Simona Anca Frati a

ermatovenero o
not:es

Editura Ljniversitatii din Oradea,

nns ~
 SIMONA ANCA FRATILA

DERMRTOWENEROEOQYNOTES

Editura Universitagii din Oradea

20I3
 Referenti ytiintifici:

Conf.dr. FIoarea Sarac — University of Oradea

Conf.dr. Francisc Benedek — University of Oradea

Descrierea CIP a Bibiiotecii Nationale a Romaniei

FRATILA, SIMONA ANCA
Dermatovenerology notes / Sirnona Anca Fratila. -

Ed. a 2-a, rev.. - Oradea: Editura Universitatii din Oradea,

2013
Bibliogr.
ISBN 978-606-10-1138-4

616.5

Editura Universitatii din Oradea este recunoscuta de CNCSIS,

cod 149

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 CONTENT

STRUCTURE AND FUNCTION OF THE SKIN, HAIR AND NAILS...........11

T HK DIAG N O S IS OF THE DER M A T O L O G I C A L DISEA SES .....
...............15
F UNGAL INFECTIONS ........ • ..•.......•.................... . . .... . . .......23
Superficial fungal infections 23
Pityriasis (tinea) versicolor . 23
Dermatophyte infections . .24
.

Mucocutaneous candidosis . ....27

Deep fungal infections . 29
BAC T E R IAL INFECT IONS OF THE SKIN . . ....... ................33
Pyodermas ... 33
Non-folicular pyodermas ...34
Follicular pyodermas. ...36
Other bacterial infections of the skin. ...38
Mycobacterial infection ...38
Cutaneous tuberculosis - Typical forms. ... 3 8
Cutaneous tuberculosis - atypical forms (tuberculids). . 40
Leprosy (Hansen's disease) ...40
Atypical mycobacteria INFECTIONS. 42
ECTOPA R A SITE INFECTIONS. • ...........47
Scabies ....47
Pediculosis
Ticks . ....49
Cutaneous Larva Migrans. 50
VIRAL INFECTIONS .... • ..•.... . ........51
Warts (Verrucae) 51
Molluscum contagiosum ....53
Milker's nodules. . . . . . . . . . . . . . . . . . . . . 53
Or f. ...54
Herpes simplex
Herpes zoster (Shingles).
SEXUALLY TRANSMITTED DISEASES (STD) ..... ............. • • • • • •• •• •• •• •• •o63
Syphilis. .... 63
Acquired Syphilis .... 64
Congenitalsyphilis. ....68
Differential diagnosis of Genital Ulcer Diseases .... 7 1
Gonorrhea (Blenorrhea) . 72
Direct mucosal infection. ....72
Local extension of gonococcal infection 73
Extragenital direct gonorrhoea 74
Disseminated gonococcal infection (gonococcemia), ... 74
Diseases caused by Chlamydiae ... 75
Aquired immunodeficiency syndrome (AIDS) . .... 76
 • ee • oe oo e o • • • o o osooS 1
A < < K R G I C S K I N D I S O R D K R S e• eoooooooooooooeooo
ooeoooee sooeee o e o o s o o
Urticaria. 82
dermatitis or eczema. 86
Contact dermatitis/eczema (Exogenous eczema) 86
Atopy andatopic eczema (Endogenous eczema) 87
Mixt Eczema (Exo-/Endogenous). 88
Prurigo . 92
drug eruptions. 93
DISEASES OF CONNECTIVE TISSUE ----- • .99
Lupus erythematosus (LE) . 99
Cutaneous lupus erythematosus. 99
Systemic lupus erythematosus. 101
Dermatomyositis 102
Sclerodermas. 104
Localized or circumscribed scleroderma (morphea) 104
Progressive systemic scleroderma (systemic sclerosis) 105
BUL O U S D I S E A S E S oooeoeooo
o o oe o oo oo eo o o oo • oo • • so o ooo o o o o o o oo o oo o o oe • • eo eo oe oo e • • 109
Pemphigus vulgaris . 109
Other forms of pemphigus 111
Pemphigusvegetan
s. 111
Pemphigus foliaceus. 111
Pemphigus erythematosus 111
Paraneoplastic pemphigus. 111
Drug-induced pemphigus 111
Bullous pemphigoid .. 111
Herpes gestationis (pemphigoid gestationis) 113
Dermatitis herpetiformis Duhring-Brocq . 113
Epidermolysis bullosa aquisita . 114
porphyrias. 115
Porphyria Cutanea Tarda 116
Erythema multiforme . 117
Stevens-Johnson Syndrome And Toxic epidermal necrolysis. 117
ERYTH K M A T O - SQ U A M O U S SKIN DISEASES......
....................................121
Psoriasis vulgaris. 121
Parap
soriasis. 126
Lichen planus 127
Pityriasis rosea.. 128
GKNODKRMATOSES. .................................................................•........133
Disorders of keratinization. 133
Ichthyosis. 133
Darier's disease (Keratosis Follicularis). 134
Benign familial chronic pemphigus (Hailey-Hailey Disease) . .... 135
Inherited epidermolysis bulosa .... 135
N EVI (moles, Ibu-ihmarks) ....... • oooooessooooosoeseeoooooeoo • eoooooeoeoseoooseosoeeooeoooe • s 1 3 9

