidermis.
4. Trichilemmal cyst
The head is affected in about 90% of cases. A trichilemmal
cyst pathologically resembles an epidermal cyst. Histopathologi- g
a b c d e f h i
cally, there are epithelial cells that consist of cyst walls, and the
epithelial cells on the luminal side of the cyst wall keratinize Fig. 21.25 Histopathology of trichilemmal
cyst.
without forming a granular cell layer (trichilemmal keratiniza- a: A cyst in the lower dermal layer. b: Trichilemmal
tion, Fig. 21.25). keratinization is observed; tumor cells keratinize
without formation of a granular cell layer.
5. Steatocystoma multiplex
A firm, dome-shaped tumor with a diameter of 1 mm to 5 mm
in most cases and a color ranging from that of normal skin to
light yellow or light blue occurs, frequently on the axillary fos- Clinical images are available in hardcopy only.
sae, upper chest or upper arm (Fig. 21.26). It is follicle-associat-
ed in some cases. Some cases are autosomal dominant; mutation
in the keratin 17 gene is associated with the condition.
Histopathologically, there are flattened sebaceous glands near or
directly attached to the tumor. The cyst wall is composed of intri- Fig. 21.26 Steatocystoma multiplex.
Multiple subcutaneous cysts ranging in diameter
cately multilayered epithelial components. from 5 mm to 10 mm occurred on the axillary
fossa.
6. Eruptive vellus hair cyst
This is an asymptomatic follicular papule that occurs most fre- 21
quently on the chest. The cyst is superficial, crusted and umbili-
cated. It may be accompanied by steatocystoma multiplex. The
cyst wall may contain a sebaceous structure.
7. Pilonidal sinus Clinical images are available in hardcopy only.
Synonyms: Pilonidal cyst, Pilonidal disease
Young men whose buttocks, particularly their sacral division,

are hairy are most frequently affected. Ingrowth of hair leads to
formation of a fistula. The fistula is surrounded by granuloma-
tous tissue or squamous epithelia. Pilonidal sinus may also occur
on the occipital division, eyelids, genitalia, axillary fossae, Fig. 21.27 The opening of a fistula caused by
umbilical fossae or interdigital areas. Most cases with interdigital pilonidal sinus on the sacral region.
involvement occur occupationally, such as in barbers and shear-

ers. The affected site, including the scar tissue, should be com-
pletely excised (Fig. 21.27).
Clinical images are available in hardcopy only. 8. Branchial cyst

A branchial cyst is an epidermal-cyst-like cyst that occurs on
the preauricular region and neck. As it is caused by branchial
debris, mobility is not fully present at the bottom of the cyst.
There is a palpable cordlike substance in the cyst. Excision
should not be decided quickly. Branchial cysts caused by thy-
rolingual debris are called thyroglossal duct cysts.
9. Median raphe cyst of the penis

A tumor of several millimeters in diameter occurs in the penile
Clinical images are available in hardcopy only. raphe of young men (Fig. 21.28). It occurs solitarily at the ure-
thral openings in most cases. The cyst may reach several cen-
timeters in diameter. Its wall is histopathologically composed of
single- or several-layered cylindrical epithelia or cubical epithelia
that resemble urethral transitional epithelia.
Fig. 21.28 Median raphe cyst of the penis.
F. Neural tumors
1. Neurofibroma
A neurofibroma is thought to be a benign tumor that derives
from peripheral nerve Schwann cells or from perineurial or
Clinical images are available in hardcopy only. endoneurial cells. The tumor is sharply margined, dome-shaped,
soft and of normal skin color or light pink (Figs. 21.29 and
21.30). It lacks a covering membrane and contains myxoid stro-
21 ma. The tumor slowly enlarges (Figs. 21.29 and 21.30). There
are almost no symptoms; however, subcutaneous neurofibroma
(nodular plexiform neurofibroma) is often accompanied by ten-
Fig. 21.29 A soft, elevated skin tumor
derness. In neurofibromatosis type 1 (NF1), neurofibromas occur
caused by neurofibroma. multiply on the whole body. In NF5, localized areas, such as on
the trunk, may be affected by mosaicism. Nearly all of the subcu-
taneous tumors caused by NF1 are nervous neurofibromas, and
neurilemmomas are not usually found (also see Chapter 20).
2. Neurilemmoma
Synonym: Schwannoma
Clinical features
Fig. 21.30 Histopathology of neurofibroma. A neurilemmoma is a Schwann-cell-derived benign tumor that
F. Neural tumors 369
usually occurs solitarily. However, multiple neurilemmoma is

caused by neurofibromatosis type 2 (NF2). An axonal myelin
sheath forms. The tumor is palpable, elastic, firm, spherical, and
intradermal or subcutaneous. When it softens, palpable pulsation
is present. It may appear singly or in beaded pattern. It is accom-
panied by tenderness, and pain may radiate from the pressured
site to the periphery. Malignant transformation occurs in rare
cases (malignant neurilemmoma) (Fig. 21.31).
Fig. 21.31 Histopathology of neurilemmoma
Pathology (schwannoma).
Neurilemmomas are characterized by a biphasic pattern of
Antoni A areas and Antoni B areas that is visible by microscopy.
Antoni A areas form the cellular component of the lesion and are
composed of fairly closely packed spindle cells with tapering,
elongated, wavy nuclei. Nuclear palisading is a prominent fea-
ture. Antoni B areas are characterized by irregularly scattered
spindle or stellate cells set in abundant loose myxoid stroma.
Treatment
Excision should be conducted carefully, to avoid injuring the
displaced nerves.
3. Traumatic neuroma Fig. 21.32 Histopathology of a granular-cell

tumor.
A traumatic neuroma, also called amputation neuroma, is a
tumor that occurs in the peripheral nerve stump. Intense sponta-
neous pain and tenderness are present. Histopathologically, nerve
fibers proliferate in all directions and are surrounded by Schwann
cells and fibrotic tissue. Excision may be necessary, depending
on the severity of pain. Neuroanastomosis is performed when
possible.
4. Rudimentary polydactyly
A small tumor of 1 cm to 2 cm in diameter is present in a fin-
ger, often the thumb, at birth. Histopathologically, natural ampu-
tation of embryonic polydactylism is thought to cause outgrowth 21
of nerve fiber bundles and nerve end corpuscles such as Meissner
corpuscles and Vater-Pacini corpuscles.
5. Granular-cell tumor
A small tumor of 3 cm or less in diameter occurs on the skin
and in the genitalia, tongue, lung, esophagus, stomach, intestine,
bladder or uterus (Fig. 21.32). The tumor is histopathologically
composed of large polygonal cells that contain eosinophilic gran-
ules. It is covered by epidermis. It is easily misdiagnosed as
squamous cell carcinoma. It is thought to originate from
Schwann cells. The cytoplasm contains numerous eosinophilic
granules. It is resistant to diastase, PAS positive and S-100 posi-
tive. There is malignant transformation in some cases.
G. Hemangiomas and vascular malformations

Classification of vascular anomalies is still confusing and changing MEMO
Vascular anomalies described in this textbook are categorized on conventional, descriptive terms or histopathologic terms. How-
ever, it is a confusing classification, because “hemangioma” simplex is not tumorous but a malformation of normal capillaries. In
1982, Mulliken and Glowacki proposed a novel classification system for vascular anomalies based on cellular features and natural
history. Now classification proposed by International Society for the Study of Vascular Anomalies (ISSVA) has been updated and
used. According to the classification, cutaneous vascular anomalies described in this textbook could be classified as follows.
Note that some syndromes demonstrate various types of hemangiomas and vascular malformations, such as Klippel-Trenaunay-
Weber syndrome and Maffucci syndrome.
Classifications of vascular anomalies.

Vascular anomalies Representative diseases and associated conditions
Hemangiomas Congenital Infantile hemangioma (GLUT1 positive) (Chapter 21) Old terms
Congenital hemangioma (Chapter 21) Strawberry mark (Chapter 21)
Rapidly involuting congenital hemangioma (RICH) Strawberry mark (Chapter 21)
Noninvoluting congenital hemangioma (NICH)
Kaposiform hemangioendothelioma
Tufted angioma (infantile) (Chapter 21) Main cause of Kasabach-Merritt syndrome
Acquired Cherry angioma (Chapter 21)
Glomeruloid hemangioma (Chapter 21)
POEMS syndrome (Chapter 21)
Tufted angioma (acquired) (Chapter 21)
Spindle-cell hemangioendothelioma (Chapter 21)
Maffucci syndrome (Chapter 20)
Hemangiopericytoma (Chapter 21)
Pyogenic granuloma (Chapter 21)
Intravascular papillary endothelial hyperplasia (Chapter 21)
Angiolymphoid hyperplasia with eosinophilia (Chapter 21)
Cutis marmorata (Chapter 4)
Kaposi's sarcoma (Chapter 22)
Angiosarcoma (Chapter 22)
Vascular malformations Capillary Capillary malformation
Sturge-Weber syndrome (Chapter 20) Hemangioma simplex, salmon patch
Klippel-Trenaunay-Weber syndrome (Chapter 20)
Phakomatosis pigmentovascularis (Chapter 20)
Telangiectasia
Osler's disease (Chapter 20)
Ataxia telangiectasia (Chapter 11)
Cutis marmorata telangiectasia congenita (Chapter 20)
Spider angioma (Chapter 21)
Venous Venous malformation (Chapter 21)
Blue rubber bleb nevus syndrome (Chapter 20) Cavernous hemangioma (Chapter 21)
Maffucci syndrome (Chapter 20)
Venous lake (Chapter 21)
21 Glomuvenous malformation
Lymphatic Lymphatic malformation (Chapter 21) Glomangioma
Arterial Cutaneous arteriovenous malformation (Chapter 21), etc. Lymphangioma
Combined Capillary-lymphatic malformation (Chapter 21)
Other combinations Angiokeratoma
Fast-flow type
Slow-flow type
Klippel-Trenaunay-Weber syndrome (Chapter 20), etc.
1. Hemangioma simplex
Synonyms: Capillary malformations, Port wine stain, Nevus
flammeus
Clinical features
A flat, sharply margined red patch results from capillary
G. Hemangiomas and vascular malformations 371
telangiectasia in the shallow dermal layer. It is present at birth

(Figs. 21.33-1 and 21.33-2). The skin lesion remains through life,
deepening in color slightly with age. When the face is involved,
it may thicken after puberty and multiple nodular elevations may
occur (hypertrophic port wine stain).
A light pink patch may be caused on the midline region of the
face in a specific type of hemangioma simplex called medial
nevus. Hemangioma on the forehead and eyelids, called salmon Clinical images are available in hardcopy only.
patch, disappears spontaneously by age 2; hemangioma on the
neck, called nevus Unna, does not disappear spontaneously.
Complications
Hemangioma simplex may occur as a symptom of Sturge-
Weber syndrome or Klippel-Trenaunay-Weber syndrome.
Dilation and increase of capillaries are found in the upper der-
mal layer (Figs. 21.34 and 21.35).
Treatment
Dye laser therapy is the first-line treatment. Concealing cos- Clinical images are available in hardcopy only.
metics are useful.

● Telangiectasia in the superficial
● Dilation of capillary vessels.
dermis.
● Light-red erythema.

● Well-demarcated, flat erythema.
● Lesions on the forehead and Clinical images are available in hardcopy only.

● No spontaneous regression. eyelids spontaneously regress by
Redness and elevation worsen the age of 2. Nuchal lesion does 21
gradually. not regress.
Hemangioma simplex Salmon patch

● Proliferation of epithelial cells.
● Proliferation of small vessels in

● Fresh-red nodule/tumor. the deep dermis. Fig. 21.33-1 Hemangioma simplex.

● Regresses with scarring.
● Soft subcutaneous tumor. Various
colors with small erythema on the

surface.

● No spontaneous regression.
Strawberry mark Cavernous hemangioma
Fig. 21.34 Classification of hemangiomas.

2. Strawberry mark
Synonyms: Congenital/infantile hemangiomas.
Outline
●A bright red, elevated lesion results from proliferation of
premature capillaries. It appears 3 to 4 weeks after birth,
Clinical images are available in hardcopy only. enlarging until the age of 6 to 7 months.
● The face and arms are often involved. It heals sponta-
neously with soft scarring in several years.

● Dye laser irradiation is the main treatment. Follow-up
without treatment may be chosen.
Clinical features
Shortly after birth, telangiectatic erythema occurs on the face
or arm, expanding gradually to form an elevated red tumor by the
Fig. 21.33-2 Hemangioma simplex. age of 3 to 6 months. A strawberry mark, a soft tumor, is seen in
1% of newborns; it resembles a halved strawberry stuck on the
skin (Figs. 21.36-1 and 21.36-2). The color disappears by dias-
copy. A tumor may develop on the lesion. After its peak, the
strawberry mark subsides at the stationary phase, in most cases
disappearing with light scarring by later childhood.
The primary lesion is proliferation of vascular endothelial
cells. The tumor is bright red and composed of the proliferation
of premature vessels. Strawberry mark is vascular dysplasia
caused by an angioblast mass; it does not differentiate into nor-
mal capillary tissue (Fig. 21.34).
Fig. 21.35 Histopathology of hemangioma
simplex.
The blood vessels in the dermis are dilated and Treatment
filled with erythrocytes, which gives the skin sur- Doctors used to take a wait-and-see policy of observation with
face of the lesion a reddish appearance. regard to strawberry mark. However, in recent years, laser therapy
21
Fig. 21.36-1 Strawberry mark.

Clinical images are available in hardcopy only. Clinical images are available in hardcopy only.
Fig. 21.36-2 Strawberry mark.
has been performed for cosmetic purposes even at infancy,

because scarring may remain after spontaneous healing. The ear-
lier the laser therapy begins, the more effective it is. Systemic
administration of steroids may be necessary in cases in which the Clinical images are available in hardcopy only.
lesion continues to enlarge 6 months after birth or when eyelid
involvement may cause visual disturbance.
3. Cherry angioma
Fig. 21.37 Cherry angioma.
Synonym: Senile angioma
Multiple, punctate, glossy, bright red papules occur on the

trunk. The onset is after the second decade of life, and the
papules become more numerous with age. The pathogenesis is
thought to be reactive vascular proliferation. Localized capillary Clinical images are available in hardcopy only.
proliferation is histopathologically found in the lower papillary
dermis (Fig. 21.37).
4. Glomeruloid hemangioma
This is vascular proliferation. Hemangioma of 1 cm or less in Fig. 21.38 Glomeruloid hemangioma. 21
diameter occurs in about half of patients with POEMS syndrome
(MEMO) (Fig. 21.38). There is secretion of vascular prolifera-
tion factors and elevated levels of estrogen in the blood.
Although glomeruloid hemangioma clinically resembles senile
angioma, it appears suddenly on the trunk, extremities, and head
POEMS syndrome MEMO

Synonyms: Crow-Fukase syndrome, Takatsuki disease Fig. 21.39 Venous lake.
POEMS is an initialism for polyneuropathy, organomegaly of liver,
spleen or lymph nodes, endocrinopathy, monoclonal gammopathy and
skin changes. Various skin lesions, such as glomeruloid hemangioma,
pigmentation, trichosis, scleroderma, diffuse sclerosis, livedo reticu-
laris and Raynaud’s disease, and clubbed fingers are caused by
POEMS syndrome.
and neck region of persons in their second third decade of life.

Dome-shaped nodules that are too firm to be displaced by digital
pressure and whose color is lighter pink than those in senile
Clinical images are available in hardcopy only. angioma appear.
5. Venous lake
A small, slightly elevated, dark blue nodule occurs mainly on
Fig. 21.40 Vascular spider.
There are cobweb-like capillaries at the periphery the face, or lips of the elderly (Fig. 21.39). Histopathologically,
of a papule-like angiokeratoma. the underlying disease is telangiectasia.
6. Spider angioma
Synonyms: Nevus araneus, Vascular spider
Capillaries extending radially from a red papule of several mil-

limeters in diameter give the appearance of a spider spreading its
legs (Fig. 21.40). The face, neck, shoulders, chest and upper arms
Fig. 21.41 Angiokeratoma of Mibelli. are frequently involved. It is most common in pregnancy or
hepatopathy, when estrogen levels are elevated, although it may
appear even under normal conditions. The eruptions fade by dias-
copy. Dye laser therapy and electrocauterization are the main
treatments. Spider angioma in children disappears spontaneously.
7. Angiokeratoma
Synonym: Capillary-lymphatic malformation
Angiokeratoma is caused by proliferation of capillaries in the
dermal papillae. The epidermis that proliferates around the capil-
laries becomes hyperkeratotic, leading to verrucous surface
(Figs. 21.41, 21.42 and 21.43). Histopathologically, there is cap-
illary telangiectasia immediately below the epidermis. Angioker-
atoma is classified into five subtypes. Various factors are
associated with the occurrence of angiokeratomas, which are
classified into five subtypes.
21 ① Solitary angiokeratoma
Fig. 21.42 Angiokeratoma (angiokeratoma
circumscriptum naeviforme). It results from injury.
② Angiokeratoma of Mibelli
Chilblains present as a prodrome. The hands and legs are fre-
quently affected. It is autosomal dominant.
③ Angiokeratoma scroti (Fordyce)
It is an angioma that occurs in large numbers.
④ Angiokeratoma circumscriptum naeviforme
Verrucous vascular papules arrange themselves linearly on the
unilateral extremities and trunk at birth. Crusting is present.
⑤ Angiokeratoma corporis diffusum
Small, multiple, papular angiomas occur on the trunk of
patients with lysosomal storage diseases such as Fabry’s disease
Fig. 21.43 Histopathology of angiokeratoma.
Marked dilation of capillaries in the papillary and Kanzaki disease (Chapter 17).
layer directly under the epidermis.
8. Cavernous hemangioma
Synonym: Venous malformation
Outline
● Malformed veins proliferate in the deep dermal layer.
●A soft, subcutaneous tumor of normal skin color or light
purplish-pink occurs in early childhood.
● Strawberry mark may occur on the surface of the lesion. Clinical images are available in hardcopy only.
● It is surgically removed.
Clinical features
Small, mature, malformed vessels (mainly veins) proliferate in
the deep dermal layer (Figs. 21.44 and 21.34). Cavernous heman-
gioma is present at birth as a large, soft, subcutaneous tumor. The
color is in the range of normal skin color to light blue or reddish
purple. Small erythemata are dispersed on the surface of the
tumor. The surface may have strawberry mark. Bleeding may Fig. 21.44 Cavernous hemangioma.
result from platelet consumption (Kasabach-Merritt syndrome). There is infiltrative hemangioma in the left chest.
The blood vessels in the heart are affected.
Tenderness is not present. Cavernous hemangioma does not heal
spontaneously.
Complications
Cavernous hemangioma is usually solitary. When it occurs
multiply, blue rubber-bleb-nevus syndrome and neurocutaneous
syndromes such as Maffucci’s syndrome are suspected.
Treatment
It is surgically removed. Intratumor coagulation (sclerothera-
py) may be performed. Radiation therapy is ineffective.

9. Kasabach-Merritt syndrome
Outline
● Platelet consumption occurs from large angioma, leading
to thrombocytopenia and disseminated intravascular 21
coagulation (DIC).
● Subcutaneous induration appears in the first 3 months of
life. It enlarges relatively rapidly to form a giant angioma

that is dark red to purple.
● Radiation therapy, oral steroids and treatments for DIC
are the main treatments. Fig. 21.45 Kasabach-Merritt syndrome.

Large hemangioma in the left leg.
Clinical features
Angioma occurs most frequently on the extremities and the
head and neck region. Extremely firm, light pink subcutaneous
induration first occurs in the first 3 months of life (Fig. 21.45). It
is followed by intratumor bleeding and edematous enlargement,
resulting in the formation of a giant, dark purple, tense tumor.
Purpura is easily caused by thrombocytopenia. Persistent
coagulopathy and thrombocytopenia result in DIC.
Pathogenesis
Intratumor bleeding is caused by rapid enlargement of a large
angioma in newborns, leading to platelet consumption. Cuta-
neous angioma resembles strawberry mark. Premature cutaneous
angioma is thought to result in congestion, platelet consumption
and coagulation-factor consumption. Histopathologically, most
cutaneous angiomas causing Kasabach-Merritt syndrome resem-
ble Kaposi’s sarcoma, which is called kaposiform hemangioen-
dothelioma.
Treatment
DIC is symptomatically treated. The treatment for Kasabach-
Merritt syndrome is the same as for angioma. Radiation therapy
is effective, because the angioma in Kasabach-Merritt syndrome
is highly sensitive to radiation. Oral steroids are also useful.
10. Cutaneous arteriovenous malformation

Congenital vascular deformity and several embryonic arteri-
ovenous fistulae are the underlying condition. The skin lesion
may appear hemangioma-simplex-like or indistinct. It begins to
enlarge at a certain point, and swelling accompanied by heat sen-
sation on the surface of the lesion occurs. Pulsation and tremor
are present. When the extremities are involved, the lesion
enlarges and may cause Klippel-Trenaunay-Weber syndrome.
11. Tufted angioma

Synonym: Angioblastoma of Nakagawa
It begins as erythema that gradually enlarges to form a flatly

elevated, infiltrating plaque. Tufted angioma is a vascular tumor
in which immature endothelial cells and peritcytes proliferate.
The color ranges from light pink to dark purplish-red. The patho-
21 genesis is unknown.
12. Spindle-cell hemangioendothelioma

A bluish subcutaneous tumor occurs, most frequently in the
distal areas of the extremities in young persons. Histopathologi-
cally, it is composed of dilated vascular lumens and portions of
proliferated spindle cells. Multiple tumors are caused in localized
areas; however, it is benign and does not metastasize.
13. Glomus tumor
Fig. 21.46-1 Glomus tumor formed under Outline

the nail.
Deformity of nail and severe tenderness occurred. ● It is a benign tumor that is derived from glomus cells in
the neuromyoarterial glomus of skin on the distal fingers.

●A firm, dark red to bluish-brown tumor forms in the finger
or toe, often under the nail plate. Intense tenderness is
present.
● Paroxysmal pain intensifies at night or with exposure to
extreme cold.
Clinical features
Glomus tumors are either solitary or multiple, with most being
solitary. A solitary glomus tumor occurs most frequently under
the nail plate of individuals older than age 20. A firm, painful
nodule of 1 cm or less in diameter and ranging in color from dark Clinical images are available in hardcopy only.
red to purplish red occurs (Figs. 21.46-1 and 21.46-2). Glomus
tumors are characterized by extreme pain from pressure or expo-
sure to cold water. In multiple glomus tumors, the tumors are
autosomal dominantly inherited and can occur in persons of any
age. Asymptomatic, disseminated, soft tumors of normal skin
color to blue and about 1 cm in diameter appear on the whole
body. They may appear in linear pattern in rare cases.
Pathogenesis
A glomus tumor is a hamartoma caused by proliferation of
glomus cells.
Pathology Fig. 21.46-2 Multiple glomus tumors.
Glomus cells surround blood vessels. Pericyte-originated

smooth muscle cells proliferate, and the luminal structure is sur-
rounded by single-layered endothelium in the tumor (Fig. 21.47).
Glomus cells stain in desmin and myosin. A solitary glomus
tumor is covered by a richly enervated membrane. In multiple
glomus tumors, vascular lumens extend in a spongiform pattern.
Multiple glomus tumors are differentiated from cavernous
hemangioma and blue rubber-bleb-nevus syndrome. Glomus
tumors underneath the nail plate should be differentiated from
subungual exostosis. 21
Treatment
The tumor is excised.
14. Hemangiopericytoma
A firm, elastic, relatively sharply margined nodule occurs in
the lower leg, the thigh in particular. Histopathologically, round
or spindled cells that resemble peritcytes proliferate around the
capillary lumens, which are covered by a single-layered endothe-
lium.
Fig. 21.47 Histopathology of glomus tumor.

15. Lymphangioma
Synonym: Lymphatic malformation
Outline
● It is a benign lesion caused by lymphangial hyperplasia
and dilation resulting from dysplasia of lymph vessels.
Clinical images are available in hardcopy only. ● Vesicles of 1 mm to 2 mm in diameter aggregate.
Bleeding in the vesicles may result in papules whose

color ranges from red to black.
● It is surgically removed.
● Postoperative lymphangioma in the axillary fossae or
groin after breast cancer or uterus cancer is called lym-

phangiectasis (acquired lymphangioma).
Fig. 21.48 Lymphangioma (lymphangioma Classification, Clinical features, Pathology

cysticum). Lymphangiomas are classified into the three types.
Lymphangioma circumscriptum: Transparent vesicles of sev-
eral millimeters in diameter aggregate to form irregularly shaped
plaques. The vesicles appear reddish from bleeding. The thick-
ened epidermis may appear verrucous. Histopathologically, lym-
Clinical images are available in hardcopy only. phangiectasia is found in the dermal papillary layer.
Lymphangioma cavernosum: This is a large, deep-seated, sub-
cutaneous tumor. The color ranges from light pink to bluish pur-
ple. The tumor pulsates. Lymph fluid is discharged from the
tumor by puncture. The tongue, face and genitalia are frequently
involved. Histopathologically, irregular lymphagiectasia occurs
in the subcutaneous and deep dermal layers.
Lymphangioma cysticum: The lateral region of the head is most
Clinical images are available in hardcopy only. commonly affected (Fig. 21.47). Lymphangiactasia is histologi-
cally observed in the deep dermal layer.
Laboratory findings
The depth and three-dimensional structure of the tumor are
clearly shown by MRI and CT diagnostic imaging.
21 Treatment
Surgical removal and sclerotherapy are the main treatments.
16. Pyogenic granuloma

Synonym: Telangiectatic granuloma
Clinical features
An angioma whose main symptoms are proliferation of capil-
laries and dilation of vascular lumens is induced by injury. The
tumor is soft and pedunculated, ranging in color from bright red
Fig. 21.49 Soft, pedunculated tumors rang- to dark red. It is elevated in a dome shape, with a diameter of 5
ing in color from bright red to dark red mm to 20 mm (Fig. 21.49). Bleeding is easily caused by injury,
caused by pyogenic granuloma.
leading to ulceration. The face of children and the trunk and
extremities of adults are most commonly involved. The skin
H. Fibrous tumors 379
lesion appears suddenly, forms erosion and bleeds. Pyogenic gran-

uloma should be differentiated from amelanotic melanoma.
Pathology
Pathologically, there is an angioma accompanied by secondary
inflammatory granuloma, or there is granuloma that is non-
angiomatous in structure.
Treatment
Excision, cryotherapy and laser therapy are conducted; there
may be recurrence in cases of incomplete treatment.
17. Intravascular papillary endothelial hyper-

plasia
The blood vessels proliferate as a result of thrombotic recanal-
ization in the dilated venulae. It is a reactive change of thrombot-
ic vessels often seen in adults. A purplish-red nodule occurs,
most frequently in the veins of the palmar surfaces of fingers.
Thrombus formation may cause pain.
H. Fibrous tumors
1. Soft fibroma
Synonyms: Fibroma pendulans, Acrochordon, Skin tag
Clinical features
A soft, dome-shaped or pedunculated tumor with wrinkles on
the surface and a color of normal skin or light brown occurs on
the neck, axillary fossae or groin (Fig. 21.50). Small, multiple,
threadlike tumors 2 mm to 3 mm long on the neck and axillary
fossae are called acrochordon. A solitary, relatively large tumor
of about 1 cm on the trunk is called soft fibroma. An enlarged
soft fibroma hanging from the skin is called a soft fibroma pen- 21
dulum. Soft fibroma tends to occur in obese persons and women;
it is thought to relate to skin aging.
Pathology
The primary condition of soft fibroma is proliferation of colla-
gen bundles with few fibroblasts. In soft fibroma, fat cells are
contained in tumors in many cases.
Treatment Clinical images are available in hardcopy only.

The peduncle of the soft fibroma may be excised and the site
treated by cryotherapy.
Fig. 21.50 Soft fibroma.
2. Dermatofibroma
Synonym: Fibrous histiocytoma
Outline
Clinical images are available in hardcopy only. ● It is a firm benign tumor in which fibroblasts or
macrophages proliferate in the dermis. It may be caused
by external injury, such as an insect sting.
● Elevated brown nodules of several millimeters to 2 cm in
diameter are produced, most commonly on the extremi-

ties of adults.
A dermatofibroma is an intradermal nodule often described as
“a button buried in the shallow area of skin.” The skin surface of
the nodule is pigmented (Fig. 21.51). Dermatofibroma is solitary
in most cases, but it may occur multiply. Tenderness may be
Clinical images are available in hardcopy only. present. Connective tissue factors are thought to proliferate reac-
tively against a minor injury and cause dermatofibroma; some
dermatologists do not consider it a tumor in the strict sense. Der-
matofibroma develops slowly and usually stops changing when it
reaches a certain size. In rare cases, a giant dermatofibroma (benign)
a b c d e f g h
with
i
a diameter
j k
of 5 cml
or larger
m
occurs
n
on othe lower
p legs.q r
Fig. 21.51 Dermatofibroma. Pathology
a: A small nodule caused by dermatofibroma on
the lower leg. b: Giant dermatofibroma of 6 cm Dermal and subcutaneous proliferation of collagen fibers,
in diameter on the lower leg. fibroblasts and histiocytes occurs (Fig. 21.52). When the main
finding is histiocytic proliferation, it is called cellular dermatofi-
broma, and the tumor is slightly reddish and soft. Dermatofibro-
mas in which fibroblasts and collagen fibers proliferate are called
fibrous dermatofibromas. Fibroblasts scatter among collagen
fibers.
When the lesion is firm and blackish or relatively quick-grow-
ing, differentiation from malignant melanoma is necessary. Der-
21 matofibrosarcoma protuberans, xanthoma, lentigo and blue nevus
are also differentiated from dermatofibroma.
Treatment
Excision is conducted. As dermatofibroma is asymptomatic
and there is no malignant transformation, it can be left untreated
if it has been differentiated from malignant melanoma.
3. Hypertrophic scar, Keloid
Outline
Fig. 21.52 Histopathology of dermatofibro- ● A flat, sharply margined, red or brown elevation is
ma. caused by proliferation of connective tissue.
● It usually occurs secondarily after external injury or
H. Fibrous tumors 381
operation, but it may occur spontaneously in some cases.

● There is itching and tenderness.
● Local injection and ODT of steroids are the main treat-
ments. It is intractable.
Classification
An elevated, reddish-brown lesion occurs on preexisting scar-
ring from excessive production of collagen fibers in fibroblasts.
A lesion that atrophies spontaneously within a few years after
onset is called a hypertrophic scar. However, a lesion with a per- a b c d e f g h
sistent elevation in which the hyperplastic scar does not disap-
pear is called a scar keloid; it is known to be a pathologic
response of skin. Cases in which proliferation expands beyond
the edge of the scar are called true keloids; these are highly
intractable.
Clinical features
Hypertrophic scars and keloids are flat or dome-shaped,
a b c d e f g h i
sharply demarcated, and elevated. They range in color from
bright red to brown (Fig. 21.53). True keloids are characterized
by gradual enlargement as they progress. When pinched firmly
from the side, they are painful (lateral tenderness). Scar keloids
and hypertrophic scars do not enlarge beyond the scar width. Lat-
eral tenderness is not present in scar keloids and hypertrophic Clinical images are available in hardcopy only.
scars.
Treatment
Hypertrophic scars and keloids are intractable, althougha pres-b c d e f g h i j
sure dressing, topical ODT of steroids, local injection of steroids,
and oral Tranilast are useful at the early stages. For severe cases
and when dysfunction is present, these treatments and radiation
therapy are performed after surgical removal. Particularly for true
keloids, simple excision may double the probability of tumor
recurrence versus leaving it untreated.
a b c d e f g h i j
4. Palmoplantar fibromatosis 21k
Fig. 21.53 Hypertrophic scar and keloid.
Synonym: Dupuytren’s contracture a, b, c: Hypertrophic scar and keloid on the trunk.
d: Hypertrophic scar and keloid at the former site
of a granuloma in the pieced earlobe.
A superficial fibroma of firm cordlike substance occurs in the
aponeuroses of palms and soles. The fingers flex and contract
(Dupuytren’s contracture) (Fig. 21.54). Palmoplantar fibromato-
sis may accompany diabetes mellitus (Chapter 17).
5. Dorsal fibromatosis Clinical images are available in hardcopy only.
Synonym: Knuckle pad
Multiple keratotic elevations of 1 cm to 2 cm in diameter and

ranging in color from normal skin color to brown occur on the
joint regions of dorsal fingers and toes. Fig. 21.54 Dupuytren’s contracture.
6. Pearly penile papule

Multiple, systematized, dome-shaped, whitish papules 1 mm to
Clinical images are available in hardcopy only. 3 mm in diameter occur on the coronary sulcus of the penis.
Pearly penile papules are angiofibromas; they are considered a
normal variant, and require no therapy.
7. Acquired digital fibrokeratoma

A small, dome-shaped or cylindrical, protruding, elastic, firm
nodule with a keratinous surface and normal skin color occurs
Clinical images are available in hardcopy only. (Fig. 21.55), frequently on the fingers and toes but sometimes on
the palms and soles.
8. Fibrous papule of the nose

Fig. 21.55 Acquired digital fibrokeratoma. A solitary, firm, dome-shaped papule ranging in color from
normal skin color to brown or red and with a diameter of 10 mm
or less occurs on the face and neck (Fig. 21.56). Angiofibroma is
histopathologically observed.

9. Elastofibroma
A dome-shaped or flat, discoidal tumor occurs, usually to the
side of the subscapular region. There is proliferation of elastic
fibers (Fig. 21.57).
Fig. 21.56 Fibrous papule of the nose.
10. Sclerotic fibroma
A dome-shaped tumor of 2 cm in diameter occurs. Histopatho-
logically, firm collagen fibers are packed densely in the tumor.
Because cellular components are largely absent, sclerotic fibroma
appears as be a well-defined tumor in the dermis.

11. Nodular fasciitis
21 Fibroblasts around the fasciae rapidly proliferate, forming a
subcutaneous nodule of 2 cm to 3 cm in diameter (Fig. 21.58).
External injury may induce nodular fasciitis. The forearms of per-
sons in their 30s are most frequently affected. The condition is
often accompanied by tenderness and spontaneous pain. Patholog-
Fig. 21.57 Elastofibroma.
ically, premature fibroblast-like cells proliferate in irregular pat-
terns, such as bundles or spirals. Nuclear division is seen.
Differentiation from sarcoma (fibrosarcoma, malignant fibrous
histiocytoma, leiomyosarcoma, myxoid liposarcoma, dermatofi-
brosarcoma protuberans) is necessary. Nodular fasciitis tends to
heal spontaneously.
12. Giant cell tumor of the tendon sheath

A painless, intradermal or subcutaneous, firm, multilobular
I. Histiocytic tumors 383
nodule of several millimeters to 4 cm in diameter occurs, most

commonly on the proximal joints of fingers. It is thought to be a
tendon-derived or synovial membrane-derived tumor that is char-
acterized by proliferation of histiocyte-like cells. It should be
completely removed surgically. Clinical images are available in hardcopy only.
13. Desmoid tumor

It is a firm, deep-seated tumor of several centimeters to 10 cm
in diameter and normal skin color. The muscles of the shoulders,
chest wall, thighs and aponeurosis are most frequently involved. Fig. 21.58 Nodular fasciitis.
It is a benign tumor that histologically consists of differentiated
fibroblasts and collagen fibers. It slowly enlarges and infiltrates,
and it has a high probability of recurring after it resolves.
14. Cutaneous myxoma

This is an asymptomatic, soft, nodular benign tumor of up to
several centimeters in diameter. Histopathologically, star-shaped
or spindled tumor cells appear to float in mucous-membrane-like
tissue. Cutaneous myxoma is not a focal mucinosis, but an inde-
pendent disease.
15. Digital mucous cyst, Ganglion

A false cystic lesion containing mucin occurs on the dorsal
surface of a finger or toe (Fig. 21.59). It presents a blistered or
verrucous appearance. Digital mucous cysts are divided into
Fig. 21.59 Histopathology of digital mucous
myxomatous and ganglionic. A myxomatous digital mucous cyst cyst/ganglion.
is caused by overproduction of hyaluronic acid by fibroblasts and
is essentially focal mucinosis. A ganglionic digital mucous cyst is
a joint capsule or tendovaginal hernia. Incomplete removal of the
lesion leads to recurrence. Needle aspiration of accumulated
mucin is useful.
16. Mucous cyst of the oral mucosa 21

A soft, dome-shaped tumor of 2 mm to 10 mm in diameter
occurs, predominantly on the lower lip, or on the buccal mucosa
and tongue in rare cases (Fig. 21.60). When incised, the tumor
discharges transparent yellowish mucin. The pathogenesis is
thought to be rupturing of the salivary excretory duct by a bite,
leading to salivary flow and granuloma.
17. Pseudocyst of the auricle

An intense, pulsating cyst occurs unilaterally in the cartilage of
the upper part of the auricle. Inflammatory symptoms including
reddening and sharp pain are rarely present. The treatment is
local injection of steroids, although the condition is intractable.
Fig. 21.60 Mucous cyst of the oral mucosa.
I. Histiocytic tumors
1. Juvenile xanthogranuloma
A flat-topped, yellowish papule or nodule of several millime-
ters to 1 cm in diameter occurs, most frequently on the face,
extremities and trunk (Fig. 21.61). The onset is the time of birth
or several months thereafter. It disappears spontaneously by the
age of 5 to 6. Serum lipid is not elevated. The condition should
be differentiated from neurofibromatosis and Langerhans cell
histiocytosis, which may cause similar eruptions. Histopathologi-
cally, juvenile xanthogranuloma is a reactive granuloma com-
posed of histiocytes, xanthoma cells and Touton giant cells (Fig.
21.62).
2. Verruciform xanthoma
A granular-surfaced, pedunculated tumor ranging in color
from normal skin color to red and resembling a mulberry occurs,
frequently in the genitalia. Histopathologically, there is infiltra-
tion of multiple fat-rich foam cells to the dermal papillary and
subpapillary layers.
Clinical images are available in hardcopy only. 3. Multicentric reticulohistiocytosis

Firm brown or yellowish papules or nodules occur on the dor-
sal surfaces of hands and fingers, around the nail plates, and in
the elbow regions (Fig. 21.63). They may coalesce and form
Fig. 21.61 Juvenile xanthogranuloma. plaques. Multiple, proliferative, destructive arthritis also occurs.
The pathogenesis is thought to be reactive proliferation of phago-
cytic and activated monocytes or macrophage-derived histio-
cytes. Infiltration of histiocyte-like cells containing frosted
frosted-glass-like eosinophilic cellular cytoplasm is histopatho-
logically observed.
21
a b c d e f g h 4. Benign
i j cephalic
k histiocytosis
l m n o p q r
Fig. 21.62 Histopathology of juvenile xan-
thogranuloma.
Dispersed reddish-brown patches, papules and nodules of 3
a: Touton giant cells that have phagocytosed fat. mm to 10 mm in diameter occur, most commonly on the face,
earlobe, and neck of infants. Intradermal infiltration of mononu-
clear histiocyte-like cells are found histopathologically. Infiltrat-
ing cells are CD68 positive and S-100 protein negative. The skin
lesion usually disappears spontaneously; benign cephalic histio-
cytosis is thought to be a juvenile xanthogranuloma.
Fig. 21.63 Multicentric reticulohistiocytosis.

Multiple, firm, yellowish nodules and papules
occurred on the dorsum of hand and fingers.
J. Adipocellular tumor
Lipoma
Lipoma may appear on any site of the body surface, singly or
multiply (Fig. 21.64). It ranges in diameter from 1 cm to 10 cm
and usually occurs subcutaneously. The skin lesion is soft, palpa-
ble and usually highly mobile. Lipoma is asymptomatic in gener- Clinical images are available in hardcopy only.
al; however, pressure on nerves may produce pain.
Although the tumor cells resemble normal fat cells, they are
characterized by a thin covering of connective tissue. Depending
on the mesenchymal tissue elements in the skin lesion, lipoma
may be called fibrolipoma, angiolipoma or myolipoma. Lipoblas-
tic cells may also be seen. All these tumors are benign.
Malignant transformation is rarely seen. Lipomas extend grad- Fig. 21.64 Lipoma.
ually, and excision may be conducted if necessary.
K. Myogenic tumor
Leiomyoma
Leiomyoma derived from the arrector pili muscle is cutaneous
leiomyoma, that from the vascular smooth muscle is angi-
oleiomyoma, and that from the dartos fascia is genital leiomy- Clinical images are available in hardcopy only.
oma. A solitary or sometimes multiple tumor of 1 cm in diameter
occurs, often accompanied by paroxysmal pain (Fig. 21.65).
Angioleiomyoma is the most painful of the three types. Scrotal
leiomyoma is painless.
Fig. 21.65 Leiomyoma.
L. Osteogenic tumors 21
1. Osteoma cutis
Osteoma cutis is ectopic bone formation on the head and on
the skin of the extremities. It is divided into primary osteoma
cutis, which occurs in newborn and infants; and secondary osteo-
ma cutis. In primary osteoma cutis, multiple papules as firm and Clinical images are available in hardcopy only.
large as fine gravel occur, most frequently on the face.
2. Subungual exostosis
A tumor at the distal end of a finger or toe pushes the skin up
and appears under the nail plate. It occurs in persons between the Fig. 21.66-1 Subungual exostosis.
ages of 10 and 30 (Figs. 21.66-1 and 21.66-2). The big toes are
most frequently involved. Intense pain is present. Subungual
exostosis is differentiated from glomus tumor. X-ray is useful.
Clinical images are available in hardcopy only. Excision is the main treatment.
Fig. 21.66-2 X-ray of subungual exostosis.
M. Hematopoietic tumors
1. Lymphocytoma cutis
Synonyms: Lymphadenosis benigna cutis, Pseudolym-
phoma
Clinical images are available in hardcopy only. A lymphoid follicle structure forms as the result of an insect
sting, external injury, sunlight or Lyme disease, leading to a dark
red, dome-shaped tumor 1 cm to 2 cm in diameter, usually on the
face (Fig. 21.67). The lesion is elastic and smooth-surfaced.
Ulceration does not occur. The lesion appears solitarily in most
cases and disappears spontaneously several months after onset.
Differentiation from cutaneous B-cell lymphoma is important;
follicle formation is the main characteristic of lymphocytoma
cutis, and atypism is not found in lymphocytes. Lymphocytoma
cutis has a good prognosis, although it progresses to lymphoma
in rare cases.
2. Lymphocytic infiltration of the skin

(Jessner)
An asymptomatic, infiltrative plaque ranging in color from
light pink to reddish brown occurs, most frequently on the face.
21 Although it disappears spontaneously, it may recur. Dense lym-
Fig. 21.67 Lymphocytoma cutis.
phocytic infiltration is found in the dermis, especially in the
peripheral appendages. Lymphocytic infiltration of the skin is
differentiated from discoid lupus erythematosus and lymphoma.
M. Hematopoietic tumors 387
3. Kimura’s disease
Kimura’s disease, whose cause is unknown, occurs commonly
on the face of pubertal men. Cutaneous lymphoreticular tissue
proliferates reactively to cause the disease. Solitary or multiple,
flat or dome-shaped, soft, elastic, partially nodular, and subcuta-
neous or intradermal tumors of 5 cm to 10 cm in diameter appear.
The surface of the lesion is brownish, and itching may be present
(Fig. 21.68). Subcutaneous lymphatic follicle formation and
eosinophilic infiltration are observed histopathologically. Kimu- Clinical images are available in hardcopy only.
ra’s disease is characterized by the marked increase of
eosinophils in the peripheral blood and bone marrow, and elevat-
ed IgE level. It may be accompanied by atopic dermatitis and
pruritus. Local steroid injection is effective. Differentiation
between Kimura’s disease and angiolymphoid hyperplasia with
eosinophilia (ALHE, see the next section) has been controversial.
4. Angiolymphoid hyperplasia with

eosinophilia (ALHE)
Fig. 21.68 Kimura’s disease.
A firm, bright or dark red nodule of several centimeters in An intradermal and subcutaneous nodule and
diameter occurs, frequently on the peripheral auriculae, forehead tumor in the auricular region.
or temporal area (Fig. 21.69). The skin lesion is vascular prolifer-
ation of epithelial cells that contain abundant cytoplasm. Dense
infiltration of eosinophils and lymphocytes is often found in the
peripheral blood vessels. Although angiolymphoid hyperplasia
with eosinophilia (ALHE) has some similarities with Kimura’s
disease, these two diseases are in different categories. The main
treatment for ALHE is local injection of steroids; nevertheless,
the disease is intractable. Dye laser therapy is effective in some
cases.
5. Mastocytosis
Synonyms: Urticaria pigmentosa, Mastocytoma
Outline 21
● Mast cells proliferate and become tumorous.
● Urticaria is caused by rubbing (Darier’s sign).
● It occurs most frequently in infants, healing spontaneous-
ly by adulthood. When the onset is in adulthood, the dis-

ease is intractable.
● Urticarial attacks may recur in some cases.
Clinical features
Fig. 21.69 Angiolymphoid hyperplasia with
The onset of mastocytosis is in the first year after birth, in eosinophilia (ALHE).
most cases. The adult type, which is rare, has an onset of puberty Multiple, firm, itching, dark red nodules up to 1
or thereafter. In infant mastocytosis, multiple round or spindled cm in diameter appear.
brown patches or small nodules of 1 cm or less in diameter occur
after recurrent urticaria on the face and trunk. A solitary nodule
of several centimeters may occur in rare cases (Table 21.1).
Table 21.1 Classification of mastocytosis When mechanical stimulation is given to sites with eruptions,
(eruption types).
histamine is released from the mast cells, leading to the forma-
Urticaria pigmentosa tion of urticaria (Darier’s sign, Figs. 21.70 and 21.71). Urticaria
(Solitary) mastocytoma may be caused on the whole body skin by bathing or rubbing
Diffuse cutaneous mastocytosis with a towel, leading to systemic symptoms such as flushing,
Telangiectasia macularis eruptiva perstans nausea, vomiting, diarrhea, stomachache, fever, cardiac palpita-
tion, breathing difficulty and shock (urticarial attacks).
In adult mastocytosis, these symptoms first appear at puberty
or thereafter, and the eruptions and systemic symptoms tend to be
moderate. Darier’s sign is not significantly noticeable. In some
cases, extremely itchy diffuse eruptions may occur. There is
malignant formation in rare cases. Systemic mastocytosis is
accompanied by lymph node enlargement, splenohepatomegaly,
osteoporosis and osteosclerosis. Thrombocytopenic bleeding ten-
dency is present. It may become leukemia (mast-cell leukemia).