Organoid nevi. .. 139

Melanocytic nevi (nevocytic nevi) .... 139
B ENIGN TUMORS .......................... . . ..........................................................143
Benign epithelial tumors . .... 143
 Seborrheic keratosis (seborrheic wart) 143
Keratoacanthoma. 143
Syringoma (hidradenoma). 143
Epidermal and pilar cysts. 144
Benign mesenchymal tumors 144
Dermatofibroma 144
Fibroma pendulum (acrochordon, skin tag) . 144
Keloid. 144
Hemangiomas 145
Pyogenic granuloma (lobular capilary hemangioma). 145
PRECANCEROSES . 149
Actinic keratosis (solar keratosis, keratosis senilis) 149
Actinic keilitis 149
Radiation keratoses .............................. 150
Xeroderma pigmentosum. 150
Bowen disease (sqamous cell carcinoma in situ) . 150
Paget disease of the nipple................. 150
Lentigo mal igna (melanosis Dubreuilh) . 153
Other precanceroses . 153
M ALIGNANT EPITHELIAL TUM O R S . 155
Basal cell carcinoma. 155
Squamous cell carcinoma. 156
Malignant melanoma 158
 PREFACE

This book was written in order to provide basic in formation for the students of the
Faculty of Medicine. I have been teaching dermatology for 16 years and throughout this
time I have done my best to offer visual information (examining patients or digital images)
to the students, aiming for a better understanding of the theoretical notions. Dermatology
is a visual specialty and there is no substitute for the clinical photography to illustrate
cutaneous disease. Thus, within this book clinical photographs were selected from my
p ersonal c o l l ection t o i ll u s trate t h e m o s t Pequently e n countered d e r matological
conditions.
The recognition o f t h e e l e inentary l e sions i n t h e c l i n i ca l p i c t ur e of t h e
dermatological disorders of fers the f i rst p at h t o t h e c o r r ect d i agnosis. Paraclinical
investigations add supplementary in formation that will aid in di fferential diagnosis. This
book contains th e m ai n c u t aneous diseases with t h ei r p a t hogeny, description and
illustration of the clinical aspect, paraclinical characteristics and updated treatment.
I hope that this book will both educate and stimulate interest in this truly fascinating
medical specialty.

Oradea, September 2013 Simona Fratila, MD, PhD

 Chapter 1

STRUCTURE AND FUNCTION OF THE SKIN, HAIR

AND NAILS
k' ' p 'd
d l l y k
: k ~ —l l y l k k'
'

derived from the ectoderm and h) the dermis — the major support layer, with mesodermai
ri in.
o~
The nda es - h air, nails, sebaceous glands and sweat glands — are
composed of cells derived from b o derm a n dm esoderm.
In addition, there is the subcutaneous fat that may be involved in some cutaneous
diseases, such as erythema nodosum.