Mast cells that become tumorous and proliferate in the skin or
in the whole body are stimulated, leading to the release of hista-
mine and heparin, which results in urticaria. Mastocytosis in
which localized cutaneous lesions occur is called mastocytoma.
When tumorous lesions spread to the bone marrow, gastrointesti-
nal tract or spleen, it is called systemic mastocytosis. The patho-
genesis is unknown.
Pathology
There is proliferation of polygonal mast cells of various sizes.
Fig. 21.70 Mastocytosis. In the upper dermal layer, there is abnormal proliferation of
polygonal mast cells of various sizes that stain metachromatically
in toluidine blue (Fig. 21.72). It is classified by the proliferative
pattern into Unna mastocytosis and Róna mastocytosis. In the
former, multiple proliferative foci form map-like shapes resem-
bling islands. In the latter, a few dispersed perivascular foci form.
21

a b c d e a f b g c h d i e j f ka g lb h mc i nd j oe k pf l qg m rh
Fig. 21.71 Mastocytosis.
a: Solitary mastocytosis in an infant. b: Darier’s sign: urticaria is artificially caused by mechanical stimulation. c: Mastocytosis with
blistering.
M. Hematopoietic tumors 389
In pigmented areas of the skin lesion, the concentration of

melanin increases in the epidermal suprabasal cell layer and basal
layer in pigmented areas of the skin lesion.
Any stimulation that may induce release of histamine, such as
bathing or rubbing the skin, should be avoided. Treatment for
urticarial attacks is that same as for general urticaria (administra-
tion of histamine). Infant mastocytosis heals spontaneously in
several years to over a dozen years. It does not need treatment, as
long as there are few eruptions and no severe attacks. Adult mas- a b c d e f g h
tocytosis does not heal spontaneously and is intractable.
a b c d e f g h i
Fig. 21.72 Histopathology of mastocytosis
(Unna mastocytosis).
a: Mast cells of mastocytosis in HE-staining. b:
The mast cells stain metachromatically purple –
not blue – with toluidine blue (metachromasia).
21
Chapter
22 Malignant Skin Tumors and Melanomas
Tumors, whether malignant or benign, should be examined to determine the skin component from which they
originate. The clinical features, course of progression, and prognosis differ according to the cells from which the
tumor derives. Malignant skin tumors may derive from ① epidermal or follicular keratinocytes, ② intradermal
mesenchymal cells, ③ skin appendages such as sweat glands, or ④ neural crest cells. Benign tumors
described in Chapter 21 may become malignant and have malignant diagnostic names. This chapter introduces
malignant tumors that have relatively high incidences.
Malignant skin tumors
A. Epidermal and follicular tumors
1. Basal cell carcinoma (BCC)

Synonym: Basal cell epithelioma
Outline
● Itis a malignant skin tumor whose incidence is high.
● It is induced by UV and occurs most commonly in the
elderly, on the midline of the face.
● Small grayish-black nodules arrange themselves at the
edge of the tumor. The center of the tumor may be ulcer-

ative.
● Localized intense infiltration may be present. Metastasis
rarely occurs. The prognosis is good.

● Excision is the basic treatment.
Clinical features
Basal cell carcinoma (BCC) occurs most frequently in men
and women aged 40 to 60. In all subtypes, there are small, firm,
waxy, glossy, blackish-brown nodules at the periphery of the skin
22 lesion (Fig. 22.1). Telangiectasia often occurs in the lesion and at
the periphery. The face, especially its midline, is affected in 80%
of cases; the most notable exceptions to this are the superficial
type and fibroepithelial basal cell carcinoma of Pinkus, which
often appear on the trunk. The lesion appears blackish-brown in
most cases in Asians; however, it is usually normal skin color in
Caucasians. BCC may manifest various subtypes and clinical fea-
tures.
Ulceronodular type: More than 80% of BCCs are of this type.
Small, firm, black nodules coalesce, accompanied by epidermal
telangiectasia. The center of the lesion often ulcerates (rodent
ulcer).
Superficial type: A flatly elevated, infiltrative plaque ranging in
390
Malignant skin tumors / A. Epidermal and follicular tumors 391
Clinical images are

Clinical images are available Clinical images are available in Clinical images are available in
available in
in hardcopy only. hardcopy only. hardcopy only.
hardcopy only.
a b c ad be cf dag ebh fci gdaj hebk i fcl jgm

d khe
n l iof mjg
p q
nkh o
Clinical images are available Clinical images are available Clinical images are available Clinical images are available
in hardcopy only. in hardcopy only. in hardcopy only. in hardcopy only.
c ad be cf adg beh cf i ad g j be h k cf i l dg j m eh k n fi l o gj mp hk n q il o r jmp kn q lo r mp
Clinical images are

Clinical images are available Clinical images are available Clinical images are available in
available in
in hardcopy only. in hardcopy only. hardcopy only.
hardcopy only.
dg b eh c fi a
d gj b
e hk cf g
il d jm e
h kn fi lo gj mp h
k nq il j
or m p n
k q ol p
r m q
n or p q
Clinical images are available in Clinical images are available

hardcopy only. in hardcopy only.
k fb l gc m hd n ie o jf p kg q l h r mi nj ok pl qm rn o p q r
Fig. 22.1 Various clinical types of basal cell carcinoma (BCC).
a-j: Nodular BCC. k, l: Superficial BCC. m: BCC. Because the BCC was left untreated, it damaged the bone and infiltrated into the
brain. n: BCC infiltrated into the eyeball. o: Morphea-form BCC.
color from red to blackish brown gradually expands.

Sclerosing type (morphea-form): It is an oval, infiltrative
22
plaque with a slightly concave center.
Pinkus type (fibroepithelial basal cell carcinoma of Pinkus):
Small, multiple, pedunculated tumors occur, often in the midline Clinical images are available in hardcopy only.
of the lumbar and back sacral region. This type is histopathologi-
cally diagnosed; it is characterized by deeply expanded strands of
tumor cells within fibrous stromata.
Pathogenesis
a b c d e f g h
BCC results from proliferation of embryonic epithelium (pri-
Fig. 22.2-1 Basal cell carcinoma (BCC) from
mary epithelial germ cells) that differentiates into various organs. underlying disease.
There are hamartomatous factors; however, embryonic epitheli- a: BCC in a patient with xeroderma pigmento-
um continues to proliferate, destroying normal tissue. sum (group D).
392 22 Malignant Skin Tumors and Melanomas
Sunlight, traumatic injury, radiation and scarring are associat-

ed with the occurrence of BCC. It may occur secondarily with an
underlying disease, such as xeroderma pigmentosum, basal cell
nevus syndrome, chronic radiodermatitis, chronic arsenic poison-
ing, or nevus sebaceus. In such cases, the young may also be
affected, and the skin lesions are multiple (Figs. 22.2-1 and 22.2-2).
Pathology
BCC is the proliferation of tumor cells that resemble epidermal
basal cells (Fig. 22.3). The cells have a large oval nucleus, a
small amount of cytoplasm, and low atypicality. The tumor cells
arrange in a palisading pattern (palisading arrangement) at the
a b c d e f g h i j Connective
periphery. k l tissuem and mucin
n o p around
proliferate q ther
Fig. 22.2-2 Basal cell carcinoma (BCC) from tumor. BCC is characterized by the presence of spaces between
underlying disease. tumor and stroma that result from sectioning (separation artifact).
b: On a sebaceous nevus. Epidermis-derived and follicle-derived melanocytes are found
mingled. The abundance of melanophages in the stroma results in
the clinical blackish color. BCCs are histopathologically divided
into nodular, adenoid, keratotic, cystic and other types (Fig.
22.4).
BCC should be differentiated from lentigo, blue nevus, Spitz
nevus, seborrheic keratosis, chronic ulcer and chronic granuloma.
Dermoscopy is useful in many cases (Chapter 5). The superficial
type is further differentiated from psoriasis and Bowen’s disease.
The sclerosing type is differentiated from localized scleroderma,
discoid lupus erythematosus, granuloma annulare and keloid.
Treatment
Surgical removal is the basic treatment. As the face is fre-
quently affected, cosmetic surgery may be necessary. Cryothera-
py and topical chemotherapy may be chosen.
Fig. 22.3 Histopathology of basal cell carci- Prognosis

noma (BCC).
BCC does not metastasize in general: The prognosis is good.
However, it continues proliferating, destroying normal tissue
unless excised. Surgical treatment at an early stage is preferable.
22
nodular adenoid keratotic cystic

Fig. 22.4 Clinical and histological features of basal cell carcinoma.
2. Squamous cell carcinoma (SCC)

Synonym: Squamous cell cancer

● This cancer is caused by malignant proliferation of epi-
dermal keratinocytes.
● In situ lesions including those of solar keratosis and
a b c d e f g h
Bowen’s disease are often caused. Scarring lesions are
sometimes accompanied by SCC.
● There is often a preexisting lesion, such as scarring or
precancerous lesion.
● A firm nodule occurs, frequently on a sun-exposed area Clinical images are available in hardcopy only.
of the body. It often necrotizes and ulcerates, and gives
off a foul odor.
● Pathologically, individual cell keratinization and cancer
a b c d e f g h i
pearls are seen. The less keratinous are the cells, the
more undifferentiated and malignant the cancer is.
● Surgical removal, lymph node dissection, radiation thera-
py and chemotherapy are the main treatments.

Clinical features
Squamous cell carcinoma (SCC) occurs in the elderly solitarily
on sun-exposed areas of the body, such as the face and dorsum of
hands. Small papules and nodules appear on preexisting alesions,b c d e f g h i j
gradually extend, and form tumors or intractable ulcers (Figs.
22.5-1 and 22.5-2). They proliferate, taking on a cabbage-like
appearance. The skin lesion is often accompanied by keratinous
substance and crusts. When the surface of the lesion ulcerates,
bacterial secondary infection accompanied by distinct odor
occurs. SCC tends to spread to the regional lymph node, which
then feels firm when palpated.
Pathogenesis
SCC frequently occurs on a preexisting chronic a b
epidermalc d e f g h i j k
lesion. In addition to the preceding lesions shown in Table 22.1,
carcinogenic factors such as exposure to sun (UV), arsenic, tar
and irradiation are associated with the onset.
22
Table 22.1 Preexisting lesions of squamous cell carcinoma (SCC).

Type of disease Disease or condition
Scarring Burn, chronic radiodermatitis, lupus
a vulgaris,
b chronic
c d e f g h i j k l
pyoderma, discoid lupus erythematosus
Fig. 22.5-1 Squamous cell carcinoma (SCC).
Precancerous Bowen’s disease, actinic keratosis, leukoplakia, a: Actinic keratosis progressed to SCC. b: SCC
xeroderma pigmentosum, porokeratosis, lichen sclerosis on the lower lip. c: SCC on the abdominal
et atrophicus region. d: SCC on the buttocks. e: SCC on the
Other Phimosis, congenital poikiloderma, dystrophic epidermolysis dorsum of the hand.
bullosa, condyloma acuminatum, lichen planus
Table 22.2 TNM classification and stage grouping of SCC (UICC,

2002).
T classification (primary lesion)
Clinical images are T0 Primary lesion is not found.
available in Tis Carcinoma in situ
hardcopy only. T1 Lesions of 2 cm or less in diameter
T2 Lesions of 2 cm to 5 cm in diameter
T3 Lesions of 5 cm or more in diameter
a b c d e f g hT4 Lesions
i that jinvade tissues
k deeper
l than
m skin (e.g.,
n cartilage,
o p
muscle, q r
bone)
N classification (regional lymph nodes)
N0 Lesions without metastasis in regional lymph node
N1 Lesions with metastasis in regional lymph node
Clinical images are available in M classification (distant metastasis)
hardcopy only.
M0 Lesions without distant metastasis
M1 Lesions with distant metastasis
Staging
g Stage I T1N0M0 p q
a b c d e f h i j k l m n o r
Stage II T2,3M0N0
Fig. 22.5-2 Squamous cell carcinoma (SCC). Stage III T4N0M0 ; anyTN1M0
a: SCC in the palm where chronic radiodermatitis Stage IV anyTanyNM1
had occurred. b: SCC in a patient with recessive
dystrophic epidermolysis bullosa. (Sobin LH, et al. TNM classification of malignant tumors. 6th ed. Wiley-Liss; 2002).
Pathology
Abnormal keratinocytes that destroy the epidermal basal layer
are found within the infiltrative and thickened epidermis (Fig.
22.6). SCC is characterized by individual cell keratinization, dis-
turbance in cellular arrangement, nuclear atypicality, cancer
pearls and cellular division. The more undifferentiated and
malignant are the cells, the less keratinization may occur.

Differential diagnosis is histopathologically made. Lymph
node involvement and distant metastasis are examined by image
analysis to identify the disease stage (TNM classification, Table
22.2). Keratoacanthoma, actinic keratosis and basal cell carcino-
Fig. 22.6 Histopathology of squamous cell ma are differentiated from SCC.
carcinoma (SCC).
22 Treatment
Surgical removal is the first-line treatment. Lesions are excised
together with 4 mm to 10 mm of adjoining normal skin. Radical
lymph node dissection is conducted in cases with lymph node
available in available in involvement. However, prophylactic lymph node dissection tends
hardcopy only. hardcopy only. not to be conducted. Combined modality therapies, such as irra-
diation therapy and chemotherapy (Fig. 22.7), are conducted on
progressive cases.
Fig. 22.7 Chemotherapeutic example of

squamous cell carcinoma (SCC).
The lesion markedly reduced in size after intra-
arterial injection of cisplatin.
3. Actinic keratosis
Synonyms: Senile keratosis, Solar keratosis
Outline
● UV exposure induces keratinocytic atypia, particularly in
the basal cell layer. The atypical keratinocytes proliferate
in the epidermis. It is the early stage of squamous cell a b c d e f g h
carcinoma in situ.
● Asymptomatic, vaguely margined erythema or keratotic
lesions accompanied by scaling and crusting occur in the

elderly, on sun-exposed sites of the body.
● Horn-like protrusions (cutaneous horns) form in cases Clinical images are available in hardcopy only.
with marked keratinization.
● Cryotherapy, excision and topical anti-cancer agents are

a b c d e f g h i
Clinical features
A light-pink erythematous plaque several millimeters to 1 cm
in diameter occurs on a sun-exposed area of the body, such as the
face or dorsal hand. The plaque is covered with scales and crusts.
The margin of the plaque is often vague. Keratinization is usually
intense. Grayish-white keratotic nodules or horn-like protrusions
(cutaneous horns) may form (Fig. 22.8). The skin lesion occurs
singly or multiply, most frequently in persons over age 60. Near-
ly all elderly Caucasians are affected. Actinic keratosis occurs in
infancy in patients with xeroderma pigmentosum.
Pathogenesis a b c d e f g h i j
Epidermal keratinocytes that are damaged by UV proliferate
abnormally in the dermis.
Pathology
There are three histological types of actinic keratosis (Fig. Clinical images are available in hardcopy only.
22.9, Table 22.4). Malignant changes are localized in the cover-
ing epidermis, and follicular and sweat pore regions remain nor-
mal. Atypism is found in the lower epidermal basal layer.
Diagnosis, Differential diagnosis a b c d e f g h i j 22k

Fig. 22.8 Actinic keratosis.
Skin biopsy is conducted when it is difficult to differentiate a: Multiple actinic keratosis on the face. b: Ery-
actinic keratosis from seborrheic keratosis and senile lentigo. thematous lesion is present. c: Cutaneous horn
formed on the preauricular area. d: Actinic ker-
atosis in a patient with xeroderma pigmentosum
(group D).
Table 22. 4 Three histological types of actinic keratosis.
Type Characteristics
Hypertrophic Acanthosis, hyperkeratosis, parakeratosis, atypism of
actinic keratosis suprabasal cells, infiltration of inflammatory cells
Atrophic actinic Atrophy in the basal cell layer of the epidermis
keratosis
Bowenoid Cellular atypia resembling that of Bowen’s disease
actinic keratosis
Treatment
The main treatments are surgical removal, cryotherapy and
topical application of anticancer agents such as 5-FU and
bleomycin.
Prognosis
Some cases progress to squamous cell carcinoma. Aggravation
and enlargement of the peripheral erythema and rapid enlarge-
ment of ulcers often indicate progression of actinic keratosis.
4. Bowen’s disease
Fig. 22.9 Histopathology of actinic keratosis.
Marked atypism is observed, especially in the
lower epidermal layer. Outline
● It is a squamous cell carcinoma in situ. Highly atypical
cells proliferate in all epidermal layers.
● It presents as a sharply-margined plaque, ranging from
reddish brown to blackish brown, with a diameter of 1 cm

to 10 cm.
Clinical images are available in hardcopy only. ● Multiple lesions may be induced by chronic arsenic poi-
soning.
● It is pathologically characterized by individual cell kera-
tinization and cell clumping.

● Surgical removal and cryotherapy are the main treat-
ments.
Clinical features
Bowen’s disease occurs solitarily, in the elderly. A round or
oval, flatly elevated, relatively sharply edged, infiltrative plaque
Clinical images are available in hardcopy only. of several centimeters in diameter, ranging from brown to red-
dish brown, forms. Underneath the scales and crusts that cover
the plaque, red erosion is present (Figs. 22.10-1 and 22.10-2).
Small nodules and granuloma may be present.
Pathology
Fig. 22.10-1 Bowen’s disease
The pathology of Bowen’s disease corresponds to that of squa-
mous cell carcinoma in situ. Hyperkeratosis, parakeratosis, indi-
vidual cell keratinization and multinuclear dyskeratotic cells are
22 found in the epidermis. These atypical cells proliferate in all the
MEMO epidermal layers (Fig. 22.11).
Arsenical keratosis
This disease typifies skin diseases caused by
chronic arsenic poisoning. The clinical fea- Pathogenesis
tures are diffuse thickening of the horny cell The cause of solitary Bowen’s disease is unknown in many
layer and the formation of multiple verrucous
keratinized plaques. Multiple Bowen’s dis- cases. UV exposure and human papillomavirus may induce the
ease frequently occurs regardless of whether disease. Multiple Bowen’s disease is highly associated with
the area is exposed to the sun. Arsenical ker- arsenic intake. Therefore, history-taking on preexisting condi-
atosis may progress to squamous cell carcino-
ma, an infiltrative cancer. Basal cell carcinoma tions such as mass arsenic-poisoning or chronic pesticide poison-
may occur as a complication. ing and treatments such as arsenic antisyphilitic therapy are
Chemicals other than arsenic may induce important.
malignant skin tumors, such as keratosis from
machine oil or tar, and tar carcinoma from tar.
Clinical images are available in Clinical images are available

Clinical images are available in hardcopy only. hardcopy only. in hardcopy only.
Fig. 22.10-2 Bowen’s disease.

It is differentiated from chronic eczema, psoriasis, actinic ker-
atosis, extramammary Paget’s disease, and superficial type of basal
cell carcinoma. Differential diagnosis is made by skin biopsy.
Treatment
Surgical removal is the first-line treatment. Application of
ointments containing anticancer agents (5-FU and bleomycin)
and cryotherapy are also useful.
Fig. 22.11 Histopathology of Bowen’s dis-
Prognosis ease.
Dyskeratotic cells and clumping cells are present
Unless treated, the lesion destroys the basement membranes in all epidermal layers.
and progresses to squamous cell carcinoma; it may spread to the
lymph nodes.
5. Erythroplasia of Queyrat
This is Bowen’s disease on the mucous membranes and at the
mucocutaneous junction. Red, characteristically velvety-surfaced
plaques appear, mainly on the penis (Fig. 22.12). It may also
occur in the female genitalia and oral region. Erythroplasia of
Queyrat tends to progress to SCC.
22
6. Leukoplakia
Definition
A white keratinous plaque occurs in the mucous membranes
and at the mucocutaneous junction. Leukoplakia used to be a
diagnostic name for precancerous leukodermas; however, the Clinical images are available in hardcopy only.
term has come to include leukodermas caused by various dis-
eases. Leukoplakia may be benign or malignant.
Clinical features
The oral cavity and lips are most frequently involved. The
tongue, nipples and genital membranes (glans penis, vagina, Fig. 22.12 Erythroplasia of Queyrat.
perianal region) are affected. Leukoplakia that occurs as a pre-

cancerous lesion is slightly infiltrative, smooth-surfaced, kerati-
nous, verrucous, papillary and/or erosive. The epidermis thickens
from keratinous proliferation. There is high malignancy when an
erythroplasia-like lesion is produced (Fig. 22.13). Men over age
50, especially smokers, are most commonly affected.
Pathogenesis
When leukoplakia occurs as a precancerous skin lesion, chron-
ic stimulation such as from smoking may induce cellular atyp-
ism, leading to leukoplakia of the mucosa. Benign leukoplakia
may be caused by lichen planus, discoid lupus erythematosus,
syphilis, candidiasis or external injury.
Pathology
In malignant leukoplakia, varying degrees of atypism and
dyskeratosis are found in the epidermal cells.
Diagnosis
Skin biopsy is necessary to determine whether the lesion is
malignant or benign. If there is malignancy, treatment should be
done accordingly. If benign, investigation should be made for the
Fig. 22.13 Leukoplakia. underlying disease.
Treatment
When there is the possibility of leukoplakia being precancer-
ous, surgical removal, topical 5-FU application, laser therapy or
cryotherapy is conducted. Smoking must be stopped.
7. Oral florid papillomatosis

A keratotic or infiltrative plaque varying in shape from papil-
lary to cauliflower-like occurs on the lip or oral mucosa of the
Fig. 22.14 Verrucous carcinoma. elderly. It clinically resembles lip cancer at first sight. The patho-
genesis in some cases is thought to be a type of condyloma
acuminatum (Chapter 23), with which human papillomavirus is
associated. Severe thickening and keratinization of the epidermis
are pathologically observed; however, infiltrative proliferation is
22 not present.
8. Verrucous carcinoma
This is a squamous cell carcinoma with low-grade malignancy
in which elevated keratotic nodules form (Fig. 22.14). Although
localized proliferation of the nodules is marked, they rarely
metastasize to other organs. Verrucous carcinoma is classified by
the affected site into oral mucous verrucous carcinoma, genital
verrucous carcinoma and plantar verrucous carcinoma. Surgical
removal is the most reliable treatment; the disorder may recur if
treated by irradiation or electrosurgery.
Clinical images are available in Clinical images are available Clinical images are available Clinical images are available
hardcopy only. in hardcopy only. in hardcopy only. in hardcopy only.
a b c d a e b f c g ad h be i c f j ad g k be h l cf i m dg j n eh k o f i l p gj m q hk n r
Fig. 22.15-1 Natural history of keratoacanthoma (from onset to spontaneous resolution).
a: Onset. It begins as a dome-shaped tumor of 1 cm in diameter. b: The tumor gradually grows. c: It grows further. The center rup-
tures spontaneously. d: The lesion heals without treatment, with slight scarring.
9. Keratoacanthoma
Outline
● It is a clinically benign tumor that occurs in a hair follicle. Clinical images are available in hardcopy only.
Histopathologically, it closely resembles squamous cell
carcinoma.
● It appears suddenly and solitarily on the face or dorsal
hand, grows rapidly, and forms a dome-shaped,

a b cratered
c d e f g h i j k l
nodule.
● Most cases heal spontaneously in several months. Total
resection including skin biopsy is generally performed.

● It is important to differentiate it from squamous cell carci-
noma. Clinical images are available in hardcopy only.
Clinical features
More than 90% of cases involve the face. Middle-aged and
older men are most frequently affected.a b c
Keratoacanthomad is soli-e f g h i j k l m
tary in most cases; however, multiple lesions occur in many cases
of young persons, and these lesions usually accompany Muir-
Torre syndrome.
A small papule occurs and rapidly enlarges in several weeks to
22
a diameter of 1 cm to 2 cm, resulting in formation of a dome- Clinical images are available in hardcopy only.
shaped or hemispheric nodule (Figs. 22.15-1 and 22.15-2). The
nodule is elastically soft or firm, centrally umbilicated, cratered
and accompanied by a red halo. It ranges in color from normal
skin to light pink or dark red.a After bit rapidly
c enlarges
d to ae certainf g h i j k l m n
size, keratinization occurs at the center of the nodule, to form a Fig. 22.15-2 Keratoacanthoma.
large keratin plug. Many cases heal spontaneously in several Keratoacanthoma is characterized by dome-
shaped nodules with a volcano-like center (e-g).
months, with scarring.
Pathogenesis
Many years of exposure to sun (UV) or tar, and viral infection
or external injury are associated with the occurrence of
Table 22. 5 Clinical differences between keratoacanthoma and

squamous cell carcinoma (SCC).
Keratoacanthoma SCC
Site of onset Most frequently the face The whole body
Shape of eruption Volcano-like Various
Eruption size change Does not grow larger Grows larger
Multiple, or solitary Solitary in many cases, Solitary in most cases
multiple in some cases
Age of onset Younger than SCC Elderly persons
Development of Proliferates by the week Proliferates by the
eruption month
Spontaneous Yes No
regression?
Lymph node invasion? No Yes
keratoacanthoma.
Pathology
Hyperkeratosis is found at the center of the tumor, whose
periphery is surrounded by proliferating keratinocytes (Fig.
22.16). The keratinocytes are characterized by clear eosinophilic
cytoplasm and atypia. Tumor cells tend not to infiltrate the base-
ment membrane, but lymphocytes and neutrophils infiltrate
below the tumor. Keratoacanthoma is thought to be well-differ-
entiated squamous cell carcinoma or pseudocarcinoma.
Fig. 22.16 Histopathology of keratoacan-
thoma. Differential diagnosis
There is marked hyperkeratosis at the center of
the tumor. Suprabasal cells proliferate to enve- The main distinguishing characteristics of keratoacanthoma
lope the tumor. are listed in Table 22.5. Skin biopsy is necessary to differentiate
keratoacanthoma from squamous cell carcinoma. In squamous
cell carcinoma, the border between the edge of the tumor and
normal tissue is unclear, and there is asymmetrical morphology
and a high tendency of infiltration. Squamous cell carcinoma
enlarges far more slowly than keratoacanthoma. Keratoacan-
thoma is also differentiated from large molluscum contagiosum,
in which keratinization does not occur, and from basal cell carci-
noma.
22 Treatment
For diagnosis, it is necessary to examine the overall structure
of the skin lesion. Total resection of the skin lesion is conducted,
which is simultaneously a treatment. If pathological diagnosis is
made, follow-ups may be given instead of treatment until the
condition resolves. Irradiation, topical application or local injec-
tion of steroids or bleomycin ointments, and administration of
oral etretinate and cryotherapy are useful.
B. Sebaceous gland tumors
Sebaceous carcinoma
An orangey nodule occurs, most frequently on the Meibom Clinical images are available in
glands in the palpebra sebaceous glands and less frequently in the hardcopy only.
skin (Fig. 22.17). Histopathologically, the tumor cell nest contains
atypical clear sebaceous cells. In the autosomal dominantly inher-
ited Muir-Torre syndrome, multiple benign or malignant seba- Fig. 22.17 Sebaceous carcinoma in the Mei-
ceous tumors occur, often accompanied by visceral malignancies. bom gland.
C. Sweat gland tumors
1. Mammary Paget’s disease
Outline
● Infiltrative eczema-like erythema or erosion occurs in the
nipples and at their periphery.
● It occurs most commonly in the opening of the lactiferous
ducts of middle-aged women. It is a carcinoma in situ

that derives from the lactiferous duct epithelia. It corre-
sponds to breast cancer.
● A tumor does not form in most cases.
● It is not itchy, nor does it respond to steroids. Mammary Fig. 22.18 Mammary Paget’s disease.
Infiltrative erythema is present on the nipple. The
Paget’s disease can be distinguished from eczema by treatment for mammary Paget’s disease is gener-
these characteristics. ally the same as for breast cancer.
● The treatments are the same as those for breast cancer.
Clinical features
A plaque with clearly circumscribed erythema, infiltration and
crusts appears on the nipple and areola (Fig. 22.18). The lesion is
slightly firm and palpable, and usually unilateral. Middle-aged
women are most frequently affected. Bilateral mammary Paget’s
disease and mammary Paget’s disease in men are extremely rare.
22
Mammary Paget’s disease accounts for 1% to 4% of all breast
cancer cases. The symptoms progress gradually with each year.
As they progress, a palpable tumor forms in the breast and metas-
tasizes to a regional lymph node (mainly the axillary lymph node).
Pathogenesis
Mammary Paget’s disease is thought to originate from cancer
in the excretory duct cells of the mammary glands (intraductal
carcinoma) or carcinoma from epidermal keratinocytes.
Pathology
Large, clear Paget’s cells replace wall cells in the ducts and
glands. The Paget’s cells may also proliferate in cavities in the

lactiferous ducts and mammary glands. Although the skin lesion
does not clinically appear to be severe, Paget’s cells infiltrate lac-
tiferous ducts and mammary glands more extensively than is
clinically obvious. With further progression, Paget’s cells infil-
trate into the dermis. Immunostaining is positive for CEA.
Chronic breast eczema, tinea corporis, and basal cell carcino-
ma should be distinguished from mammary Paget’s disease.
Intractable eczematous lesions on the breast that do not respond
to topical agents should be suspected of being mammary Paget’s
disease.
Treatment
The treatments are the same as those for breast cancer. Mastec-
tomy and regional lymph node dissection are the basic treatments.
2. Extramammary Paget’s disease
Outline
● This is Paget’s disease on areas other than the breasts.

a b c d e f a g b h c i d j e ak f bl g cm h dn i eo j fp k gq l hr m
22

c d e a f b g c h d ai e bj f ck g dl h em i fn j go k hp l iq m jr nk ol pm
Fig. 22.19 Extramammary Paget’s disease.
a: Sharply demarcated erythematous plaques. b: Mix of hypopigmented macules and erythematous plaques. c: Paget cells present in
hypopigmented macules around the anus. d, e: Extramammary Paget’s disease on the labia majora of an elderly woman. f: Extra-
mammary Paget’s disease on the axillary fossa.
Malignant skin tumors / C. Sweat gland tumors 403
The elderly are affected.

● Sharply margined eczematous erythema and erosion
occur.
● It is thought to be intraepidermal cancer that originates
from the apocrine glands. The genitalia, anal region and

axillary fossae are most frequently involved.
● It occasionally destroys the basement membranes and
progresses to invasive carcinoma.

● Extensive resection and lymph node dissection are nec-
essary, if regional lymph node metastasis may occur.
Clinical features
Extramammary Paget’s disease occurs most commonly in the
elderly. A bright red infiltrative plaque resembling mammary Fig. 22.20 Invasive extramammary Paget’s
disease that had been left untreated for a
Paget’s disease appears (Fig. 22.19), most frequently on the geni- long period of time.
talia, less frequently on the perianal region, perineum, axillary A flat lesion elevated gradually, forming infiltra-
fossa or umbilical region. Itching is often present. The lesion tive nodules. The lesion destroyed the basal
membrane and infiltrated in the deep portions of
gradually spreads, with melanin deposition at the periphery in the dermis. Metastasis to the regional lymph node
some cases. Extramammary Paget’s disease occasionally was observed.
destroys the basement membranes and develops a palpable small
tumor in the lesion (Fig. 22.20). Regional lymph node metastasis
occurs in advanced cases; the prognosis is poor.
Pathogenesis
Extramammary Paget’s disease is thought to originate from
apocrine sweat gland cells.
Pathology
Large, bright, scattered or aggregated Paget’s cells are found
in the epidermis and sweat ducts (Fig. 22.21).
Differential diagnosis Fig. 22.21 Histopathology of extramammary

Eczema, candidiasis, genital tinea, Bowen’s disease, Hailey- Paget’s disease.
There are scattered Paget’s cells with large, clear
Hailey disease and pemphigus vegetans are distinguished from cytoplasm.
extramammary Paget’s disease. Diagnosis can be made by patho-
logical observation of Paget’s cells.
Treatment
The basic treatment is extensive surgical removal with a 1-to
22
3-cm margin including the peripheral normal skin.
3. Eccrine porocarcinoma
This is a malignant form of eccrine poroma (Chapter 21). A
red plaque or nodule, often ulcerative, occurs, most frequently on
the lower legs of the elderly (Fig. 22.22). In most cases, eccrine
porocarcinoma is clinically observed as a tumor that is mix of
eccrine poroma and eccrine porocarcinoma. It often metastasizes.
4. Microcystic adnexal carcinoma (MAC)

Synonym: Syringoid eccrine carcinoma
A firm, discoidal, intradermal nodule 1 cm to 3 cm in diameter

occurs, most commonly around the mouth of persons of middle
Clinical images are available in hardcopy only. age and older. Some think it to be a sclerosing eccrine porocarci-
noma or a cancer derived from a hair follicle or apocrine sweat
gland. After extensive resection, the site should be examined
pathologically for any remaining lesions because of the high fre-
quency of local recurrence. For this reason, Moh’s microsurgery
is also effective. Distant metastasis rarely occurs.
Fig. 22.22 Eccrine porocarcinoma arising 5. Mucinous carcinoma of the skin

from eccrine poroma.
a: Eccrine porocarcinoma (malignant). b: Eccrine A nodule of 2 cm to 3 cm in diameter occurs, frequently on the
poroma (benign). eccrine secretory part of the face or scalp. The tumor is covered
by abundant mucin. The nuclei of tumor cells show slight atyp-
ism. Metastatic carcinoma of the skin with mucus production
should be distinguished from mucinous carcinoma of the skin.
D. Nervous system tumors
Merkel cell carcinoma

Outline
● Itis a skin cancer that originates from Merkel cells of the
epidermis. These cells are thought to be tactile receptor
cells.
● A highly malignant, domed red tumor forms on the face,
Fig. 22.23 Merkel cell carcinoma. head, neck or extremities of the elderly.
● Extensive resection, irradiation and chemotherapy are
Clinical features
22 A firm, domed nodule varying in color from light pink to pur-
plish red and with a diameter of 1 cm to 3 cm occurs, most fre-
quently on the face of the elderly (Fig. 22.23).
Pathology
Deep-staining small cells arrange densely in a palisading pat-
tern, resembling the tumor cells of small-cell lung cancer (Fig.
22.24). Merkel cell carcinoma is characterized by dense-core
granules that resemble Merkel cells (Fig. 22.25). Immunohisto-
chemically, neuron specific enolase (NSE) and cytokeratin 20 are
positive in many cases.
Fig. 22.24 Histopathology of Merkel cell car-
cinoma.
Malignant skin tumors / E. Mesenchymal tumors 405

Merkel cell carcinoma is diagnosed by clinical features and
histopathological tests. Adnexal malignant tumors, amelanotic
malignant melanoma, and lymphoma are differentiated from it.
Metastasis of small-cell lung cancer to the skin presents the same
symptoms and pathology as Merkel-cell carcinoma. If this carci-
noma is suspected, examination for lung cancer should be per-
formed.
Merkel cell carcinoma tends to be highly malignant. At the rel-
atively early stages, there is lymph node involvement or
hematogenous metastasis. Because of its recurrent tendency, Fig. 22.25 Electron microscopic image of
extensive excision and lymph node dissection are conducted. Merkel cell carcinoma, enlarged image of
dense-core granules.
Radiation therapy and chemotherapy are also useful. Cases with
spontaneous healing have been reported.
E. Mesenchymal tumors
a. Fibrous tissue tumors
1. Dermatofibrosarcoma protuberans (DFSP) Clinical images are available in hardcopy only.
Dermatofibrosarcoma protuberans (DFSP) is a malignant

tumor that is thought to derive from fibroblasts, myofibroblasts
or histiocytes. The trunk of adult men is most commonly
involved. It begins as an intradermal or subcutaneous nodule that
slowly forms a dome-shaped or fungiform tumor at the local site
(Fig. 22.26). The tumor is firm and dark reddish brown, often
accompanied by erosion or crusts. A characteristic swirl arrange-
ment of tumor cells and fibers called storiform pattern is
histopathologically observed (Fig. 22.27). The tumor cells are Clinical images are available in hardcopy only.
usually factor XIIIa negative and CD34 positive. DFSP rarely
metastasizes (fewer than 10% of cases); however, extensive
resection is necessary because of its high tendency to recur.
22
2. Malignant fibrous histiocytoma (MFH)
Fig. 22.26 Dermatofibrosarcoma protuber-
This is the most frequently occurring soft-tissue sarcoma. The ans (DFSP).
proximal limb muscles and retroperitoneum of adults are most
commonly involved. Skin is rarely affected primarily. A painless,
lobulated, multinodular subcutaneous tumor occurs in most
cases. Hematoma-like lesions (angiomatoid type) may form.
Malignant fibrous histiocytoma (MFH) is histopathologically
composed of highly atypical fibroblast-like cells and histiocyte-
like cells. It displays various pathological features, including
peculiarly shaped giant cells and inflammatory cellular infiltra-
tion. MFH is classified by pathological findings into several
types: storiform-pleomorphic (the highest incidence), myxoid,
giant-cell, inflammatory and angiomatoid. MFH is highly malig-

nant, and the prognosis tends to be poor.
3. Atypical fibroxanthoma
A lesion composed of histiocyte-like cells with low malignant
potential forms, most frequently on a sun-exposed area. Some
consider it as identical to superficial MFH.
4. Epithelioid sarcoma
Fig. 22.27 Histopathology of dermatofi- This is a rare malignant tumor. It occurs most commonly at the
brosarcoma protuberans.
ends of the extremities and progresses relatively slowly. It begins
as intradermal or subcutaneous nodules that gradually increase in
number and size (Fig. 22.28). Epithelial cells with abundant
eosinophilic components histopathologically proliferate in sheet-
like formation. The center of the nodule is necrotic in many
cases. At the early stages, epithelioid sarcoma resembles granulo-
ma annulare and rheumatoid nodule; differential diagnosis can be
made by the immunohistochemical finding of keratin-positive
cells in epithelioid sarcoma. Extensive resection is the basic treat-
a b c d e f g ment.
h When
i epithelioid
j k sarcoma
l metastasizes,
m n lymph
o nodes
p areq r
often involved. The prognosis is poor.
5. Synovial sarcoma
Clinical images are available in hardcopy only. A soft, painful tumor occurs, frequently in the large joint of an
extremity, particularly in the knee. In rare cases, it occurs subcu-
taneously or subfascially. Although synovial sarcoma used to be
attributed to abnormal production of synovial tissue, that idea has
a b c d e f g h been
i disproven
j k in recent
l years.
m Chromosomal
n o translocation
p q t (X;r
18) (p11.2; q11.2) occurs in the cells of the sarcoma. The tumor
grows slowly and metastasizes to the lymph nodes. The progno-
Clinical images are available in hardcopy only. sis is poor. Extensive resection is essential.
b c d e f g h i j k l of the
m fat
n cells
o p q r
b. Tumors
Fig. 22.28 The course of epithelioid sarcoma.
a: It begins as nodules of 1 cm in diameter. b, c:
22 The number of nodules increases gradually. The Liposarcoma
tumors become infiltrative and enlarged.
A liposarcoma is a malignant mesenchymal tumor that differ-
entiates into fat cells. It is deep-seated, clearly defined, large and
nearly asymptomatic. According to the new WHO classification,
the malignant types are the well-differentiated type, myxoid type,
round cell type, pleomorphic type, and dedifferentiated type.
Well-differentiated liposarcoma has a good prognosis and is also
called atypical lipomatous tumor. Extensive resection is the main
treatment.
c. Vascular tumor
1. Angiosarcoma
Synonym: Malignant angioendothelioma Clinical images are available in hardcopy only.
Outline
● Vaguely margined, dark-reddish-violet erythema, bloody
blisters and easily bleeding elevated plaques form on the
a b c d e f g h
head and face of the elderly.
● It is a malignant tumor caused by proliferation of
endothelial cells in the blood vessels and lymph vessels.

● It tends to metastasize to the lungs. The prognosis is
extremely poor, with a 5-year survival rate of less than 10%.

Clinical features
Angiosarcoma is induced in some cases by minor external
injury. A small black nodule first appears and progressively
enlarges to present an edematous dark red plaque (Fig. 22.29).a b c d e f g h i
The plaque easily bleeds and forms erosion and crusts, resulting
in exudative ulceration. As it progresses, tumorous nodules
appear, metastasizing to the lungs, liver and lymph nodes, lead-
ing to hemopneumothorax and death in many cases.
Angiosarcoma that occurs at sites with prolonged postopera-
tive lymphedema is called Stewart-Treves syndrome, which usu-
ally occurs on the arm with lymphedema after mastectomy.
Pathology
Markedly atypical tumor cells proliferate, forming a luminal
structure (Fig. 22.30). Immunostaining is positive for UEA-I
lectin and factor VIII related antigen (von Willebrand factor) in
many cases.
Diagnosis
Angiosarcoma can be diagnosed by the characteristic clinical
features; however, differential diagnosis is made by skin biopsy.
As most cases have already progressed at the time of diagnosis,
a b c d e f g h i j
various tests are performed to examine the systemic condition.
22
Because metastasis to other organs, the lungs in particular, influ-
ences the prognosis, chest X-ray, CT, MRI and nuclear medicine
imaging are conducted.
Local recurrence and hematogenous metastasis often occur in
angiosarcoma. In cases at the early stages with good systemic
condition and no metastasis, combination therapy of extensive
a b g j
resection and irradiation or chemotherapy is conducted. Local orc d e f h i k
arterial injection of IL-2 may also be given. The average survival Fig. 22.29 Angiosarcoma.
a, b: Dark red erythema and an elevated plaque
period between the patient’s first consultation and death is about form. c: The lesion partially ulcerates. d: Angiosar-
one year. The 5-year survival rate is only 12%. coma on lymphedema.
2. Kaposi’s sarcoma
Outline
● The lower legs of the elderly and patients with immunod-
eficiency are most frequently affected.
● It is characterized by endothelial and vascular prolifera-
tion. Edema first appears, forming a firm nodule that is

accompanied by intense pain and easy bleeding.
● The lymph nodes and internal organs are involved.
Patients may die from bleeding of the internal organs.