THE EPIDERMIS
The epidermis is multilayered and renews itself by the division of the basal layer.
'
The princi al 1 cell e i s t h e keratinocyte.It is formed in the basal cell layer and
ascends to the surface of the skin in ap r o x imat 1 3 0 da s (epidermal transit time). The
kerati nthesize keratin.
The basal layer is composed of one row of keratinocytes of columnar shape. They
undergo cell division, after which one daughter keratinocyte remains in the basal layer
and the other moves upwards through the epidermis, to differentiate and finally die. The
basal cells are anchored throu h hemidesmosomes to the basement membrane.
Interspersed amongst the basal cells there are the melanocytes,dendritic cells
d erived f r o m t h e n e u ra l c r est. T hese cells c o ntai n to las m i c organelles called
osomes that produce the melanin pigment from t y r osine. The melan
transferred from the dendrites the keratinocytes in the prickle cell
layer, being responsible for the skin color (fototype). In white eo le the me os o mes are
grouped to e ther i n "melanosome complexes" t h at r adu a l l de ene r a te a s t h e
keratinocytes move towards the surface the epidermis. In black e o l e t h e s kin contains
mb te s in bu t t e m e lanosomes are lar er, remain
karate and do not degenerate.
Melanin synthesis is increased by UV radiation, resulting in the sun tan. This is a
natural protective mechanism for the keratinocytes. When the sun exposure exaggerates, the
keratinocyte nuclei are damaged, thus cellular atypia can appear and progress in time (years)
to skin cancer. In dark-skin people, skin cancer can also be observed, but much more rare.
The prickle cell layer contains keratinocytes connected together by intercellular
bridges called desmosomes, with a spiky appearance in optic microscopy. The cytoplasm
of basal and prickle keratinocytes contains tonofilaments formed from the keratin. These
tonofilaments are grouped in bundles and are continuous with the desmosomes to connect
the keratinocytes and give strength to the epidermis.
Scattered between keratinocytes in the prickle cell layer there are dendritic cells
called Langerhans cells or antigen presenting cells (APC), which are modified macrophages

11
originating in the bone marrow. They are responsible for the first line of immunological
defense in the skin. APC take up and process environmental antigen and then migrate to the
lymphoid tissue where the antigen is presented to the immunocompetent T lymphocytes.
The granular layer, above the prickle cell layer, is com o sed of f l a ttened c
containin keratohyalin granules (darkly staining particles) and lamellar a n ules (Odland
bodies). The lamellar granules are vesicles (liposomes) that dascharge their lipidic and
enz matte content into the intercellular ~saces,~rovidin "mortar" between the cellular
"bricks "

The stratum corneum is composed of flattened, corn letel k e r a tinized dead cells
l acking nuclei and cytoplasmic organelles and filled with keratin filaments embedde m
an amorfous protein matrix. The superficial cells are gradually abraded, every d ay .
Stratum corneum forms a barrier w hich is i m permeable to substances from inside or
outside the body. The thickness of the stratum corneum varies on different regions of the
body, for example it is the thickest on palms and soles.

THE BASEMENT MEMBRANE

The basement membrane divides the epidermis from the dermis. It is a complex
m ultilayered structure, f ormed b y l a m i n a l u c id a ( r ara), l amina d e nsa an d l a m i n a
fibroreticulara.
Hemidesmo some s attach th e b a sal k e ratinocytes t o t h e l a m in a l u cida.
Hemidesmosome defects are seen in some forms of epidermolysis bulosa, a genetically
determined blistering disease. Lamina fibroreticulara, rich in collagen, is deficient in other
forms of e p i dermolysis bulosa. Autoantibodies to t h e c o m ponents of t h e b a sement
membrane are found i n d i f f erent bullous disorders (e.g. to l a m ina l u cida i n b u l ous
pemphigoid).
The basement membrane is not a rigid structure, as cells like lymphocytes and
Langerhans cells pass it with relative ease. Also, it is a convoluted layer, forming dermal
papillae and rete ridges, maximizing the contact area between dermis and epidermis and
minimizing the chance of discohesion between the two layers.

THE DERMIS
The dermis lies beneath the epidermis and forms the bulk of the skin. It is formed of
c onnective tissue with u p w ard p r ojections (dermal papillae) that interdigitate with t h e
downward epidermal projections (rete ridges). The dermal connective tissue is composed of:
• cells:
o f i b r oblasts — produce collagen and the connective tissue matrix,
o m a s t c e lls — contain g r anules w i t h m e d i ators i m p o rtant i n t y p e I
immunological reactions (such as histamine, prostaglandins, leucotrienes)
and in the interaction with eosinophils and neutrophils (eosinophil and
neutrophil chemotactic factors)
o m a c rophages — general scavengers that originate in the bone marrow
a network of protein fibers of collagen, elastin and reticulin that give strength and
elasticity to the dermis
ground substance of mucopolysaccharides.

12
 The outer layer of the dermis, called papillary dermis, contains finer collagen fibers
than deeper reticular dermis.
The dermis is richly supplied with blood vessels, lyrnphatics, nerves and sensory
receptors. There are two vascular networks in the dermis: a superficial one at the interface
between papillary and r eticular dermis and a l o we r an d m o r e v i g orous one located
between dermis and subcutis. The tw o v a scular networks are connected by v e rtical
vessels. In normal conditions, the blood supply operates at 10-20% of capacity, but in some
skin diseases it is greatly increased, causing body redness (erythema) or even high-output
cardiac failure. The epidermis has no blood vessels; all the nutritive substances diffuse to
the intercellular spaces of the keratinocytes through the basement membrane.