● HHV-8 is associated with the onset.
● Irradiation therapy and chemotherapy are the main treat-
ments.
Clinical features
Kaposi’s sarcoma occurs on the extremities, particularly on the
feet, gradually spreading to the proximal areas. Multiple, pur-
plish-brown patches or angioma-like papules appear in the skin,
mucosa and internal organs (Fig. 22.31), rapidly spreading and
forming elevated plaques that become firm nodules. The progres-
sion begins with a patch stage, followed by a plaque stage and
Fig. 22.30 Histopathology of angiosarcoma. then a nodule stage.
The eruptions themselves are largely painless; however, sec-
ondary lymphedema causes sharp pain. In progressive cases,
infiltration occurs in the lymph nodes, gastrointestinal tract, liver,
lungs and bones, causing various symptoms.
Clinical images are available in hardcopy only. Classification, Pathogenesis

Kaposi’s sarcoma is caused by various factors related to
immunodeficiency, race and country of residence. It is divided
into four types: classic, African endemic, immunosuppressive-
treatment-related, and epidemic HIV-associated. The epidemic
HIV-associated type progresses rapidly, whereas the others
Fig. 22.31 Multiple Kaposi’s sarcoma on a
patient with AIDS. progress slowly.
When human herpes virus type 8 (HHV-8) infection occurs in
patients with immunodeficiency – such as those with AIDS or
leukemia, or those who have been administered steroids or
22 immunosuppressants – the result in canceration of primitive mes-
enchymal cells. The mechanism is unknown. Association of
HLA-DR5 with Kaposi’s sarcoma has been suggested. Kaposi’s
sarcoma occurs in about 5% of patients with AIDS in Japan.
Pathology
There are three stages.
Patch stage: Early lesions show uncharacteristic features.
Fig. 22.32 Histopathology of Kaposi’s sar- Perivascular and periadnexal proliferation of endothelial cells
coma. with little atypia is seen.
Plaque stage: There is more extensive angio-proliferation with
vascular spaces. Inflammatory lymphocytes and extravascular
red cells with siderophages are numerous throughout the dermis.
Nodular stage: Well-defined nodules containing spindle cells

with mitosis are seen.
Treatment
Irradiation therapy and combination chemotherapy are the
main treatments. Surgical removal may be conducted on local- Clinical images are available in
ized lesions. hardcopy only.
Prognosis
Cases in which patients died within 2 to 8 years after onset
have been reported. The immediate cause of death is bleeding
from the gastrointestinal tract or liver. Kaposi’s sarcoma heals a b c d e f g h
spontaneously in about 2% of cases.
d. Histiocytic tumors
Langerhans cell histiocytosis (LCH) hardcopy only.
Synonym: Histiocytosis X
Malignant Langerhans cells proliferate in systemic organs such

as the skin, liver, spleen, lymph nodes and lungs, and in the bonea b c d e f g h i
marrow. Langerhans-cell histiocytosis (LCH) had been classified Fig. 22.33 Langerhans cell histiocytosis.
by the onset age and clinical features into Letterer-Siwe disease, a: Multiple, keratotic, erythematous plaques on
the trunk. b: Eczema-like plaques on the scalp.
Hand-Schüller-Christian disease, and eosinophilic granuloma. In Alopecia, pustules and crusts are present.
recent years, these types have come to be unified under the name
of LCH. The cutaneous symptoms are hemorrhagic papules and
eczema-like lesions that frequently appear on the seborrheic areas
(Fig. 22.33), and juvenile xanthogranuloma-like eruptions. Histo-
logically, the tumor cells are positive for CD1a and S-100 pro-
teins (Fig. 22.34).
Letterer-Siwe disease: It occurs suddenly in infancy, rapidly on
the whole body. Hemorrhagic papules appear on the whole body,
accompanied by fever, splenohepatomegaly and pulmonary
lesion. Seborrheic dermatitis-like lesions occur on the scalp. The
prognosis is poor. a b c d e f g h
Hand-Schüller-Christian disease: It occurs most frequently in
early childhood. The three main symptoms are pericranial defi-
ciency in osteolytic areas including the skull, ocular proptosis,
22
and diabetes insipidus. Granulomatous and xanthomatous erup-
tions appear.
Congenital self-healing reticulohistiocytosis MEMO

It is also called congenital self-healing Langerhans cell histiocytosis a b c d e f g h i
and Hashimoto-Pitzker disease. Within several weeks after birth, multi-
ple or disseminated, red to brownish papules or nodules 2 mm to 20 Fig. 22.34 Histopathology of Langerhans
mm in diameter occur on the whole body. There is proliferation of cell histiocytosis.
Langerhans cells. Langerhans cell histiocytosis may be difficult to dif- a: HE-staining image of Langerhans cells. There
ferentiate from congenital self-healing reticulohistocytosis; however, in is marked infiltrative proliferation of Langerhans
the latter, the eruptions disappear spontaneously in several weeks to 1 cells in the upper dermal layer. b: CD1a chromat-
year. ic-staining of Langerhans cells. There are CD1a-
positive infiltrative cells.
Table 22.6 WHO/EORTC classification of Eosinophilic granuloma: It occurs in late childhood and adult-
cutaneous lymphomas.
hood. Granulomas form in the bones. The prognosis is good.
Cutaneous T-cell and NK-cell lymphomas
Mycosis fungoides (MF)
MF variants and subtypes
e. Hematopoietic tumors (also refer to e-2
Folliculotropic MF and e-3 on p. 418-9)
Pagetoid reticulosis
Granulomatous slack skin
Sézary syndrome e-1. Cutaneous lymphoma
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30+ lymphoproliferative Lymphoma is a malignant tumor of the lymphoid linage cells.
disorders Primary cutaneous lymphoma, classified as a non-Hodgkin’s dis-
Primary cutaneous anaplastic large-cell ease, is the second most common extranodal lymphoma after
lymphoma
Lymphomatoid papulosis those that occur in the gastrointestinal tract or nasopharyngeal
Subcutaneous panniculitis-like T-cell lymphoma region. Ninety percent of cases with cutaneous lymphoma are T-
Extranodal NK/T-cell lymphoma, nasal type cell derived. Primary cutaneous lymphoma is defined as a lym-
Primary cutaneous peripheral T-cell lymphoma,
unspecified (PTL) phoma that presents in the skin with no evidence of
Primary cutaneous aggressive epidermotropic extracutaneous disease at the time of diagnosis.
CD8 T-cell lymphoma (provisional) There are several systems for classifying cutaneous lym-
Cutaneous g/d T-cell lymphoma (provisional)
Primary cutaneous CD4+ small/medium-sized
phoma; however, classification has been standardized by the
pleomorphic T-cell lymphoma (provisional) European Organization for Research and Treatment of Cancer
Cutaneous B-cell lymphomas (EORTC) and WHO (Table 22.6). Cutaneous lymphoma is first
Primary cutaneous marginal-zone B-cell lymphoma
categorized according to the cells from which it derives, clinical
Primary cutaneous follicle center lymphoma features, pathological features and response to treatment. It is
Primary cutaneous diffuse large B-cell then subcategorized according to malignancy and prognosis into
lymphoma, leg type indolent, intermediate and aggressive.
Primary cutaneous diffuse large B-cell
lymphoma, other Histopathological features are important for diagnosis. The
Intravascular large B-cell lymphoma origin and monoclonality of the tumor cells and the severity of
Precursor hematologic neoplasm infiltration can be determined by the surface marker, T-cell
Precursor hematologic neoplasm receptors (TCR) and immunoglobulin (Ig) using monoclonal
CD4+/CD56+ hematodermic neoplasm (blastic antibodies, and gene rearrangement of TCR and Ig.
NK-cell lymphoma)
(Willemze R. et al. WHO-EORTC classification for cuta- Cutaneous T-cell lymphomas
neous lymphomas. Blood. 2005; 105: 3768-85).
This section broadly defines and classifies cutaneous T-cell

lymphomas (Figs. 22.35-1 and 22.35-2). They are classified into
the several subtypes listed in Table 22.6.
1. Mycosis fungoides (MF)

22
Outline
● It is a T-cell lymphoma that occurs primarily in the skin
and presents characteristic cutaneous symptoms.
● It progresses slowly. The three stages are classified mor-

phologically as patch, plaque and tumor. It does not
spread to other organs until the final stage.
● Atypical lymphocytic infiltration (Pautrier’s microabscess)
in the epidermis is a characteristic histopathological find-

ing.
● PUVA therapy is the first-line treatment. Combination
Fig. 22.35-1 Cutaneous T-cell lymphoma. chemotherapy is conducted at the final stage.
A solitary skin tumor occurred in this case.
Clinical features
Mycosis fungoides (MF) follows a course that is divided into
three stages, according to the skin clinical features of eruptions
(Figs. 22.36-1 and 22.36-2). At the early stage, dermatitis or pso-
riasis-like eruptions occur and persist for several to ten years Clinical images are available in hardcopy only.
(patch or erythematous stage). The skin lesion becomes infiltra-
tive and flatly elevated (plaque stage). Several years later, cuta-
neous nodules and tumors form, metastasize to lymph nodes, and
infiltrate other organs (tumor stage).
① Patch stage (erythematous stage)
Fig. 22.35-2 Cutaneous T-cell lymphoma.
Multiple erythema of various shapes and sizes, accompanied Generalized follicular papules occurred in this
by moderate scaling, occur on the trunk and extremities. MF at case (folliculotropic mycosis fungoides).
this stage is sometimes clinically indistinguishable from sebor-
rheic dermatitis, psoriasis, and pityriasis rosea (Gibert) and para-
psoriasis. It may respond to topical steroids; however, eruptions
spread with repeated exacerbation and remission for several to
ten years. As the eruptions progress, they are often accompanied Clinical images are available in hardcopy only.
by atrophy of skin and pigmentation. The large-plaque type of
parapsoriasis en plaque is considered to be the early patch stage
of MF (Chapter 15).
② Plaque stage a b c d e f g h
Circular or horseshoe-shaped, flatly elevated, red or reddish-
brown eruptions with palpable infiltration appear. They progress
to the tumor stage with repeated exacerbation and remission.
③ Tumor stage
Dome-shaped, elevated, elastic, dark red tumors occur. The
surface is smooth at first; however, they may become partly ero-
sive and ulcerate later on. After the tumor stage, the lesions
progress rapidly and infiltrate the lymph nodes and internal Clinical images are available in hardcopy only.
organs. They rarely become leukemic. Immunodeficiency and
lesions of internal organs lead to death in 1 to 2 years in many
cases.
Pathology
Patch stage: Lymphocytic infiltration occurs in the superficial
g
dermis. As MF progresses, lymphocytic infiltration also occurs ina b c d e f h i
the epidermis (epidermotropism). Atypical lymphocytes are
observed in some cases.
Plaque stage: Markedly dense, band-like cellular infiltration
22
occurs in the upper dermal layer. Large atypical cells containing
deeply constricted nuclei, called mycosis cells, are found in the
infiltrative lymphocytes. Epidermotropism becomes distinct. Clinical images are available in hardcopy only.
Multiple honeycomb epidermal lymphocytic infiltration, called
Pautrier’s microabscess (Fig. 22.37), is observed.
Tumor stage: Epidermotropism is lost. Mycosis cells infiltrate
all dermal layers and subcutaneous tissue.
Diagnosis, Differential diagnosis a b c d e f g h i j

There are few abnormal findings in blood tests and biochemi- Fig. 22.36-1 Mycosis fungoides.
cal tests until MF progresses to the final stages. MF is diagnosed a, b, c: Mycosis fungoides at the erythematous
by clinical features and histopathological findings. As characteristic stage.
Clinical
images are Clinical images are
Clinical images are Clinical images are available in
available in hardcopy only. hardcopy only.
hardcopy hardcopy only.
only.
ba cb dca edb f ec gaf d hbge ich f jdi g kej h lfk i gl j

m nhmk oin l pjom qkpn rlqo mr p nq
bf cg dh a ei b fj c gk d hl e m
i f jn g ko h lp q
i m j nr k o l p m q n r o p
Fig. 22.36-2 Mycosis fungoides.
d, e: Plaque stage. f-j: Tumor stage. Severely infiltrative ulcers form.
findings of MF are difficult to obtain at the early stages, skin

biopsies may be conducted repeatedly at certain intervals in sus-
pected cases. Immunohistological tests are conducted on the
Gene rearrangement MEMO biopsy specimen: The surface marker of helper T-cells is con-
analysis firmed in the infiltrating lymphocytes. Monoclonality of T-cell
Rearrangement of the TCR and immunoglob- receptor gene rearrangement is identified (MEMO). Dermatitis,
ulin (Ig) genes occurs during lymphocyte dif-
ferentiation for recognition of non-self, which psoriasis, parapsoriasis, adult T-cell leukemia, and other types of
leads to various antigenic recognitions. In malignant lymphoma are differentiated from MF.
lymphoma, lymphocytes proliferate mono-
clonally and there is often one rearrangement Treatment
pattern to the TCR/Ig gene. Thus, southern
blotting from skin lesion tissue is useful for Phototherapies such as PUVA and narrow-band UVB inhibit
22 differentiating between lymphoma and benign the progression of lesions in the patch and plaque stages to some
diseases. When the gene encoding TCR/Ig is extent. Topical steroids and interferon are also useful. For pro-
excised by a restriction enzyme and the tissue
is lymphoma (monoclonal), a single band is gressive cases such as MF in the tumor stage, electron beam irra-
observed in electrophoresis; in the case of a diation and chemotherapy (e.g., CHOP therapy; the treatment is
benign reactive disease (polyclonal), there is the same as for non-Hodgkin’s disease; Table 22.7) are per-
no specific band in electrophoresis. These
findings are helpful for diagnosing the malig- formed.
nancy of tissues and blood (gene rearrange-
ment analysis, GRA).
GRA of the Jg chain and the Cb1 chain of the 2. Sézary syndrome (SS)
TCR gene are performed in T-cell lymphoma.
A similar analysis is made for diagnosis of B-
cell lymphoma, using southern blotting for Outline
IgH-JH, a gene that codes for an immunoglob-
ulin fragment.
● It is a T-cell lymphoma that occurs primarily in skin,
lymph nodes and peripheral blood.
Table 22.7 Therapeutic examples of CHOP used in the tumor stage of mycosis fungoides.
day
Drug Dose Administration example
1 2 3 4 5
Cyclophosphamide 750 mg/m2 Instillation for 3 hours ↓
Doxorubicin 50 mg/m2 Instillation for 1 hour ↓
Vincristine 1.4 mg/m2 Instillation for 1 hour ↓
Prednisolone 100 mg/body Oral administration ↓ ↓ ↓ ↓ ↓
● Intense itching is present. The main symptoms are ery-

throderma, swelling of lymph nodes and the appearance
of atypical lymphocytes in the peripheral blood.
● The laboratory findings and treatments are largely the
same as those for mycosis fungoides.
Clinical features
Men over age 50 are most frequently affected by Sézary syn-
drome (SS). Erythema accompanied by scaling on the whole
body surface occurs diffusely, presenting as erythroderma (Fig.
22.38). Intense itching is often present. There is enlargement of
lymph nodes and splenohepatomegaly. The systemic symptoms
tend to be mild, and fever is not present. As SS progresses, nodu-
lar eruptions occur and may infiltrate into the internal organs.
Pathology, Laboratory findings Fig. 22.37 Histopathology of mycosis fun-

goides.
Leukocytosis and lymphocyte atypicality are found in the Histological image of mycosis fungoides at
peripheral blood. These atypical lymphocytes, called Sézary somewhere between the erythematous and infil-
cells, have a nucleus with a deep slit as seen in the cells found in trative stages. Atypical lymphocytes invade the
tissue with mycosis fungoides, and they contain superficial mark- epidermis and form microabscess (Pautrier’s
microabscess).
ers of helper T cells. Band-like or perivascular lymphocytic infil-
tration including Sézary cells are found in the upper dermal layer
of the areas with erythroderma. Pautrier’s microabscess may
occur in the epidermis (Fig. 22.36).
Treatment
The treatments are the same as for mycosis fungoides. The
prognosis is generally worse than that of mycosis fungoides.
22
3. Primary cutaneous anaplastic large-cell hardcopy only.
lymphoma
This is a T-cell lymphoma caused by infiltration of CD30-pos-
itive lymphocytes. Solitary nodules or papules, tumors that may
ulcerate, and infiltrative erythema occur (Fig. 22.39). Pathologi-
cally, there is infiltration of atypical cells and histological mor-
phology of undifferentiated large tumor cells resembling that of
Hodgkin’s disease. Diagnosis of primary cutaneous anaplastic
large-cell lymphoma (ALCL) is confirmed if the tumor cells
Fig. 22.38 Sézary syndrome.
react to anti-CD30 antibodies (Ki-1 antibodies). When cutaneous Flushing accompanied by intense itching occurs
lymphomas including mycosis fungoides, Sézary syndrome or on the whole body.
adult T-cell leukemia/lymphoma are present as a precursor or a

current symptom, the condition is not diagnosed as ALCL even if
there is infiltration of CD30-positive cells in the skin lesion. The
prognosis is generally good.

Supplement: Lymphomatoid papulosis
Lymphomatoid papulosis begins as papules of several mil-
limeters to 1 cm in diameter, usually several to several dozen in
number, which are accompanied by scaling and bloody crusts.
The center of the papules may be necrotic or crusted. The
papules may reach several centimeters in diameter. The eruptions
Fig. 22.39 Primary cutaneous anaplastic
large-cell lymphoma. heal spontaneously in 2 to 3 weeks, with moderate scarring and
pigmentation (Fig. 22.40). Infiltrative atypical cells are CD30-
positive. Histopathologically, there is infiltration of polymorphic
lymphocytes whose atypical chromatin stains deeply, cellular
division, leakage of erythrocytes, and eosinophilic infiltration:
These findings seem to suggest malignancy. However, whether
lymphomatoid papulosis is a benign disease or a subtype of
ALCL is still controversial. Mycosis fungoides or other lym-
phoma occurs as a complication in fewer than 20% of cases.
Clinical images are available in hardcopy only. When it does not heal spontaneously, topical steroids and PUVA
therapy are applied.
4. Pagetoid reticulosis (Woringer-Kolopp)

Tumor cells are markedly epidermotropic and resemble
Paget’s cells. Clinically distinctive parapsoriasis-like or psoria-
sis-like plaques form. Pagetoid reticulosis is considered to be a
specific type of mycosis fungoides.
5. Adult T-cell leukemia/lymphoma (ATLL)
Outline
Clinical images are available in hardcopy only. ● It is a hematopoietic malignancy caused by human T-cell
leukemia virus type-1 (HTLV-1).
● Multiple, firm, reddish-brown skin tumors with dome-
22 shaped elevation appear. Erythroderma and elevated,
scaling plaques form.
● Serum anti-HTLV-1 antibodies are positive. Characteris-
tic “flower cells” are found in the peripheral blood.
Clinical features
Clinical images are available in hardcopy only. Adult T-cell leukemia/lymphoma (ATLL) is classified by the
course into several types, including smoldering, chronic, acute
and lymphoma types. Cutaneous lesions may be seen in all vari-
ants. Multiple, firm, dome-shaped, reddish-brown tumors ranging
in size from several millimeters to 10 cm occur. They may be
accompanied by scaling, infiltrative elevated reddish-brown
Fig. 22.40 Lymphomatoid papulosis. plaques, and erythroderma (Figs. 22.41-1 and 22.41-2). Besides
the characteristic eruptions, non-specific eruptions caused by

immunodeficiency, various infections such as mycosis and her-
pes zoster, erythema, urticaria, acquired ichthyosis, palmoplantar
keratosis and eczema-like eruptions also appear. There are sys-
temic symptoms such as fever, lymph node enlargement, and
splenohepatomegaly. As ATLL progresses, opportunistic infec-
tion is caused by fungus or virus resulting from cellular immun-
odeficiency. Clinical images are available in hardcopy only.
The main complications are HTLV-1-associated myelopathy
(HAM/TSP), HTLV-1-associated arthropathy (HAAP), and
HTLV-1-associated uveitis.
Epidemiology
The incidence varies by region. In Japan, about 1.2 million
persons have tested positive for anti-HTLV-1 antibodies, and it is
estimated that 500 to 600 of these persons will develop ATLL
every year. Worldwide, many patients are from the Caribbean
and parts of Africa.
The routes of infection may be through sexual activity or
blood. Most cases are transmitted materno-fetal by breast milk.
In sexual activity, it is transmitted from male to female in semen.
The incubation period between transmission and development of
ATLL is usually more than 40 years. Most persons who are
infected in infancy do not have the symptoms throughout life.
Most patients are over age forty. Cases in youths are rare.
Pathogenesis
HTLV-1, an RNA virus, is known to induce monoclonal pro-
liferation of T cells. HTLV-1 proviral DNA is integrated in the
malignant T cells.

Serum anti-HTLV-1 antibodies are positive. The antibody titer
is measured first for diagnosis. For patients whose serum is posi-
tive for anti-HTLV-1 antibodies, Southern blot is performed to
identify monoclonal integration of HTLV-1 proviral DNA into
tumor cells. There is a marked increase of leukocytes and atypi-
cal lymphocytes called flower cells in the peripheral blood (Fig. Fig. 22.41-1 Adult T-cell leukemia/lym-
22.42), increased LDH in the blood from tumor cell destruction,
phoma. 22
increased serum Ca, and increased soluble IL-2 receptor. ATLL
is classified into subtypes according to the severity of these
changes (Table 22.8).
Follow-ups are given to patients with chronic and smoldering
types of ATLL, to check for any signs of acute transformation.
The acute, lymphoma, and acute transformation types are treated
with conventional chemotherapy. The prognosis is remarkably
poor, most patients dying within 2 years from the initiation of
treatment. Pneumocystis carinii pneumonia is treated by preven-
tive administration of trimethoprim-sulfamethoxazole combination.
Table 22.8 Clinical characteristics and types of adult T-cell

leukemia/lymphoma.
Smoldering Chronic Lymphoma Acute
Anti-HTLV-1 antibody ＋＋＋＋
Clinical images are available in hardcopy only. Number of lymphocytes (x109/L) <4 ≧ 4a <4 *
Atypical T-cells ≧ 5% ＋ ≦ 1% ＋
Flower cells Often Often None ＋
LDH ≦ 1.5N ≦ 2N * *
Ca concentration (mg/dl) <11 <11 * *
Lymph node infiltration None * ＋ *
Fig. 22.41-2 Adult T-cell leukemia/lym-
phoma. Tumor Skin ** * * *
lesion
Lungs ** * * *
Liver None * * *
Spleen None * * *
Central nervous system None None * *
Bones None None * *
Ascites None None * *
Pleural effusion None None * *
Digestive tract None None * *
N: Uppermost normal value, *: Unnecessary for diagnosis, **: Necessary for diagno-
sis of cases in which peripheral atypical T cells account for 5% or less of total leuko-
cytes. a: T lymphocyte density is 3.5x109/L or more.
b: When atypical T lymphocytes account for 5% or less of total leukocytes, histologi-
cal diagnosis is necessary.
(Adapted from; Shimoyama M. Diagnostic criteria and classification of clinical sub-
types ofadult T-cell leukaemia-lymphoma. A report from the Lymphoma Study
Group (1984-87). Br J Haematol 1991; 79: 428-37).
IV fluid and calcitonin are administered for hypercalcemia.
6. Natural killer (NK)/ T-cell lymphoma

In natural killer (NK)/T-cell lymphoma, abnormally increased
NK/T-cells damage various normal tissue cells, resulting in the
clinical appearance of destruction, such as ulcers. NK cells may
be difficult to distinguish from T cells and are sometimes
described as NK/T cells. A hydroa vacciniforme-like eruption
that is associated with viral infection, chronic active Epstein-Barr
22 (EB) virus infection and hypersensitivity to mosquito bites may
progress to NK/T-cell lymphoma several years to several decades
after onset.
Extranodal nasal T/NK-cell lymphoma (lethal midline granu-
loma): This is a typical type of extranodal T/NK cell lymphoma.
It occurs in the nasopharynx region. The positivity of an NK cell
marker (CD56) in the lymphoma cells is typical. There is an
association between EB virus and extranodal nasal T/NK-cell
lymphoma. It may be misdiagnosed as sinusitis resulting from
rhinophonia. Cutaneous symptoms are panniculitis-like lesions
that are prone to ulceration (Fig. 22.43), swelling in the eyelids,
Fig. 22.42 Histopathology of adult T-cell face and lips, aphtha in the lips, and chilblain-like eruptions.
leukemia/lymphoma. Cases with multiple lesions or infiltration in multiple organs have
a poor prognosis.
CD4+/CD56+ hematodermic neoplasm (blastic NK cell lym-
phoma): This is caused by NK precursor cells. It is not associat-
ed with the EB virus. The pathogenesis is unknown. A purplish
red, infiltrative erythematous plaque or tumor occurs.
Lymphoma associated with hydroa vacciniforme: Hydroa vac-
ciniforme used to be attributed to photosensitivity (Chapter 13);
the cause is now thought to be proliferation of NK/T cells from EB
viral infection. Papules or blisters accompanied by central umbil-
ication and necrosis occur on sun-exposed areas such as the dor-
sal hands and cheeks. Edema appears on the eyelids, lips and face.
7. Subcutaneous panniculitis-like T-cell

lymphoma
Panniculitis-like clinical features resemble those of erythema
nodosum (Fig. 22.44). The tumor cells derive from cytotoxic T
cells. The prognosis is poor. It may worsen rapidly in some cases.
Cutaneous B-cell lymphoma
Cutaneous B-cell lymphoma that remains localized in the skin Fig. 22.43 Natural killer/T-cell lymphoma.
at the time of diagnosis is called primary cutaneous B-cell lym-
phoma (PCBCL). The classification of cutaneous B-cell lym-
phoma has not been completely clarified; however, terminology
adopted from the WHO/EORTC classification is widely used
(Table 22.6). The main subtypes of PCBCL are follicle center
lymphoma, marginal-zone B-cell lymphoma, and diffuse large B-
cell lymphoma.
A nodule or tumor appears solitarily, leading to a localized red
or purplish-red plaque. Multiple papules, nodules or infiltrating
erythema occur in some cases. The eruption rarely ulcerates.
Although the skin surface is normal, erosive lymphocytic infiltra-
tion occurs in the dermis; the deeper the infiltration, the severer it
tends to be (bottom-heavy appearance). B-cell-specific antigens
are expressed, and T-cell surface antigens are not detected (Table
22.9). When single B-cells abnormally proliferate, monoclonality
of immunoglobulin gene becomes apparent; gene rearrangement
analysis (described previously; MEMO) is useful for differential
22
diagnosis. The main treatment is radiation therapy. Chemothera-
py and CD20 monoclonal antibodies (rituximab) are adminis-
tered in cases with multiple lesions.
Fig. 22.44 Subcutaneous panniculitis-like T-

1. Primary cutaneous marginal zone cell lymphoma.
B-cell lymphoma Erythema nodosum-like erythema is accompa-
nied by tenderness and panniculitis. Histopatho-
The trunk and extremities are most frequently affected. The logical observation revealed an infiltration of
tumor is composed of the cells that form the marginal zone, lymphoma cells.
mature B cells that passed the germinal center, and plasma cells
(Fig. 22.45). 5-year survival rate is almost 100%. The main treat-
ments are excision and radiation.
2. Primary cutaneous follicle

center lymphoma
The head, neck, and trunk are most frequently involved. There
is proliferation of the centrocytes or centroblast-like cells that are
normally seen in lymphoid follicles. The prognosis is good; the
5-year survival rate is 95%. The main treatments are excision and
radiation (Fig. 22.46).
3. Primary cutaneous diffuse large

B-cell lymphoma
It occurs most commonly on the lower legs of elderly people.
There is proliferation of centroblasts and/or immunoblasts. The
prognosis is rather poor; the 5-year survival rate is 50% to 70%.
The first line treatment is chemotherapy (Fig. 22.47).
e-2. Leukemia cutis

This specific eruption is caused by infiltration of leukemic
tumor cells from blood into the skin. Papules, nodules, tumors
and erythroderma are the main cutaneous symptoms (Fig. 22.48).
It occurs frequently in adult T-cell leukemia, acute monocytic
leukemia, and acute transformation of chronic myelogenous
leukemia. Skin lesions that accompany leukemia but are not
caused by direct infiltration of tumor cells are called non-specific
Table 22.9 Differentiation of B cells and cellular surface traits.

Fig. 22.45 Primary cutaneous marginal zone
B cell lymphoma. Mature phase Tumor TdT Cellular surface trait clg
Top: Red plaques and nodules are seen on the
chest. Middle: Negative for IgG l chain staining. Lymphatic stem B-ALL ＋ HO/RLO
Bottom: IgG k chain stains positively. cell B-ALL CD19 HRLO
B-ALL ＋ CD19, CD10 HRLR/O
B-ALL ＋ CD19, CD10, CD20 HRLR/O
Pro B cell B-ALL ＋ CD19, CD10, CD20 HRLR/O
Pre B cell B-ALL, CLL ＋ CD19, CD20, CD21, m HRLR
IgM
Clinical images are available in Immature B cell CLL CD19, CD20, CD21, Ig HRLR
hardcopy only. CD35, IgM, IgD,Fc,
22 (CD5)
Mature B cell ML, PL, CD19, CD20, (CD21), Ig HRLR
HCL Fc, (CD10), CD35,
IgG, IgA, IgM
Plasma-cell-like ML, MG, CD19, CD20, CD35, Ig HRLR
B cell HCL CD38, IgM, Fc, PCA-1,
(PC-1)
Plasma cell MM CD38, PC-1, PCA-1 Ig HRLR
hardcopy only. TdT: terminal deoxynucleotidyl transferase, clg: Immunoglobulin class, H:
Immunoglobulin heavy chain, L: Immunoglobulin light chain,
O: No rearrangement, R: gene rearrangement, Fc: Fc receptor of IgG, B-ALL: B-cell
acute lymphocytic leukemia, CLL: Chronic lymphocytic leukemia, PL: Prolymphocyt-
ic leukemia, ML: Malignant lymphoma, HCL: Hairy-cell leukemia, MG: Macroglobu-
linemia, MM: Multiple myeloma.
Fig. 22.46 Primary cutaneous follicle center (Hase T, et al. B-cell lymphomas. In: Hori Y, et al., editors. Cutaneous lymphoma
lymphoma. atlas. Bunkodo; 1996: 82-5).
Melanoma 419

Clinical images are available in Clinical images are available in hardcopy only.
a b c d e f g
Fig. 22.48 Leukemia cutis.
eruptions, and they may appear as urticaria, erythema multi-

forme, erythema nodosum, ichthyosis or pigmentation.
e-3. Multiple myeloma

a b c d e f g h
Atypical plasma cells proliferate in the bone marrow. As a
Fig. 22.47 Primary cutaneous dif-
result of bone and skin involvement, skin nodules appear. Rarely, fuse large B-cell lymphoma.
multiple nodules caused by hematogenous metastasis and a: Bright red nodule of primary cuta-
extramedullary plasmacytoma occur. Multiple myeloma may be neous diffuse large B-cell lymphoma.
b: Proliferation of large atypical lym-
accompanied by cryoglobulinemia. Purpura may be caused by phocytes with distinct nucleoli.
amyloidosis as a cutaneous symptom in some cases. Nuclear division is also discernable.
F. Metastatic carcinoma of the skin

This is a visceral cancer that metastasizes to the skin
hematogenously or lymphogenously. The primary cancer in
many cases is in the mammary glands, stomach, lungs, intestines,
uterus and ovaries. Metastatic carcinoma of the skin is a terminal
symptom of a primary cancer. Multiple, asymptomatic, intrader-
mal or subcutaneous nodules occur in most cases (Figs. 22.49-1 Clinical images are available in hardcopy only.
and 22.49-2). The clinical types are as follows.
Carcinoma erysipelatodes: Reddening and palpable infiltration
suddenly appear, resembling erysipelatodes.
Alopecia neoplastica: Tumor cells metastasize to the scalp.
Localized alopecia occurs.
The primary cancer in most cases is at the terminal stages; the
22
Fig. 22.49-1 Metastatic carcinoma of the
prognosis is poor, and most patients die in several months. skin.
Melanoma
Outline
● It is a malignant tumor of the melanocytes. It is classified
into the following melanomas: nodular, superficial
spreading, acral lentiginous and lentigo maligna. Lesions
of all types are blackish and vaguely margined.
● It tends to metastasize lymphogeneously or hematoge-

Fig. 22.49-2 Metastatic carcinoma of the skin.
Hodgkin’s disease, Non-Hodgkin’s disease MEMO

Malignant lymphomas are classified into Hodgkin’s disease and non-Hodgkin’s dis-
ease. In Japan, 90% of malignant lymphomas are non-Hodgkin’s disease.
Hodgkin’s disease begins as painless swelling in the lymph nodes and progresses
slowly. Specificity is rarely seen in the skin lesion; however, Hodgkin’s disease
metastasizes from swollen lymph nodes, causing papules or nodules. Prurigo nodu-
laris and herpes zoster result from decreased resistance against infection. Clinical images are available in
Non-Hodgkin’s disease tends to multiply and may appear first at sites other than hardcopy only.
lymph nodes (photo). Although there had been many pathological classifications of
cutaneous malignant lymphoma, a unified WHO-EORTC classification was pro-
posed recently. See Table 22.6 for non-Hodgkin’s disease of the skin.
Staging notation of Hodgkin’s disease according to the Codtwolds-modified Ann Arbor classification.
Stage I Involvement of a single lymph node region or lymphoid structure (spleen, thymus, Waldeyer’s ring)
Stage II Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is a single site, whereas hilar
lymph nodes are considered bilaterally).
Stage III Involvement of lymph node regions or structures on both sides of the diaphragm
III1: With splenic, hilar, celiac or portal nodes
III2: With para-aortic, iliac, mesenteric nodes
22 Stage IV Diffuse or disseminated involvement of one or more extranodal organs or tissue, with or without associated lymph node involvement
Designations applicable to any disease stage
A: No systemic symptoms
B: B symptoms present, one or more:
・ Unexplained weight loss >10% during previous 6 months
・ Unexplained fever (>38 ℃) during the previous months
・ Recurrent drenching night sweats during the previous months
X: Bulky disease is present when:
・ A palpable lymph node defined by the largest dimension is >10 cm
・ The maximum width of a mediastinal mass is > one-third of the internal transverse diameter of the thorax at the level of T5/6 interspace
on a chest X-ray
E: The subscript 'E' is used for documented limited extranodal extension continuous or proximal to the known nodal site. More extensive
extranodal disease is designed stage IV
CS: Clinical stage
PS: Pathological stage (as determined by laparotomy)
（Lister TA, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds
meeting. J Clin Oncol 1989 ; 7 : 1630-6).
Melanoma 421
nously, and to infiltrate the lungs and bones.

● Early detection and surgical removal are essential. Other
treatments are largely ineffective.
Classification
a. nodular melanoma b. superficial spreading
Melanoma is classified by clinical features and pathology into melanoma
nodular, superficial spreading, acral lentiginous, and lentigo
maligna (Fig. 22.50, Table 22.10). There are many other types
that do not fit these categories, such as an intermediate type and a
non-classifiable type.
c. acral lentiginous d. lentigo maligna
melanoma melanoma
Clinical features
The distinguishing clinical features of the four types are listed individual atypical melanocytes
alveolar configuration of atypical melanocytes
in Table 22.10. All types of melanoma begin as horizontal prolif-
eration of tumor cells in the epidermis (radial growth phase). At Fig. 22.50 Classification of melanoma
this phase, a dark brown or black patch is clinically observed. (Clark’s level).
After the patch enlarges to a certain size, the tumor cells begin to
proliferate vertically (vertical growth phase). The patch partially
elevates and forms a black nodule, erosion and ulcer (Figs.
22.51-1 and 22.51-3). When the patch infiltrates beyond the der-
mis, the risk of metastasis sharply increases. Metastasis is lym-
phatic in most cases; satellite lesions form around the primary
location and metastasize to the regional lymph nodes, resulting in hardcopy only.
Table 22.10 Clinical and pathological findings of the 4 major

types of melanoma.
1. Nodular melanoma (NM)
A dome-shaped nodular lesion occurs, often accompanied by ulceration. g
a b c d e f h
The lesion progresses to the vertical growth phase without undergoing
the radial growth phase in most cases. Therefore, rapid metastasis may
occur. The prognosis is poor. It may occur on any site of the body.
Atypical tumor cells proliferate in the vertical direction. Proliferation of
tumor cells is almost never seen around the nodules. Clinical images are available in
2. Superficial spreading melanoma (SSM) hardcopy only.
Pigmented spots appear. They enlarge over the course of several months
to several years. Some of the spots elevate and progress to the vertical
growth phase. The epidermis thickens slightly. There are large, clear a b c d e f g h i
melanoma cells that resemble Paget’s cells in all epidermal layers.
3. Acral lentiginous melanoma (ALM)
The ends of extremities, fingernails and toenails are most frequently 22
involved. ALM begins with light brown macules that continue to enlarge Clinical images are available in
over the course of several to a dozen years. Nodules appear on the hardcopy only.
macules. When a nail is affected, a black macule may spread beyond the
nail fold (Hutchinson’s sign). There is acanthosis and extension of the
epidermal rete ridges. Atypical melanocytes proliferate in the lower
epidermal layer. a b c d e f g h i j
4. Lentigo maligna melanoma (LMM) Fig. 22.51-1 Melanoma.
A blackish-brown spot first appears. It gradually enlarges over the course a: Nodular melanoma (NM). b: Superficial
of decades. Because of the mild progression over a long period of time, spreading melanoma (SSM). c: Acral lentiginous
the primary black spot is often misdiagnosed as lentigo. The precursor melanoma (ALM).
pigmented macule of LMM is called lentigo maligna. Sun-exposed areas
of the body such as the face are most frequently involved. The epidermal
rete ridges disappear. Atypical melanocytes are scattered in the
basement of the atrophied epidermis. Solar elastosis is caused in the
upper dermal layer.
distant metastasis. Melanomas occur not only in skin, but also in

the eyeballs, oral cavity and nasal mucosa. Melanocytes continue
to produce melanin after they become malignant; the skin lesion
Clinical images are available in hardcopy only. in most cases becomes blackish brown. There are five character-
istic clinical features of melanoma, whose initials read ABCDE
(Table 22.11). In rare cases, melanoma cells lack melanin pro-
c d e f g h i j k
duction. l This m n amelanotic
is called o pmelanoma
q andr has an even
worse prognosis.
Melanoma is caused by malignant melanocytes in normal skin,
or it may originate from nevus-cell nevus, blue nevus, lentigo
available in available in maligna or xeroderma pigmentosum. External injury, excision,
hardcopy only. hardcopy only. sunlight, UV, blisters caused by footwear, clavus removal,
scratching, chilblains and burn scarring may also induce
melanoma.
The incidence and the site of origin depend greatly on environ-
mental factors and on intrinsic factors, including race and inherit-
d
b e
c df g
e hf gi hj ki lj genotype.
mk nl m
o p q
nis the most
o pr q r
ed Sun exposure notable environmental
factor. The disorder occurs frequently in Caucasians, from a lack
of natural protection against UV (i.e., little melanin pigment in
the skin), particularly on sun-exposed areas. It rarely occurs in
persons of African descent, whose protective capacity is high,
and when it does it is most frequent at the ends of the extremities.
Asians fall between these two extremes.
The global increase in melanoma in recent years is attributed
to demographic aging, changes in lifestyle such as clothing, and
ozone layer depletion.
f g h i j k l m n o p q r
Pathology
In all types of melanoma, atypical melanocytes of various
sizes proliferate in the epidermis and dermis. Cells often coalesce
to form defined tumor nests of various sizes (Fig. 22.52). Each
type of melanoma presents a characteristic infiltration pattern of
atypical cells (Table 22.10).
g h i j k l m n p
oDiagnosis q r
Fig. 22.51-2 Melanoma. Clinical findings of tumors are essential for diagnosis. When-
22 d-h: Acral lentiginous melanoma (ALM).
ever a blackish-brown lesion is found, melanoma should be sus-
pected. Dermoscopic findings such as parallel ridge pattern and
atypical pigment network are useful for diagnosis.
Table 22.11 Clinical characteristics of

melanoma (ABCDE). Melanoma is differentiated from nevus-cell nevus, Spitz nevus,
Finding Feature basal cell carcinoma, pyogenic granuloma, squamous cell carci-
A Asymmetry noma, verruca, angiosarcoma and subungual hematoma.
B Borderline irregularity
Treatment
C Color variegation
Treatments are chosen according to the stage of melanoma. If
D Diameter enlargement (over 6 mm)
the tumor is shallower than 2 mm, it should be removed with a 1-
E Elevation of surface cm margin. When the tumor is thicker than 2 mm, total resection
Melanoma 423
a b c d e f g h i j k l m n o p
a b c d e f g h i j k l m n o p q
Fig. 22.52 Histopathology of melanoma.