THE SKIN APPENDAGES

The pilosebaceous unit, the apocrine and eccrine sweat glands and th e n ails
represent skin appendages. The pilosebaceous unit includes: hair follicle, sebaceous gland
and arrector pili muscle.
The hair follicle results from the interaction between the hair shaft, derived from
the fetal ectoderm, and the vascular papilla of the hair bulb, derived from the mesoderm.
There are three types of hair: a) lanugo hair present in utero and shed by the 8th
month of fetal life; b) vellus hair, fine, thin, covering most of the body, except the areas of
the terminal h air and c) terminal hair, that is thick and pigmented, found on the scalp,
beard, eyebrows, eyelashes, axillae and pubic area. The development of the terminal hair is
under hormonal control on some areas (beard, axillae, pubic region), where hairs are of
vellus type until the onset of puberty. On the scalp, the reverse occurs in male pattern
balding, where terminal hairs are replaced by vellus hair.
The hair bulb is at the lower end of the follicle and contains the hair matrix, a zone
of rapidly dividing cells. The cells become gradually keratinized as they ascend and from
the hair shaft. Terminal hairs have a central core (medulla) with air spaces, a cortex formed
of keratinized spindle-shaped cells and a cuticle at the surface, formed of cells which
overlap like the tiles on a roof.
The arrector pili muscles extend from beneath the epidermis to the side of the follicle
just under the opening of the sebaceous gland. They are supplied by adrenergic nerves and
are responsible for the erection of hairs during cold or emotional stress ("goose flesh").
The growth of the hair is cyclical, periods of active growth (anagen, 85 % of the
hair, 2-5 years on the scalp) alternating with resting phases (telogen, 15 % of the hair, 3-4
months on the scalp). The duration of these cyclical phases are genetically determined and
depend upon the age of the individual and the location of the follicle on the body. The
activity of each follicle is independent of that of its neighbors.
T he color o f t h e h a i r i s p r o d uced b y t h e m e l anin p i g m ent f o r med i n t h e
melanocytes of the hair bulb (eumelanin in black and brown hair, phaeomelanin in auburn
and blond hair). Graying of h air i s the result of g r adually decrease of the tyrosinase
activity in the melanocytes of the hair bulb, which is genetically determined.
Sebaceous glands are particularly numerous and prominent on the head, neck,
chest and the back. These glands are under hormonal influence: they are prominent at
birth due to maternal hormones, but atrophy soon after, and enlarge after puberty due to
androgenic stimulation. Sebum i s p r o d uced by t h e d i s integration of g l andular cells
(holocrine secretion), then drained into the hair follicle and discharged on the surface of
the skin through the hair follicle opening. Some modified sebaceous glands open directly
on the skin surface (eyelids, lips, nipples, glans penis, prepuce, oral mucosa).
Apocrine sweat glands are found principally in the axillae and anogenital region;
specialized apocrine glands are in the ear (wax glands) and breast (milk glands). Apocrine
glands are composed of a secretory coil found in the deep dermis and a duct that opens
into a hair follicle. The secretion forms by a "nipping off" of the tops of the cells in the coil
(decapitation secretion). The glandular secretion is oily, without smell, controlled by the
adrenergic nerve fibers and starts only after puberty. Pungent axillary body odour is the
result of the action of bacteria on apocrine secretion.
Eccrine sweat glands are important for the body temperature regulation and are
seen all over the body, being particularly numerous on the palms and soles. They are
anatomically independent from the other appendages and are formed from a secretory coil
deep in the dermis and a d uct t o th e surface of the skin. The sweat made of w ater,
electrolytes, lactate, urea and ammonia is i sotonic in th e secretory coil, but becomes
hypotonic on the surface of the skin as sodium chloride is reabsorbed in the duct. Eccrine
g lands ar e i n n ervated b y t h e s ympathetic n ervous s y stem, bu t t h e m ediator i s
acetycholine.
The nails are transparent plates of keratin on the dorsum of the terminal phalanx
of the digits. The nail matrix, which produces the nail plate, lies deep to the proximal nail
fold and is partly visible as a pale "half moon" (lunula) at the base of the nail. The nail
plate adheres firmly to the underlying nail bed. The cuticle is an extension of the proximal
nail fold onto the nail plate, to seal these two structures, in order to prevent penetration of
extraneous material.
Nails growth is more rapid in youth than in old age, taking an average of 6 months
to grow from matrix to free edge for finger nails and 18 months for toenails.