Atypical melanocytes proliferate in the epidermis and dermis. When the
melanomas are clinically blackish, the tumor cells contain large quantities
of melanin pigment. g j p q
Fig. 22.51-3 Melanoma.
with 2 cm margin should be conducted. Dissection of the region- i: Lentigo maligna melanoma (LMM). j:
al lymph node and amputation of fingers, toes or other extremi- Metastatic melanoma to the skin. k: Leukoderma
ties may be conducted. In recent years, sentinel node biopsy has in a patient with progressive melanoma.
been frequently conducted to measure the necessary range of sur-
gery.
In progressive cases with distant metastasis, surgery is rarely
22
performed; instead, chemotherapy, radiation therapy and
immunotherapy are conducted. Interferon may also be used. The
patient responds to chemotherapy in fewer than 30% of cases.
Prognosis
The prognosis is estimated by Breslow thickness (mm), which
is the thickness of melanoma cells from the deepest area of the
skin to the epidermal granular layer (Table 22.14). Nearly all
cases with lesions 1 mm or thinner have a 100% survival rate; the
5-year survival rate in cases with lesions thicker than 4 mm is
50%. TNM classification made by Union Internationale Contra le
Cancer (UICC) is shown in Tables 22.14 and 22.15.
Table 22.15 Staging classification of melanoma Table 22.14 TNM classification for melanoma (AJCC/UICC, 2002).
(AJCC/UICC, 2002).
T classification (primary tumor)
Clinical stage Pathological stage T0 No evidence of primary tumor
0 Tis N0 M0 0 Tis N0 M0
Tis Melanoma in situ
IA T1a N0 M0 IA T1a N0 M0 T1 Tumor thickness ≦ 1.0 mm
IB T1b N0 M0 IB T1b N0 M0 T2 Melanoma 1.01 mm to 2.0 mm in thickness, with or without ulceration
T2a N0 M0 T2a N0 M0 T3 Melanoma 2.01 mm to 4.0 mm in thickness, with or without ulceration
IIA T2b N0 M0 IIA T2b N0 M0 T4 Melanoma greater than 4.0 mm in thickness, with or without ulceration
T3a N0 M0 T3a N0 M0 T1 through T4 without ulceration (a), with ulceration (b)
IIB T3b N0 M0 IIB T3b N0 M0 N classification (regional lymph nodes)
T4a N0 M0 T4a N0 M0 N0 No regional lymph node metastasis
IIC T4b N0 M0 IIC T4b N0 M0 N1 Metastasis to 1 regional lymph node
III Any T N1-3 M0 IIIA T1a-4a N1a-2a M0 N1a Micrometastasis
IIIB T1a-4a N1b,2b,2c M0 N1b Macrometastasis
T1b-4b N1a,2a,2c M0
N2 Metastasis to 2 or 3 regional nodes, or intralymphatic regional
metastasis without nodal metastasis
IIIC T1b-4b N1b-2b M0
N2a Micrometastasis
Any T N3 M0
N2b Macrometastasis
IV Any T Any N M1 IV Any T Any N M1
N2c Satellite or in-transit metastasis without regional nodal metastasis
(Adapted from; Balch M, et al. Final version of the American N3 Metastasis to 4 or more regional lymph nodes, or matted
Joint Committee on Cancer staging system for cutaneous metastatic, or in-transit metastasis or satellites(s) with metastasis
melanoma. J Clin Oncol 2001; 19 : 3635-48). to regional node(s)
M classification (distant metastasis)
M0 No distant metastasis
M1a Metastasis in skin, subcutaneous tissues, or distant lymph nodes
M1b Metastasis to lung
M1c Metastasis to all other visceral sites or distant metastasis to any
site associated with an elevated serum LDH
(Adapted from; Balch M, et al. Final version of the American Joint Commit-
tee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;
19; 3635-48).
The thickness of melanoma is the same as in Breslow’s tumor thickness; it is
the vertical length between the granular uppermost layer and the bottom of
the tumor.
Micrometastasis: Lymph node metastasis is pathologically identified
Macrometastasis: Lymph node is clinically palpable. Metastasis is pathologi-
cally identified, or infiltration spreads beyond the lymph node membrane.
In-transit: Lesion between the primary tumor and regional lymph node
Satellite metastasis: Isolated lesion within 2 cm of the primary tumor
22
Sentinel lymph node biopsy MEMO

When radioactive isotope or pigment such as indigo carmine is inject-
ed locally into a malignant tumor, the substance flows in the lymph
vessel and temporarily accumulates in the regional lymph node. A
lymph node that takes in pigment or radioactive isotope is called a
sentinel lymph node (SLN). Early detection for lymph node metastasis
of a malignant tumor is possible if the sentinel lymph node is selec-
tively biopsied. When the biopsy is negative, it is possible to avoid
highly invasive lymph node dissection, leading to improvement in
quality of life. This biopsy is called sentinel lymph biopsy and may be
conducted on melanomas.
Chapter
23 Viral Infections
A virus is a particle of DNA or RNA enclosed by structural proteins. Viruses infect cells and proliferate to cause
viral infections. Viral skin diseases are classified by clinical features into three types: ① degeneration of epider-
mal cells and blistering (e.g., in herpes simplex and herpes zoster), ② tumorous changes in epidermal cells
(e.g., in verruca vulgaris), and ③ allergic eruptions on the whole body (e.g., in measles and rubella). The first
two types are caused by viral infection in epidermal keratinocytes; the last type is caused by systemic viral
infection (viremia). This chapter introduces various viral skin diseases, including HIV infection.
A. Viral infections whose main symptom is blistering
1. Herpes simplex
sensory
Outline ganglion
● Itis caused by infection or reactivation of herpes simplex
virus type 1 (HSV-1) or herpes simplex virus type 2
① De novo infection; virus invades
(HSV-2). through mucous membranes, and
● HSV-1 causes herpes labialis, herpes gingivostomatitis latent infection occurs in the ganglion.
and, Kaposi’s varicelliform eruption. HSV infection de novo
● HSV-2 causes herpes genitalis. In recent years, the herpes gingivostoma
number of herpes genitalis cases caused by HSV-1 has genital herpes
been increasing. VZV infection de novo
● Detection of the viral antigen and Tzanck test are useful varicella
for diagnosis. The main treatment is administration of
acyclovir.
Pathogenesis
Herpes simplex is caused by herpes simplex virus type 1
(HSV-1) or type 2 (HSV-2). The oral cavity, eyes and genitalia
are affected by HSV-1, whereas the genitalia are mainly involved
in HSV-2. The infection pattern of HSV is shown in Fig. 23.1.
The virus enters the skin through a minor external injury, or
through the oral mucosa, eyes or genitalia. It travels along the
sensory nerve axons to reach the trigeminal ganglia or lum- ② Viruses are reactivated by
immunosuppression or
23
bosacral spinal cord ganglia. In 90% of cases, primary infection
stress.
does not progress beyond latency, however, symptoms may be
apparent in infants or in people with immunodeficiency. After HSV reactivation
the symptoms subside, viral DNA remains in the gangliocytes labial herpes
and becomes reactivated by stress or a common cold. Some genital herpes
viruses may travel along the axons anterogradely to reach the VZV reactivation
skin and become reactivated. herpes zoster
Clinical features Fig. 23.1 Mechanism of infection by HSV and

VZV.
The initial latency is between 2 and 10 days. Localized aggre- HSV: Herpes simplex virus. VZV: Varicella
gation of small herpetic blisters occurs in primary infection. It zoster virus.
425
426 23 Viral Infections
may occur on any site of the body, particularly the lips, genitalia
and fingers (Fig. 23.2). In severe cases, small blisters spread on
the whole body. Recurrent herpes simplex may cause serious
mental distress.
① Herpes labialis (cold sore)
Clinical images are available in hardcopy only. This is the most common clinical form of herpes simplex seen
in adults. Most cases are caused by reactivated HSV-1. It begins
with prodromes such as itching and discomfort in the lips and
their periphery, including the anterior naris cheeks and orbital
region. After a day or two, edematous erythema appears and
a b c d e f g small
h blisters
i jwith central
k umbilication
l m occur
n and p
o aggregate, q r
sometimes coalescing to form irregularly shaped blisters. The
blisters soon form pustules, erosions and crusts. They heal in
about 1 week.
② Herpes gingivostomatitis
This type occurs most frequently in initial infection of HSV-1
Clinical images are available in hardcopy only. in infancy. It begins 2 to 10 days after infection, with discomfort,
fever and pharyngeal pain. Accompanied by a high fever, multi-
ple painful small blisters and erosions occur in the oral mucosa,
tongue and lips.
③ Herpes genitalis (genital herpes)
a b c d e f g h j
i This type k
occurs asl an initial
m infection
n p
o recurrently.
or qHerpesr
genitalis is often transmitted through sexual activity and can be
regarded as a sexually transmitted disease (STD). Although men
and women in adolescence and older are frequently affected, it
may also occur in infants in rare cases. It may be transmitted to
Clinical images are available in hardcopy only. an infant by the hands of the mother or nurses. The causative
virus in most cases is HSV-2; however, the number of cases
caused by HSV-1 has been increasing in recent years. In initial
infection, small blisters form in the glans penis or foreskin of
b c d e f g h i j
adult men,
k or inl the labia
m or perineal
n oregionpof adultq women. r The
blisters become severely painful small ulcers. The inguinal
lymph node becomes painful and enlarged. The lesions usually
disappear spontaneously in 2 to 4 weeks; however, when the
sacral nervous root is involved it may leave urinary disturbance.
The symptoms of recurrent cases are moderate.
Clinical images are available in hardcopy only. ④ Kaposi’s varicelliform eruption
HSV-1 infection may spread widely on the face and over the
whole body when the local skin is weak or damaged, especially in
infants or atopic dermatitis patients. It is described in the next section.
23
⑤ Herpetic whitlow
c d e f g h i j k HSV-1 l (or m HSV-2 nin some o cases) p invades
q ther body from a
minor injury in the tip of a finger, leading to aggregated forma-
Fig. 23.2 Herpes simplex.
a, b: Vesicles aggregated around the lips (herpes tion of painful blisters and pustules in fingers. The blisters on the
labialis) caused by herpes simplex. c: Affected fingers are not as fragile as those on other sites of the body.
eyebrow. d: Genital herpes. Infants who have a habit of finger-sucking and dentists may be
infected. It is recurrent and heals in 2 to 4 weeks.
Pathology
Repetitive replication of viral DNA leads to ballooning degen-
eration and reticular degeneration of infected epidermal cells.
A. Viral infections whose main symptom is blistering 427
These degenerated epidermal cells are observed as ballooning

cells containing intranuclear inclusion bodies by smear staining
of the blister contents (Fig. 23.3).
Laboratory findings
Tzanck test, detection of the virus using monoclonal antibod-
ies, and serological diagnosis are conducted. HSV-infected epi-
dermal cells are easily and quickly observed by Tzanck test.
Monoclonal antibody detection is conducted to differentiate
between HSV-1, HSV-2 and varicella zoster virus (VZV). Sero-
logical diagnosis is made by ELISA.
Fig. 23.3 Histopathology of herpes simplex.
Treatment There is necrotic degeneration in epidermal cells.
The giant cells contain inclusion bodies (balloon-
Antiviral drugs such as acyclovir are given topically, orally or ing cells).
intravenously, depending on the severity of the symptoms.
2. Kaposi’s varicelliform eruption

Synonym: Eczema herpeticum
Outline
● The cause in most cases is infection of herpes simplex
virus type 1 (HSV-1). The virus infects a skin lesion, lead-
ing to severe blistering and erosion on the whole body.
● Infants are frequently affected. It is often induced by HSV
reactivation in patients with atopic dermatitis.

● Oral or intravenous administration of antiviral drugs and
systemic management are the main treatments.
Clinical features
Kaposi’s varicelliform eruption occurs most frequently in
infants with atopic dermatitis or eczema. In recent years, the
number of recurrent cases of Kaposi’s varicelliform eruption in Clinical images are available in hardcopy only.
adults with atopic dermatitis has been increasing. Acute high
fever and swelling in systemic lymph nodes occur. Multiple blis-
ters appear on eczematous plaques. Slightly larger than those in
herpes simplex, the blisters rapidly disseminate. They are sur-
rounded by red halo, coalesce, and form large erosions (Fig. 23.4-1
and 23.4-2). Pustules, bleeding, and secondary bacterial infection
occur in many cases. The face and upper body are commonly
23
involved; in breast-fed infants, the lesions often occur on the
whole body. The eruptions usually form crusts in 4 to 5 days.
Because eruptions occur successively, the course of Kaposi’s
varicelliform eruption may be from 10 days to more than 1 month. Clinical images are available in hardcopy only.
Pathogenesis
Primary viral infection or reactivation affects localized areas of
skin with deficient barrier function, such as areas affected by
atopic dermatitis, eczema, Darier’s disease or burns. Autoinocu- Fig. 23.4-1 Kaposi’s varicelliform eruption.
lation causes extensive lesions. The causative virus is usually The eruptions are rimmed with a vivid red halo.
HSV-1 but sometimes HSV-2. The vesicles coalesce into a large erosion.
Treatment
Antiviral drugs are given orally or intravenously.
Prognosis
Kaposi’s varicelliform eruption responds well to treatment.
Nevertheless, dehydration and multiple organ failure accompany-
ing high fever may be fatal.
3. Varicella
Synonym: Chickenpox
Outline
● It is commonly known as chickenpox. Infants are most
frequently affected.
Fig. 23.4-2 Kaposi’s varicelliform eruption. ● It is caused by primary infection of varicellazoster virus
(VZV) and is highly infectious.

● A fever emerges concurrently with erythematous papules
on the whole body. Eruptions progress in the course of

vesicles, pustules and crusts, and healing. New erup-
tions continue to occur such that preexisting eruptions
appear together with new eruptions.
● It heals in 7 to 10 days.
● Symptomatic treatments are helpful. Aspirin is contraindi-
cated.
Clinical features
After a latency of 2 to 3 weeks, erythematous papules appear
on the whole body, accompanied by fever (37 to 38˚C) and sys-
temic fatigue. The eruptions are accompanied by itching. They
progress in the order of erythema, papules, blisters, pustules and
crusts, over the course of several days. Varicella is characterized
by small blisters that resemble insect bites and blisters that form
on the scalp. Because the eruptions continue to appear, preexist-
ing eruptions are found together with newly formed ones (Figs.
23.5-1 and 23.5-2). Blistering also occurs in the oral mucosa and
palpebral conjunctiva. Varicella heals in 7 to 10 days, without
scarring (Fig. 23.6). If the eruptions are scratched or secondarily
infected, they heal with moderate scarring.
The main complications are pneumonia, encephalitis, unilater-
23
al high-frequency deafness (thought to be a symptom of Ramsay-
Hunt syndrome), and Reye’s syndrome (cerebritis and fatty liver).
Varicella is caused by infection of the varicella zoster virus
(VZV). This virus enters the upper respiratory tract by droplet
infection or contact infection and proliferates in the regional
lymph nodes, inducing primary viremia. The virus further prolif-
erates in the liver and spleen, leading to secondary viremia, and
reaches the skin, resulting in blistering. Varicella occurs most
Fig. 23.5-1 Varicella in an adult. frequently between weaning and early childhood. Ninety-five
40
body temp.(˚C)
39
38
37

days 1 2 3 4 5 6 7 8 9 10 11
symptoms
papules/
vesicles
crust
incubation 2 weeks
period
Fig. 23.6 The clinical course of varicella/chickenpox.
percent of children aged 9 have the antibodies. The age of initial

infection has risen in recent years; varicella in adults is increas-
ing. In adult cases, varicella is often accompanied by encephalitis
and pneumonia, and it can easily become severe.

Tzanck test is useful for early diagnosis. Varicella is character-
ized by balloon cells, the epidermal cells that are infected by VZV.
Treatment
Symptomatic therapies such as oral antihistamines against
itching, and topical petrolatum or antibiotic ointments for erup-
tions are the main treatments for infants. In recent years, oral
antiviral drugs have been used increasingly to keep the infection
from worsening. Aspirin is contraindicated because of the danger
of Reye’s syndrome. Antiviral drugs are administered intra-
venously to adults, patients with immunodeficiency, and new-
borns.
Prevention
Within 72 hours after infection, the onset can be inhibited by
varicella vaccine in 60% to 80% of cases. Oral antiviral drugs
23
may reduce the symptomatic severity in patients who have had
contact with an affected individual within the previous week. Clinical images are available in hardcopy only.
Varicella can be fatal in patients with immunodeficiency; human
immunoglobulin containing high anti-VZV antibody titer is used
in some cases.
4. Herpes zoster
Fig. 23.5-2 Varicella.
Outline
● Latent VZV in the ganglia reactivate to form band-like
herpetic aggregations of small blisters on certain inner-

vated regions. Pain is present in areas over the involved
nerves. It occurs in individuals with history of varicella
infection.
● The blisters may disseminate on the whole body in cases
with immunodeficiency, such as when there is malignant

tumor, regardless of the affected nervous regions.
● The main examinations are Tzanck test, detection of viral
antigens, and evaluation of the antibody titer in the blood.

There is permanent immunity after the first infection.
● The pain that persists after healing is called post-herpetic

neuralgia (PHN). When the ears and the peripheral
regions are involved, hearing loss and peripheral facial
paralysis may occur (Ramsay-Hunt syndrome).
Clinical features
Herpes zoster symptoms are divided into cutaneous and nerv-
ous. There are several specific types of herpes zoster.
① Mucocutaneous symptoms
Multiple herpetic vesicles appear in band-like patterns over
certain innervated regions. The skin over the intercostal nerve is
most frequently involved, followed in frequency by the trigemi-
nal area of the face (Figs. 23.7-1 and 23.7-2). Prodromes such as
neuralgic pain and abnormal paresthesia occur several days
before the eruptions manifest. Later, edematous erythema and
papules occur and transform into blisters. All these blisters
progress in the same course; this differs from varicella, in which
preexisting blisters are found concurrently with newly formed
ones. The blisters soon rupture and become erosions. They heal
after crust formation in 2 to 3 weeks.
② Nervous symptoms
Neuralgic pain is often present several days before the onset of
eruptions. The pain is severest 7 to 10 days after the eruptions
Clinical images are available in hardcopy only. occur. The severity of pain ranges from moderate to intense,
causing sensory disturbance, insomnia or paralysis. The pain in
most cases subsides with remission of the eruptions.
③ Types of herpes zoster
Generalized herpes zoster: In patients who are immunocompro-
mised as a result of steroid or immuno-suppressant intake or a
primary disease, small widespread blisters resembling varicella
23
may spread on the whole body 4 to 5 days after manifestation of
typical eruptions of herpes zoster.
Eye symptoms (Hutchinson’s sign): Complications involving
Clinical images are available in hardcopy only. the eyes, such as conjunctivitis and keratitis, may occur in herpes
zoster at the first division of the trigeminal area (ophthalmic
nerve). Herpes zoster on the nasal dorsum is called Hutchinson’s
sign. It often induces eye complications. In rare cases, a severe
complication called acute retinal necrosis occurs.
Ramsay-Hunt syndrome: The external auditory canal and auri-
Fig. 23.7-1 Herpes zoster on various sites cle are involved. Peripheral facial palsy and acoustic nerve
of the body. impairment are present. The pathogenesis is thought to be
pressure exerted on the facial nerve by genicular ganglia. In some

cases, facial palsy is the only symptom and there is no blistering.
Post-herpetic neuralgia (PHN): Neuralgia may persist after the
eruptions disappear. The pathogenesis is thought to be irre-
versible nerve degeneration. It often occurs after the onset of her-
pes zoster in the elderly and is often accompanied by sharp pain.
Antidepressants and nerve block are administered. It may be
treated at a pain clinic.
Herpes zoster is caused by reactivation of latent VZV. During
the course of varicella, VZV travels to the sensory nerves to
reach the ganglia, whose dorsal-root cells remain latently infect-
ed after varicella heals and the anti-VZV antibodies increase.
Stress, aging, malignant tumor and immunodeficiency can trigger
re-proliferation of VZV (Fig. 23.1). Herpes zoster occurs most
frequently in persons between the ages of 10 and 30 and over 50.
Pathology
Ballooning cells are observed by Tzanck test, as in herpes sim-
plex (Fig. 23.8).
Tzanck test, detection of viral antigens, and serological diag- Clinical images are available in hardcopy only.
nosis are conducted, as in the cases of herpes simplex and vari-
cella. Cases in the elderly or with generalized herpes zoster
should be carefully observed, because there is the possibility of
malignant tumor immunodeficiency as an underlying disease.
Ophthalmologic examination is conducted on any lesions
involved in the first division of the trigeminal area.
Fig. 23.7-2 Herpes zoster on the first divi-
Treatment sion of the trigeminal nerve.
As a basic treatment, antiviral drugs are administered, orally at Eye symptoms such as conjunctivitis and kerati-
tis occur as complications in some cases.
the early stages and intravenously in severe cases. The main pur-
pose of treatment is to alleviate the sharp pain in the acute stages
to prevent sequelae that may include post-herpetic neuralgia and
motor palsy. NSAIDs are used as a symptomatic therapy. The
prognosis tends to be good. After first infection, patients obtain
permanent immunity due to reactivated cell-mediated immunity.
23
Variola (Synonym: Smallpox) MEMO

Variola is caused by infection of the upper respiratory mucosa by the
Orthopoxvirus variola virus. Infection is by droplet or contact. This
pathogen is so virulent that it used to be fatal in many cases; however,
Jenner’s cowpox vaccine made prevention possible. A smallpox eradi-
cation program was developed in 1958 by WHO, and no cases of vari-
ola have occurred since 1977. In 1980, WHO declared the disease
eradicated. The virus is kept at secure institutions in biosafety level 4
labs in the U.S. and Russia.
Fig. 23.8 Histopathology of herpes zoster.
5. Hand, foot and mouth disease (HFMD)
Outline
● An eruption is caused by coxsackievirus A16 or
enterovirus 71. Breast-fed infants are most frequently
affected.
● Blistering is present in the distal portions of the extremi-
ties and oral mucosa. It disappears in 4 to 7 days. Oral
enanthema occurs on the buccal mucosa and tongue.
Erythema or aphtha-like eruptions may also occur.
● The only treatment that is usually necessary is oral
hydration.
Clinical features
a b c d e f g h Hand,i foot and
j mouthk disease
l (HFMD)
m occurs
n suddenly
o pafter 2q r
to 5 days of latency. In about half of cases, slight fever is present
for 1 or 2 days. Dispersed small blisters with red halos appear on
the hands, soles, knee joints and buttocks (Fig. 23.9). The blisters
are oval, and their long axis is often parallel to the dermatoglyph-
ic line. Some degree of tenderness, but not itching, may accom-
Clinical images are available in hardcopy only. pany these. The blisters disappear in 4 to 7 days without
rupturing. Painful erythema, blisters, or aphtha-like erosions that
number from a few to several dozen occur on the buccal mucosa
and tongue. They resolve in several days. When caused by
enterovirus 71, HFMD may be accompanied by aseptic meningitis.
The main causative viruses are coxsackievirus A16 and
enterovirus 71. These proliferate in the intestinal tract and are
found in stool and in pharyngeal secretions. The viruses are
Clinical images are available in hardcopy only. spread by droplet and oral infection. The infectiousness is so high
that widespread outbreaks sometimes occur in hospitals. HFMD
occurs most commonly in 1- to 2-year-old breast-fed infants and
in summer epidemics.
Fig. 23.9 Hand, foot and mouth disease. Treatment
a: Vesicles accompanied by red halo and slight No treatment is necessary. Symptomatic therapy is performed
tenderness. b: Eruptions on the knees. c: Vesicles
accompanied by sharp pain and aphtha in oral
only in cases with severe symptoms.
23 mucosa .
B. Viral infections whose main symptom is verruca
1. Verruca vulgaris
Outline
● It is caused by human papillomavirus (HPV) infection.
● It occurs most frequently on the fingers, toes, soles and
B. Viral infections whose main symptom is verruca 433
dorsal surfaces of hands. It is largely asymptomatic.

● Liquid nitrogen cryotherapy, topical glutaraldehyde appli-
cation, carbon dioxide gas laser therapy, and electro-
surgery are useful. Some cases heal spontaneously.
Pathogenesis
Verruca vulgaris is caused by human papillomavirus (HPV), a
virus in the Papovaviridae family. The most frequent HPV infec-
tion is HPV-2, followed by HPV-4, HPV-7, HPV-26, and HPV-
27 (Table 23.1). The virus invades the skin from minor external
injury and infects the epidermal cells. It replicates simultaneously
with differentiation of epidermal cells, leading to maturation of
viral particles in the granular cell layer. The viral particles are
released concurrently with exfoliation of verruca, causing spread-
ing to other areas.

Verruca vulgaris occurs most commonly on the hands and feet
of infants, after a latency of 3 to 6 months. It begins with small
papules. They enlarge, elevating in verrucous shape and becom-
ing several millimeters to several centimeters in diameter (Fig.
23.10). Usually multiple but sometimes solitary eruptions of ver-
ruca vulgaris aggregate, coalesce, and may form plaques. It is
largely asymptomatic and has specific clinical features. There are
some types of verruca vulgaris that are given characteristic clini-
cal diagnostic names according to the clinical features, type of Clinical images are available in hardcopy only.
virus and the affected site.
① Plantar wart
Verruca vulgaris occurs on the soles. A keratotic lesion forms
without distinct elevation. It resembles tylosis and clavus, but can
be differentiated from those by scraping. If surface scraping of
the keratotic lesion causes petechiae, the diagnosis is plantar wart. Fig. 23.10 Verruca vulgaris.
② Myrmecia
A small, dome-shaped nodule forms on the soles. It is caused
by HPV-1 infection (Fig. 23.11) and may resemble molluscum
contagiosum. It is also called deep palmoplantar wart. It has a
red, cratered appearance. Tenderness is often present. It is a type
of plantar wart.
Table 23.1 HPV types and clinical symptoms.
Type Symptoms 23
1 Myrmecia
2,4,7,26-29 Verruca vulgaris
3,10 Flat warts (verruca plana juvenilis)
5,8,9,12,14,15,17,19-26,36,47,50 Epidermodysplasia verruciformis
57,60 Epidermal cyst in the soles
6,11 Condyloma acuminatum
Fig. 23.11 Myrmecia.
16,18,31, 33-35, 39-41, 51-60 Cervical dysplasia, endocervical cancer
A dome-shaped nodule accompanied by tender-
13, 32 Oral focal epithelial hyperplasia ness occurred. Scraping the nodule revealed that
the lesion had invaded the deep intradermal por-
30, 40 Pharyngeal carcinoma
tion.
③ Pigmented wart
This is caused by infection of HPV-4 or HPV-65, or of HPV-
60 in rare cases. It has the clinical features of verruca vulgaris
and blackish pigmentation; it is also called a black wart.
④ Punctate wart
This is caused by HPV-63 infection. Multiple, punctate, white
keratotic lesions of 2 mm to 5 mm in diameter occur on the hands
and soles.
Fig. 23.12 Filiform wart. ⑤ Filiform wart
A long, small, thin protrusion of several millimeters in diame-
ter occurs on the face, head region or neck (Fig. 23.12).
Pathology
There is hyperkeratosis, incomplete keratinization and thicken-
ing of the papillary epidermis, accompanied by thickening of the
granular cell layer in the epidermis. Cells with vacuolar degener-
ation and large keratohyaline granules are found in the granular
cell layer. These cellular changes, called koilocytosis, are charac-
teristic of HPV infection (Fig. 23.13).
Treatment
Fig. 23.13 Histopathology of verruca vul- The main treatment for verruca vulgaris is liquid nitrogen
garis. cryotherapy. Local injection of bleomycin and cauterization by
electrical scalpel or carbon dioxide laser are conducted on sites
where cryotherapy is not fully effective, including hands and
soles. For multiple lesions, coix seed (Coix lacryma-jobi L.)
extract may be administered orally. Topical application of glu-
taraldehyde is useful. Topical vitamin D and oral retinoids have
been reported effective for severe cases.
2. Flat wart
Synonym: Verruca plana juvenilis
Clinical features
Multiple, slightly elevated, flat papules of 2 mm to 10 mm in
diameter occur on the face (forehead and cheeks). These may
coalesce or appear in linear pattern from autoinfection (Köbner
phenomenon) (Fig. 23.14). The papules are normal skin color or
light pink and nearly asymptomatic. They may disappear sponta-
23
Clinical images are available in hardcopy only. neously with scaling, which is followed by inflammatory symp-
toms such as itching and reddening. However, flat wart may
persist for several years.
Pathogenesis
Flat wart is a viral wart that is often caused by HPV-3 or HPV-10.
Fig. 23.14 Flat wart.
Treatment
Some cases heal spontaneously. Liquid nitrogen cryotherapy is
conducted. Coix seed (Coix lacryma-jobi L.) extract may be
administered orally.
B. Viral infections whose main symptom is verruca 435
3. Condyloma acuminatum
Outline
● Genital verrucous papules are caused by HPV-6 or HPV-
11. This is an STD.
● Latency is 2 to 3 months.
● Cryotherapy and laser surgical removal are the main Clinical images are available in hardcopy only.
treatments.
Clinical features
The latency of condyloma acuminatum is 2 to 3 months. Mul-
tiple verrucous papules of papillary or cauliflower shape occur in
the genitalia or perianal region (Fig. 23.15). Keratinization is
rarely present. The papules are infiltrative at the surface and may
give off foul odor. Condyloma acuminatum may enlarge. Kera-
tinization and ulceration may closely resemble squamous cell
carcinoma (Buschke-Lowenstein tumor).
Pathogenesis Clinical images are available in hardcopy only.

Condyloma acuminatum is caused by HPV-6 or HPV-11.
Most cases occur in the sexually active years, transmitted through
sexual activity. The virus invades through minor external injury
of the genitalia, perianal region, or vaginal introitus, and infects
epidermal basal cells, inducing abnormal cellular proliferation.
Proliferation of the epidermis results in formation of papillary Fig. 23.15 Condyloma acuminatum.
tumors (warts). The verrucous papules resemble cauliflower.

Condyloma acuminatum can be diagnosed by the clinical fea-
tures; however, biopsy may be needed for differential diagnosis,
such as from Bowenoid papulosis, a tumor that is often caused by
HPV-16 and that histologically resembles Bowen’s disease.
Treatment
Treatment for condyloma acuminatum is the same as for verru-
ca vulgaris. Liquid nitrogen cryotherapy and surgical removal
using electrical scalpel or carbon gas laser are conducted. Local Clinical images are available in hardcopy only.
injection of bleomycin is used in intractable cases.
23
4. Bowenoid papulosis
Multiple black papules of 2 to 20 mm in diameter occur on the
genitalia of young people (Fig. 23.16). Small papules may coa-
lesce and form plaques. HPV-16 is detected in the lesion.
Bowenoid papulosis is histopathologically indistinguishable from
Bowen’s disease. It rarely becomes malignant, and it may heal
spontaneously. The prognosis is good. Liquid nitrogen cryothera-
py and electrical cauterization are the main treatments. Bowenoid Fig. 23.16 Bowenoid papulosis.
The papules caused by Bowenoid papulosis are
papulosis is thought to be an atypical type of condyloma acumi- blackish in most cases or close to normal skin
natum. color in some cases.
5. Epidermodysplasia verruciformis
The main causes are HPV-5, HPV-8, HPV-17 and HPV-20
infection. Susceptibility to the virus is inherited, usually autoso-
Clinical images are available in hardcopy only. mal recessively; however, some cases with autosomal dominant
and X-linked dominant patterns have been reported. Congenital
cellular immunocompromise against HPV is thought to be asso-
ciated with the occurrence. Relatively large, flat-wart-like, red-
dish-brown keratotic patches appear on the dorsal surfaces of the
hands and trunk of infants, often coalescing to form plaques or
reticular arrangements. Pityriasis-versicolor-like leukoderma and
erythema may occur (Fig. 23.17). Multiple cells containing
bright and enlarged cytoplasm are histopathologically observed
in the upper suprabasal cell layer. The eruptions gradually spread
on the whole body surface. Malignant skin tumor (e.g., squamous
cell carcinoma, basal cell carcinoma, Bowen’s disease) occurs in
about half of adolescent and older patients. There is no specific
treatment for epidermodysplasia verruciformis. Sunscreen is used
for prevention, because lesions on sun-exposed areas tend to
worsen. Oral retinoid administration is effective.
Clinical images are available in hardcopy only. 6. Molluscum contagiosum
Outline
●A wart forms as a result of infection by the molluscum
contagiosum virus.
● Infants are most frequently affected.
● Small, multiple, dome-shaped nodules of 2 mm to 10 mm
in diameter occur. Autoinfection is caused by wart con-

tents adhering to the epidermis.
● Tweezer excision of the wart is the most effective treat-
ment.
● Multiple molluscum contagiosum may appear on the face
of patients with AIDS.

Clinical features
The latency of molluscum contagiosum is between 14 and 50
days. Small, multiple, flat-surfaced, glossy, centrally concave,
dome-shaped nodules of 2 mm to 10 mm in diameter occur (Fig.
23
23.18). They contain an opaque white gruel-like substance. They
are asymptomatic except for mild itching. The trunk and extremi-
ties of infants are most frequently affected. When sexually trans-
Fig. 23.17 Epidermodysplasia verruciformis. mitted, the genitalia, lower abdomen, and medial thighs are
Large, flat, verrucous, reddish-brown keratotic involved.
macules occur. The eruptions elevate and form
tumors in some cases. Pathogenesis, Epidemiology
Warts are produced by molluscum contagiosum, a virus in the
Poxviridae family. Cells at the center of the skin lesion are dis-
torted or destroyed, giving the appearance of large hyaline bodies
(molluscum bodies) that contain large amounts of cytoplasmic
C. Viral infections whose main symptom is erythematous eruptions 437

Fig. 23.18 Molluscum contagiosum.

The small papules are glossy on the surface and umbilicated at the center.
virus material. Molluscum contagiosum is spread by contact

infection. The virus enters through a break in the skin or a hair
follicle, and proliferates in the suprabasal cell layer of the epider-
mis. When a wart is scratched, the contents adhere to the epider-
mis and cause autoinfection. Children with atopic dermatitis are
most commonly affected. In recent years, the numbers of infec-
tions in healthy children at swimming schools, in adults from STDs,
and in patients with immunodeficiency have been increasing.
Pathology
Molluscum contagiosum is characterized by lobulated, endo-
phytic hyperplasia that produces a circumscribed intracutaneous
pseudotumor. The keratinocytes contain very large intracytoplas- Fig. 23.19 Histopathology of molluscum
mic inclusions (molluscum bodies). contagiosum.
Diagnosis
Molluscum contagiosum is easily diagnosed by the clinical
features. In sudden occurrence of multiple molluscum contagio-
sum in adults, AIDS involvement is highly suspected.
Treatment
Tweezer excision of the lesions is most effective. Cryo-coagu-
lation therapy and application of 40% silver nitrate are also use-
ful. Molluscum contagiosum heals spontaneously in some cases.
1. Measles
Outline
● Itis an infectious disease caused by the measles virus.
Young children are most frequently affected. It occurs in
epidemics with intervals of several years, often during
the spring.
● A fever and common-cold-like symptoms occur after an
incubation period of about 2 weeks. When the fever sub-

sides, white macules called Koplik’s spots appear. Fever
recurs and eruptions and catarrhal symptoms and skin
lesion appear on the whole body. The fever subsides
rapidly in 3 to 4 days with exfoliation of the eruptions. It
heals with pigmentation.
Clinical images are available in hardcopy only. ● Otitis media, encephalitis, and subacute sclerosing
panencephalitis (SSPE) may occur as complications.

● It is diagnosed by the clinical features or serologically.
Clinical features
The clinical features of measles appear after an incubation
period of 10 to 14 days. There are prodromal symptoms such as
Fig. 23.20 Measles. fever, cough and nasal congestion for about 5 days. Grayish-white
papules on the buccal mucosa called Koplik’s spots appears as
41 the prodrome subsides, and then enanthema spreads on the fore-
body temp.(˚C)
40 head, behind the ears, and on sites on the long axis of the body. It
39 is accompanied by high fever. Measles eruptions are character-
38 ized by coalesced pink macules and elevated papules (Figs. 23.20
37 and 23.21). The course of measles is divided into three stages:
first (catarrh or prodrome), second (eruption), and third (recovery).
days 1 5 10 15 20
① First stage (catarrh)
erythema A fever of about 38˚C and catarrhal symptoms such as nasal
symptoms
scales/pigmentation discharge, sneezing, eye discharge and cough persist for 3 to 4

Koplik’s spot days. The respiratory secretions, lacrimal fluid and saliva at this
common cold-like stage are at their most infectious. On the last 1 to 2 days of the
symptoms
2 weeks
catarrhal symptoms, punctate white macules called Koplik’s
incubation period
spots appear on the buccal mucosa and sometimes on the gums at
almost the same time as the fever subsides (Fig. 23.22).
Fig. 23.21 The course of measles. ② Second stage (eruption)
After the fever subsides, it recurs (diphasic fever), accompa-
nied by eruptions and aggravation of the catarrhal symptoms. It
persists for 3 or 4 days. Eruptions first appear behind the ears and
cheeks, spreading to the trunk and extremities. Small erythema
coalesces and enlarges, forming irregular shapes with a reticular
pattern. By this time Koplik’s spots have already disappeared.
The measles virus is not found at the lesion; the mechanism is
thought to be allergic reaction. Dehydration and various compli-
cations often occur from the persistent high fever.
③ Third stage (recovery)
23
Fig. 23.22 Koplik spots.
The fever subsides in several days. Healing is with exfoliation
of eruptions and pigmentation.
Complications
Complications of measles include otitis, pneumonia, encephali-
tis, myocarditis and subacute sclerosing panencephalitis (SSPE).
In atypical measles, vaccination leads to measles with symptoms
different from those of usual measles. Atypical measles in recipi-
ents of killed measles vaccine (used from 1963 to 1968 in Japan)
and immunocompromised persons have been reported.
Pathogenesis
active phase postdisease
The causative viruses are in the family Paramyxoviridae,
genus Morbillivirus. Infants in the first three months after birth
are not infected by the measles virus because of maternal-to-fetal
transfer of passive immunity. Infants between the age of 3 Koplik’s spot pigmentation
months and early childhood are most commonly affected. The
measles virus is highly infectious and invades by droplet infec-
tion. It proliferates in the epithelial cells of the nasopharynx,
resulting in viremia. Subclinical infection rarely occurs; more
than 95% of the infected patients show apparent infection.
Affected individuals obtain strong permanent immunity.
disseminated
Diagnosis and coalescent
erythema and
A decrease of both neutrophils and lymphocytes (leukocytope- papules
nia) and an increase of LDH are observed by peripheral blood
examination. Serologic assay of antibody responses, viral isola-
tion of respiratory secretions, and PCR are useful for diagnosis. Measles
no pigmentation
It is differentiated from other viral infection including rubella postauricular
and exanthema subitum, hemolytic streptococcal infection (scar- lymph
node swelling
let fever), drug eruption, erythema multiforme, Kawasaki disease
and sepsis (Fig. 23.23).
Treatment
There is no effective treatment for measles. Bed rest, keeping
the body warm, and oral antipyretics and antitussives are recom-
mended as symptomatic therapies. Bacterial complications are erythema
treated with antibiotics. Human immuoglobulin may be used in and papules
(without
severe cases. coalescence,
milder than
those of
Prevention measles)
When the route of infection has been defined and no more than Rubella
5 days has passed after infection, the onset can be prevented or
the symptoms can be mitigated by intramuscular injection of malar flush
human immunoglobulin. Attenuated live vaccine is used for perioral pallor
strawberry tongue exfoliative
immunization. scales
erythema
on the chest
2. Rubella
23
Outline
● Caused by the rubella virus, it is commonly known as
diffuse
German measles or “three-day measles.” small
● The main symptoms are eruptions, enlarged lymph erythema lamellar
scales
nodes (the postauricular lymph node, in particular) and
fever.
● Eruptions and fever occur concurrently. Papular erythe-
ma accompanied by moderate itching on the face Streptococcal infection

spreads to the whole body surface and does not coa-
lesce. Healing is without scaling or pigmentation. Fig. 23.23 Differential diagnosis of measles.
● Thrombocytopenic purpura and arthritis occur as compli-

40
body temp.(˚C)
cations. Arthritis is the only symptom in many adult

39 cases.
38 ● Rubella infection in early pregnancy may induce congen-
37 ital rubella syndrome in fetus. Pregnant women must

avoid rubella infection and vaccination.
days 1 2 3 4 5 6 7 8 9 10 11
symptoms
papules Clinical features

lymph node swelling Rubella is commonly known as “three-day measles.” The clin-
incubation
period 2-3 weeks ical course is shown in Fig. 23.24. After a latency of 2 to 3
weeks, the systemic lymph nodes enlarge. Enlargement in the
Fig. 23.24 The course of rubella postauricular region and cervical lymph node is particularly
noticeable and persists for several weeks. In some cases it begins
with eruptions and fever without lymph node enlargement. Sev-
eral days later, papular erythema accompanied by moderate fever
and itching spread on the whole body (Fig. 23.25). Unlike
measles, the eruptions of rubella are solitary and do not usually
coalesce. They disappear without scaling or pigmentation in 3 to
5 days. Petechiae-like enanthema called Forschheimer spots
occur in the palate mucosa in about half cases.
Complication
Encephalitis, meningitis, thrombocytopenic purpura in infan-
cy, and arthritis in adulthood occur as complications.
If a woman is infected in or before her 5th month of pregnancy
the newborn may also be affected (congenital rubella syndrome,
CRS) (Table. 23.2).
Pathogenesis
The rubella virus, an RNA virus in the family Togaviridae,
genus Rubivirus, invades the body from the upper respiratory
tract by droplet infection or contact infection, proliferates in the
regional lymph node, and causes viremia resulting in the onset of
rubella. Permanent immunity is obtained after the first infection,
although reinfection occurs in rare cases. Most patients are
between 5 and 15 years old. Rubella tends to occur in spring and
summer epidemics at intervals of 3 to 10 years.
Leukocytopenia, thrombocytopenia and atypical lymphocytes
23
are found by peripheral blood test. Increased antibody titer is
observed by serological assay. Differential diagnosis can be
made by detecting IgG and IgM, which is specific to rubella.
Cases with moderate symptoms are diagnosed by the clinical
course and epidemic circumstances.
a b c d e f g h j
i Rubella k l m measles,
n o p q
is differentiated from exanthema subitum andr
Fig. 23.25 Rubella. hemolytic streptococcus infection (scarlet fever) (Fig. 23.23).
a: Erythematous papules on the face and upper
chest. b: Erythematous papules on the trunk. Most cases are clinically difficult to diagnose, so serological
examination is necessary.
Treatment, Prevention Table 23.2 Symptoms of congenital rubella

syndrome.
Rubella is treated symptomatically. Vaccination is effective
for prevention, but pregnant women must not be immunized with 3 classic symptoms
live vaccine. Eye symptoms
Cataract
Microphthalmia
3. Roseola infantum
Congenital heart disease
Synonym: Exanthema subitum Patent ductus arteriosus
Ventricular septal defect
Outline
Pulmonic stenosis
● Itis caused by human herpes virus (HHV) types 6 and 7.
Sensorineural hearing loss
Breast-fed infants are most commonly affected.
● A high fever occurs suddenly and persists for 3 or 4 Other symptoms
days. As the fever subsides, measles-like eruptions Low birth weight
appear on the whole body. They do not coalesce, but Thrombocytopenia
disappear without pigmentation in 2 to 3 days. Liver disorder (e.g., hepatitis,
● Febrile convulsions may occur as a complication. splenohepatomegaly)
Microencephaly
Clinical features Mental impairment
After 2-week latency, an acute high fever of 38˚C to 39˚C
occurs and persists for 3 to 4 days. Infected children in most
cases appear normal. About when the fever subsides, mild
measles-like eruptions occur on the face and trunk. They do not
coalesce but disappear in 2 to 3 days without leaving pigmenta-
tion (Fig. 23.26). Diarrhea and moderate cough often occur. Seiz-
ers may occur during the febrile period in up to 10% of patients.
Acute encephalitis and liver dysfunction are complications in rare
cases.
Pathogenesis
The causative viruses are thought to be HHV-6 type B and
HHV-7. Although HHV-6 is spread by saliva transfer, newborns
are not infected because of maternal passive immunity; infants
between the ages of 6 months and 3 years are affected.
Diagnosis
Roseola infantum can be diagnosed by the characteristic clini-
cal features. In more than half cases, enlargement and reddening
occur in the lymph follicles at the base of the uvula. These find-
ings are helpful for diagnosis.
body temp. (˚C)
40
23
39
Treatment
38
The entire course is between 4 and 6 days, and the prognosis is
37
good. Most cases of roseola infantum are mild and respond well
to antipyretics during the febrile period. days 1 2 3 4 5 6 7 8 9 10 11
symptoms
measles-like erythema
diarrhea
incubation
period 2 weeks
Fig. 23.26 The course of exanthema subi-

tum/roseola infantum.
4. Erythema infectiosum
Outline
● Eruptions, commonly known as fifth or “slapped cheek”
disease, are caused by human parvovirus B19.
● Flush appears in the cheeks, and papular erythema occurs
a b c d e f g h on the
i extremities,
j k coalescing
l to present
m n lacy,
o reticulated
p q r
eruptions that predominate in the extremities. These heal
without scaling or pigmentation in about 1 week.
● Infection in pregnancy may lead to fetal hydrops. If
patients with hemolytic anemia are infected, acute pure

red cell aplasia occurs, resulting in marked anemia, fetal
hydrops or death.
Clinical features
Clinical images are available in hardcopy only. Erythema infectiosum is commonly known as fifth or “slapped
cheek” disease. It tends to occur in spring and summer epidemics
at intervals of 4 to 6 years. It occurs most frequently in children
between 4 and 10 years of age; however, there are also cases in
which adults, especially mothers and nurses, are infected by
infants and children. Latency is between 2 and 3 weeks. Erythe-
ma infectiosum may begin with mild prodromal symptoms.
Influenza-like catarrhal symptoms occur in some cases. Erythe-
g
ma that j resembles a hand-slap occurs suddenly on p
both qcheeks
and disappears in 1 to 4 days (Fig. 23.27). A day or two after the
Fig. 23.27 Erythema infectiosum.
a: Erythema on the cheeks (“slapped cheek”). b:
facial lesion manifests, erythematous lesions of about 1 cm in
Erythema on the upper arm. diameter occur on the extensor surfaces of arms and legs. These
coalesce gradually and begin to heal at the center, leaving the
characteristic lacy, reticulated pattern. When the trunk is
involved, no lacey pattern is present. The eruptions disappear
without scaling or pigmentation in about 1 week.
When a pregnant woman is infected, prenatal infection occurs
in 30% of cases and may cause fatal edema (fetal hydrops) or
fatal death. Rapid decrease of erythrocytes (aplastic crisis caused
by acute pure red cell aplasia) occurs in cases with hemolytic
anemia as an underlying disease, leading to marked anemia.
Pathogenesis
Erythema infectiosum is caused by droplet infection of human
23
parvovirus B19, which is in the Parvovirus genus of DNA virus-
es. The virus invades the body by respiratory infection and prolif-
erates within erythroblasts of the bone marrow in 4 to 7 days,
resulting in viremia. About 2 weeks after infection, production of
antibodies begins. At the same time, eruptions appear; involve-
ment of immunocomplex is suggested. Manifest infection occurs
in 70% of infant cases and 30% of adult cases.
Laboratory findings
Specific IgG and IgM antibodies are examined by serological
assay. In adult cases, antinuclear antibodies are sometimes
detected, which may lead to a misdiagnosis of erythema infectio-

sum as lupus erythermatosus.
Treatment
No specific antiviral therapy is available. Intense accessory
symptoms are treated symptomatically.

5. Gianotti-Crosti disease
Synonyms: Gianotti disease, Infantile papular acrodermati-
tis, Papular acrodermatitis of childhood
Outline
● Liver dysfunction and eruptions are caused by initial
infection of hepatitis B virus. It occurs most frequently in
infants.
● Papules appear on the legs, ascending to the arms and
face.
● There is a risk that the patient may eventually become a
hepatitis B carrier.
Clinical features
Gianotti-Crosti disease occurs most frequently in infants
between the ages of 6 months and 12 years. After a latency 50 to
180 days, multiple, flat, light pink papules of 3 mm to 4 mm in
diameter suddenly appear solitarily on the distal portions of the
lower legs. They rapidly ascend to the buttocks, upper arms and Fig. 23.28 Flat, red erythema caused by
face in 3 to 4 days (Fig. 23.28). The trunk is almost never involved. Gianotti-Crosti disease.
The papules are nearly asymptomatic and disappear spontaneous-
ly in about 1 month. Enlargement in the superficial lymph node
and liver is present, and hepatic symptoms such as elevated liver
enzyme occur; nevertheless, jaundice does not occur.
Pathogenesis
Gianotti-Crosti disease is caused by infection of the hepatitis B
virus (HBV) in infancy. In most cases there are hepatitis B
patients or HBV carriers in the family; the cause is thought to be
horizontal transmission.

23
Increases in serum AST, ALT, LDH and ALP are observed
from hepatic symptoms. HBs antigens are positive. The eruptions
disappear in about 1 month, and HBs antigens disappear in sever-
al months. Gianotti-Crosti disease is relatively easily diagnosed Clinical images are available in hardcopy only.
by the clinical features and enlargement of the lymph nodes and
liver. HBs antigens are observed by blood test; if they are nega-
tive, there is high possibility of Gianotti-Crosti syndrome
(described below).
Treatment, Course of disease

When HBs antigens persist after the eruptions disappear, the Fig. 23.29-1 Gianotti-Crosti syndrome.
patient may progress to become a carrier. About half of patients

under the age of 1 become carriers. Prevention of such progres-
sion is of primary importance. Interferon, anti-HBV antibody
hyperimmune globulin, and glycyrrhizinate are used.
Gianotti-Crosti syndrome
The eruptions caused by Gianotti-Crosti syndrome closely
resemble those of Gianotti-Crosti disease; however, the former
are accompanied by intense itching and often occur on the trunk
(Figs. 23.29-1 and 23.29-2). The main causative viruses are
cytomegalovirus, Epstein-Barr virus, and coxsackievirus. HBs
antigen is negative. There are no findings of liver dysfunction.
6. Infectious mononucleosis
Outline
● It is caused by infection of Epstein-Barr virus. It occurs
most frequently in puberty.
● The main symptoms are high fever, pharyngeal pain, and
Fig. 23.29-2 Gianotti-Crosti syndrome.
swelling in the cervical lymph nodes. Rubella-like and
measles-like eruptions and erythema multiforme appear
in 30% of cases.
● Symptomatic therapy is the main treatment. Penicillin-
containing drugs and aspirin are contraindicated.

The latency of infectious mononucleosis is 1 to 2 months.
After prodromes such as headache and generalized fatigue that
persist for several days, a high fever (higher than 39˚C) and
g intense pharyngeal
j pain occur. Eruptions appear 4 to 10p daysq
after the onset in about 30% of cases (Figs. 23.30-1 and 23.30-2).
The eruptions may present as rubella-like eruptions, measles-like
eruptions, or erythema multiforme. Drugs (penicillin in particu-
lar) induce hypersensitive reaction and aggravate the eruptions.
Marked swelling is seen in the whole body, particularly in the
cervical lymph nodes. There is tenderness but no spontaneous
pain. Splenohepatomegaly accompanied by hepatic dysfunction
often occurs. The fever subsides in 7 to 10 days, after which
23 Clinical images are available in hardcopy only. symptoms gradually subside. Thrombocytopenia, hemolytic ane-
mia, encephalomeningitis and Guillain-Barre syndrome occur as
complications.
Infectious mononucleosis is caused by infection of Epstein-
Barr virus (EBV). Permanent immunity is obtained from the first
a b c d e f g h infection.
i j EBVk is always
l present
m in nthe oralo cavity,
p and itq easilyr
spreads orally or through inhalation. The virus invades the body,
Fig. 23.30-1 Infectious mononucleosis.
a: Lesion on the soft palate. b: Lesion on the proliferates in the epithelial cells of the pharyngeal mucosa, and
shoulder and upper arm. travels to the regional lymph node. It immortalizes B cells by
latently infecting them through CD21 on their surface. The

pathogenesis is thought to be reactivation of B cells against the
organic immune mechanism, which induces inflammation. In
Japan more than 80% of infants experience EBV exposure
through mother-to-child infection, but they are subclinical. Con-
versely, when the first infection occurs in adolescence, apparent Clinical images are available in hardcopy only.
infection takes place as infectious mononucleosis. Patients are
often infected by the opposite sex; infectious mononucleosis is
commonly called kissing disease. In recent years, antibody
prevalence has decreased, and the incidence of infectious
mononucleosis is increasing. It occurs most frequently in adoles-
cents between the ages of 14 and 18, regardless of the season.
a b c d e f g h i j
Fig. 23.30-2 Infectious mononucleosis.
Laboratory findings c: Lesion on the trunk.
The leukocyte count approaches 10,000 per microliter, and
more than half of it is mononuclear cells, of which 10% are par- recovery
incubation acute
ticularly large atypical lymphocytes. These cells are not B cell phase phase
period
titers of antibodies (AB)

640
but CD8+T cells that are activated to exclude infected cells. onset
anti-VCA-IgG Ab.
Increased serum AST, ALT and ALP titers resulting from liver 160 anti-VCA-
IgM Ab.
dysfunction and antibodies produced by B cells lead to elevated
levels of polyclonal human immunoglobulin. Paul-Bunnel test, 40
which measures an antibody reaction in blood to sheep erythro- anti-EA-IgG Ab.
anti-EBNA-Ab.
cytes, used to be helpful for diagnosis. However, because of the 10
more diagnostically valuable measurement of viral antibody titer
(Fig. 23.31), it is no longer used.
Fig. 23.31 Changes of antibody titer related
to EBV, and staging of infectious
Diagnosis mononucleosis.
Infectious mononucleosis is diagnosed by the clinical features, VCA: viral capsid antigen, EA: early antigen,
EBNA: EB nuclear antigen.
which include marked lymph node enlargement, findings of the (Adapted from; Ito A, et al., editors. Textbook of
blood, and serological findings (Table 23.3). internal medicine. 6th ed. Nakayama Shoten;
2002: 1123-5).
Treatment
There are no specific treatments for infectious mononucleosis,
other than bed rest and symptomatic therapies. Drugs containing
aspirin or penicillin are contraindicated: Aspirin may cause
Reye’s syndrome and penicillin may induce hypersensitive reac-
tion as severe eruptions.
Table 23.3 Diagnostic criteria for infectious mononucleosis.

3 major symptoms Remittent fever swelling of systemic lymph nodes, elevated atypical lymphocytes in the peripheral
23
blood
Hematological findings Rate of lymphocytes + monocytes >50% (typically >60%)
Rate of atypical lymphocytes >10% (typically >20%)
Liver function findings Increases in AST, ALT, and LDH Abnormality of TTT and ZTT
Serological findings EB virus antibody titer rise
1. Anti-VCA IgG antibody 1: >160
2. Anti-VCA IgM antibody 1: >10 or anti-EA-DR IgG antibody 1: >10
3. Anti-EBNA antibody negative in acute phase
All criteria (1.-3.) are generally met. In some cases, 3. and either 1. or 2. are met.
Auxiliary findings Palpebral edema, palate ecchymosis, pharyngitis, fever unresponsive to antimicrobials for 5 days or
more (young person), liver pain by tapotement, and splenohepatomegalies
D. Specific viral infectious diseases
Acquired immunodeficiency syndrome (AIDS)
Outline
● Diagnosis is confirmed when the CD4+T cell count is
Clinical images are available in hardcopy only. found to be reduced by HIV and the diagnostic criteria
are met.
● The infection routes are sexual activity, blood infection
and mother-to-child transmission.

● Opportunistic infections produce various skin eruptions,
but they display atypical clinical features and are difficult

to diagnose.
Fig. 23.32 Candidiasis of the tongue in a
● Mucocutaneous symptoms such as Kaposi’s sarcoma,
patient with HIV.
oral candidiasis, molluscum contagiosum and seborrheic
dermatitis may be helpful for diagnosis. Generalized her-
pes zoster, cryptococcus, tinea and drug eruptions often
occur.
Cutaneous symptoms of AIDS

The symptoms of AIDS are listed below. A decreased CD4+T
cell count is associated with AIDS.
① Kaposi’s sarcoma
In Japan, homosexual males are most commonly affected.
Multicentric nodules ranging from reddish purple to blackish
brown occur most frequently. See Chapter 22 for details.
② Mucocutaneous infectious disease
Candidiasis occurs in the oral cavity in all cases of AIDS; it
has diagnostic value (Fig. 23.32). Herpes simplex and herpes
zoster are easily caused and tend to become generalized and
severe. Multiple molluscum contagiosum appears on the face.
Verruca vulgaris, cryptococcus, tinea and impetigo also occur
and become intractable, displaying atypical clinical features in
many cases. Viral infection such as in herpes zoster may recur
Names of HHV MEMO

23
Diagnostic name Common name Abbreviation
human herpes virus 1 herpes simplex virus type 1 HSV-1
human herpes virus 2 herpes simplex virus type 2 HSV-2
human herpes virus 3 varicella zoster virus VZV
human herpes virus 4 Epstein-Barr virus EBV
human herpes virus 5 cytomegalovirus CMV
human herpes virus 6 human herpes virus type 6 HHV-6
D. Specific viral infectious diseases 447
(/ml)
1,000
asymptomatic
herpes zoster
500 Kaposi’s sarcoma
CD4 ＋ T cells
400 HAART therapies should be started.
tuberculosis
300
oral candidiasis
diarrhea, weight loss

200
Prevention of carinii pneumonia should be started. carinii phneumonia cryptococcal meningitis
esophageal candidiasis
CMV infection toxoplasmosis
100
atypical mycobacteriosis
Monthly funduscopy is recommended.
malignant lymphoma AIDS encephalopathy
0
1-2 months several years to decades 1-3 months
Acute phase Asymptomatic period ARC AIDS
Fig. 23.33 Relation between the number of CD4 ＋ T cells in an HIV patient and the course of opportunistic infection.
ARC: AIDS-related complex, HAART: highly active antiretroviral therapy. (Adapted from; the Textbook of internal medicine of
Hokkaido University).
and aggravate.
③ Other symptoms
Seborrheic dermatitis, psoriasis vulgaris and eosinophilic pus-
tular folliculitis often occur. Drug eruptions are induced by drugs
that are taken for other diseases, including for pneumocystis
carinii pneumonia.
Systemic symptoms of AIDS

Primary HIV infection progresses to the asymptomatic stage
and then to symptomatic HIV infection, resulting in the onset of
23
AIDS (Fig. 23.33).
① Primary HIV infection
Three to 6 weeks after infection, fever, fatigue, sore throat,
headache, diarrhea, arthralgia or enlarged lymph nodes as well as
papular eruptions on the body occur and resolve.
② Asymptomatic stage
This stage lasts for 5 to 10 years. The CD4+T cell count gradu-
ally decreases. There is AIDS-related complex (ARC), which
includes swelling in two or more lymph nodes (persistent gener-
alized lymphadenopathy (PGL)).
③ Symptomatic HIV infection

The lymph nodes and tissues become damaged. The symptoms
are non-specific, such as fever, weight loss and persistent diar-
rhea. Reduced immune response also leads to herpes zoster,
oropharyngeal candidiasis, and seborrheic eczema.
④ Progression from HIV to AIDS
HIV antigens begin to increase and the CD4+T cell count falls
below 200 per microliter. Opportunistic infection, malignant
tumor and exhaustion syndrome occur.
Epidemiology
HIV/AIDS infected patients numbered 40.3 million worldwide
at the end of 2005. The main endemic areas are Africa, Asia and
the U.S. The disease has been increasing rapidly in Asia. Japan
reported 7,338 cases of HIV infection and 3,623 cases of full-blown
Table 23. 4 Revised WHO clinical staging of HIV/AIDS for adults and adolescents (2005).
Primary HIV infection Clinical stage 4
Asymptomatic Conditions where a presumptive diagnosis can be made
Acute retroviral syndrome on the basis of clinical signs or simple investigations
Clinical stage 1 HIV wasting syndrome
Pneumocystis pneumonia
Asymptomatic
Recurrent severe or radiological bacterial pneumonia
Persistent generalized lymphadenopathy (PGL)
Chronic herpes simplex infection (orolabial, genital or anorec-
Clinical stage 2 tal of more than one month’s duration)
Oesophageal candidiasis
Moderate unexplained weight loss (<10% of presumed or
Extrapulmonary TB
measured body weight)
Kaposi’s sarcoma
Recurrent respiratory tract infections (RTIs, sinusitis, bronchi-
Central nervous system (CNS) toxoplasmosis
tis, otitis media, pharyngitis)
HIV encephalopathy
Herpes zoster
Angular cheilitis Conditions where confirmatory diagnostic testing is
Recurrent oral ulcerations necessary:
Papular pruritic eruptions Extrapulmonary cryptococcosis including meningitis
Seborrhoeic dermatitis Disseminated non-tuberculous mycobacteria infection
Fungal nail infections of fingers Progressive multifocal leukoencephalopathy (PML)
Clinical stage 3 Candida of trachea, bronchi or lungs
Cryptosporidiosis
Conditions where a presumptive diagnosis can be made Isosporiasis
on the basis of clinical signs or simple investigations Visceral herpes simplex infection
Severe weight loss (>10% of presumed or measured body Cytomegalovirus (CMV) infection (retinitis or of an organ other
weight) than liver, spleen or lymph nodes)
Unexplained chronic diarrhoea for longer than one month Any disseminated mycosis (e.g. histoplasmosis, coccidiomy-
Unexplained persistent fever (intermittent or constant for cosis, penicilliosis)
longer than one month) Lymphoma (cerebral or B cell non-Hodgkin)
23 Oral candidiasis Invasive cervical carcinoma
Pulmonary tuberculosis (TB) diagnosed in last two years Visceral leishmaniasis
Severe presumed bacterial infections (e.g. pneumonia,
empyema, pyomyositis, bone or joint infection, meningitis,
gingivitis or periodontitis
Conditions where confirmatory diagnostic testing is nec-
essary
Unexplained anaemia (<8 g/dl), and/or neutropenia
(<500/mm3) and or thrombocytopenia (<50,000/mm3) for
more than one month
The UN defines adolescents as persons aged 10-19 years but, in this table, the category of adults and adolescents comprises people
aged 15 years and over for surveillance purposes. For the details of each clinical events or conditions, and the staging of HIV/AIDS for
infants and children, please refer to: http://www.who.int/hiv/pub/guidelines/clinicalstaging.pdf.
D. Specific viral infectious diseases 449
AIDS as of January 2006. Although the main infection route in HIV

Japan used to be blood products, the number of sexually transmit- RNA
ted patients has been increasing in recent years (UNAIDS: http://
CD4 RNA/DNA
www.unaids.org/en/HIV_data/2006GlobalReport/default.asp). RNA hybrid double-strand
DNA
chemokine
Pathogenesis, Mechanism receptors
reverse
AIDS is caused by infection of human immunodeficiency transcriptase proviral DNA
virus (HIV), which can be isolated from blood, serum, genital LTR LTR
secretions, breast milk, cerebrospinal fluid, urine, saliva and CD4＋ T cells nucleus RNA
lacrimal fluid. The main infection routes are sexual activity, HIV RNA
blood infection (from blood products, transfusion, sharing of nee-
dles for drugs, needle-stick accidents), and mother-to-child infec-
ribosome proteins
tion. protease
The cells targeted by HIV are CD4+T cells and macrophages.
The virus invades the cells by binding gp120 on the virus to CD4
on the target cells. In recent years, coreceptors besides CD4 have
been found to be involved.
When HIV invades the cells, proviral DNA is produced by Fig. 23.34 Life-cycle of human immunodefi-
ciency virus (HIV).
HIV reverse transcriptase and transcribed into lymphocytic
DNA, leading to latent infection. Viral particles synthesized from
the implanted DNA mature from the action of protease, and they
bud (Fig. 23.34).
Anti-HIV antibody screening is conducted by ELISA. Although
the test is highly sensitive, it is ineffective for differential diagno-
sis because there are false positives in patients with autoimmune
disease and it takes 6 to 8 weeks after HIV infection for antibod-
ies to be produced (window period). Screenings that show posi-
tive must be re-examined by more specific tests, such as Western
blot or PCR. The clinical staging of HIV/AIDS proposed by
WHO is shown in Table 23.4.
Treatment
Reverse transcriptase inhibitors such as azidothymidine (AZT)
work effectively as anti-HIV drugs. Highly active antiretroviral
therapy (HAART) of reverse transcriptase inhibitors and protease
inhibitors improve the prognosis significantly. Combination ther-
apy of anti-HIV drugs is helpful.
23
Chapter
24 Bacterial Infections
Cutaneous bacterial infections are caused by resident or transient bacteria in the epidermis and mucosa. These
bacteria invade the skin where its barrier function is weaker, such as at hair follicles, sweat glands or sites of
minor trauma. The severity of infection tends to depend on the relative balance between the amount and viru-
lence of the bacteria and the defenses of the host. When a cutaneous bacterial infection is suspected, the
causative bacteria must be identified by culture and microbial sensitivity test in order to choose the appropriate
antibacterial drugs. This chapter introduces four main subtypes of bacterial infections, classified by the clinical
features, and the representative diseases of each subtype: ① acute cutaneous infections (acute pyoderma), ②
chronic cutaneous infections (chronic pyoderma), ③ systemic infections caused by toxins that are produced by
bacteria, and ④ diseases with specific clinical features that are caused by specific bacteria.
A. Acute pyodermas
1. Impetigo
Synonym: Impetigo contagiosa
Outline
● Bacterial infection occurs under the horny cell layer, pro-
ducing toxins that cause blisters and crusts. The infec-
tion spreads by autoinoculation.
● Infants are most frequently affected. Impetigo is divided
into bullous impetigo, in which blistering is caused by

Staphylococcus aureus, and nonbullous impetigo, in
which crusts form from group-A b -hemolytic Streptococ-
cus infection.
● Antibiotics and keeping skin clean are the main treat-
ments.
1) Bullous impetigo

Bullous impetigo occurs most commonly in infants under age
24 3, during the summer. It often spreads through epidemic out-
breaks at daycare centers or nursery schools. It first occurs at a
minor trauma, eczema, or atopic dermatitis that is scratched and
affected. Bullous impetigo begins as an itching and slightly
inflammatory vesicle that enlarges and forms flaccid blisters. The
blisters easily break and become erosive, forming new blisters by
spreading peripherally or by being dispersed to distant locations
Fig. 24.1-1 Impetigo. (Figs. 24.1-1 and 24.1-2). Bullous impetigo is transmitted by contact
Erosions, blisters, pustules and crusts are present. with an infected person. Nikolsky’s sign is negative. It tends to heal
without scarring; however, it may progress into staphylococcal
450
A. Acute pyodermas 451
scalded-skin syndrome (SSSS, described later).
Pathogenesis
Staphylococcus aureus proliferate in the horny cell layer, produc-
ing exfoliative toxin (ET), which leads to intraepidermal blisters.
Insect bites, in which blisters are severely inflammatory and
contain sterile components, can be distinguished from bullous
impetigo. In staphylococcal scalded-skin syndrome, there are the
characteristic features of lesions around the eyes and mouth, and
positive Nikolsky’s sign; it should be differentiated from bullous
impetigo. Cases whose onset is in adulthood should be differenti-
ated from pemphigus foliaceus.
Treatment
The skin should be kept clean. To prevent transmission, patients
should not share towels until crusts form. Topical application of
antibiotic ointments and oral cefem antibiotics are useful.
2) Nonbullous impetigo
Synonym: Streptococcal impetigo

A few blisters form. Nonbullous impetigo begins as small ery- Clinical images are available in hardcopy only.
thema, followed by multiple pustules and formation of yellowish-
brown crusts. The crusts are thick and firmly adherent; they
discharge pus when pressured. Pain and swelling occur in the
regional lymph node, often accompanied by pharyngeal pain and
fever. Unlike in bullous impetigo, the onset of nonbullous impeti-
go is acute and is independent of age and season. The prevalence
has been increasing among patients with atopic dermatitis.
Pathogenesis
It is mainly caused by subcorneal infection of group-A b-
hemolytic Streptococcus (Streptococcus pyogenes).
It is difficult to distinguish nonbullous impetigo from Kaposi’s Clinical images are available in hardcopy only.
varicelliform eruption, particularly in children with atopic der-
matitis. The two conditions may occur at the same time. 24
Treatment
Oral antibiotics are the first-line treatment. Urine analysis is
conducted in cases with streptococcal nonbullous impetigo, Fig. 24.1-2 Impetigo.
because glomerulonephritis may occur as a complication. To pre- Disseminated vesicles and pustules appear on the
arm and face.
vent nephritis, administration of oral antibiotics is continued 10
days after remission of the eruptions.
452 24 Bacterial Infections
2. Erysipelas
Outline
● It is most often caused by group-A b-hemolytic strepto-
Clinical images are available in hardcopy only. coccal infection (Streptococcus pyogenes).
● It occurs with sudden fever. The face is most frequently
affected. Sharply demarcated edematous erythema rap-

idly spreads. Intense tenderness and heat sensation are
present.
● Because Streptococcus pyogenes is not easily detected
by culture, ASO and ASK values are also measured.

● Penicillin antibiotics are the first-line treatment.
Clinical features
Sharply demarcated edematous erythema accompanied by
chills and fever occurs suddenly, frequently on the face and legs.
The erythema surface is tense and glossy. There is intense tender-
ness. The eruptions spread rapidly and centrifugally. Blistering
may occur on the edematous erythema (erysipelas bullosa).
When the face is involved, first one side is affected and soon the
other side is affected (Fig. 24.2). Systemic symptoms such as
fever, nausea and vomiting are present. In about 1 week, the
eruptions and fever disappear. However, the eruptions may recur
repeatedly on previously affected sites; this is called recurrent
erysipelas.
Pathogenesis
Erysipelas is a purulent inflammatory disease that affects pri-
marily the dermis. It is most frequently caused by group-A b-
hemolytic streptococcus (Streptococcus pyogenes). Streptococcus
pyogenes of other groups (group B in newborns), Staphylococcus
aureus, and pneumococcus may cause symptoms similar to those
of erysipelas. The pathogenesis of recurrent erysipelas is thought
to be local lymphatic blockage or inadequate treatment of
erysipelas; the details are unknown.
Laboratory findings
Antistreptolysin O (ASO) and antistreptokinase (ASK) increase
as a result of streptococcal infection. Elevated erythrocyte sedi-
mentation rate, leukocytosis (left shift of the nuclei in leukocytes),
Clinical images are available in hardcopy only. and CRP positive are observed. The rate of bacterial detection from
24
tissue fragment or aspirated tissue fluid is low. Streptococcal
Erysipeloid MEMO
Erysipeloid is caused by the gram-positive bacillus Erysipelothrix rhu-
siopathiae. It occurs most frequently in those who handle animals, meat
or seafood. The bacilli invade a minor trauma in a hand or finger. After
Fig. 24.2 Erysipelas. 1- to 4-day incubation, sharply circumscribed, painful, edematous ery-
Sharply demarcated, edematous erythema on the thema appears. The lesion enlarges centrifugally, and the center tends to
face. It is accompanied by flush and tenderness. heal. Oral penicillin and tetracycline drugs are extremely effective.
bacteria can be detected by PCR.
dermis epidermis
folliculitis,
Differential diagnosis furuncle,
carbuncle erysipelas
Cellulitis is more deeply seated than erysipelas, (Fig. 24.3),
and its erythema edges are less clearly defined. Necrotizing fasci- necrotizing
fascitis
itis can be distinguished from erysipelas by the rapidly progress-
subcutaneous
ing necrotic lesions and intense systemic symptoms. Insect bites, cellulitis
tissue
thrombophlebitis, Sweet’s disease, herpes zoster, and carcinoma
erysipelatodes also must be differentiated from erysipelas.
muscle
Treatment gas
gangrene
Antibiotics such as penicillin drugs and next-generation oral
cefem are administered. Treatment is continued for 10 days after Fig. 24.3 Acute pyoderma classified by the
remission to avoid recurrence and to prevent the complication of depth of the affected skin.
nephritis.
3. Cellulitis
Outline
● This acute purulent inflammation occurs extensively in the
deep dermal layer and subcutaneous tissue (Fig. 24.3). Clinical images are available in
● Vaguely demarcated erythema, swelling, localized heat hardcopy only.
sensation, and sharp pain occur suddenly in the face and
extremities.
● It may progress to necrotizing fasciitis or septicemia.
● The main treatments are bed rest and parenteral antibi-
otics.
Clinical features
The face and extremities, particularly the lower legs, are most
frequently involved. Cellulitis begins with ill-demarcated erythe-
ma, swelling and localized heat sensation, quickly becoming
intense infiltration that is accompanied by tenderness and sponta-
neous pain (Figs. 24.4-1 and 24.4-2). Although the infiltration is
usually absorbed in the skin over time and heals, a pustule may
form at the soft center of the lesion. Systemic symptoms such as
fever, headache, chills and arthralgia are present. Cellulitis may
progress to necrotizing fasciitis or septicemia. Clinical images are available in
hardcopy only.
Pathogenesis
Most cases of cellulitis are caused by Staphylococcus aureus. 24
Group-A b-hemolytic Streptococcus and Hemophilus influenzae
are among the causative species. Bacteria usually invade the skin
through a minor trauma, cutaneous ulcer, folliculitis or tinea pedis,
causing cellulitis secondarily; however, the entry route may not be
identifiable. Localized impairment in venous circulation and lym-
phatic edema may induce cellulitis.
Fig. 24.4-1 Cellulitis.
Laboratory findings Vaguely demarcated erythema, swelling, local
Elevated erythrocyte sedimentation rate, leukocytosis (left heat, localized flush and tenderness are present.
shift of the nuclei in leukocytes), and CRP positive are observed.

Hepatic enzyme levels increase in some cases. Bacteria are easily
detected from the pus in the lesion. Bacterial culture is more dif-
ficult to perform in cases without pus discharge.
Lesions caused by erysipelas are superficial and the progres-
sive lesions are sharply circumscribed; however, differentiation
from cellulitis is difficult. Necrotizing fasciitis is accompanied by
purpura, blisters, bloody blisters and severe systemic symptoms.
Fig. 24.4-2 Cellulitis.
Thrombophlebitis, erythema nodosum, insect bites and herpes
zoster should also be differentiated from cellulitis.
Treatment
Systemic administration or intravenous cefem antibiotics and
bed rest are the main treatments. Necrotizing fasciitis is suspect-
ed when non-localized symptoms present, including high fever,
abnormally high leukocyte and CRP levels, and marked systemic
symptoms.
4. Folliculitis
Synonym: Acne vulgaris
Outline
● It is a localized bacterial infection in a single hair follicle.
It is a pustule accompanied by erythema.
● Folliculitis that occurs on the face in puberty is called
Fig. 24.5 Folliculitis caused by Malassezia
furfur (Chapter 25). acne vulgaris.
● It may progress to furuncle or carbuncle.
● The main treatments are skin care and topical or oral
antibiotics.
Clinical features
Erythema and pustule occur at the hair follicle (Fig. 24.5). The
skin lesion forms crust in several days and heals without scarring
in most cases. Superficial folliculitis that causes multiple erup-
tions on the face especially in puberty is called acne vulgaris
(Chapter 19). Deep-seated folliculitis is accompanied by intense
inflammatory symptoms and may progress to furuncle or carbun-
cle in some cases. The deep-seated folliculitis in the barba areas is
24 called sycosis vulgaris.
Pathogenesis
A hair follicle is infected by Staphylococcus aureus or Staphy-
lococcus epidermidis. A minor trauma, obstruction and scratch
around a hair follicle, or topical application of steroids may
induce the infection. The hair follicle becomes inflamed.
Treatment
When there are only a few eruptions, folliculitis heals
spontaneously and can be left untreated. Topical or oral antibi-

otics are used in cases with multiple eruptions.
5. Furuncle, Carbuncle
Outline
● It is advanced folliculitis. Pustular plug forms at the cen-
ter of the skin lesion. There is purulent swelling.
● It is called a furuncle when a single hair follicle is
involved, and a carbuncle when the furuncle spreads to

multiple hair follicles. When a furuncle occurs over a long
period of time or when multiple furuncles occur at the
same time, it is called furunculosis.
● Administration of antibiotics, and incision and drainage of
pus are the main treatments.

Clinical features
A small red follicular papule or pustule (folliculitis) appears
and is accompanied by induration. Reddening, tenderness, spon-
taneous pain, and localized heat sensation become marked. The
pustule develops a pustular plug. The induration softens and
becomes an abscess. Inflammatory symptoms quickly subside Fig. 24.6 Furuncle (top) from folliculitis that
when the pus discharges, and in 1 or 2 weeks the furuncle heals progressed to form an abscess.
leaving a small scar. When a furuncle repeatedly recurs over a A carbuncle (bottom) results from a furuncle that
further progresses and aggregates into a large
long period of time or when multiple furuncles occur, it is called abscess.
furunculosis. Immunodeficiency from diabetes or malignant
tumor underlies many cases of furunculosis.
A carbuncle is a further aggravated furuncle whose inflamma-
tion spreads to multiple peripheral hair follicles. It is accompa-
nied by sharp pain, fever and systemic fatigue. Areas of stretching,
such as the back, thighs and nape of the neck, are often involved.
Carbuncles are dome-shaped, reddening or swelling induration
with several pustular plugs at the top (Fig. 24.6).
Pathogenesis
In most cases, Staphylococcus aureus invades a hair follicle
and causes follicular inflammation (Fig. 24.7). An underlying
hair pustular plug
24
inflammation
inflammation
abscess
folliculitis furuncle carbuncle
Fig. 24.7 Classification of bacterial infectious diseases of hair

follicles.
condition such as diabetes is present in the most severe cases of

furuncle or carbuncle.
Diagnosis
Painful, pointy red swelling occurs in a hair follicle. Diagnosis
can be confirmed when a pustular plug is seen in the center of the
eruption. It may be difficult to differentiate infectious epidermal
cyst from furuncle or carbuncle.
An infectious epidermal cyst is an inflamed cyst that develops
abscesses. White gruel-like contents and the cyst wall discharge
from the dome-shaped elevation by small incision. Hidradenitis
suppurativa occurs, most frequently on sites with apocrine sweat
glands, such as axillary fossae. It progresses slowly, and pustular
plugs do not form.
Treatment
Antibiotics effective against Staphylococcus aureus are admin-
istered orally, or intravenously in severe cases. Incision and
drainage of pus is conducted in cases with palpable pulsation.
6. Bacterial paronychia
Outline
Fig. 24.8 Bacterial paronychia. ● Itis purulent inflammation in the fingers and toes from
Purulent inflammation occurs in the fingers, toes, paronychia.
nails and their periphery. It is accompanied by ● The widely used term “whitlow” often refers to herpetic
severe tenderness.
whitlow.
● The main symptom is pulsating reddening accompanied
by sharp pain.
● Bed rest, administration of antibacterial drugs, and inci-
sion and drainage of pus are the main treatments.

Intense throbbing pain, swelling, reddening and heat sensation
occur in the periungual region and distal portion of the finger
(Fig. 24.8). The nail plate may appear green when the infection is
caused by Pseudomonas aeruginosa, which produces that pig-
ment. The nail may exfoliate.
24 Pathogenesis
The main causes of bacterial paronychia are Staphylococcus
aureus, Staphylococcus pyogenes, coliform bacilli, and
Pseudomonas aeruginosa. Minor trauma and ingrown nails often
induce it.
Mucous cyst, glomus tumor, metastatic cancer, Osler’s node,
herpes whitlow and candidal paronychia should be differentiated
B. Chronic pyodermas 457
from whitlow.
Treatment
Cooling the affected site and administering antibiotics that are
effective against Staphylococcus aureus and Staphylococcus pyo-
genes are the main treatments. Incision and drainage of pus are
necessary in many cases.
7. Multiple sweat gland abscesses in infants

Multiple painful pustules and subcutaneous induration occur
on the face, scalp and buttocks of newborns and infants, most fre-
quently in summer. The eruptions mix with miliaria. Miliaria
appears first as a precursor in which Staphylococcus aureus
infection occurs, resulting in multiple sweat gland abscesses.
Eccrine sweat glands are mainly involved. Antibacterials against
Streptococcus are administered. The skin should be kept clean
for preventive purposes by frequent changing of clothes.
B. Chronic pyodermas
Perifolliculitis
Definition, Classification abscedens et suffodiens
Chronic pyoderma is a general term for chronic purulent dis- Scalp/face
Dermatitis
papillaris capillitii
eases in which multiple obliterative lesions of hair follicles are Folliculitis
infected by bacteria, leading to prolonged inflammatory reaction decalvans
or granulomatous inflammation. Many diagnostic names for Hidradenitis
chronic pyoderma exist; in fact, they all refer to the same disease. Chronic suppurativa
pyoderma Other
The axillary fossae, scalp and buttocks are most commonly Pyoderma chronica
than head glutealis
involved. Diseases that are typically classified as chronic pyoder- Acne conglobata
ma are listed below (Fig. 24.9). Squamous cell carcinoma may Entire body
(especially in Multiple infected
originate from these conditions. hairy area) epidermal cysts
Fig. 24.9 Classification of chronic pyoderma.

hardcopy only.
Clinical images are available in hardcopy only. hardcopy only.
24
Fig. 24.11 Dermatitis papillaris
capillitii.
Thickening and scarring plaques on
the back of head and neck.
Fig. 24.10 Hidradenitis suppurativa.

Subcutaneous nodules of several millimeters in
diameter on the axillary fossae rupture sponta-
neously. The lesion softens and coalesces, lead-
ing to formation of scarring plaques.
Clinical features, Treatment

① Hidradenitis suppurativa
This is hidradenitis in the opening of a hair follicle that is con-
tained in the apocrine sweat gland. The follicular opening is
blocked by a keratin plug, leading to secretion deposition where
Staphylococcus aureus infects (Fig. 24.10). One or several sub-
cutaneous nodules about 5 mm in diameter occur, most frequent-
ly on the axillary fossae of women. The nodules soften, rupture,
excrete pus, and heal with scarring. Hidradenitis suppurativa
often becomes chronic. Other sites with apocrine sweat glands,
such as the genitalia, anus and breasts, may also be involved.
Administration of antibiotics and incision and drainage of pus are
② Dermatitis papillaris capillitii
This is also known as keloidal folliculitis. Folliculitis appears
multiply and continuously on the occipital and nuchal region of
middle-aged men. Infiltration of the lesion gradually becomes
Clinical images are available in intense, and connective tissue proliferates and forms a keloidal
hardcopy only. plaque (Fig. 24.11). Abscess formation and secretion of pus may
be present in severe cases. Administration of antibacterials is the
first-line treatment. Plastic surgery may be necessary.
③ Pyodermia chronica glutealis
Middle-aged men are most frequently affected. Acne-like pus-
tules or papules appear on the lumbar region, genitalia, and
thighs, gradually coalescing into a large infiltrative plaque.
Abscesses with intricately netted fistulae form, and these excrete
pus when pressed (Fig. 24.12). There is hidradenitis suppurativa
Fig. 24.12 Pyodermia chronica glutealis.
Large infiltrating plaques accompanied by pus- or acne conglobata as an underlying disease in many cases. Sys-
tules, papules, fistulas and abscesses spread to temic administration of antibiotics, incision and drainage of pus,
the crotch. and removal and skin graft are the main treatments.
C. Systemic infections
1. Staphylococcal scalded-skin syndrome

(SSSS)
Synonym: Staphylococcal toxic epidermal necrolysis (S-TEN)
Outline
24 ● It is caused by exfoliative toxins of Staphylococcus

aureus in the epidermis.
● It occurs most frequently in infants and children up to
age 6. A fever and reddening around the mouth or eyes

first appear, followed by painful exfoliation, erosion and
blistering.
● Nikolsky’s sign is positive.
● Systemic management and care, and administration of
antibiotics are the main treatments.
C. Systemic infections 459
Clinical features
Staphylococcal scalded-skin syndrome (SSSS) occurs most
frequently in infants and children up to age 6; it is extremely rare
in adults. It begins with reddening and blistering around the
mouth, nostrils, and periocular area. This is accompanied by sys-
temic symptoms, such as a fever of about 38°C, irritability, and
poor appetite. Wrinkles and fissures around the mouth, eye dis-
charge and crust formation result in characteristic facial features.
Erythema occurs on the neck, axillary fossae, and groin, and the Clinical images are available in hardcopy only.
whole body skin begins to exfoliate as if burned, which leads to
erosion (Figs. 24.13-1 and 24.13-2). Skin at normal sites also exfo-
liates easily by friction (Nikolsky’s sign is positive). Sharp pain is
present. The mucous membranes tend not to be affected. Exfolia-
tion in the scalp can occur in rare cases. SSSS begins to heal after
exfoliation is accelerated by systemic administration of antibiotics.
The entire course of SSSS is 1 to 2 weeks (Fig. 24.14).
Pathogenesis
SSSS is caused by exfoliative toxin (ET) produced by Staphy-
lococcus aureus. The nasopharynx, conjunctivae, external ears,
and navel are most frequently infected. When ET spreads to the
whole body by blood circulation, desmoglein 1, a desmosome Clinical images are available in hardcopy only.
structural protein, is broken. Pemphigus foliaceus-like acan-
tholytic and intraepidermal blisters form on the upper epidermal
layer.
Pathology
Acantholysis, lacunae and infiltration of polymorphonuclear
cells are observed under the horny cell layer and in the granular
cell layer. Clinical images are available in hardcopy only.
Diagnosis
SSSS can be diagnosed by the characteristic facial features,
burn-like systemic epidermal exfoliation, marked Nikolsky’s
sign, and normality of oral mucosa.
Most cases of toxic epidermal necrolysis (TEN) are induced by
drugs. Histopathologically, there is necrosis in all epidermal lay-
ers and severe infiltration to the mucous membranes. Infants are
rarely affected by TEN. In widely spread multiple bullous
impetigo, the characteristic facial features of SSSS do not occur 24
and Nikolsky’s sign is negative.
Treatment
Hospitalization and systemic care including transfusion and
intravenous antibiotics that are effective against Staphylococcus Fig. 24.13-1 Staphylococcal scalded-skin
aureus are given. The affected site is sterilized and treated with syndrome (SSSS).
topical application of ointments that contain antibiotics or petro- SSSS is characterized by the facial features that
include wrinkles around the mouth, eye dis-
latum. SSSS tends to have a good prognosis; however, it may charge and crust formation.
become severe, with sepsis or pneumonia appearing as complica-
tions in infants and in adults with immunodeficiency.
39
body temp. (˚C)

38
37
days 1 2 3 4 5 6 7 8 9 10 11
periocular/perioral
erythema
erythema on
the neck
erythema on the
symptoms
axilla/genital region
perioral fissure
Milia-like vesicles
Clinical images are available in hardcopy only. pityriatic scales
lamellar scales on extremities
disease most severe

stages erythema period scale
Fig. 24.14 Clinical course of staphylococcal scalded-skin syn-

drome (SSSS).
2. Toxic shock syndrome (TSS)

Synonym: Staphylococcal toxic shock syndrome (STSS)
TSS is caused by an exotoxin called toxic shock syndrome

toxin (TSS toxin-1 or TSST-1), which is produced by infection
and proliferation of Staphylococcus aureus. It may occur in burn
patients and women who use sanitary tampons. TSS is a systemic
Clinical images are available in hardcopy only. toxic disease whose main symptoms are acute fever, decreased
blood pressure, scarlet-fever-like erythema, and multiple organ
dysfunction (Fig. 24.15). Diffuse erythema, chills, headache, and
arthralgia on the whole body are present, leading to systemic
fatigue, vomiting and diarrhea. Antibiotics, mainly b-lactum
24 drugs, are useful in large doses, in combination with
immunoglobulin preparations.
3. Scarlet fever (Streptococcal infection)
Fig. 24.13-2 Staphylococcal scalded-skin Outline

syndrome (SSSS).
bottom: There is burn-like exfoliation and ero- ● Itis erythematous exanthema and enanthema caused by
sion of the skin of the whole body. Nikolsky phe- group-A b-hemolytic streptococci (GAS).
nomenon is positive. ● It begins with pharyngeal pain and high fever. It is
characterized by reddening of the tongue (strawberry

tongue) and dense erythema on the whole body.
● Eruptions do not appear around the mouth (perioral pal-
lor).
● Increased antistreptolysin O has diagnostic value. Peni-
cillin is administered. Clinical images are available in hardcopy only.
Clinical features
Scarlet fever most frequently occurs in late childhood. The
incubation period is known to be 2 to 3 days. It begins with a
sudden fever and pharyngeal pain, soon followed by strawberry
tongue. At the early stages, tongue fur which is often referred to Fig. 24.15 Toxic shock syndrome.
as “white strawberry tongue” is seen in many cases. However,
the tongue fur resolves in a day or two, leaving the typical straw-
berry tongue. Eruptions appear 1 to 2 days after onset of strepto-
coccal infection. Patchy, vivid red papules appear on the neck,
axillary fossae, and medial thighs, spreading over the whole
body. The eruptions may be accompanied by itching and burning.
Diffuse erythema appears on the face, except at the peripheries of
the mouth and nasal alae (perioral pallor). Hemorrhagic lesions
and systemic lymph node enlargement also occur. As the fever
subsides on the third or fourth day after onset, the eruptions begin
to disappear. After exfoliation, the eruptions heal without post-
inflammatory pigmentation. Clinical features that characterize
scarlet fever are shown in Fig. 24.16.
Pathogenesis
Eruptions are caused on the whole body by an exotoxin pro-
duced by Streptococcus pyogenes. This bacterium first infects the
palatal tonsil or skin.
Complications
40
Post-infectious complications of Streptococcus pyogenes may
body temp. (˚C)
occur, such as acute glomerulonephritis and rheumatic fever. 39
Elevated levels of ASO and ASK, leukocytosis, and left shift 37

of the nuclei in leukocytes are caused by streptococcal infection.
Bacteria are detected from the primary infection site, such as the
days 1 2 3 4 5 6 7 8 9 10 11
pharynx. The rapid diagnostic test kit is also useful, although the
detection sensitivity is relatively low. eruption
24
symptoms
nausea
Rubella, Kawasaki disease and drug eruptions should be dif- strawberry
ferentiated from streptococcal fever (Fig. 23.23). tongue
tonsilitis
Oral penicillin G is the first-line treatment. Although eruptions incubation period of several days
disappear in 2 to 3 days, administration of penicillin G should be
continued for at least 2 weeks because if the medication is Fig. 24.16 Clinical course of scarlet fever
stopped early, Streptococcus may proliferate again in the phar- (streptococcal infection).
Toxic-shock-like MEMO ynx, causing complications such as nephritis or rheumatic fever.

syndrome (TSLS) After termination of medication, periodic examinations such as
Synonym: Severe invasive streptococcal urine test are necessary to detect bacteria.
infection
The main cause is streptococcal pyogenic
exotoxin (SPE), produced by streptococci and 4. Necrotizing fasciitis
so-called “killer bugs.” Swelling in the
extremities and fever occur, rapidly progress-
ing to necrotizing fasciitis (described later), Outline
multiple organ failure and shock.
● It is an acute bacterial infection in subcutaneous tissue
and superficial fascia (Fig. 24.3). The extremities and
genitalia of persons middle-aged and older are most fre-
Superantigens MEMO
quently affected.
The immunological response between anti-
● The main systemic symptoms are reddening and
gen-presenting cells and T cells is usually
mediated by a certain antigen. However, swelling of skin, ulceration, and fever accompanied by
recent study has discovered molecules that intense pain.
induce T-cell activation whether or not the ● High doses of antibiotics at the early stages and surgical
antigen is specific to the T-cell receptor.
Those molecules are called superantigens. T débridement are the main treatments. Multiple organ fail-
cells are activated abnormally by superanti- ure may lead to death.
gen TSST-1 and SPE-C, leading to severe,
systemic inflammatory reaction.
Clinical features
The extremities (lower legs in particular), genitalia and
abdomen of persons over age 40 are most frequently affected.
Necrotizing fasciitis begins with localized reddening and
swelling that rapidly progress with marked systemic symptoms.
In 1 to 3 days, purpura, blisters, bloody blisters, concave necrosis
and ulceration occur (Fig. 24.17). The sensation of touch is
reduced according to the progression of the fasciitis. Even when
the periphery of the lesion appears normal to the naked eye, the
subcutaneous tissue is affected. Necrotizing fasciitis is character-
ized by intense systemic symptoms such as high fever, severe
arthralgia, muscle pain, shock and multiple organ failure. Necro-
tizing fasciitis of the genitalia is called Fournier’s gangrene.
Necrotizing fasciitis frequently occurs as a complication of toxic-
shock-like syndrome (MEMO).
Pathogenesis
The main causative bacteria are Streptococcus pyogenes and
anaerobes such as Bacterioides fragilis and Peptostreptococcus
anaerobius. Streptococcus pyogenes may infect healthy persons,
leading to a sudden onset of necrotizing fasciitis. Anaerobic bac-
teria tend to infect individuals with an underlying disease, such
24 as diabetes. In some cases, a micro-injury or tinea pedis induces
necrotizing fasciitis; however, details of the pathogenesis are
unknown.
Pathology
Edema is marked throughout the dermis. Panniculitis, necrosis,
blockage of the blood vessels, and infiltration of polymorphonu-
clear leukocytes occur from the lower dermal layer to the under-
lying fat tissue and fascia.
Laboratory findings
Leukocytosis, left shift of the nuclei in leukocytes, elevated
levels of CRP, liver failure and coagulation abnormality (when
DIC is caused) are present. Prior to administration of antibiotics,
bacteria are detected from the puncture fluid, necrotizing tissue at
débridement, and blood. MRI, CT, and X-ray images are helpful
in testing for the depth and size of lesion and for any retention of
gas.
Diagnosis Clinical images are available in hardcopy only.