SKIN FUNCTIONS
• Prevents loss of body fluids
• Protects against entry of environmental toxic chemicals and microorganisms
• Protects against damage from UV radiation
• R egulates t h e bo d y temperature b y vas o c onstriction/vasodilatation and
perspiration
• Synthesis of vitamin D (cholecalciferol)
• Important in social interaction
 Chapter 2

THE DIAGNOSIS OF THE DERMATOLOGICAL

DISEASES

There are three important elements for the dermatological diagnosis:

history:
o e v olution of lesions: site of onset, spread, duration, resolution and reactivation
o s y m p t oms associated with the eruption: itching, burning, pain; systemic
symptoms: fever, chills, malaise, arthralgias
o c u r r ent or recent medication
o p a st history (previous illness, allergies, photosensitivity), family history,
occupation and hobbies
examination of the patient (type of elementary lesions, distribution of the lesions,
arrangement of individual lesions)
diagnostic techniques:
o sk in biopsy:a skin sample is removed, fixed in formaldehyde, embedded in
paraffin, colored, cut in very thin slices and examined under a microscope
o po t assium hydroxide( KOH) p r e p aration: w h en t h e f u n g al e t i o logy i s
suspected, the skin or nail is scraped with a scalpel, causing dead cells to
fall off on a glass slide; potassium hydroxide is then added and the slide
slightly heated; KOH dissolves the keratinocytes releasing the fungus that
will be observed under a microscope
o Tz a nck smear is a cytological technique performed on liquid lesions that are
unroofed and the base is scraped gently with a scalpel blade; the material
placed on a glass slide is stained with Giemsa stain to identify the types of
cells, for example in herpes simplex, bullous diseases
o di a scopyis performed by pressing a microscopic slide against a skin lesion to
determine whether a red lesion is hemorrhagic (purpura) or only blood-filled
(erythema); granulomas often have an "apple jelly" appearance on diascopy
o de r matoscopyis the examination of a skin lesion with a dermatoscope (a
magnifier with light) that illuminates the lesion without reflecting light;
melanin distribution and disposition is visualised, as well as fine vessels;
the technique aids i n d i s t inguishing benign f ro m m a l i gnant l esions,
especially melanoma
o Wo o d's tightis a 360 nm ultraviolet light that aids the evaluation of certains
skin disorders. For example, under Wood's light, erythrasma will appear
coral red, pigmented lesions of the epidermis (freckles) are augmented,
while dermal pigment (postinflammatory hyperpigmentation) fades
o pa t ch testsare designed to document contact allergic sensitivity to a specific
antigen. A battery of suspected allergens, diluted, are applied on the back
of the patient under occlusive dressings, left in contact with the skin for 48
hours and then examined for type IV hypersensitivity.

15
 TYPES OF ELEMENTARY LESIONS
Dermatological diseases are characterized by the presence of elementary lesions.
The original lesions are known as the primary lesions (e.g. macules, papules, nodules,
tumors, wheals, vesicles, bullae etc ), which are v ery i m p o rtant i n t h e d e r matologic
physical examination. They may b e m o d i fied by r e gression, trauma or o t her factors,
producing secondary lesions (e.g. scales, crusts, excoriations, erosions, ulcers, scars ).

1. D i s coloration of the skin, called macule: a flat, nonpalpable, circumscribed area

of color change; macules that are larger than 1 cm are called patches.
Disorders of pigmentation
• melanic macules
o h y p e rpigmented
• congenital: cafe-au-lait spots
• acquired:
• pr i m a r y:epheli des, melasma(Fig.2.1)
• secondary (postlesional): l ic h en p la n u s (Fig.11.19),
pemphigus vulgaris (Fig.10.4)
o a cr omic
• congenital: albinism
• acquired: vitiligo (Fig.2.2)
• hemosideric macules: posttrombotic syndrome (Fig.2.3)
Vasculo-sanguin macules
• erythema: red s k in , w i t h r a i sed l o cal t e mperature, d isappears on pressure
(diascopy); it is caused by vasodilatation; types:
o l ocalized erythema
(halo, plaque)
o e x anthema: disseminated erythematous macules
o s c arlatiniform: diffuse red patches with numerous red points
o r o seoliform: alternation of red and normally colored macules
o r u b eoliform: raised erythematous macules
o e r y t hroderma: the whole skin is red ("red man"-Fig.11.14)
• cyanosis: the skin is cold, violaceous, due to the decrease of amount of oxygen
delivered to the tissues, secondary to the spasm or constriction of small blood
vessels (in acrocyanosis)
• pu r p u r a: red macules that do not disappear on pressure (diascopy); the cause is
the extravasation of red cells
o n o n -palpable purpura — caused by extravasation of red blood cells, with
minimal inflammation; through evolution the lesions change colors from
red-blue or purple to green, yellow or brown before complete fading
• pe t e chiae — round to oval, <3 mm diameter purpura(Fig.8.29) —ex.
thrombocytopenia < 50 000/mm', traunza(linear aspect)
• macular purpura (5-9 mm d i ameter) —ex.hypergamaglobulinemic
purpura Waldenstronz
• macular echymosis (>1 cm) (Fig.2.4): ex. hepatic insuffi'cienny, vit.K
defi'cienny, actinic purpura, corticosteroid purpura
o p a l p able purpura — due to inflammatory hemorrhage