Prompt diagnosis and initiation of treatment are important.
Necrotizing fasciitis is diagnosed by its sudden onset, rapid pro-
gression, intense systemic symptoms, purpura, blisters, bloody
blisters and the depth of necrosis measured by débridement. Bac-
terial culture and skin biopsy are conducted for differential diag-
nosis.
Some cases are difficult to differentiate from ordinary celluli-
a b c d e f g h
tis; however, necrotizing fasciitis is characterized by rapid pro-
gression of skin lesion, purpura and bloody blisters, and intense
systemic symptoms. The spread of inflammation and involve-
ment of fascia can be determined by MRI. Gas gangrene is found
in the muscle layer of the lesion. Marked retention of gas is
observed by X-ray. The causative bacteria are Clostridium. Clinical images are available in hardcopy only.
Large doses of antibiotics that are effective against the
pathogen (e.g., drugs containing penicillin, clindamycin) and sur-a b c d e f g h i
gical débridement in the early stages are essential. Unless treated
in the early stages, the prognosis is extremely poor.
5. Gas gangrene
Outline
● Most cases are caused by anaerobic bacteria such as
those of the genus Clostridium. Mortality is high. Clinical images are available in
hardcopy only.
● Intense systemic symptoms, muscular necrosis and
aerogenesis occur. There is crepitation from gas in the

tissues.
● Rapid incision and lavage of the lesion, large doses of
24
antibiotics, and hyperbaric oxygen therapy are the main
treatments.
Clinical features a b c d e f g h i j
Six to 72 hours after injury, gas gangrene begins with a local- Fig. 24.17 Necrotizing fasciitis.
ized sharp pain. Systemic symptoms such as chills and tachycar- a, b: Generalized purpura, blisters, bloody blis-
dia occur. The skin becomes dark purple or blackish. Hematoid ters, necrosis and ulcer progress quickly. c: Sur-
gical débridement was performed on the lesion.
serous blisters form. Liquefactive necrosis occurs in muscle tis- The subcutaneous tissues including fascia had
sue. The lesion swells with the gas. The affected site releases foul been affected.
odor. When the site is pressed, the gas moves, causing crepita-
tion. Bubbles are observed by X-ray. If left untreated, exotoxin
circulates through the bloodstream to the entire body, leading to
jaundice, DIC or shock, and resulting in death.
Pathogenesis
Gas gangrene is most frequently caused by Clostridium per-
fringens (formerly Clostridium welchii), Clostridium oedemati-
Clinical images are available in hardcopy only. cus, Clostridium septicum and Clostridium histolyticum, but in
some cases by non-Clostridium bacteria. The causal bacteria
exist in soil and sometimes in the feces of humans and animals,
invading the body through a severely crushed and contaminated
wound. These bacteria grow in the anaerobic environment and
produce an exotoxin containing proteolytic enzymes, which
induce hemolysis and shock.
Fig. 24.18 Osler’s node.
Quick incision, lavage and surgical débridement are important.
Painful erythema on the fingers. At the same time, penicillin G or cefem antibiotics are adminis-
trated in large doses. Proliferation of anaerobic bacteria can be
prevented by opening the lesion. When the bacteria are anaero-
bic, hyperbaric oxygen therapy is useful. Systemic care is per-
formed for shock, kidney failure and DIC. Amputation of
extremities may be necessary in severe cases.
6. Sepsis
Sepsis occurs when a localized cutaneous infection such as in
abscess, cellulitis or erysipelas aggravates and disseminates in
the blood flow. The bacteria themselves or thrombosis caused by
bacteria in the blood induces septic vasculitis, resulting in sep-
ticemide formation including erythema, purpura, bloody blisters
and pustules.
7. Osler’s node
This is transient, painful, nodular erythema that often accom-
panies subacute bacterial endocarditis. Elevated erythema of 5
mm in diameter occurs on the finger pads, thenar and hypothenar
eminences (Fig. 24.18). Sharp pain occurs as a precursor, and a
brown patch appears and disappears in 1 or 2 days. Osler’s node
24 accompanied by painless erythema or infiltrative purpura is
called Janeway lesion. Allergic reaction against the bacteria and
vascular blockage are thought to be the causes in all cases.
Osler’s node is known to appear in 15% of infectious endocardi-
tis cases.
D. Other bacterial infections
1. Trichomycosis palmellina
It occurs most frequently in young patients with hyperhidrosis
and poor hygiene. Bacteria in colloidal suspension, ranging from
yellowish brown to white, attach in clusters to axillary or pubic
hairs. The hairs appear to be yellowish and swollen. The condi-
tion may be accompanied by foul odor. The pathogenesis in most
cases is infection caused by Corynebacterium tenuis, which fluo-
resces as yellow, white, or blue under Wood’s lamp. The treat-
ments are hygiene improvement, antisepsis, shaving of hair, and
topical tetracycline.
2. Erythrasma
Clinical features
Moist intertriginous regions such as the genitocrural region,
axillary fossae and interdigital clefts are most commonly
involved. Erythrasma presents as sharply margined, red or red-
dish-brown patches on whose surface thin and fine scales attach.
Papules or blisters do not occur. The center of the lesion does not
heal, whereby erythrasma can be distinguished from tinea. Ery-
thrasma tends to be asymptomatic, and there may be itching and
burning in rare cases.
Pathogenesis
Erythrasma is caused by infection in the horny cell layer by
Corynebacteria called diphteroids. It often occurs in patients
with diabetes, obesity or hyperhidrosis. It is thought to be an
opportunistic infection.
It is difficult to differentiate erythrasma in the toe clefts from
tinea pedis; however, coral-red fluorescence of erythrasma
observed under Wood’s lamp is diagnostic. Since erythrasma and
tinea pedis are present together in many cases, mycological
examination of scales is necessary. Gram-positive short bacilli
are observed in the scales of the lesion. 24
Treatment
Topical imidazole antifungal agents and oral erythromycin are
effective.
3. Actinomycosis

Actinomycosis is classified by the primary site into cervicofa-
Clinical images are available in hardcopy only. cial actinomycosis, thoracic actinomycosis and abdominal actino-
mycosis. Of these three subtypes, cervicofacial actinomycosis,
which is often induced by dental caries and accompanied by skin
lesions, accounts for about half of all actinomycosis cases. Tho-
racic actinomycosis and abdominal actinomycosis are accompa-
nied by a lesion in the internal organs; unless there is a fistula
Fig. 24.19 Actinomycosis. that affects the skin, these two subtypes are not addressed in der-
A small nodule in the lower lip. Actinomyces matology.
israelii was detected by excision. Reddening, swelling and induration occur, forming a dark red
subcutaneous nodule (Fig. 24.19). The nodule partly softens and
forms an abscess, leading to a fistula from which pus excretes for
a long period of time. A chronic suppurative granulomatous
lesion is produced. Mild fever and pain are present in most cases.
Actinomycosis is nearly asymptomatic; however, there is diffi-
culty opening the mouth when the masticatory muscle is
involved.
Pathogenesis
Actinomyces israelii, a microbe resident in the human oral cav-
ity, tonsillar fossae and dental plaques, invades the body from a
minor injury, proliferates and forms a lesion. Once believed to be
a fungus, Actinomyces israelii has been found to be a bacterium.
Fig. 24.20 Histopathology of actinomycosis.
A cluster of Actinomyces israelii called a granule Pathology
or Drüse is observed in the microabscess. Microabscess forms in parts of fibrotic inflammatory granulo-
matous tissue. Actinomycosis is characterized by bacterial mass
in the microabscess called “sulfur granule”(Fig. 24.20).
Nocardia infection causes lesions similar to those of actinomy-
cosis. External dental fistula and inflammatory epidermal cyst
should be differentiated from actinomycosis.
Treatment
Penicillin, tetracycline and cefem antibiotics are administered
orally.
24
4. External dental fistula
As a result of progression of dental caries or alveolar osteitis, a
fistula forms from which pus is excreted (Fig. 24.21). Dental
treatment is necessary. It may be misdiagnosed as subcutaneous
ulcers such as epidermal cyst or actinomycosis.
D. Other bacterial infections 467
5. Nocardiosis
Clinical features
Skin lesions caused by nocardiosis are divided by morphology
into three subtypes: nocardia mycetoma, which progresses in a Clinical images are available in hardcopy only.
process very similar to that of actinomycosis; localized cutaneous
nocardiosis, in which subcutaneous abscess forms; and cutaneous
lymphatic nocardiosis, in which the lesion enlarges on skin over
the lymph vessels. This section focuses on nocardia mycetoma.
The legs are most frequently involved. Dark red subcutaneous
nodules appear after multiple reddening, swelling and induration.
The nodules form abscesses where fistulae are produced, excret-
ing pus for a long period of time. Some of the pus may be granu-
lar. Opportunistic infectious nocardiosis invades the lung and
progresses in a course similar to that of bacterial pneumonia. A
skin lesion and a cerebral abscess occur in cases with hematoge-
neous dissemination.
Pathogenesis
Nocardiosis is infection by the anaerobic bacteria of the genus
Nocardia. In developing countries, Nocardia in the soil causes
skin lesions. The bacteria may invade the lung and cause an
opportunistic infection and systemic nocardiosis. Nocardia aster- Fig. 24.21 External dental fistula.
oids is the causative species in most cases. A fistula in the lower jaw from inflammation of
the dental root, which was caused by dental
Laboratory findings, Diagnosis caries.
Pus or sputum smears are examined after Gram staining. Cul-
tures are obtained on Sabouraud glucose medium. Or Nocardia
are identified by skin biopsy. Infiltration of Nocardia into bone is
investigated by bone X-ray. Drugs for treatment are chosen by
measuring MIC.
Treatment
The most effective drug for each case is chosen from among
sulfate drugs, minocycline, or penicillin. The treatment is contin-
ued for several months. For cases in which all drugs are ineffec-
tive or bone is involved, surgical removal is performed.
24
Chapter
25 Fungal Diseases
Fungi are eukaryotic microorganisms that have a cellular wall and do not photosynthesize. They parasitize
organisms or exist as spores. In superficial mycoses, fungi invade keratinized tissue such as the horny cell
layer, hair and nails. In deep fungal infection, fungi tend to parasitize the dermis and deeper layers.
A. Dermatophytoses
Table 25.1 Classification of dermatophytes. Outline
Trichophyton ● They are caused by dermatophytes that parasitize the
T. rubrum skin, the horny cell layer in particular.
T. mentagrophytes ● They have various common names, depending on the
T. verrucosum
affected site. The main subtypes are tinea pedis (com-
T. violaceum
T. schoenleinii
monly called athlete’s foot; it accounts for more than half
T. tonsurans of tinea cases), tinea capitis (scald head, which occurs
T. concentricum frequently in childhood), tinea corporis (serpigo, which
T. equinum heals in the center to present a ring shape or lesion) and
Microsporum tinea cruris (jock itch, which involves the genitalia).
● The causative dermatophyte is microscopically identified
M. canis
M. gypseum from scales of the lesion or nail using KOH solution.
M. audouinii ● The treatments are topical or oral antifungal agents.
M. cookei
M. equinum Classification
M. ferrugineum
Fungi called dermatophytes parasitize the horny cell layer,
M. gallinae
M. nanum
causing dermatophytosis. Dermatophytes are divided into three
genera, each with various species (Table 25.1). The most com-
Epidermophyton
mon dermatophytes are Trichophyton rubrum and Trichophyton
E. floccosum
mentagrophytes.
Because dermatophytes feed on keratin, they usually infect the
Table 25.2 Classification of tinea. epidermal horny cell layer, nails and hair follicles, causing
Tinea superficialis lesions (tinea superficialis). Dermatophytosis in which dermato-
Tinea pedis phytes proliferate in the dermis and deep dermal layers is called
Tinea unguium tinea profunda (Table 25.2). The name of the dermatophytosis
Tinea manus differs by the location.
Tinea cruris
Tinea corpooris Laboratory findings, Diagnosis
Tinea faciei
25 Tinea capitis Diagnosis of dermatophytosis is confirmed when dermato-
Tinea incognito phytes or segmental spores of 3 mm to 4 mm in diameter contain-
Tinea profunda ing septum are found microscopically with KOH solution in a
Kerion celsi
specimen taken from a scale, blister covering, nail or hair (Figs.
Sycosis trichophyica 25.1 and 25.2). For observation by light microscopy, a specimen
Granuloma trichophyticum is placed on a slide glass with 1 or 2 drops of 20% KOH solution
Trichophytid and then covered with glass and heated for a few minutes. Use of
DMSO-added KOH solution makes rapid microscopic examination
468
A. Dermatophytoses 469
possible, because heating is unnecessary. Microscopy with KOH

solution is always used when dermatophytosis is suspected.
Other major tests are ① culture in Sabouraud’s glucose agar for
color tone and morphological observation of the colony, ② mor-
phological observation of conidium by slide culture, ③ molecu-
lar examination by PCR or in situ hybridization, and ④ regular
hematoxilin-eosin stain.
Treatment
The basic treatment for all sites infected with tinea superfi-
cialis except hairy areas is topical application of antifungal
agents such as imidazole. For tinea superficialis in hairy areas,
intractable tinea, and tinea profunda with cutaneous and subcuta-
neous symptoms (e.g., hyperkeratotic tinea pedis, tinea unguium, Fig. 25.1 Trichophyton rubrum.
kerion celsi and granuloma trichophyticum), useful treatments Filamentous hyphae (arrows) are microscopically
are systemic itraconazole and terbinafine hydrochloride. Griseo- observed in the horny cell layer with the addition
of KOH solution.
fulvin is no longer commonly used in Japan.
a. Superficial dermatophytic infections
1. Tinea pedis
It is commonly called athlete’s foot. More than half of tinea
cases are tinea pedis. Multiple dermatophytes are seen in the
scales. The most common causative fungus is Trichophyton
rubrum, followed in frequency by Trichophyton mentagrophytes.
Tinea pedis is classified by clinical features into three clinical
Fig. 25.2 Histopathology of tinea.
subtypes. Filamentous hyphae (arrows) are observed in the
Interdigital erosive: This is the most common of the three sub- horny cell layer.
types. The fourth toe cleft is most commonly affected. It begins
with erythema and vesicles on the interdigital region, leading to
scaling. The skin lesion is often infiltrative, softening to become
whitish, then exfoliating and becoming erosive (Fig. 25.3). Itch-
ing is intense. Secondary infection from erosion causes sharp
pain or cellulitis. Clinical images are available in hardcopy only.
Vesicular scaling: The plantar arch and the base of the toes are
most frequently involved. Multiple vesicles occur and dry, lead-
ing to scaling. It tends to appear during the rainy season and sub-
side in autumn.
Hyperkeratotic: It occurs most frequently on the heels. Hyperk-
eratosis causes roughness of the skin. Itching is rarely present,
but sharp pain results from cracking. This type is resistant to topi-
cal agents; oral antifungals are effective.
25
2. Tinea unguium
Synonym: Onychomycosis (referring to nondermatophytic
and dermatophytic infections of nail plate)
Tinea unguium frequently occurs on the first toe, often second- Fig. 25.3 Tinea pedis.
arily after tinea pedis. Usually, white nail (leukonychia) first bottom: Tinea pedis with secondary infection.
470 25 Fungal Diseases
Fungi and molds MEMO

Molds and mushrooms are fungi. Yeasts, which are used for food prod-
ucts and are mononucleated, are also regarded as fungi. A fungus is
composed of a long, thin hypha and a spore that is usually spherical
Clinical images are available in hardcopy only. and proliferates by germination. Spores parasitize humans by becom-
ing airborne and attaching to the body, where they form hyphae and
reproduce sexually or asexually.
Spores may be elongated, depending on the environment, resembling
hyphae (pseudohyphae). In culture media such as slide culture, hyphae
with a characteristic shape (conidiophores) and asexual spores called
conidia form. The conidium consists of the macroconidium and the
microconidium. Disease-causing fungi may be identified by the fea-
tures of the hyphae.
Clinical images are available in hardcopy only. appears at the tip of the toenail and gradually spreads to the nail
matrix. The nail becomes fragile and pulverizes when cut with
clippers (Fig. 25.4). The fungal elements occur mostly in the
deeper portions of the nail plate and in the hyperkeratotic nail
bed, rather than on the surface of the nail plate. It is often left
untreated for a long period because of its asymptomatic nature.
Dermatophytes spread in a patient from a tinea unguium skin
lesion to a tinea pedis skin lesion, causing autoinfection and
intrafamilial infection. It is sometimes difficult to improve with
Clinical images are available in hardcopy only. topical agents. Oral antifungal drugs are more effective.
3. Tinea manus
The skin lesion may be hyperkeratotic, vesicular or scaling.
Fig. 25.4 Tinea unguium. One hand, rather than both, tends to be involved (Fig. 25.5). The
majority of patients have tinea pedis as a complication. Topical
antifungal agents are the main treatment.
4. Tinea cruris
It is commonly called “jock itch.” The crotch and buttocks of
adult men are most frequently affected; the scrotum is rarely
involved. The same type of skin lesion as in tinea corporis
appears, often symmetrically. Itching is intense. The treatments
are topical and oral antifungal agents.
Clinical images are available in hardcopy only. 5. Tinea corporis

Commonly known as serpigo, it appears as small erythematous
papules on the trunk and extremities, gradually spreading cen-
25 trifugally. The papule tends to heal centrally, giving the lesion a
ring shape (Fig. 25.6). Although the center of the lesion subsides
with mildly abnormal pigmentation, the periphery is elevated,
and papules, vesicles and scales form there. Itching is present. As
in tinea pedis, the causative dermatophyte in most cases of tinea
corporis is Trichophyton rubrum. Tinea corporis is occasionally
Fig. 25.5 Tinea manus.
The interdigital areas, fingers and fingernails are
caused by Microsporum canis, which parasitizes dogs and cats.
frequently affected. Tinea corporis caused by Microsporum canis is characterized by
A. Dermatophytoses 471

hardcopy only.

hardcopy only.

hardcopy only.
Fig. 25.6 Tinea corporis.

Erythematous lesions enlarge centrifugally. The center tends to heal and the rim elevates in a banked shape.
intense inflammatory symptoms. Topical and oral antifungal

agents are the main treatments.
6. Tinea faciei
It is a Trichophyton infection on the face. Unlike in eczema,
the plaques have a slightly elevated rim and tend to heal centrally Clinical images are available in hardcopy only.
(Fig. 25.7).
7. Tinea capitis
Commonly known as “scald head,” this occurs most frequently
in children. Trichophyton infection in hair follicles results in
sharply edged alopecia of the scalp. There are dry pityroid scales
Fig. 25.7 Tinea faciei.
and short, broken off hairs in the lesion. Subjective symptoms
such as pain are not present. Head hair is sparse. Inflammation is
absent. Tinea capitis accompanied by itching and black dot for-
mation at the follicles after the hairs break off is called black dot
ringworm; it is associated with misuse of topical steroid oint-
ments, and its incidence has been increasing (Fig. 25.8). Oral 25
antifungal drugs are the first-line treatment. The affected site Clinical images are available in hardcopy only.
should be kept clean and dry.
8. Tinea incognito
The tinea lesion heals centrally; however, if tinea is misdiag-
nosed as eczema and topical steroids are misused for treatment, Fig. 25.8 Tinea capitis.
the inflammation subsides and the characteristic central healing

in the lesion is not distinctly observed. This complicates diagno-
sis, and such manifestation is called tinea incognito. Tinea incog-
nito presents clinically atypical cutaneous symptoms in such a
Clinical images are available in hardcopy only. case (Fig. 25.9).
b. Deep dermatophytic infection

Instead of remaining in their usual location of the epidermal
horny cell layer or nail plate, fungi of the genus Trichophyton
invade the dermis or subcutaneous tissue, causing skin lesions.
1. Kerion (celsi)
Clinical images are available in hardcopy only. Kerion is most common on the scalp but can be produced in
other sites. Pityriatic scales appear in the scalp, as in tinea capitis.
Inflammation soon occurs, leading to erythema, follicular
papules, pustules, and flat or dome-shaped abscesses (Fig.
25.10). The lesions are accompanied by sharp pain, mild pulsa-
Fig. 25.9 Tinea incognito causes different tion and discharge of pus. The hairs in the lesion fall out. There
clinical symptoms from typical tinea. are systemic symptoms such as swelling of the regional lymph
node and fever. Most cases are caused by misuse of steroid oint-
ments on tinea capitis of the scalp, and the incidence has been
increasing in recent years. The most common causative agent of
kerion celsi is Microsporum canis, which infects humans through
their pets. Infants are most frequently affected. Histopathologi-
cally, Trichophyton infection is found in hairs; inflammatory cel-
lular infiltration occurs in peripheral follicles. However,
Trichophyton does not proliferate in the dermis. The main treat-
ment is oral antifungal agents. The incidence of Trichophyton
tonsurans has been increasing in recent years (MEMO).
Fig. 25.10 Kerion (celsi).
2. Tinea barbae
This is equivalent to kerion celsi at sites with barbae (mus-
tache, beard). The upper lip and its periphery are most frequently
Clinical images are available in hardcopy only. involved (Fig. 25.11). Reddening and swelling occur in the entire
area with barbae. Pus is discharged from the hair follicles. The
hairs come out easily when pulled. Most cases are caused by
shaving or misuse of steroids. The treatments are the same as for
kerion celsi.
Fig. 25.11 Sycosis trichophytica.
25 Trichophyton tonsurans MEMO

Group infection of Trichophyton tonsurans occasionally occurs in
Japan. The main skin lesions caused by this fungus are kerion celsi,
black-dot ringworm, and tinea corporis. There are cases in which annu-
lar erythema, characteristic of tinea, is only vaguely seen. Athletes of
sports with much physical contact, such as wrestling and judo, are most
frequently affected; all team members should receive a medical check-
up. Oral antifungal drugs are the first-line treatment, followed by the
same treatments as for tinea.
B. Candidiases 473
3. Trichophytic granuloma
Synonym: Majocchi’s granuloma
A nodule appears intradermally, subcutaneously, or in a skin

lesion caused by tinea superficialis. Flat infiltrative plaques or Clinical images are available in hardcopy only.
tumorous plaques may form (Fig. 25.12). The granuloma may
occur locally (localized granuloma trichophyticum) or multiply
on the whole body (generalized ganuloma trichophyticum).
Localized ganuloma trichophyticum may be associated with mis-
use or abuse of topical steroids. Oral antifungal drugs are the
main treatment. The condition often occurs in immunocompro- Fig. 25.12 Granuloma trichophyticum.
mised individuals such as organ transplantation recipient. Infiltrative skin lesion from prolonged use of top-
ical steroids on granuloma trichophyticum. This
was misdiagnosed as eczema.
Trichophytid MEMO
Trichophytid is thought to be an allergic reac-
tion to fungal components or metabolites. Like
tuberculid, this is an “id” lesion, which reflects
the intense inflammatory reaction that accom-
panies tinea infection. Patients with severe
tinea are most frequently affected. Erythema,
papules and vesicles occur on contralateral
sites of the body that are not affected by tinea.
Trichophytid often occurs during the exacerba-
tion of kerion celsi or tinea pedis. Fungi of the
genus Trichophyton do not exist at sites of
eruptions.
B. Candidiases
Table 25.3 The Candida species most fre-
Outline quently cultured from humans.
● It is an infection of the skin or mucous membrane caused C. albicans
by yeasts of the genus Candida. C. tropicalis
● It is classified by location and clinical features into three C. guilliermondii
subtypes: cutaneous candidiasis (e.g., candida intertrigo, C. krusei
erythema mycoticum infantile, candidal paronychia), C. kefyr
mucosal candidiasis (thrush, genital candidiasis), and C. glabrata
C. parapsilosis
atypical candidiasis (e.g., chronic mucocutaneous can-
C. lusitaniae
didiasis). C. zeylanoides
● It may also occur as an occupational disease in workers
C. glabrata
whose hands are in frequent contact with water, or as a
sexually transmitted disease or an opportunistic infection 25
resulting from immunodeficiency.
● The affected site should be kept clean and dry. The anti-
fungal imidazole is topically applied.
Classification, Pathogenesis, Clinical features

There are seven to ten virulent species in the genus Candida
(Table 25.3). The main causative species is known to be Candi-
Table 25.4 Classification of candidiasis. da albicans. Candidiasis cannot be diagnosed only by culturing
Cutaneous candidiasis fungi taken from the skin lesion, because the fungi inhabit the
Candida intertrigo oral cavity, stool and vagina even in healthy individuals. Prolifer-
Interdigital candidiasis (Erosio interdigitalis ation of Candida should be confirmed directly by microscopy of
blastomycetica) scales, leucorrhoea, or nail fragments. Candidiasis can also be an
Candidal paronychia and onychia (Onychia et endogenous mycosis or an opportunistic infection.
paronychia blastomycetica) Candidiasis in dermatology is classified by location and clini-
Canidida onychomycosis cal features into three main subtypes: cutaneous, mucosal and
Mucosal candidiasis atypical. These are subdivided into various diseases (Table 25.4).
Oral candidiasis
Genital candidiasis Diagnosis
Atypical candidiasis Racemose spores and pseudohyphae are observed by direct
Chronic mucocutaneous candidiasis: CMCC microscopy with KOH solution (Fig. 25.13). For candidal
Monilial granuloma paronychia, a small amount of horny cell layer scraped by scalpel
is examined. Tongue fur or leucorrhea is examined for mucosal
lesion. When cultured in Sabouraud’s glucose agar at 25˚C, white
or cream-colored aggregation of candida forms in 2 to 3 days.
Treatment
Most cases are improved by bathing, cleansing, topical appli-
cation of zinc oxide ointment, and keeping the affected site dry.
Topical antifungal agents such as imidazole are extremely effec-
tive against cutaneous candidiasis. In oral candidiasis, gargling
with amphotericin B syrup or oral miconazole gel is useful. Vagi-
Fig. 25.13 Microscopy of Candida in KOH nal suppositories containing miconazole are given to treat genital
solution. candidiasis in women. Oral antifungal drugs (e.g., itraconazole
Filamentous pseudohyphae and racemose spores and fluconazole) and intravenous fluconazole may be necessary
are present.
in severe cases.
a. Cutaneous candidiasis
1. Candida intertrigo
Sharply margined erythema with scales at the periphery, ero-
sive in some cases, is induced by sweating or poor hygiene in
intertriginous regions, such as the genitocrural region, buttocks,
neck and nuchal region, and axillary fossae, or in the inframam-
mary region. Mild itching and sharp pain may be present. Dia-
betes, malignant tumor or immunodeficiency tend to be
associated with the occurrence of candida intertrigo. It is neces-
sary to differentiate candida intertrigo from eczema and Paget’s
disease.
Candida intertrigo in healthy infants under the age of 3 months
25 is called erythema mycoticum infantile or napkin candidiasis. In
this disorder, sharply margined erythema covered with thin scales
occurs in the genitocrural region, perianal region, buttocks and
thighs. The incidence is highest during summer, from increased
perspiration. Candida intertrigo should be differentiated from
Fig. 25.14 Interdigital candidiasis (erosio miliaria and diaper dermatitis.
interdigitalis blastomycetica).
The third interdigital area is most frequently
involved.
C. Malassezia infections 475
2. Interdigital candidiasis
Synonym: Erosio interdigitalis blastomycetica
The third interdigital cleft is most frequently involved. Erythe-

ma appears on the interdigital areas and gradually enlarges. The Clinical images are available in hardcopy only.
center of the erythema becomes moist, vivid red and erosive,

with an infiltrative white rim (Fig. 25.14). It may be accompa-
nied by mild pain or itching.
3. Periungual candidiasis
As with interdigital candidiasis, it occurs often in those whose
hands are in water a great deal. Reddening and swelling occur in
the periungual region of the fingers (Fig. 25.15). Pus may be dis- Clinical images are
charged from the nail by pressure. Deformity may appear at the available in
nail root. It takes several months to heal and tends to recur. hardcopy only.
4. Candida onychomycosis
Candida albicans parasitizes nails, causing hyperkeratosis
under the nail plate and deformity and fragmentation of the nail Fig. 25.15 Periungual candidiasis and ony-
chia (onychia et paronychia blastomyceti-
(Fig. 25.16). Since candida onychomycosis cannot be clinically ca).
distinguished from tinea unguium, culture is necessary for diag-
nosis. Hyphae are the main findings obtained by direct
microscopy. Itraconazole, fulconazole and terbinafine are admin-
istered orally.
Clinical images are
available in
5. Candida granuloma hardcopy only.
It occurs in infancy and progresses slowly. The scalp, face and
mucous membranes are commonly infected by Candida albicans,
leading to multiple horn-like papules. The nail plates cloud and
thicken. Multiple hyphae are found in the granuloma.
Fig. 25.16 Candida onychomycosis.
b. Mucosal candidiasis Candida infected the entire nail, causing defor-
mity.
1. Oral candidiasis
This is also known as thrush. A white pseudomembrane or
white fur attaches to the oral mucosa and tongue, accompanied
by inflammatory flush. Burning sensation and gustatory anesthe-
sia are present. Erosive plaques form at the site where the
pseudomembrane detaches, causing sharp pain. Newborns and 25
immunocompromised children are most frequently affected. It
heals spontaneously in 1 to 2 weeks. An underlying disease such
as diabetes or immunodeficiency is often found in adult cases.
Oral candidiasis also occurs as an early symptom of AIDS.
Black hairy tongue MEMO 2. Vulvovaginal candidiasis

A hairy change varying in color from black to
brown is observed on the surface of the Synonym: Genital candidiasis
tongue. There may be blackish pigmentation
without hair. It is asymptomatic. The color
comes from the production of a pigment from Pregnant women and adult women with diabetes are frequently
abnormal hyperkeratosis of lingual papillae to affected. There is erosive reddening, formation of white fur, and
which bacteria attach. When Candida is white vaginal discharge. In male cases, reddening and scaling
found secondarily, the treatment is the same
as for oral candidiasis. occur on the corona of the glans penis and foreskin. Genital can-
didiasis may occur as a symptom of a sexually transmitted dis-
ease.
3. Chronic mucocutaneous candidiasis

Clinical images are available in (CMCC)
hardcopy only.
Various types of candidiasis appear in childhood accompany-
ing underlying disease such as immunodeficiency or endocrine
abnormality, and progress slowly. Multiple skin lesions occur.
Unlike other candidiases, chronic mucocutaneous candidiasis
(CMCC) is characterized by thick crust that may become verru-
cous. CMCC responds well to treatment; however, recurrence
often results when treatment is terminated. It is intractable.
C. Malassezia infections
1. Pityriasis versicolor
Synonym: Tinea versicolor

● Itis a superficial infection caused by Malassezia furfur, a
fungal yeast that is resident in more than 90% of adults.
● Light brown patches or hypopigmented macules 1 to 3
cm in diameter appear on the upper trunk of young men

and women and may coalesce into larger macules.
● Scales exfoliate in large amounts from the eruption when
scraped.
● For diagnosis, detection of hyphae and microscopic
examination with KOH solution or Wood’s lamp (yellow-

orange fluorescence) are important.
Clinical features
25 Pityriasis versicolor begins as light brown patches or hypopig-
mented macules of 5 mm to 20 mm in diameter, most frequently
on the trunk, but sometimes on the upper arms and neck (Fig.
25.17). They gradually enlarge and coalesce, presenting larger
macules. Pityriasis versicolor in which brown patches are pro-
duced is called pityriasis versicolor nigra; pityriasis versicolor in
Fig. 25.17 Pityriasis versicolor, tinea versi-
color. which hypopigmented macules occur is called pityriasis versicol-
or alba. The patches tend to be asymptomatic, although there
C. Malassezia infections 477
may be mild reddening or itching.
Epidemiology
Malassezia furfur, the causative fungus of pityriasis versicolor,
is resident in the seborrheic regions. It has spherical spores and
short, thin hyphae. Pityriasis versicolor tends to occur in spring
and summer, when perspiration increases. It is found most fre-
quently in young men and women of about age 20.
Laboratory findings
A mass of thin hyphae and spherical spores is observed by
KOH direct microscopy of the scales. It is easily observed when Fig. 25.18 Malassezia furfur.
Long, thin hyphae and spherical spores are
blue ink is added to the KOH solution (Fig. 25.18). Wood’s lamp observed in the scales of pityriasis versicolor by
shows yellow-orange fluorescence and the size of the skin lesion. direct microscopy with KOH solution.
Diagnosis
Diagnosis of pityriasis versicolor is confirmed by clinical fea-
tures, KOH direct microscopy and fluorescence under Wood’s
lamp.
KOH direct microscopy is necessary for differential diagnosis.
Pityriasis versicolor is differentiated from vitiligo vulgaris, pityri-
asis rosea and leukoderma pseudosyphiliticum. Clinical images are available in hardcopy only.
Treatment
Pityriasis versicolor heals relatively easily with topical imida-
zole antifungal agents in about two weeks. It is both chronic and
recurrent.
2. Pityrosporum folliculitis
This is folliculitis caused by fungi of the genus Malassezia. A Fig. 25.19 Pityrosporum folliculitis
red follicular papule of 2 mm to 3 mm in diameter occurs (Fig.
25.19), sometimes accompanied by a small pustule. Itching and
sharp pain are present. It accompanies pityriasis versicolor or
seborrheic dermatitis in some cases.
25
D. Other deep fungal infections
1. Sporotrichosis
Outline
● Sporothrix schenckii in the soil enters the human body
Clinical images are available in hardcopy only. through a minor injury. Farmers and infants are most
commonly affected.
● A red papule or a pustule first occurs, forming a firm sub-
cutaneous nodule or ulcer.

● A granuloma containing asteroid bodies is found
histopathologically. Sporotrichin test is positive.

a b c d e f g h i j
● Oral antifungal drugs
k arel the first-line
m ntreatment.
o p
Potassi-q r
um iodide and thermotherapy are also effective.
Clinical features
After a latency of about 3 weeks, a red papule or pustule
occurs at the site of bacterial invasion (Fig. 25.20). The eruption
gradually enlarges to a firm, infiltrative, subcutaneous nodule up
to 4 cm in diameter. The nodule easily ruptures, and chronic
ulcer forms at the center. Mild pain may accompany the ulcera-
tion; sporotrichosis is otherwise asymptomatic. It is clinically
subdivided into fixed, lymphangitic and systemic. The systemic
subtype features generalized subcutaneous nodules on the whole
body. In fixed sporotrichosis, eruptions appear solitarily and
enlarge gradually. The face and upper arms of children are most
commonly involved. Lymphangitic sporotrichosis causes multi-
ple skin lesions along the lymph vessels, and most frequently
g
occurs onj
the area between the dorsal hands and p
forearms
q
of
adults.
Fig. 25.20 Sporotrichosis.
It most frequently occurs in the temperate
regions. a: On the face. b: On the lower leg. Pathogenesis, Epidemiology
Sporotrichosis is caused by Sporothrix schenckii, a fungus that
lives in soil and is widely distributed in tropical and temperate
regions. It occurs most commonly in tropical and temperate
regions and in those who often are exposed to the soil, such as
farmers, gardeners, and children who play outdoors. Sporothrix
schenckii invades the dermis through a minor injury such as a
cut, scratch or splinter.
25 Pathology
A nonspecific chronic granulomatous lesion is observed by HE
staining. Eosin-chromophilic asteroid bodies may be found in the
lesion. In PAS staining, PAS-positive spherical spores may be
found at sites with abundant cellular infiltration.

To confirm the diagnosis, crust or exudative fluid is cultured in
D. Other deep fungal infections 479
Sabouraud’s glucose agar. If a mass of Sporothrix schenckii is

identified by slide culture, the diagnosis is sporotrichosis.
Sporotrichin intradermal test is a specific test for sporotrichosis:
48 hours after intradermal injection of 0.1 ml sporotrichin antigen
fluid in the flexor surface of the forearm, the site is examined for
nodule formation; a nodule of 10 mm or larger is considered a
positive. If a reddish-brown granulomatous lesion or ulcer that
does not respond to antibiotics is found, sporotrichosis is suspect-
ed. The crust should be cultured for identification. As it is diffi-
cult to find spores and asteroid bodies histopathologically,
detection of Sporothrix schenckii using an antibody against its
fungal components is also conducted.
Treatment
Sporotrichosis tends not to heal spontaneously, and progresses
for several years. It heals in 1 to 3 months with oral potassium
iodide, an extremely effective treatment. Oral itraconazole and
terbinafine, thermotherapy and surgical removal are useful.
2. Chromoblastomycosis
Synonym: Chromomycosis
Outline
● Itis a chronic fungal infection of the skin and subcuta-
neous tissues caused by dematiaceous fungi. Single or
multicelled clusters with thick walls (sclerotic or muriform
bodies) form in the tissue.
● The skin lesion is exophytic. It develops slowly.
Clinical features
Chromoblastomycosis most frequently occurs in men and
women in adolescence and later. Red papules solitarily occur on
sun-exposed areas of the extremities and face. They enlarge cen-
trifugally and form red scaling or elevated plaques. The lesion may
heal centrally. It may be patchy, ring-shaped or horseshoe shaped
(Fig. 25.21), and slightly exudative. Since abscess formation and
rupture rarely occur, the lesion tends to be dry. The surface of the
lesion may become verrucous. However, chromoblastomycosis is
nearly asymptomatic. It does not heal spontaneously and pro-
gresses slowly. Nevertheless, there have been some fatal cases of
generalized chromoblastomycosis.
Pathogenesis 25
Dematiaceous fungi invade the skin through trauma, such as a Phaeohyphomycosis MEMO
puncture from a splinter, and form a granulomatous lesion. Most According to dermatology textbooks in
Europe and the U.S., phaeohyphomycosis is
cases are caused by Fonsecaea pedrosoi, followed in frequency defined as “a group of superficial and deep
by Phialophora verrucosa and Cladophialophora carrionii (Cla- infections caused by fungi that form pigment-
dosporium carrionii). These fungi are resident in soil, plants and ed hyphae and yeast-like cells in tissue.” The
main causative fungal species are Exophiala
rotting wood. Chromoblastomycosis has been reported in North, jeanselmei and Wangiella dermatitidis.
South and Central America, the Caribbean (Cuba, Jamaica,
Fig. 25.21 Chromomycosis.

The surface of the lesion may appear verrucous.
Martinique), India, South Africa, Madagascar, Australia and

Northern Europe.
Large round or polygonal brown cells called sclerotic cells are
observed in scales from the lesion by KOH direct microscopy.
Histopathologically, a chronic granulomatous lesion forms in the
dermis. The spores are found by regular HE staining. Spores that
are phagocytosed by multinucleated giant cells are also observed.
Treatment
When the lesion is small, it is excised with a margin of 5 mm
to 10 mm of normal skin. Oral itraconazole, flucytosine (5-FC),
and terbinafine, and local injection of amphotericin B are useful.
Thermotherapy, in which a warmer or infrared light is applied for
a long time, may cure the lesion.
3. Mycetoma
Mycetoma, a localized chronic infection, is classified by the
causative microorganism as actinomycetoma (caused by Nocar-
dia brasiliensis, Nocardia otitidiscaviarum, Nocardia asteroids
and similar microorganisms) or eumycetoma. A small nodule
gradually becomes a pustular granuloma, forming a fistula.
25 Mycetoma is characterized by the formation of aggregated
causative organisms (grains) in abscesses. Skin, subcutaneous tis-
sues and bones of the feet and hands are severely affected. Grains
are discharged by sinus drainage. Granules are observed by
microscopy, appearing as a mass of bacteria 1 mm to 10 mm in
diameter. Actinomycotic mycetoma is treated with large long-
term doses of sulfa drugs or a combination of sulfamethoxazole
and trimethoprim (combined ST). For eumycetoma, intravenous
amphotericin B and itraconazole or oral terbinafine are used.
4. Cutaneous aspergillosis
Clinical features
Cutaneous aspergillosis most frequently occurs at moist sites
with chronically poor hygiene. Aspergillus fungi invade a hair
follicle or minor injury to produce folliculitis, pyoderma, acne-
like papules or carbuncle-like lesion.
The infection is caused by fungi of the genus Aspergillus,
which are found in soil. In most cases, they cause a lesion in the
lung or external auditory canal as an opportunistic infection; they
almost never cause skin lesions. When Aspergillus travels
hematogenously from a pulmonary lesion to the skin, a skin
lesion occurs (secondary cutaneous aspergillosis). Poor hygiene,
prolonged bed rest, cast immobilization or topical steroids may
induce direct parasitism on the skin (primary cutaneous
aspergillosis). The several species of Aspergillus fungi include
Aspergillus fumigatus and Aspergillus flavus.
5. Cutaneous cryptococcosis
Clinical features
The face, neck and scalp are most commonly involved. Cuta-
neous cryptococcosis begins with asymptomatic papules and
acne-like eruptions and abscess formation. The various skin
lesions include ulcers, firm subcutaneous nodules, and cellulitis.
Cutaneous cryptococcosis is a dermal or subcutaneous infec-
tion caused by Cryptococcus neoformans, a fungus that exists in
pigeon droppings and soil. The main subtypes are primary cuta-
neous cryptococcosis and secondary cutaneous cryptococcosis.
The former is caused by direct invasion by the fungi into an
external injury and may occur in healthy individuals in rare
cases. The latter is caused by hematogenous dissemination from
pulmonary granulomas. It is highly associated with immunodefi-
ciency and is a symptom of AIDS.
Pathology 25
In primary cutaneous cryptococcosis, a granulomatous lesion
forms but there are few cryptococcal capsules. In secondary cuta-
neous cryptococcosis, mild inflammatory reaction occurs, a
gelatinous lesion forms, and numerous cryptococcal capsules
appear.

Cutaneous cryptococcosis is diagnosed when microscopic
observation shows characteristically thick, capsulated spores in
the pus, or by histopathological identification of Cryptococcus
neoformans or separation of cutaneous cryptococcosis in culture.
When cultured in Sabouraud’s glucose agar, Cryptococcus neo-
formans forms glossy white colonies whose colour changes to
brown. Identification of this fungus has become possible recently
by IF or ELISA.
Treatment
Intravenous amphotericin B in combination with oral fulcyto-
sine (5-FC) is effective. Antifungal drugs containing imidazole
are useful. Primary cutaneous cryptococcosis has a good progno-
sis; systemic cutaneous cryptococcosis tends to have a poor prog-
nosis.
6. Paracoccidiomycosis
Synonym: South American blastomycosis
This chronic granulomatous fungal infection is caused by

Paracoccidiodes brasiliensis. It is characterized by the formation
Clinical images are available in hardcopy only. of a lesion in the lung caused by aspiration. The causative fungi
disseminate, leading to papules and ulceration on the skin and
mucous membranes, and further spread to the lymph nodes (Figs.
25.22-1 and 25.22-2). Histopathologically, the spores germinate
in the characteristic shape of the pilot’s wheel of a ship (Fig.
25.23). Itraconazole or amphotericin B is administered. Paracoc-
cidiomycosis has been reported from most South American coun-
tries, particularly Brazil.
Clinical images are available in hardcopy only. 7. Coccidioidomycosis

This disease is endemic to desert areas of the southwestern
United States, Mexico, and Central and South America. Coccid-
ioides immitis aspirated into the lung induces a pulmonary lesion
and disseminates hematogenously to the skin, causing a papule,
most commonly on the medial area of the face such as the nasal
region or nasolabial groove, and also on the extremities. It gradu-
ally enlarges and becomes a nodule or plaque, resembling a pus-
tule or cellulitis. When spread to the skin or central nervous
system, it may be fatal.
25
8. North American blastomycosis
It occurs in the North American continent and in parts of
Africa. A pulmonary lesion occurs and readily spreads to the skin
and bone. Verrucous papules, nodules and ulcers form on the
Fig. 25.22-1 Paracoccidiomycosis.
Papules and ulceration occur in the oral cavity face and in the oral mucosa. The causative fungus is Blastomyces
and throat. dermatitidis. Potassium iodine agents and amphotericin B are
effective.
9. Histoplasmosis
It is caused by Histoplasma capsulatum var. capsulatum and
occurs in tropical, subtropical and temperate areas of the world,
particularly in the Mississippi Valley and Africa. This fungus is
thought to inhabit bat-infested caves. It may infect humans by
aspiration, forming a skin lesion hematogenously.
10. Cutaneous zygomycosis (mucormycosis)

It is usually caused by fungi of the orders Mucorales (most
commonly by Rhizopus arrhizus). Patients with immunodeficien-
cy or severe diabetes are prone to this infection. Clinical images are available in hardcopy only.
11. Protothecosis cutanea

Caused by Prototheca wickerhamii or Prototheca zopfii, it
occurs as an opportunistic infection in patients with immunodefi-
ciency.
Fig. 25.22-2 Paracoccidiomycosis.
Fig. 25.23 Histopathology of paracoccid-

iomycosis.
25
Chapter
26 Mycobacterial Infections
Mycobacteria, which stain well in the Ziehl-Neelsen, are acid-fast bacteria that causes mycobacterial infection.
Of species in the genus Mycobacterium, three are the main pathogens to human skin: Mycobacterium (M.)
tuberculosis, the nontuberculous (atypical) M. marinum, and M. leprae. Diseases caused by these mycobacteria
are introduced in this chapter.
A. Mycobacterium tuberculosis infections

Outline
● Skin lesions are caused by M. tuberculosis complex.
● The main type is tuberculosis of the skin (true cutaneous
tuberculosis), in which M. tuberculosis causes lesions
directly in the skin. Tuberculid is allergic skin reaction to
M. tuberculosis.
● Tuberculosis of the skin is further classified into subtypes
by clinical features and mechanisms (Table 26.1). Most

cases of tuberculosis of the skin are secondary infection
in those who have a history of extracutaneous tuberculo-
sis.
a. Tuberculosis of the skin
1. Lupus vulgaris
Outline
● This was once the most common type of tuberculosis of
a b c d e f g h the skin.
i j
It rarely occurs
k today.
l m n o p q r
Fig. 26.1-1 Lupus vulgaris. ● Reddish-brown papules appear on the face and neck,
a: A large, firm, infiltrative elevated plaque coalescing into elevated, infiltrative plaques.
occurred on the right cheek. ● It is caused by M. tuberculosis that disseminates
hematogenously or lymphogenously from a focus of
Classification of MEMO Causative Diagnostic Bacterial

mycobacterial infections Bacteria Examination Treatment
Mycobacteria name culture
Mycobacteria include tuberculosis bacteria (M.
M. tuberculosis Tuberculosis ＋＋ Tuberculin Isoniazid,
tuberculosis), nontuberculosis (atypical) bacteria,
of the skin reaction (＋) Rifampicin
and leprosy bacilli (M. leprae). These are the
pathogens of diseases listed below. Tuberculid − − Tuberculin Isoniazid,
reaction (＋＋) Rifampicin
26 M. marinum Nontuberculous −∼＋＋ DNA homology Minocyclin
and other mycobacterial probing thermotherapy,
nontuberculous infection excision, etc.
mycobacteria
M. leprae Leprosy −∼＋ − Skin smear test Multidrug therapy,
（−∼＋） new quinolones
484
A. Mycobacterium tuberculosis infections 485
Table 26.1 Classification of cutaneous tuberculosis (TB).

Lesion of Caseous necrosis Tubercle bacillus
Mechanism of skin
Disease Frequent site other organs in pathological in cutaneous Remarks
infection
(e.g., lungs) tissue tissue
Tuberculosis of
the skin
1. Lupus vulgaris Exogenous infection / Face ＋／− ＋＋ Differentiate from DLE
endogenous spread and sarcoidosis.
2. Scrofuloderma Endogenous spread Neck ＋＋＋＋＋＋ Cold abscess
3. Warty TB Exogenous infection Extremities ＋／− ＋＋＋ Affects those who have
a history of tuberculosis.
Tuberculid
1. Erythema Immune response Lower legs ＋／− ＋＋＋＋／− See Chapter 18.
induratum to M. tuberculosis
(mainly extracuta-
2. Papulonecrotic Extensor surfaces ＋／− ＋ − Multiple, contralateral
neous TB)
tuberculid of the extremities eruptions
3. Lichen Trunk ＋ − − Most frequently occurs
scrofulosorum after BCG vaccination.
extracutaneous tuberculosis.
● Itprogresses slowly, and may progress to squamous cell
carcinoma in rare cases.

A single or several, unilateral, reddish-brown papules first
appear on the face, neck or arms, coalescing into erythematous
plaques. The surface of the papules exfoliates, and the centers
g
scar. Papules recur on the scarred areas, gradually and repeatedlya b c d e f h i
enlarging and coalescing. This leads to the formation of large,
firm, elevated plaques (Figs. 26.1-1 to 26.1-3). At the periphery
are small reddish-yellow or brown nodules. Yellowish-brown
papules resembling apple jelly are observed by diascopy. Lupus
vulgaris progresses extremely slowly over the course of many Clinical images are available in hardcopy only.
years. In addition to preexisting lesions, ulceration and atrophy
occur, sometimes leading to squamous cell carcinoma. Lupus
vulgaris is classified by clinical course into flat macular, ulcera-
tive, and proliferative hypertrophic. a b c d e f g h i j
Pathogenesis Fig. 26.1-2 Lupus vulgaris.

b, c: Infiltrative plaque on the nose.
M. tuberculosis is thought to disseminate hematogenously or
lymphogenously from a focus of tuberculosis in extracutaneous
organs, such as lungs and lymph nodes. In lupus vulgaris, a
tubercle forms by hematogenous dissemination at the first infec- Lupus MEMO
tion of tuberculosis reactivates. Lupus is a general term for diseases in which
erosive, erythematous ulceration occurs on
the face. The name is Latin for wolf, and it
Pathology comes from the facial appearance that was
A tubercle consisting of epithelioid cells and Langerhans giant thought to resemble the bites of a wolf. Until 26
the 19th century lupus was most commonly
cells accompanied by caseous necrosis appears in the dermis. caused by cutaneous tuberculosis. In recent
years, the prevalence of lupus vulgaris has
Diagnosis drastically decreased. The term lupus now
almost always refers to lupus erythematosus
Lupus vulgaris is diagnosed by the clinical features, pathology, (Chapter 12).
and strong positive in tuberculin skin test. Identification of M.
486 26 Mycobacterial Infections
tuberculosis is made by PCR or culture.
Chronic discoid lupus erythematosus, cutaneous sarcoidosis,
tertiary syphilis and sporotrichosis should be differentiated from
Clinical images are available in hardcopy only. lupus vulgaris.
Treatment
Lupus vulgaris responds well to antitubercular drugs.
Although the prognosis is good, it leaves distinct scarring.
2. Scrofuloderma
Outline
● This is the most common tuberculosis of the skin. The
neck and trunk are most frequently involved.
● It begins as painless subcutaneous nodules. It is charac-
terized by fistula formation and pus discharge from cold

abscesses.
● It is caused by M. tuberculosis disseminated from extra-
cutaneous tuberculosis throughout to the skin.

● Cordlike scars form in most cases.

Scrofuloderma, tuberculosis of the skin, is caused by a lesion
in the lung, lymph node, bone, muscle or tendon that continuous-
d e f g h i j k p q
lyl spreads
m to then skin.oA painless light pinkrsubcutaneous nodule
Fig. 26.1-3 Lupus vulgaris. called a cold abscess first appears. It softens and forms a fistula
d: On the face. e: On the back.
in the skin, from which pus discharges. At a previously formed
scrofuloderma, ulceration and characteristic cordlike scarring
occur. There is slight localized fever and pain for the entire
course of the disease.
Large quantities of M. tuberculosis are seen in the pus and tis-
sue of the lesion. The treatments for scrofuloderma are the same
as for lupus vulgaris. Identification of M. tuberculosis is made by
PCR or culture.
3. Warty lupus
Synonym: Tuberculosis verrucosa cutis
26 Clinical features, Pathology

Warty lupus occurs most frequently at the ends of the extremi-
ties, dorsal surfaces of joints, and buttocks, after subjection to
external stimulation or injury (Fig. 26.2). Several small, asymp-
tomatic, indurated wart-like papules with a slight inflammatory
edge coalesce and enlarge, forming erythematous plaques with
A. Mycobacterium tuberculosis infections 487
verrucous periphery. The lesions enlarge centrifugally and tend

to heal in the center. Warty tuberculosis is an infection of the
superficial layers of the skin. There is inflammation with
histopathological atypism. Ulceration does not occur. Clinical images are available in
hardcopy only.
Pathogenesis
Warty lupus is a tuberculosis of the skin caused by M. tubercu-
losis. It occurs from inoculation of organisms into the skin of a
previously infected patient who usually has a moderate or high
degree of immunity. Fig. 26.2 Warty tuberculosis, tuberculosis
verrucosa cutis.
Keratotic erythematous plaque with verrucous
Diagnosis, Differential diagnosis periphery enlarges centrifugally. The center of
Identification of M. tuberculosis is made by PCR or culture. the lesion shows a tendency to heal.
Strong positive in tuberculin skin test and pathological findings
of the skin are diagnostic. Lupus vulgaris, chromomycosis, viral
warts and tinea cruris should be differentiated from warty tuber-
culosis.
Treatment
Warty lupus responds well to antituberculosis drugs.
b. Tuberculid
Tuberculid is a disorder that is associated with a focus of inter-
nal tuberculosis. The cutaneous symptoms are thought to be
immune reactions in the skin resulting from hematogenous dis-
semination of M. tuberculosis or its antigens from a primary
infection. Individuals with strong antituberculous cell-mediated
immunity are affected.
1. Papulonecrotic tuberculid
This is thought to be vasculitis caused by allergic reaction to
M. tuberculosis. It occurs in young people, most frequently on
the extensor surfaces of extremities, particularly on the elbows
and popliteal fossae. Multiple, contralateral dark red papules with
a diameter of 1 cm or less appear and necrotize, forming pustules
and ulceration. They heal with scarring. These eruptions occur in
succession and progress slowly, presenting new eruptions mixed
with old ones. Antituberculosis drugs are useful.
2. Lichen scrofulosorum
Lichen scrofulosorum most frequently occurs after the initial
infection of M. tuberculosis or BCG vaccination. Scattered or
aggregated, red follicular papules of 1 mm to several millimeters 26
in diameter appear on the trunk or extremities. Histopathological-
ly, epithelial cells and Langerhans giant cells are found in the
dermis. There is granulomatous formation; nevertheless, necrosis
is not present nor is M. tuberculosis detected. Therefore, lichen
scrofulosorum is considered tuberculid, an allergic reaction
against fungal compounds. Antituberculosis drugs and minocy-

cline are useful. Most cases heal in several months.
See Chapter 18 for erythema induratum.
B. Nontuberculous mycobacterial infections

Table 26.2 Nontuberculous mycobacterios- Nontuberculous (atypical) mycobacteriosis is a general term
es in Japan (1969-1996). for infections caused by nontuberculous mycobacteria other than
# of reported M. tuberculosis and M. leprae. The term “nontuberculous
Pathogen (%)
cases
mycobacteria” has become more commonly used than “atypical
M. marinum 161 64.1 mycobacteria” in recent years. There are about 30 nontubercu-
M. fortuitum 26 10.4 lous mycobacteria that are pathogenic to humans. The main non-
M. avium-intracellulare complex 19 7.6 tuberculous mycobacteriosis and the number of reported cases
M. chelonae 18 7.2 are shown in Table 26.2.
M. abscessus 11 4.4
M. kansasii 9 3.6 1. Mycobacterium marinum infection
M. grodonae 2 0.8
Synonyms: Fish tank granuloma, Swimming pool granuloma
M. peregrinum 1 0.4
M. scrofulaceum 1 0.4 Outline
M. smegmatis 1 0.4 ● Aquarium staff and tropical fish breeders are most com-
M. ulcerans-like organism 1 0.4 monly affected.
M. vaccae 1 0.4 ● Contaminated water from a swimming pool or tropical
Total 251 fish tank enters a minor injury, causing infection. Nod-
(Adapted from; Nakajima H, et al. Cutaneous ules, exfoliation and ulceration occur.
mycobacterial infections, clinical aspects and case ● Tetracyclines and rifampicin are effective.
reports in Japan. Medical Sense; 1998).
Clinical features
Aquarium staff and tropical fish breeders are commonly
infected with M. marinum. The onset is after a 2-week incubation
period of infection in an external injury. Areas that are subjected
to external friction such as the dorsum of fingers and joints are
most commonly involved. Skin lesions accompanied by central
reddening and crusting progress to nodular plaques. Scaling and
verrucous plaques occur later on. The eruptions are solitary in
most cases. However, M. marinum may be disseminated by
lymph flow or spread systemically in immunodepressed patients.
Pathogenesis
Among nontuberculous mycobacteria, M. marinum is the most
common cause of skin disease. Because M. marinum favors
freshwater environments, most cases of infection are caused by
water from swimming pools or fish tanks.
26 Pathology
There are findings of pustular inflammation and epithelial cell
granuloma in M. marinum infection. It is difficult to detect the
mycobacteria from a pathologic specimen.
C. Mycobacterium leprae infection 489

M. marinum infection is suspected when skin lesions in
patients whose occupation involves fish are examined. Mycobac-
teria are detected from the pus, biopsy tissue, or cultured fish
tank water. Cutaneous mycosis such as sporotrichosis, various
forms of cutaneous tuberculoses, and foreign-body granuloma
should be differentiated from M. marinum infection. M. marinum
is detected by PCR or cultured pus.
Treatment
M. marinum infection heals in 2 to 3 months with the adminis-
tration of tetracycline antibiotics or rifampicin. Since M. mar-
inum is active in the temperature range of 25 to 33˚C, local
thermotherapy is helpful. Antibiotics and rifampicin are helpful.
2. Mycobacterium avium intracellular

complex
Nodules, ulcers and subcutaneous induration occur on areas
subjected to pressure. The extremities and buttocks are most
commonly involved. Antituberculosis drugs are used in combina-
tion with either macrolide or new quinolone drugs for most cases.
Surgical removal may be helpful for localized skin lesions.
3. Mycobacterium fortuitum infection,

Mycobacterium chelonae infection
A cold abscess, fistula, ulcer or nodule occurs (Fig. 26.3).
Antituberculosis agents are often ineffective. Incision, drainage
of pus, debridement or excision is often conducted. Fig. 26.3 Mycobacterium fortuitum infection
on a woman in her 20s.
Pulsating nodules and abscesses occurred in a
4. Mycobacterium kansasii infection large area of the trunk. Pus was discharged in
large amounts by puncture.
A verrucous plaque, nodule or ulcer occurs. Antituberculosis
drugs, new quinolone drugs and macrolide drugs are useful.
C. Mycobacterium leprae infection
Leprosy
Synonym: Hansen’s disease
Outline
● It is a chronic infection caused by M. leprae. The skin 26
and peripheral nerves are mainly involved.
● It is classified into tuberculoid leprosy (TT), lepromatous
leprosy (LL), borderline leprosy, and indeterminate lep-

rosy (IL), according to the cellular immunity against M.
leprae. In TT, there are few erythema, papules, and
slightly reduced sensory perception. In LL, M. leprae pro-

liferate in the entire body to form lepromas.
● Multidrug therapy including DDS (dapsone) is the main
treatment.
Leprosy is an infection caused by Mycobacterium leprae. The
mechanism of infection has not been fully clarified. Because the
pathogenicity of M. leprae is extremely low, the natural immune
response usually eliminates the infection. The incubation period
is usually 3 to 5 years. This makes the disease rare. Leprosy
occurs worldwide, with half of the world’s roughly 12 million
cases occurring in Asia and Africa.

Leprosy is divided by the strength of the host’s cellular immu-
nity against M. leprae into the subtypes listed below (Ridley-
Jopling classification, Table 26.3). The severity of the skin
lesions and peripheral nerve symptoms varies by subtype (Fig.
26.4).
Tuberculoid leprosy (TT): This type is mildest. It occurs in
hosts with strong cellular immunity. Sharply demarcated, local-
ized, patchy erythema or papules appear singly or multiply.
Faded patches also appear. Alopecia and reduced sensation and
Table 26.3 Ridley-Jopling classification of leprosy.

Clinical findings
Lepromin
Disease type Number and Sensation Peripheral nerve Pathological findings
distribution of Clinical features of eruptions test
eruptions abnormality hypertrophy
Indeterminate A few Vaguely demarcated, flat, macular, Mild None Slight, lymphocytic, perivascular −∼ +
leprosy (IL) light pink infiltration, perineural cellular
infiltration
Tuberculoid A few Elevated erythema with dry surface. Reduced Irregular and Epithelioid cells, giant cells, and ++ ∼ +++
leprosy (TT) Alopecia is present. sensation, marked in adja- the lymphocyte in the dermis.
paralytic cent areas of the
eruptions.
Borderline Relatively Smaller eruptions than those of TT. Paralytic Multiple and reg- Epithelioid cells enclosed by + ∼ ++
leprosy that many Macular or plate-like. Vaguely ular in adjacent lymphocyte
is close to demarcated. Satellite eruptions are areas of the
tuberculoid present. eruptions.
leprosy (BT)
Borderline Multiple ① Elevated, sharply demarcated Mild Multiple, mild Diffuse epithelioid cells ±∼+
leprosy (BB) erythema. ② Vaguely outlined
erythema with a delle-like center.
Satellite eruptions may be present.
Borderline Multiple/ Macular or plate-like erythema, Mild From the early ① Absent of foamy changes; −∼ ±
leprosy that Asymmetrical papules, or nodules. The eruptions stages onward. few lymphocytes ② Histiocytes
is close to distribution are less glossy than those of LL. with foamy changes. (Globi are
lepromatous not produced,)
26 leprosy (BL)
Lepromatous Multiple/ Multiple, macular changes from Mild. Paralytic Systemic. Occurs Collagen layer is present −
leprosy (LL) Symmetrical diffuse infiltration to small nodules. when the at late stages. between a leprous granuloma
distribution Erythema nodosum leprosum is course is pro- and epidermis. Foamy structure
present. The lesion is glossy and longed. is present in old leproma.
accompanied by alopecia.
(Based on; Ridley DS, Jopling WH. Classification of leprosy according to immunity: a five-group system. Int J Leprosy 1966; 54: 255-73).
C. Mycobacterium leprae infection 491
● Skin lesion ● Skin lesion ● Skin lesion
Large elevated erythema Macules, nodules, papules Light red erythema

Dry skin Acanthotic Not elevated
Hair loss Hair loss Vaguely-demarcated
● Sensory loss
Always ● Sensory loss ● Sensory loss
Mild Mild
● Nerve enlargement
Localized ● Nerve enlargement ● Nerve enlargement

Diffuse None
Tuberculoid leprosy (TT) Lepromatous leprosy (LL) Intermediate leprosy (IL)
Fig. 26.4 Comparison between lepromatous leprosy, tuberculoid leprosy and indeterminate leprosy.
perspiration are found.

Lepromatous leprosy (LL): M. leprae proliferates systemically
in hosts with cellular immunodeficiency. A leproma, a mass of
histiocytes containing large quantities of M. leprae, forms in the Clinical images are available in hardcopy only.
peripheral nerves, eyes and lymph nodes. Multiple nodules
appear on the skin. As the infection progresses, visual impair-
ment, neuralgia, and deformity of the face and extremities occur
(facies leontina).
Borderline leprosy (BT, BL and BB): The clinical condition is Fig. 26.5 Borderline leprosy.
intermediate in severity between those of TT and LL (Fig. 26.5).
The number of patients with borderline leprosy has been increas-
ing in recent years. Intricate clinical features of TT and LL are
observed.
Indeterminate leprosy (IL): This type easily escapes diagnosis
as leprosy. Two or three flat, poorly demarcated, light pink
patches appear. Peripheral nerve symptoms are mild or absent.
Characteristic findings of leprosy are not found in a skin biopsy.
The WHO classification published in 1995 subdivided indeter-
minate leprosy into multibacillary (MB) and paucibacillary (PB)
subtypes according to the results of skin smear examination,
cutaneous symptoms and nervous symptoms.
Nervous symptoms tend to precede eruptions. During the
course of LL and BL, the symptoms rapidly aggravate in some
cases (lepra reaction). Multiple, nodular, erythema-like eruptions 26
accompanied by perspiration and arthralgia may occur on the
whole body during the leprosy reaction (erythema nodosum lep-
rosum).
Pathology
In tuberculoid leprosy (TT), epithelioid granuloma and
Langerhans giant cells surrounded by infiltration of multiple lym-
phocytes are observed. In lepromatous leprosy (LL), lymphocytes
are not fully responsive to M. leprae, and there are few inflammato-
ry lymphocytes. M. leprae proliferates in macrophages.

Leprosy is diagnosed by skin lesions that are accompanied by
reduced sensation, thickening of peripheral nerves, and neurolog-
ical disorders. M. leprae is detected from the tissue fluid or
pathological tissue of the lesion by acid-fast stain. Lepromin test
(see Chapter 5) may be used for classification of leprosy: It is
strongly positive in TT and weakly positive in BB, BL and LL.
However, diagnostic value of lepromin test is limited because the
test may be false positive under normal conditions. When direct
detection of M. leprae is difficult, such as for the TT type, PCR is
performed.
Serological anti-PGL-1 assay, a peripheral blood test, has diag-
nostic value. There are elevated levels of human immunoglobulin
and biological false positive (BFP) for syphilis in serological
reaction.
Leprosy should be differentiated from tuberculosis, syphilis,
cutaneous mycosis, diseases that are accompanied by peripheral
nerve impairment including diabetes and syringomyelia, and
mycosis fungoides.
Treatment
Multidrug therapy of DDS, rifampicin and clofazimine is rec-
ommended by WHO. The therapy should be continued for 6
months in mild cases and 2 years in severe cases, until the cure is
complete. In recent years, new quinolone antibiotics have also
been used. NSAIDs are administered when leprosy reaction caus-
es sharp pain.
26
Chapter
27 Sexually Transmitted Diseases
Diseases whose main transmission route is sexual intercourse or sexual activity are generically called sexually
transmitted diseases (STD). Syphilis, chancroid, lymphogranuloma venereum, and gonorrhea, as well as genital
herpes, condyloma acuminatum, scabies and pediculosis pubis are the most common STDs. The rapidly
increasing number of STD cases has become a serious social issue. This chapter introduces the STDs that are
not discussed in other chapters, such as syphilis, chancroid and lymphogranuloma venereum.
1. Syphilis
Outline
● The causative bacterium is the spirochete Treponema
pallidum.
● The various mucocutaneous symptoms include ulcera-
tion in the genitalia and eruptions on the whole body.

● In primary syphilis (that in the first 3 months after infec-
tion), primary lesions in the genitalia, ulcerative hard

chancre and regional lymph node enlargement occur.
● In secondary syphilis (that up to 3 years after infection),
syphilitic roseola, papular syphilide, condylomata lata

and syphilitic alopecia occur.
● Secondary syphilis recurs every several months, with
asymptomatic intermissions (latent syphilis).

● In tertiary syphilis (that more than 3 years after infection),
syphilis nodosa and gumma occur in the skin. As sys-

temic symptoms, neurological and cardiovascular symp-
toms occur.
● There is no primary syphilis in congenital syphilis
(transplacental infection).
● Diagnosis is made by detection of the pathogenic
microbe and serologic test. Penicillin antibiotics are use-

ful for treatment.
Syphilis is caused by the spirochete Treponema pallidum. The
route is contact infection (acquired syphilis) or intrauterine infec-
tion (congenital syphilis). Acquired syphilis is caused by sexual
activity in most cases; however, it may be transmitted in health-
care workers non-sexually through work. In rare cases, syphilis
may be transmitted by transfusion or by mother-to-child trans-
mission from birth canal infection or breast feeding.
Clinical features 27
Syphilis is divided into manifest syphilis and asymptomatic
syphilis. In manifest syphilis, lesions occur on the skin and
mucosa membranes. Asymptomatic syphilis progresses gradually
493
494 27 Sexually Transmitted Diseases
Primary Secondary/Latent Tertiary
Primary syphilis ︶ Secondary syphilis Tertiary syphilis
3 months
①primary ①fever, fatigue Recurring secondary ①syphilis nodosa
Incubation (asymptomatic)
lesion ②syphilitic syphilis and latent syphilis ②gumma

period ( 3 weeks)
②hard roseola every several months. ③cardiovascular syphilis

∼ ③papular syhilide
chancre ④neurosyphilis
④condylomata lata
Asymptomatic period (
③bubo
Serological test (+)
∼
(mucous lesion)
indolenta
Serological (-) Serological (+)

infection
3 weeks
6 weeks
3 months
3 years
10 years
Fig. 27.1 Clinical course of syphilis.
and symptoms are not apparent. The course of syphilis is divided

into four stages: primary, secondary, latent and tertiary (Fig.
27.1). Primary syphilis is highly infectious; tertiary syphilis is
not. Congenital syphilis has a specific course. Syphilis was
thought to occur as manifest syphilis in various degrees in all
syphilis-infected individuals; however, the infection remains
latent in many cases.
Clinical images are available in hardcopy only. 1) Primary syphilis

After the initial incubation period of 3 weeks, a firm papule of
1 cm to 2 cm in diameter occurs at the site invaded by the spiro-
chete (Fig. 27.2), gradually ulcerating into a hard chancre. Numer-
ous Treponema pallidum organisms are observed on the surface
of the hard chancre by microscopy. Several days after the pri-
mary chancre, firm painless enlargement of the regional lymph
node occurs, which is called bubo indolenta. These asymptomatic
changes often go unnoticed by the patients. The eruption heals
spontaneously in about 3 weeks, after which is no skin manifesta-
Fig. 27.2 Primary lesion.
A firm, asymptomatic papule with a diameter of tion for 2 to 6 weeks until occurrence of an eruption in secondary
2 cm occurred on the border of the glans penis syphilis.
and foreskin.
2) Secondary syphilis
27 The period from the third month (to the third year) after infec-
tion is secondary syphilis. The Treponema pallidum organisms
that have proliferated in the regional lymph node at primary
syphilis disseminate hematogenously to the whole body, leading
1. Syphilis 495
to various asymptomatic eruptions. Antibody titer becomes high-

est at this stage and decreases thereafter. The eruptions recur and
disappear repeatedly for several years. Although eruptions first
occur symmetrically on the whole body, they gradually become
localized asymmetrically. The main symptoms of the secondary Clinical images are available in hardcopy only.
syphilis are the following.
① Syphilitic roseola
Multiple, asymptomatic, light pink erythema of 5 mm to 20 mm
in diameter occur on the whole body surface, markedly on the
palms and soles (Fig. 27.3). These are accompanied by slight fever a b c d e f g h
and systemic fatigue. The skin lesion disappears in several days.
② Papular syphilide
Two to 3 weeks after the onset of syphilitic roseola, multiple,
vivid red papules of 5 mm to 10 mm in diameter appear, most
frequently on the trunk (Fig. 27.4), and most severely on the
palms and soles. It is asymptomatic.
③ Papulosquamous eruption (Syphilitic psoriasis)
Localized psoriasis-like eruptions occur on the palms and Clinical images are available in hardcopy only.
soles; they are highly diagnostic for syphilis.
④ Condylomata lata
Highly infectious, moist, flatly elevated papules with a dirty
appearance appear on the intertriginous areas of the anus, genitalia,
axillary fossae and inframammary region (Fig. 27.5). Treponema
pallidum organisms are observed in high concentration in the
lesions. a b c d e f g h i
⑤ Pustular syphilide Fig. 27.3 Syphilitic roseola.
Multiple pustules occur. Papular syphilide may progress to a: Erythema up to 1 cm in diameter that is slight-
pustular syphilis in some cases. Immunocompromised patients ly infiltrative at the edge, on the palms. b: Close-
up of lesion in another case. The erythema is
are most likely to be affected. partially infiltrative. Both cases are secondary
⑥ Syphilitic leukoderma syphilis.
It is vaguely demarcated, incompletely hypopigmented leuko-
derma. It occurs in patients who have darkly pigmented skin.
⑦ Syphilitic paronychia
This paronychia is associated with syphilis. There are no clini-
cally characteristic findings in syphilitic paronychia.
⑧ Syphilitic alopecia
Six months after infection, multiple patches of hair loss of 5
mm to 20 mm in diameter appear and spread gradually on the
entire scalp. It should be differentiated from alopecia areata.
⑨ Syphilitic angina
A highly infectious mucosal lesion accompanied by tonsillitis
occurs in the oral cavity (Fig. 27.6).
3) Latent syphilis
Untreated secondary syphilis may resolve in 3 to 12 weeks,
leaving the patient asymptomatic. Diagnosis can be made by a
positive serology test without any clinical evidence of treponemal 27
infection. Latent syphilis is divided into an early latent stage
(within 1 year after onset of disease) and a late latent stage (1
year after onset of disease).
4) Tertiary syphilis
In tertiary syphilis, Treponema pallidum is difficult to detect
during the period of 3 to 10 years after infection. Multiple, cop-
per-colored nodules of several centimeters in diameter appear on
Clinical images are available in hardcopy only. the face at the early stage of tertiary syphilis and heal with scar-
ring in several months (syphilis nodosa). A few subcutaneous
nodules occur, soften and rupture, forming ulcers (gumma).
These eruptions are rarely seen today, thanks to improved treat-
ments using antibiotics.
After 10 years or more of infection, eruptions are no longer
seen. However, the heart, blood vessels and central nervous sys-
tem become involved (metasyphilis). The main symptoms are
myocarditis, aortic aneurysm, myelophthisis and general paresis.
Syphilis today rarely progresses to this stage.
5) Congenital syphilis
Treponema pallidum passed through the placenta from the
Fig. 27.4 Syphilis papulosa. mother infects the child. Intrauterine infection in early pregnancy
Multiple, bright red papules of 5 mm to 10 mm may result in stillbirth or miscarriage. Therefore, congenital
occur. They are accompanied by infiltration. syphilis is usually caused by infection after the first trimester,
when the placenta is completely formed. The infection is sys-
temic and hematogenous; congenital syphilis begins with second-
ary syphilis and without primary syphilis.
Within 6 months after birth, symptoms of secondary syphilis
appear (early congenital syphilis). Symptoms of tertiary syphilis
appear after late childhood (late congenital syphilis). In early
congenital syphilis, premature facial aging, radial scarring around
the mouth called Parrot’s furrow, syphilitic nephritis, and
pseudoparalysis from the sharp pain of osteochondritis (Parrot’s
pseudoparalysis) are present. In late congenital syphilis, Hutchin-
Clinical images are available in hardcopy only. son’s triad (dental abnormality, ocular interstitial keratitis,
impairment of vestibulocochlear nerve) becomes pronounced.
Pathology
Swelling and proliferation of the vascular endothelium and
perivascular infiltration of plasma cells and lymphocytes are
observed by skin biopsy of a syphilitic eruption. Central
caseation necrosis of the eruption and granulomatous infiltration
are found after second syphilis.
Fig. 27.5 Condylomata lata.
Multiple, flatly elevated infiltrative eruptions, Laboratory findings, Diagnosis
these coalesce in some areas.
Treponema pallidum is investigated by microscopy and sero-
logic test. Because Treponema pallidum cannot be cultured, speci-
mens are collected and directly investigated by microscopy from
moist lesions such as a hard chancre, condylomata lata, enanthe-
27 ma in the oral cavity, or pustules. Treponema pallidum stains
bluish black in parker ink and shines in dark-field examination.
Serological test is useful for finding, screening and judging the
progression of syphilis. Nevertheless, the test is negative in the
2. Chancroid 497
4th to 6th week after infection. The main examinations are

serologic test for syphilis (STS) using lipid antigen (cardiolipin),
treponemal hemagglutination (TPHA) test, and fluorescent tre-
ponemal antibody absorption test (FTA-ABS).
The STS results show positive at the early stages of infection,
and the elevation of antibody titer closely relates to the disease
progression. STS is effective for screening and is used as an
index of therapeutic performance. However, STS may show false Clinical images are available in hardcopy only.
positive in patients with other disorders, such as collagen disease.
Called biological false positive (BFP), it is useful for diagnosis of
lupus erythematosus and antiphospholipid syndrome.
Because of its high specificity, TPHA and FTA-ABS are used
to confirm the diagnosis for individuals who show positive by
STS screening. STS and TPHA are compared in Table 27.1. The
incidence and progression of syphilis are determined by the com-
bination of TPHA and FTA-ABS.
Fig. 27.6 Syphilitic angina.
Treatment
Penicillin antibiotics are the first-line treatment. Penicillin-resist- Serologic test for syphilis MEMO
ant strains have not been found so far. In the late stages of syphilis, (STS)
the same treatments for early syphilis are repeated every 6 months; As described in the text, STS is a nontrepone-
nonetheless, the disease tends to be intractable at that stage. mal screening test using cardiolipin. Several
tests have been used which are categorized
Macrolide or tetracycline drugs are given to patients with peni- into STS.
cillin hypersensitivity. Although administration of antibiotics at ・Glass slide test (venereal disease research
the early stage kills Treponema pallidum quickly and effectively, laboratory (VDRL))
・Rapid plasma reagin card test (RRR)
the residue of dead Treponema pallidum may cause toxic reaction; ・Complement fixation test
within several hours of drug intake, a fever of about 40˚C occurs ・Wassermann test
and the syphilis eruptions aggravate (Jarisch-Herxheimer reaction). ・Kahn’s test
NSAIDs are administered for this phenomenon. Aqueous penicillin
administered by large-bore IV is recommended for neurological
syphilis, because oral and intramuscular administration of peni-
cillin fail to reach the cerebrospinal fluid in sufficient concentration.
For the reason that HIV carriers may fail to respond well to
treatment, larger doses of drugs based on the same treatment for
neurological syphilis may be necessary for a prolonged period.
Reinfection of Treponema pallidum may occur in some cases.
2. Chancroid
Chancroid is an infection caused by the Streptobacillus HIV and syphilis MEMO
Haemophilus ducreyi and transmitted by sexual activity. This Sexually transmitted superinfection of HIV
and syphilis has been increasing. Syphilis
Gram-negative bacillus stains well in Unna-Pappenheim. Chan- patients who are immunocompromised from
croid is most common in tropical and subtropical countries. HIV infection are prone to severe symptoms
of secondary syphilis. Those cases are often
Clinical features difficult to cure by the usual syphilis treat-
ments. The spread of neurologic syphilis in
Two to three days after infection, a red papule occurs on the HIV-positive patients has become a serious 27
coronal sulcus, foreskin, labium or vaginal opening and becomes problem. HIV-positive patients may have
atypical clinical findings of syphilis, serologi-
pustular, leading to ulceration. The ulcer is accompanied by severe cal findings and response to treatments.
pain and a pustular coat in the center. The ulcer is soft to the
Table 27.1 Interpretation of STS and TPHA touch. It begins as a single lesion; however, it rapidly spreads to
results, and courses of action.
form multiple lesions from autoinoculation. Two to 3 weeks after
STS TPHA Interpretation Course of action onset, painful unilateral swelling occurs in the inguinal lymph
1. Not syphilis node in 25% to 60% of all patients with chancroid.
2. Syphilis, Perform
− − immediately after re-examination in Laboratory findings, Diagnosis
exposure to several weeks.
Treponema Chancroid is often diagnosed by the clinical features. The Ito
(incubation period) reaction test, an intradermal test using Hemophilus ducreyi vac-
1. Syphilis after cine, is no longer conducted.
treatment
2. Syphilis, many Treatment
Confirm the
years after onset Azithromycin, ceftriaxone and erythromycin are the first-line
results by FTA-
3. Nonspecific ABS. drugs. Most Haemophilus ducreyi strains are tolerant to tetracy-
inflammatory
reaction (e.g.
cline, amoxicillin and sulfamethoxazole/trimetoprim.
− ＋
alveolar pyorrhea)
4. Zone Dilute the serum 3. Lymphogranuloma venereum
phenomenon (STS and make
was false negative reexamination. Synonym: Lymphogranuloma inguinale
from high
concentration of
antigen)
Outline
● It is an infection by bacteria of the genus Chlamydia.
1. Early-stage Make
syphilis infection reexamination ● It is transmitted by sexual activity. One to two weeks
after a certain after infection, a small papule or vesicle appears in the
period of time;
confirm by FTA- genitalia. One to two weeks after the onset of the skin
ABS. lesion, fever and swelling occur in lymph nodes in the
＋ − groin and thighs.
2. BFP caused by Investigate for
other disease diseases other ● It occurs most frequently in tropics.
than syphilis,
such as
Pathogenesis
autoimmune
diseases. Lymphogranuloma venereum is caused by the Chlamydia tra-
1. Syphilis Initiate chomatis serovars L1-3.
treatment.
＋＋ Clinical features
2. BFP and Confirm by FTA-
nonspecific reaction ABS. Lymphogranuloma venereum occurs most frequently in the
STS: serologic test for syphilis tropics. Several days after infection, a small herpes simplex-like
TPHA: Treponema pallidum hemagglutination test
FTA-ABS: fluorescent treponemal antibody
papule of 1 mm in diameter occurs singly on the genitalia or
absorption test anus. The skin lesion is asymptomatic and heals unnoticed.
BFP: biological false positive About 1 week later, systemic symptoms such as fever and
(Adapted from; Sugahara T, et al. Treponema pal- splenohepatomegaly occur. The regional lymph node becomes
lidum. Nippon Rinsho 1990; S48: 408-12).
firm, swollen and ruptures, discharging pus. The inguinal lymph
node of men and the anorectal lymph node of women are often
involved. In women there may be vulvar lymphatic edema, ele-
phantiasis-like change, or urethral or rectal stenosis (esthiomène).
Laboratory findings, Diagnosis, Treatment

Antigen test and PCR are conducted. Chlamydia trachomatis
is detected from the skin lesion or lymph fluid by microscopy.
27 Frei test, an intradermal test using fluid taken from the patient’s
lymph node, is no longer conducted. Skin biopsy must not be
performed, because it may lead to fistula formation. Tetracycline
and macrolide drugs are administered orally.
Chapter
28 Skin Diseases Caused by Arthropods
and Other Noxious Animals
Various cutaneous symptoms, including blistering and contact dermatitis, allergic reaction and secondary infec-
tion, are caused by arthropods. Pathogens transmitted by insects or other noxious animals may cause systemic
symptoms. Infestation by arthropods or insects may result in cutaneous symptoms, and various pathogens car-
ried by arthropods and other noxious animals can infect humans.
A. Diseases caused by insects and other noxious animals
1. Insect bite
Insect bite is a general term for the dermatitis that is caused by
the bite or sting of a mosquito, gnat, horsefly, bee or other insect.
It is thought to be an allergic reaction to the salivary components
that the insect discharges while sucking blood or to the venom of
stings. The severity of the clinical symptoms depends largely on
the age of the patient and the severity of allergic reaction. Imme-
diately after an insect bite, itching wheals or erythema appears.
There are two major clinical types of insect bites: those of imme-
diate hypersensitivity, in which symptoms subside in 1 to 2
hours, and those of delayed hypersensitivity, in which erythema a b c d e f g h
or blistering may occur 1 to 2 days after a bite (Figs. 28.1-1 and
28.1-2). Treatments are topical steroid application for eruptions,
and oral antihistamines for itching lesions. A bee sting may cause
an anaphylactic reaction.

2. Hypersensitivity to mosquito bite
After a mosquito bite, an allergic reaction occurs against the
protein in the salivary components of the mosquito, sometimes
leading to systemic symptoms such as high fever, liver dysfunc-
tion and lymph node enlargement, and cutaneous symptomsa b c d e f g h i
including blistering. Later, swelling, induration, necrosis and
ulceration occur. During the course of hypersensitivity to mos-
quito bite, the histopathological symptoms may resemble those of
hydroa vacciniforme. Recent study has found the Epstein-Barr
virus (EBV) to be associated with hypersensitivity to mosquito Clinical images are available in hardcopy only.
bite. Cases have proven the association between chronic EBV
infection and NK/T cell lymphoma.
a b c d e f g h i j
Fig. 28.1-1 Insect bite.
a: Itching erythema on the lower leg. b: A tense
Myiasis MEMO
blister on the lower leg. c: Insect bite on the eye-
Flies lay eggs in necrotic tissue. Eggs and maggots are present at the brow. Severe edema occurred around the lesion. 28
site, requiring curettage.
499
500 28 Skin Diseases Caused by Arthropods and Other Noxious Animals
3. Caterpillar dermatitis
The urticating hairs of larval moths and butterflies (caterpil-
lars) including those of the tussock moth, tea tussock moth and
browntail moth cause caterpillar dermatitis. The affected site has
Clinical images are available in hardcopy only. tingling pain. Punctate, itching erythema is followed by a red
wheal (Fig. 28.2) that progresses to vesicles and papules.
4. Dermatitis linearis
The hemolymph of the beetle Paederus fuscipes Curtis comes
Fig. 28.1-2 Insect bite. into contact with the skin, causing dermatitis linearis (Fig. 28.3).
Small, itching papules of about 5 mm in diameter Two to three days after contact, characteristic linear skin lesions,
occur, most frequently on the lower legs. reddening, vesicles, swelling, burning sensation and sharp pain
occur.
5. Scabies
Outline
● It is an infestation caused by the mite Sarcoptes scabiei
var. hominis. Multiple papules occur. Intense itching is
present, worsening at night.
● The genitalia, trunk and interdigital areas are most fre-
quently involved. It is characterized by “tunnels” (bur-

rows) in the interdigital area.
● It may be transmitted by bedclothes or skin-to-skin con-
tact. It often occurs as a STD or in-hospital epidemic.

● Benzyl benzoate, topical g -benzenehexachloride and
oral ivermectin are the main treatments.

Fig. 28.2 Caterpillar dermatitis.
Punctate, itching erythema occurs, accompanied
by pruritus and blistering in some areas of the
lesion.

Clinical images are available in hardcopy only. hardcopy only.
28 Fig. 28.3 Dermatitis linearis. Fig. 28.4-1 Scabies on the scrotum.

Scabies is characterized by small multiple nodules.
A. Diseases caused by insects and other noxious animals 501
Clinical features
Small, multiple, light pink papules 2 mm to 5 mm in diameter
occur on the trunk, genitalia, thighs, inner arms and interdigital
areas (Figs. 28.4-1 and 28.4-2). Small nodules may form in the
genitalia and axillary fossae. Both the papules and nodules are Clinical images are available in hardcopy only.
accompanied by intense itching that worsens when the skin is
warmed, such as at bedtime. Patients with scabies often complain
of difficulty of sleeping from itching. Scratching of the skin
lesions may lead to formation of eczematous plaques. When the
interdigital areas and palms are involved, there may be slightly
elevated, grayish-white linear lesions (mite burrows) several mil-
limeters long where female insects lay eggs. Blistering occurs in
some cases (Fig. 28.4-2).
Pathogenesis
Scabies is an infestation in the epidermal horny cell layer by the
mite Sarcoptes (S.) scabiei var. hominis. This mite is ovoid and
has body dimensions of 0.4×0.3 mm for males and 0.2×0.15
mm for females, with 4 pairs of legs at the adult stage (Fig. 28.5).
A mated female forms a mite burrow in the horny cell layer and Fig. 28.4-2 Scabies on the hand and foot of
an elderly person.
lays 1 or 2 eggs daily there, dying in 4 to 5 weeks. Eggs incubate Distinct blistering is present.
for 3 to 5 days. S. scabiei var. hominis inhabits creases of the skin
or the hair follicles and grows to adult stage in 14 to 17 days.
Scabies infestation is caused by direct skin-to-skin contact or
indirect contact through bedclothes or clothing. The incubation
period is about 1 month. Scabies often occurs within a family and
at hospitals and eldercare homes. Infection may be direct, from
sexual transmission.
Norwegian (crusted) scabies is caused by a large number of S.
scabiei var. hominis in persons with poor nutrition, poor hygiene
or immunosuppression. Under such conditions, scabies is highly
contagious and may cause severe symptoms including general- a b c d e f g h
ized hyperkeratosis and crusts.
Diagnosis
When disseminated small papules accompanied by intense
itching are found on the trunk, mite burrows should be carefully
searched for in the interdigital areas. Multiple papules on the
genitalia, particularly on the scrotum or labia majora, should be
carefully examined. To confirm the diagnosis, a specimen includ-
ing the horny cell layer is removed from the skin by pinching
with tweezers, scraping the skin with a scalpel, pricking with a b c d e f g h i
needle, or exfoliating with adhesive tape for direct identification Fig. 28.5 Sarcoptes scabiei var. hominis.
of the mite body or eggs by light microscopy. Inquiry on symp- a: S. scabiei var. hominis has four pairs of legs. b:
Eggs of S. scabiei var. hominis.
toms of scabies among the patient’s family members and part-
ners, and history-taking on sexual activity are helpful.
Insect bite, eczema and urticaria are differentiated from sca-
bies. Mite burrows and the nodules on the genitalia are useful for 28
differentiation.
Treatment
Topical application of ointments containing sulfur, crotamiton
and benzyl benzoate is helpful. Previously, g -BHC (benzene
hexachloride) was most commonly used in the U.S. and Europe.
It is important to apply the ointment to the entire body skin below
the neck of all family members and partners, regardless of
whether they are symptomatic. In recent years, oral ivermectin
has become available for use. It is extremely effective, requiring
only one administration a day. Antihistamines may be used, if
Fig. 28.6 Eggs of the louse Phithilus pubis necessary. Thorough laundering and sun drying of bedclothes is
on pubic hair. recommended.
6. Pediculosis
Allergic reaction is induced by a louse that parasitizes human
skin to suck blood, causing intense itching. Lice are host-specific
and spend their entire life on the host. The three main causative
lice of pediculosis are Pediculus capitis (head lice, 2 mm to 4
mm long, inhabiting head hair), Pediculus humanus (clothing or
body lice, 2 mm to 4 mm long, inhabiting clothing), and Pthirus
pubis (pubic or crab lice, 1 mm long, inhabiting pubic hair; Figs.
Fig. 28.7 Pediculosis. 28.6 and 28.7). It is impossible to distinguish between Pediculus
capitis and Pediculus humanus by appearance.
Clinical features
A louse parasitizes a hair shaft and lays eggs on the hair. The
eggs incubate for about 1 week. The lice mature and suck human
blood. In most cases, intense itching begins 1 to 2 months after
infection. Eruptions do not usually occur.
Pathogenesis
Pediculus capitis infestation may become epidemic among
schoolchildren during kgroup activities
l m at schools
n oro daycare cen- r
ters. Pthirus pubis infestation is caused most frequently by sexual
intercourse. The eyebrows are involved in rare cases. Pediculus
humanus infestation is epidemic among individuals under envi-
Clinical images are available in hardcopy only. ronments with poor hygiene, such as in the homeless.
Itching on the head or genitalia is the main complaint of a
a b c d e f g h i
patient, jwhen pediculosis
k l is m n It is
suspected. p
o important toqsearchr
Fig. 28.8-1 A tick bite. for lice and eggs attached to the hair. Phenothrin shampoos and
a: Shoulder 2 hours after the bite. The legs of the
tick are still moving (the patient is Hiroshi
Shimizu, the author of this textbook). b: A tick Skin diseases caused by jellyfish, MEMO
bite on the eyelid.
coral and sea anemones
An eruption may be caused by the sting of jellyfish, coral or sea
anemones in the ocean. Some marine organisms sting humans with the
28 nematocysts on their tentacles or otherwise injure human skin by con-
tact. Systemic symptoms may be severe.
B. Skin diseases transmitted by insects and other animals 503
powders are helpful treatments. The family members and sexual

partners are also treated to avoid “ping-pong” infestation, in
which the disease repeatedly rebounds from untreated to treated
persons.
7. Tick bite
Clinical features g j
a b c d e f h i
Tick bite is caused by ixodid (hard) ticks. Because ticks of the Fig. 28.8 A tick bite.
family Ixodidae tend not to be felt when crawling on human skin, c: A tick on the neck.
they are able to attach insidiously to the face, arms or even the
trunk or genitals of humans (Figs. 28.8-1 and 28.8-2). The bite
tends to be painless. The main symptoms are inflammation
around the bite, erythema, edematous swelling, bleeding and blis-
tering. The mouthpart is firmly fixed in the skin while sucking
blood; a tick bite is often found when the complaint has been a
wart or skin tumor. A tick that has sucked its fill of blood falls
naturally from the skin. Borrelia spirochetes may be transmitted
by a tick bite, leading to Lyme disease (described later).
Pathogenesis
Ixodidae are 2 mm to 8 mm long (Fig. 28.9) and tend to inhab- Fig. 28.9 An ixodid tick removed from human
it grasslands or woods. They burrow into the skin of humans and skin.
animals to suck blood. It is generally 5 mm to 8 mm long.
Treatment
If a tick is forcefully pulled while sucking blood, it may tear,
leaving the mouthpart in the skin. This can lead to foreign-body
granuloma. The whole tick, including the mouthpart, should be
removed by either inserting scissors into the bite spot or punch-
ing the site out with the tick attached. Oral administration of
tetracycline 1 week after removal is advised as a prophylactic
against Lyme disease.
B. Skin diseases transmitted by insects and other animals

Table 28.1 Classification of Borrelia species.
1. Lyme disease
!
B. burgdorferi
B. burgdorferi sensu lato B. garinii
" "!
Outline B. afzelii
Borrelia
● It is an infection caused by the spirochete bacteria Borre-
lia burgdorferi sensu lato, transmitted by ticks of the fam- Other Borrelia species
ily Ixodidae.
● It occurs most frequently in USA, Scandinavia and cen-
tral Europe, during spring and summer.

● It begins as erythema chronicum migrans (first stage)
and progresses to arthritis and cerebral meningitis (sec- 28

ond stage) and then to dysfunction of the joints and central
Table 28.2 Stages and symptoms of Lyme nervous system (third stage)
disease.
● Tetracyclineis the first-line treatment.
Course of
Stage Clinical findings
disease
Clinical features
First stage Up to 1 Erythema chronicum
Erythema month migrans, influenza-like
Lyme disease occurs from Borrelia (B.) burgdorferi (Table
period symptoms (fever, 28.1) infection caused by the bite of ixodid ticks. The course fol-
headache, generalized lows repeated remissions and recurrences. It is divided into three
malaise, arthralgia)
stages. Besides the typical courses shown in Table 28.2, courses
Second stage Several Lymphocytoma cutis, with localized scleroderma, lichen sclerosus et atrophicus, and B-
Dissemina- weeks to choriomeningitis,
tion period several radiculitis, cranial cell lymphoma have been reported.
months neuritis, Bell’s palsy First stage (erythema period): After an incubation of 3 to 40
Third stage Several Acrodermatitis chronica days, an erythema or papule occurs at the bite in about half of all
Chronic peri- months atrophicans, chronic cases. Ixodid ticks tend to bite the thighs, groin and axillary fos-
od to several arthritis, chronic sae. The skin lesion enlarges within several days, forming a char-
years encephalomeningitis
acteristic ring-shaped lesion (erythema chronicum migrans,
ECM) (Figs. 28.10-1 and 28.10-2). The periphery is vivid red
and sometimes elevated. There is discoloration at the center. It is
asymptomatic and may become as large as 40 cm in diameter.
Influenza-like symptoms such as fever, headache and general
malaise, and cerebral meningitis-like symptoms are often present.
These subside in several weeks. Secondary multiple annular ery-
Clinical images are available in hardcopy only. thema occurs in about 30% of all cases.
Second stage (dissemination period): One to three months after
infection, B. burgdorferi spread to the whole body and cause var-
ious organ symptoms, such as arthritis, peripheral neuritis,
meningitis and dysfunctional transmission of cardiac muscle
impulse. Multiple erythema chronicum migrans occurs on the
whole body. Dome-shaped tumors may appear on the face
(pseudolymphoma, also called lymphadenosis benigna cutis;
Chapter 21).
Third stage (chronic period): Several months to several years
after onset, lesions develop in the joints and central nervous sys-
tem. Acrodermatitis chronica atrophicans, which is characterized
Clinical images are available in hardcopy only. by the insidious onset of painless, dull-red nodules or plaques on
the extremities leaving central areas atrophy, occurs as a late skin
trauma. Asymptomatic, infiltrative, edematous erythema occurs
and enlarges. The skin atrophies and becomes so thin that subcu-
taneous vessels can be seen.
Epidemiology
Fig. 28.10-1 Erythema chronicum migrans
(ECM) at the first stage of Lyme disease. Lyme disease was first recognized in 1975 from a study of epi-
Ring-shaped eruptions that are characterized by a demic infections whose main symptoms were erythema and
bright red periphery appear after a tick bite. arthritis, made in Lyme, Connecticut (USA). Lyme disease
occurs worldwide, especially in the U.S.A., Scandinavia and cen-
tral Europe.
Pathogenesis
Lyme disease is caused by spirochete bacteria B. burgdorferi
sensu lato, mainly by B. burgdorferi, a tick-borne spirochete bac-
28 terium, most frequently transmitted by the ixodid tick Ixodae
ovatus. B. burgdorferi inhabits the midgut of the ticks, which
burrow into human skin. The bacteria spread hematogenously,

causing systemic lesions.
Laboratory findings
Detection of specific antibody: IgM-specific antibodies are
detected at the early stage; IgG-specific antibodies are detected Clinical images are available in hardcopy only.
later. The specific antibodies may be false positive in patients
with systemic lupus erythematosus or rheumatoid arthritis.
Detection of B. burgdorferi sensu lato: The bacteria are isolated
from blood, cerebrospinal fluid or skin lesion for culturing. Bor-
relia proteins can be detected by Western blot, and Borrelia
DNA can be identified by nested PCR.
Fig. 28.10-2 Erythema chronicum migrans
Diagnosis, Differential diagnosis (ECM).
Diagnosis can be made by the tick bite and by erythema chron-
icum migrans (ECM). To confirm the diagnosis, an antibody test
is conducted.
Treatment
Doxycycline, penicillin or cefoxime is orally administered for
20 days. Cefem drugs are used at the second and third stages of
the disease because they are transported to the nerves in suffi-
cient concentrations.
2. Leishmaniasis
Definition
Leishmaniasis is a parasitic infection caused by protozoa of the
genus Leishmania. Several species in the genus cause leishmani-
asis, and each species tends to occupy a particular zoogeographi-
cal zone. Leishmania protozoa are transmitted to humans by
bloodsucking sand flies. Human leishmaniasis is usually classi-
fied as cutaneous or visceral. Leishmaniasis is endemic in 88
countries, occuring most frequently in Brazil, Iran, Afghanistan
and Sudan. Leishmaniasis is classified into three subtypes by
Leishmania species. The distribution and clinical features differ
for each type.

① Cutaneous leishmaniasis
The causative protozoan of cutaneous leishmaniasis is Leish-
mania tropica, which is predominantly distributed in Africa. The
main parasite hosts are dogs and rodents. A painless papule
appears at the bite and progresses to an ulcer that is accompanied
by induration and enlargement. The skin lesion heals with scar-
ring. The patient obtains permanent immunity.
② Mucocutaneous leishmaniasis
The causative protozoan of mucocutaneous leishmaniasis is
Leishmania braziliensis, which inhabits South America, is car- 28
ried by dogs and rodents, and is transmitted to humans by sand
flies. Tumors and odorous ulcers form. For decades after an

infection, secondary ulceration involving the skin, mucosa and
bones occurs in the ears, nasal cavity, oral cavity, pharynx and
esophagus.
③ Visceral leishmaniasis
The causative protozoan of visceral leishmaniasis is Leishma-
nia donobani, which inhibits many countries, particularly India
and parts of South America and Africa. It parasitizes human
liver, spleen, bone marrow and leukocytes. After an incubation
period of several months, remittent fever, anemia and splenohep-
atomegaly occur. At the terminal stages, black pigmentation
appears in the skin of the abdomen, hands and feet.
Examination, Treatment
History of sandfly bites or exposure to an endemic area is
important for diagnosis. The causative protozoan of Leishmania-
sis is detected from skin lesions, blood or bone marrow.
Amastigotes are observed in Gimza-stained smears from skin
lesion by direct microscopy. Leishmanial DNA is found by PCR.
Pentostam, a pentavalent antimony drug, is the first-line treat-
ment.
3. Cat scratch disease, Cat scratch fever

Infection is caused by Bartonella henselae, a gram-negative
bacillus, after a cat scratch or bite. Among cats, the bacillus is
transmitted by fleas. After a latency of several days to 2 weeks, a
red papule and crust appear at the inoculated site. One to three
weeks later, painful swelling accompanied by systemic symptoms
including fever and headache occurs in the regional lymph node.
It resolves spontaneously in several weeks to several months. In
persistent cases, trimethoprim, ciprofloxacin, cefem regimen,
tetracycline or macrolide antibiotics are administered orally.
4. Tsutsugamushi disease
Synonym: Scrub typhus
Outline
● It is a rickettsial infection caused by the obligate intracel-
lular bacterium Orientia tsutsugamushi and transmitted
by the mite Leptotrombidium akamushi.
● It is characterized by high fever and light pink eruptions 2
mm to 5 mm in diameter on the trunk and extremities.

● Careful observation may reveal the bite of the mite Lep-
totrombidium akamushi.
● Tetracycline and chloramphenicol are effective treat-
ments.
28 Clinical features
Five to fourteen days after a bite by the mite Leptotrombidium
akamushi, a fever of about 40 ˚C occurs, accompanied by sudden

40
chills and headache (Fig. 28.11). A bite can be found by careful
body temp. (˚C)

examination of the trunk, genitalia and axillary fossa. The bite 39
presents infiltrative erythema 1 to 2 cm in diameter with black
crusts at the center. Two to three days after the onset, light pink 38
eruptions appear on the trunk and extremities, disappearing in 7
to 10 days. There is systemic painful swelling of lymph nodes, 37
conjunctival congestion, pharyngeal reddening, splenohep-
atomegaly and hallucinations from high fever. days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Pathogenesis, Epidemiology erythema
symptoms
Tsutsugamushi disease is a rickettsial infection caused by the chills, headache, arthralgia
obligate intracellular bacterium Orientia tsutsugamushi and
transmitted by the mites Leptotrombidium akamushi, Leptotrom-
bidium pallidum, and Leptotrombidium scutellare. These feed on lymphadenopathy, hepatosplenomegaly,
pneumonia, conjunctivitis
field mice; however, they may attach to humans. Orientia tsut- incubation
period 10 ∼ 14 days
sugamushi in the body of Leptotrombidium akamushi invades the
human body. Fewer than 1% of all Leptotrombidium akamushi Fig. 28.11 Clinical course of tsutsugamushi
are thought to carry Orientia tsutsugamushi. Tsutsugamushi dis- disease.
ease is not transmitted from human to human.
The prevalence of tsutsugamushi disease decreased in the
1960s. Use bans on chloramphenicol initiated in 1976 for its side
effects have resulted in increased numbers of cases. There are
more than 1,000 new cases annually throughout Japan.

Leptotrombidium akamushi bites, eruptions, increased levels
of anti-Rickettsial IgM antibodies, and detection of rickettsial
DNA are diagnostic for tsutsugamushi disease. Other rickettsial
diseases such as Rickettsia japonica infection and Rocky Moun-
tain spotted fever should be carefully differentiated from tsutsug-
amushi disease (Table 28.3).
Treatment
Tetracycline or chloramphenicol is administered. With appro-
priate treatment, the mortality is less than 1%. Without proper
Table 28.3 Comparisons between tsutsugamushi disease and diseases that resemble it.
Tsutsugamushi disease Japanese spotted fever Rocky Mountain spotted fever
Rickettsia pathogen Orientia tsutsugamushi Rickettsia japonica Rickettsia rickettsii
Incubation period 10-14 days 2-8 days 3-12 days
Season of common Autumn, winter, spring (new type); April to October Early summer
infection summer (classical type)
Erythema Most commonly on the trunk, little Extremities tend to be involved. Most of the body, large
subcutaneous bleeding ecchymosis
Palms and soles are not involved. Palms and soles are also involved. Necrosis in the ends of fingers and
toes, tip of the nose, and ears
Bite Large (about 10 mm in diameter) Small (about 5 mm in diameter) Not found
Swelling in lymph nodes Systemic Localized (-) 28
Treatment Tetracycline, chloramphenicol
treatment, the disease may cause DIC and the mortality is about
30%.
5. Lymphatic filariasis
The causative filarial worms of lymphatic filariasis, Wuchere-
ria bancrofti and Brugia malayi, are carried by mosquitoes.
These parasitic nematodes invade the human body and inhabit
the lymph system, causing inflammation in lymph nodes and
lymph vessels and lymphatic obstruction. They lead to lymphatic
edema or testicular hydrocele, progressing to elephantiasis.
Diethylcarbamazine and ivermectin are administered.
C. Diseases caused by parasitic worms
Creeping eruption
A cutaneous parasitic larva causes a linear eruption called
“creeping eruption” when it moves in the skin (Fig. 28.12). In
this textbook two frequent types of creeping eruption are
described; cutaneous larva migrans and cutaneous gnathostomia-
sis.
① Cutaneous larva migrans
Ancylostoma braziliense, a larva of hookworms of dogs and
other mammals, mainly causes creeping eruption in tropical/sub-
tropical areas such as southeastern United States. A few days
after skin contact with contaminated sand or soil, characteristical-
ly pruritic linear or serpentine erythema occurs. Feet, buttocks
and genitalia are frequently involved.
② Cutaneous gnathostomiasis
Cutaneous gnathostomiasis results from ingestion of the third-
stage larvae of the nematode Gnathostoma spinigerum transmit-
ted by eating raw snakes, freshwater fish or frogs. Several weeks
to several months after eating a contaminated animal, localized
edema and induration occur. The larva continues to move, caus-
ing linear eruptions in the trunk and the thighs. Common endem-
ic areas are Southeast Asia (especially Thailand and Japan) and
Latin America (mainly Mexico and Ecuador).
Other species may cause creeping eruption, such as the larvae
of Spinometra mansoni (found in amphibian and poultry meat)
and nematodes of the superfamily Spiruroidea (found in soft-
shelled tortoises and squid). Treatment is removal of the parasite.
Oral albendazole and ivermectin are effective.
28 Fig. 28.12 Creeping eruption: cutaneous

gnathostomiasis caused by linear move-
ment of a parasitic larva in human skin.
Chapter
29 Genodermatoses: Genetic Counseling
and Prenatal Diagnosis
Prenatal diagnosis (PND) has become technically possible in cases where there is at high risk of severe genetic
disease, thanks to recent advances in molecular biology and diagnostic technology. In dermatology, PND of
severe skin diseases can be performed at the request of the parents. However, genetic counseling should be
thoroughly and carefully made from the ethical point of view, and patients and their families should be provided
with accurate information on the diseases. It is important to remember that the final decision of confirmation of
pregnancy should always be left to the client. This chapter compiles genodermatoses and their causative genes
and proteins, and introduces the latest advances in PND, genetic counseling and gene therapy.
A. Genodermatoses
Outline
● The term “genodermatoses” tends to refer to monogenic
diseases.
● In recent years, the causative genes and proteins have
been identified for many genodermatoses.

Updated information of MEMO
What are genodermatoses? the human genome and genetic
diseases
“Genodermatoses” usually refers to diseases caused by mono- The pathological conditions of genoder-
genic abnormality. This textbook addresses genetic diseases sep- matoses are being clarified every day, and
what was once common knowledge is no
arately in terms of their clinical features: It describes ichthyosis longer enough in responding to patients and
in the chapter on keratinization, epidermolysis bullosa in that on their families. Fortunately, improvements of
blistering diseases, and oculocutaneous albinism in that on disor- information technology, including the Inter-
net, have contributed to the spread of up-to-
ders of skin color. date information on the human genome and
The human genome project, which was completed in 2003, genetic diseases. This information is now
mapped and sequenced the 3 billion nucleotides in the human available for free to anyone.
genome to identify all human genes. It has been clarified that the ① The National Center for Biotechnology
human genome consists of 22,000 genes, which produce about Information (http://www.ncbi.nlm.nih.gov/)
The site provides updated information on the
100,000 proteins. Accordingly, almost all of the genes and pro- Human Genome Project.
teins that are responsible for monogenic diseases including geno- ② Online Mendelian Inheritance in Man
dermatoses are being clarified. The major genodermatoses and the (OMIM) (http://www.ncbi.nlm.nih.gov/entrez/
causative genes and proteins that have been identified so far are query.fcgi?db=OMIM/)
shown in Table 29.1. Six thousand human Mendelian disorders and
their characteristics are listed. The latest
Nevertheless, the pathogeneses of multifactorial genetic dis- information and documents on diseases
eases, such as psoriasis vulgaris and atopic dermatitis, have not caused by genetic mutation, gene maps and
been fully resolved. These diseases are not usually referred to as images are available. The diseases are catego-
rized and numbered as a matter of conven-
genodermatoses. The genes that are associated with the onset of ience. For example, autosomal dominant
these diseases are called disease-related genes or predisposing inherited diseases are designated by numbers
factors; their importance to the disease is considerably different from 100,000, autosomal recessively inherited
diseases by numbers from 200,000, X-linked
from that of monogenic causative genes for genodermatoses. inherited diseases by numbers from 300,000,
and mitochondrial inherited diseases by num-
bers from 500,000. Clinical conditions caused
by genetic mutation are compiled separately
in clinical synopsis.
29
509
510 29 Genodermatoses: Genetic Counseling and Prenatal Diagnosis
Table 29.1 Main genodermatoses and their causative genes and proteins.

α β

29
A. Genodermatoses 511
Table 29.1 Main genodermatoses and their causative genes and proteins (cont.).

α

AD: autosomal dominant inheritance, AR: autosomal recessive inheritance, XR: X-linked recessive inheritance, SD: semidominant
29
B. Genetic counseling and prenatal diagnosis

Outline
● Genetic counseling is important in dermatological prac-
tice. Estimation of genetic risks requires accuracy.
● Prenatal diagnosis (PND) may be chosen for severe
genodermatoses. It is essential that PND be based on

ethical considerations.
1. Genetic counseling
a
Genetic counseling is the process whereby a patient or family
receives advice on the prognosis of a disease, the risk of occur-
rence, inheritance, prevention and treatment.
Such counseling was first introduced in the U.S. and Europe in
the 1940s. Because neither carrier diagnosis nor fetal diagnosis
was possible at that time, the recipients of the counseling used to
have only two choices: terminate the pregnancy, or accept the
risks of continuing it. Recent advances in molecular biology,
b clarification of responsible genes for genodermatoses, and techni-
cal improvements have made it possible to perform PND on car-
riers and fetuses. Accordingly, the process and details of genetic
counseling have been greatly changing.
For genetic counseling, accurate diagnosis of the disease is
essential. Careful family history-taking, physical examinations,
and evaluation of inheritance patterns are necessary, and the pen-
etration rate of the disease should be discussed thoroughly each
case (Fig. 29.1).
2. Estimation of genetic risk

c
Newborns with relatively severe inherited disorders account
for approximately 2% of all pregnancies. A pregnancy with 10%
Male or greater risk of severe genetic abnormality is considered highly
risky.
Female
Estimating genetic risk, i.e., the risk of a fetus being affected
by a genetic disease, is one of the most important parts of genetic
counseling. Monogenic diseases are caused by abnormality in a
Unaffected single gene and are inherited as Mendel’s law of segregations.
Genetic risk can be estimated mathematically as a probability of
Affected severe genetic abnormality. Autosomal dominant, recessive and
X-linked inheritance are monogenic inheritances.
In multifactorial diseases and many cases of congenital or
Carrier
chromosomal abnormality, the risk calculated statistically based
on family history is used (empirical genetic risk). However, it is
Fig. 29.1 Examples of inheritance patterns. impossible to accurately calculate genetic risk in many cases.
a: Autosomal dominant inheritance (AD). b:
Autosomal recessive inheritance (AR). c: X-
linked recessive inheritance (XR).
29
B. Genetic counseling and prenatal diagnosis 513
3. Prenatal diagnosis and its ethics

Prenatal diagnosis (PND) and medical genetics have a long Clinical images
Clinical images are
history of association and improvement. In the 1970s, diagnosis are available in
available in hardcopy only.
based on amniotic fluid played a central role in PND. Then diag- hardcopy only.
nosis of metabolic anomaly from cultured cells collected from
amniotic fluid became possible. In the 1980s, improvements in
ultrasonography made it possible to perform villus sampling and
fetal tissue biopsy of skin and other fetal materials for PND.
Before PND became common, some patients and parents available in available in
whose first child had been affected with a genetic disease would hardcopy only. hardcopy only.
choose to terminate the pregnancy. For example, if a child with
a b c d e f g h
an autosomal recessive inherited disease was born to healthy par-
ents, it was clear that the parents were carriers of the disease. In
this case, the risk of the second child being affected by the same
disease would be 25%. Many parents were afraid of those odds,
choosing to terminate the pregnancy after long suffering (Fig.
29.2).
In cases with a PND that does identify a fetus as being affected
by a genetic disease, the parents are likely to terminate the preg-
nancy. This means PND can influence life-or-death choices. For
this reason, the decision of whether PND should be conducted
should be carefully justified. It is necessary for the hospital ethics staining for type VII collagen
committee to discuss the appropriateness of PND in each case.
The final decision regarding the confirmation of pregnancy
should be left to the parents.
Of the numerous genetic skin diseases, the only ones for which
PND is indicated are those severe enough to cause serious mor-
bidity or mortality. Providing accurate and proper PND to clients
no stain→patient stain (+)→normal baby
is an important part of dermatology. The genetic skin diseases for b
which PND is common include severe subtypes of epidermolysis
Fig. 29.2 Prenatal diagnosis.
bullosa and ichthyosis (particularly harlequin ichthyosis). a: Examples of an autosomal recessive inherited
disease (Hallopeau-Siemens recessive dystrophic
epidermolysis bullosa (RDEB)). b: It is possible
4. Prenatal diagnosis in practice to make prenatal diagnosis of Hallopeau-Siemens
RDEB by embryonic skin biopsy in the 19 th
When the clients are considering whether to terminate a preg- week of pregnancy. If type VII collagen is found
nancy, PND must be made by the 21st week of pregnancy so that in the epidermal basement membrane, the
embryo is normal.
artificial abortion can be performed as early as possible to reduce
the physical and emotional burden on the parents. DNA-based
PND is widely used in the early stages of pregnancy, in the 10th
to 14th week.
PND of genodermatoses used to be conducted by fetal skin
biopsy in the 19th week of pregnancy in most cases. When genet- Clinical images are available in hardcopy only.
ic mutation has been identified in a family, PND is now com-
monly made from fetal DNA, which is possible in the earlier
stages of pregnancy.
Common techniques for sampling fetal DNA are chorionic vil- a b c d e f g h
lus sampling, which can be performed from the 10th week of Fig. 29.3-1 Embryonic skin biopsy is available
pregnancy onward, and amniocentesis, which is possible from from the 19th week of pregnancy onward.
a: The position of the embryo is confirmed by
the 13th week onward. It is essential to enlist the cooperation of a ultrasound scan, and then the skin biopsy site is
skilled gynecologist. determined.
29
514 29 Genodermatoses: Genetic Counseling and Prenatal Diagnosis
1) Fetal skin biopsy

Fetal skin biopsy is useful when the causative gene of a geno-
dermatosis is unknown or there is an unidentified genetic muta-
Clinical images are available in hardcopy only. tion in the family. The biopsy can be performed from the 19th
week of pregnancy onward, when the fetal skin has formed com-
pletely. A punch biopsy of fetal skin 1 mm to 2 mm in diameter
is removed with biopsy forceps while confirming the position of
g the fetusj using ultrasound (Figs. 29.3-1 and 29.3-2).
p The qpheno-r
a b c d e f h i k l m n o
typic change in fetal skin is examined by electron microscopy
and immunohistochemistry.
2) Chorionic villus sampling and amniocentesis

These tests are conducted when a causative genetic mutation
has been identified in a family. In chorionic villus sampling,
which can be conducted from the 10 th week of pregnancy
onward, fetal placental villi are collected. In amniocentesis,
b c d e f g h i j k o 13 th pweek qof pregnancy
which can be l performed
m n
from the r
onward, fetal cells are collected from amniotic fluid. Fetal DNA
is extracted from the specimen and investigation is made for
genetic mutation (Fig. 29.4). The diagnosis of the fetus is deter-
mined by direct sequencing of fetal DNA, restriction enzyme
digestion, and allele-specific oligonucleotide hybridization.
5. Prospects in prenatal diagnosis

c d e f g h i j k In recent
l years,
m pre-implantation
n o pgenetic
q diagnosis
r has been
Fig. 29.3-2 Embryonic skin biopsy is avail-
introduced for genetic diseases such as cystic fibrosis. In such
able from the 19 th week of pregnancy diagnosis, 1 or 2 cells are taken from an in-vitro fertilized egg
onward. when it is at the stage of 4 or 8 cells, and investigation is made of
b: Skin biopsy. c: Devices used for embryonic the target genetic mutation using nested PCR (polymerase chain
skin biopsy. d: Electron microscopy of biopsied
embryonic skin (low magnification). reaction). Only fertilized eggs without the mutation are selected
for artificial implantation: This can prevent the need for artificial
abortion. Problems remain in pre-implantation genetic diagnosis,
such as those of ethics, low success rate, procedural safety, phys-
ical burden on the mother, and cost. There are few opportunities
for clinical application of pre-implantation genetic diagnosis
other than for the skin diseases that are reported in skin fragility
syndrome and epidermolysis bullosa.
It has recently been clarified that fetal cells exist in the blood
of women in their 8th to 11th week of pregnancy. Special tech-
niques have made the selection of fetal cells possible. PND has
been successfully made in certain diseases by DNA extracted
from fetus-derived cells to determine the genetic pattern. It is
expected that minimally invasive, accurate and safe PND of gen-
odermatoses will one day be available.
extraction of fetal DNA
Fig. 29.4 Biopsy of the chorionic villus is

performed in about the 10th week of preg-
nancy.
29
C. New treatments for genodermatoses 515
C. New treatments for genodermatoses

Techniques for diagnoses and PND of genodermatoses have
significantly improved; however, there are no specifically effec-
tive treatments for these conditions. Diseases whose causative patient’s cultured Clinical
genes have been identified are theoretically targets for gene ther- epidermal sheet images are
apies (Figs. 29.5 and 29.6). Such therapies consist of replacement available
in
therapy and gene expression inhibition therapy. hardcopy
Clinical images are
For example, recessive dystrophic epidermolysis bullosa is available in only.
caused by genetic mutation in type VII collagen and lack of hardcopy only.
anchoring fibrils, a structural component of the epidermal base-
ment membrane. For treatment of genodermatoses, transplanta-
synthesized type VII collagen
tion of autologous cultured epidermal or dermal sheets has come
into use. However, it has little effectiveness, because the cells of Fig. 29.5 Example of a newly improved
the patients have genetic mutation and are unable to produce nor- treatment method.
Synthetic type VII collagen is injected into the
mal type VII collagen. Therefore, studies have focused on trans- skin ulcer of a patient with recessive dystrophic
planting the patient’s cultured cells that have been supplied with epidermolysis bullosa. In this condition, genetic
the normal type VII collagen gene and on applying type VII col- mutation prevents the patient from producing
type VII collagen. Epidermal sheet cultured from
lagen cDNA directly to the patient’s skin (Fig. 29.5). New tech- the patient’s own skin is grafted over the injected
niques are being studied, such as allogenic bone marrow site.
transplantation, in which bone marrow stem cells are differentiat-
ed to epidermal stem cells to cure genodermatoses.
Fig. 29.6 Type XVII collagen knockout mouse,

a model animal for epidermolysis bullosa.
This mouse can survive and can be used in thera-
peutic experiments (adapted from; Nishie W, et
al. Humanization of autoantigen. Nat Med
2007;13: 378-83).
29
APP
Appendix : Dermoscopy
Dermoscopy, also known as dermatoscopy, epiluminoscopy and epiluminescent microscopy, is an
effective non-invasive diagnostic technique. Dermoscopy improves the accuracy of diagnosis for pig-
mented skin lesions and has been used increasingly for differential diagnosis of nonpigmented lesions.
It allows the in vivo evaluation of colors and microstructures of the epidermis, the dermo-epidermal
junction, and the papillary dermis that are not visible to the naked eye. Dermoscopy can be used on
lesions to examine the distribution of pigment, the skin surface horney layer, vascular patterns, borders
and ulceration. The procedure serves as a valuable aid in diagnosing various skin changes, particularly
those of pigmented skin lesions. Dermoscopic patterns are particularly helpful in diagnosing
melanomas, moles, freckles, atypical nevi, blue nevi, seborrheic keratoses, basal-cell carcinomas, and
hemangiomas.
Dermoscopy involves using dermoscope (dermatoscope), a hand-held imaging device with a built-in
illuminating system and a high-quality magnifying lens. A dermoscope is a simple and inexpensive
direct skin microscope. Examination takes only short time, and the device is able to record images.
Magnification at a power of ten works well for diagnosing pigmented skin lesions. Gel is applied to the
skin lesion to reduce reflectivity and to increase the transparency of the stratum corneum.
Examination can be by contact non-polarized light dermoscopy (NPD), polarized light non-contact
dermoscopy (PNCD), or contact polarized light dermoscopy (PCD). These give complementary views
of skin lesions. Cross-polarized light is capable of showing the subsurface morphology either with or
without direct skin contact.
The appendix demonstrates fundamental dermoscopic patterns.
a
a b
a b c
b c d
c d e
d e af
e af b
af b c
b c d
c d e
d e f
Ae range of dermoscopy equipment. f
a: Delta10 (Heine), b: DermLite (3Gen), c: DermoGenius (Biocam), d: Epilight (Ondeko), e: Derma9500 (Derma Medical), f:
f
Lumio (3Gen).
517
518 APPENDIX
APP
Reticulation
A grid of thin brown lines on a diffuse,

light brown background, covering
Images are available in hardcopy only
most of a melanocytic lesion. The
color tone may vary with changes in
the biologic behavior of the
melanocytic lesion.
Frequently seen in...

All categories of melanocytic lesion
Parallel furrow
pattern
Bandlike brownish pigmentation on

the sulci of skin markings It is seen
in acral skin, palms and soles. It
reflects the proliferation of
melanocytes in the crista profunda
limitans of the epidermis.

Acral lentiginous nevus (benign)
Images are available in hardcopy only Images are available in hardcopy only
APPENDIX 519
APP
Lattice-like
pattern
Linear pigmentation follows and

crosses the sulci of skin markings.
It is a variant of the parallel furrow
pattern.

Acral lentiginous nevus (benign)
Globular pattern
Characterized by the presence of

numerous, variously sized, round to
oval structures in various shades of
brown and grayish-black. They
distribute regularly or irregularly within
the lesion. This pattern reflects
aggregations of pigmented
melanocytes, melanophages or
even clumps of melanin within the
cornified layer, the epidermis, the
dermo-epidermal junction or the
papillary dermis.

Dysplastic (Clark) nevus, Unna
nevus Images are available in hardcopy only Images are available in hardcopy only
520 APPENDIX
APP
Cobblestone
pattern
Closely aggregated globules

resemble cobblestones. It is quite
similar to the globular pattern.

Unna nevus, Congenital nevus
Parallel-ridge
pattern
Bands of brownish pigmentation are

seen on ridges of skin markings. It
occurs in acral skin. The pattern
reflects the proliferation of
melanocytes in the crista profunda
intermedia of the epidermis.

Malignant melanoma in situ
APPENDIX 521
APP
Multicomponent
pattern
Three or more distinct dermoscopic

structures present in combination.
For instance, the pattern may be
made up of pigmented networks,
clusters of dots/globules, and areas
of diffuse hyper- or hypo-
pigmentation.

Malignant melanoma, Basal cell
carcinoma, Seborrheic keratosis
Fibrillar pattern
Fine fibrillar or filamentous

pigmentation runs perpendicular to
the furrows. It resembles the sweep
of a paintbrush.
This pattern is seen in all categories
of melanocytic lesion, including
malignant melanoma in situ and
lentiginous nevus on palms and soles.
It reflects melanin granules oriented
slanting to skin surface in the horny
cell layer.
All melanocytic lesions of acral sites
522 APPENDIX
APP
Homogenous blue
pigmentation
Sharply demarcated, round to oval,

blue or blue-gray pigmented areas
without a pigmented network or
other distinctive local feature. It
reflects the abundance of melanin
granules in dermal tumor
components.

Blue nevus
Blue-whitish veil
Gray-blue to bluish-white, diffuse

pigmentation overlies a whitish film
of ground glass appearance. Bluish
areas reflect the abundance of
melanin granules in dermal tumor
components and whitish areas
reflect compact orthokeratosis.

Malignant melanoma (invasive),
Spitz nevus
APPENDIX 523
APP
Streaks
Brownish-black linear structures are

observed at the periphery of the
lesion. They reflect discrete nests of
pigmented junctional nevus.

All categories of melanocytic lesion
Atypical pigment
network
A black, brown or gray network of

irregular meshes is distributed
irregularly throughout the lesion,
usually ending abruptly at the
periphery.

Malignant melanoma
524 APPENDIX
APP
Light-brown
fingerprint-like
structures
The light brown, finely meshed

pigmentation of the peripheral
lesion resembles fingerprints. It
reflects basal melanosis of the
elongated epidermis.

Seborrheic keratosis
Comedo-like
openings
These sharply circumscribed

structures are yellowish-brown or
dark brown, and round to oval.
They reflect keratin plugs within
dilated follicular openings.

Seborrheic keratosis, Unna nevus
APPENDIX 525
APP
Multiple milia-like
cysts
White or yellowish-white, round

bodies of various sizes. They reflect
intraepidermal keratin cysts.

Fissures/ridges
(brain-like appearance)
Light brown fissures alternate with

dark brown ridges, giving the
wrinkled appearance of a brain.

526 APPENDIX
APP
Leaf-like areas
(structures)
These are brown to blue-gray,

independent, bulbous extensions
around the lesion. When big, they
sometimes resemble maple leaves.
They reflect aggregation of tumor
cells that were distributed
throughout the epidermis.

Basal cell carcinoma
Arborizing vessels
Telangiectasia with distinct tree-like

branching. It reflects dilated vessels
of the papillary dermis.

APPENDIX 527
APP
Large blue-gray
ovoid nests
Well-circumscribed, uniform,
pigmented, ovoid or elongated
areas larger than blue-gray globules.
They reflect large tumor nests with
melanin granules.

Spoke-wheel areas
Well-circumscribed radial projections.

They tend to be more heavily
pigmented at the center. When big,
they are called leaf-like structures.
They reflect tumor nests that are
oriented perpendicular to the run of
the epidermis.

528 APPENDIX
APP
Red-blue lacunae
Sharply demarcated, round to oval

areas with reddish, bluish-red or
dark-red to black coloration. They
reflect dilated vascular spaces and
pooling of red blood cells in the
upper dermis.

Hemangioma, Angiokeratoma,
Subungual and subcorneal
hematomas
Hairpin vessels
Long, visible vascular loops that

sometimes twist and bend. The
diameter remains constant for the
entire length of the vessel. They are
often seen in the peripheral zone of
the lesion.

Malignant melanoma

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Preface

Welcome to Shimizu's Textbook of Dermatology. This is an upgraded edition of Japan's

arrector pili muscle

with the direction in which the differentiated cell clones extend

Fig. 1.5 Ultrastructural anatomy of the epi-

desmosome gap basement hemidesmosome

Fig. 1.6 Intracellular positions of desmosomes, gap junction and

2. Suprabasal cell layer

granular cell layer 3. Granular cell layer

4. Horny cell layer

Fig. 1.10 Microstructure of the basement membrane zone.

keratin intermediate filaments

Fig. 1.11 Electron micro-

The gap junction which is composed of connexin subunits,

phosphorylation of serine 3. Horny layer (stratum corneum)

Melanocytes (pigment cells) are neural crest (ectoderm)-

which is black (intrinsic melanin), or pheomelanin (yellow

neural crest cell melanin

reticular dermis dermis

Pacinian corpuscle collagen fiber elastic fiber ground substance

Fig. 1.22 Structure of the dermis.

3. Ground substance, Matrix

Fig. 1.31 Blood vessels (hematoxylin and

Sympathetic nerves distributed in the MEMO

Fig. 1.35 Pacinian corpuscle (hematoxylin

D. Subcutaneous fat tissue

sheath cuticle inner root 1. Hair follicle

outer longitudinal connective

Henle’s layer inner root sheath (IRS)

hair matrix cell

Fig. 1.38-1 Structure of the hair follicle (longitudinal section).

2) Outer root sheath (ORS) connective

Fig. 1.39 Hair cycle.

b. Arrector pili muscle

eccrine sweat gland

Fig. 1.40 Sweat glands, hair follicles and sebaceous glands.

2. Apocrine sweat glands

Fig. 1.44 Apocrine secretion of the sweat

lunula granular layer and is continuously keratinized to connect with the

Fig. 1.45 Anatomy of the nail.

Bleeding in cuticle MEMO

Preparation of a skin biopsy MEMO

2 Table 2.1 Specific stains used in dermatology.

1. Acanthosis (epidermal hyperplasia)

2. Epidermal atrophy (epidermal hypoplasia)

Fig. 2.3 Patterns of acanthosis.

is often found in senile skin, discoid lupus erythematosus, lichen

2 cell layer; however, keratinocyte formation in inflammatory dis-

7. Granular degeneration, Epidermolytic

8. Spongiosis, Intercellular edema

9. Intracellular edema (ballooning

and become spherical (ballooning degeneration). If the cytoplasm 2

11. Blister, Bulla

13. Exocytosis (cell infiltration into the

2 erythrocytes into the dermis. It is mostly found in spongiotic

1. Vacuolar degeneration (hydropic

Fig. 2.16 Kogoj’s spongiform pustule.

Fig. 2.17 Pautrier’s microabscess.

1. Inflammatory cell infiltration

Table 2.2 Diseases with inflammatory infiltration into the skin.

Fig. 2.20 Foreign-body granuloma. Choles- 3. Giant cell

4. Changes in connective tissue

lation of serous fluid (scleredema) and dermis elevation caused 2