16
 • pu r p u r ic papules, vesicles and necrosis:leukocytoclastic vasculitis of
small vessel(Fig.8.29), erythema multiforma, rheumatic vasculitis (LES,
rheumatoid arthritis)
• retiform p u r p ura — serpentine, branching o r s t elate aspect of
purpura due to hemorrhage around small dermal vessels prior to
complete obstruction of th e vessel : a ) n o n-inflammatory type:
heparin necrosis, monoclonal cryoglobulinemia, cholesterol emboli,
spider bite reaction; b) inflammatory type: mixed cryoglobulinemia,
rheumatic vasculitis (LES, rheumatoid arthritis), polyarteritis nodosa,
septic vasculitis

2. Solid lesions
Wheals (hives = urtica) are transient, plateau-like, sharply demarcated elevations of various
size and shape associated with severe itching. The dermal edema is responsible for the aspect of
the wheal and also for the sudden appearance and rapid resolution (pathognomonic, in a few
hours). Their color may be red, due to vasodilatation or whitish, due to the compression of the
capillaries by the dermal edema (Fig.8.1). Wheals are characteristic for urticaria.
Papule: a circumscribed solid elevation of the skin, less than 0.5 cm in diameter
o e p idermal papules result from thickening of the epidermis (e.g. plane wart - Fig.6.5)
o d e r mal p a pules are due t o cellular proliferation in t h e d e rmis (inflammatory
infiltrations in syphilitic papules- Fig.7.5-7. 12)
o d e rmoepidermal papules result from the thickening of both epidermis and dermis
(lichen planus-Fig.11.18)
Plaque —elevated, circumscribed lesions that are larger than elevated (Fig.11.1). The
elevation is due to thickening of the epidermis (psoriasis, neurodermitis, nummular eczema)or
dermis (keloid, morfeea).Secondary changes may add, like scales, crusts.
A tuber - an elevation resembling a papule, but deeper and very liable to ulceration
and scarring (tuberculosisand tertiary syphilis)
Nodule or node - a circumscribed visible or only palpable lump, larger than 0.5 cm and
with greater mass beneath the skin surface, within dermis or subcutaneous
• acute nodes (erythema nodosum-Fig.8.32)
• subacute nodes (gumma of syphilis or tuberculosis-Fig.4.20) —they evolve in four
stages: 1) firm node, 2) abcedation, 3) ulceration with fistulisation 4) scarring
• chronic (cysts, lipoma, skin metastases)
Lichenifi'cation - flat thickening of the skin characterized by accentuated skin-fold
markings; secondary to scratching (in chronic eczema, Fig.8.9)
Vegetations - soft pathlogical excrescences of the skin with i r r egular, papilomatous
surface; may be primary (condiloma acuminate,also called venereal vegetations-Fig.6.10,
6.11) or may appear secondary, in other skin diseases(pemphigus vegetans).
Verucosity —hard papilomatous, pathological excrescens covered by keratosis (common
wart —Fig.6.1,6.2)
Tumors are solid masses of tissue in the skin. A tumor may be benign (well delimited
with no distal spreading- Fig.14.2) or malignant (rapid growth, recurrence after excision,
metastatic spreading at long distance from the original tumor and alteration of the general
health-Fig.16.10).

17
 3. Lesions containing fluid
Vesicle (small blister): elevated, circumscribed collection of clear fluid, with diameter
less than 0.5 cm; on histopathologic examination we can distinguish between:
o i n t erstitial v esicles - fl u i d a c cumulates between th e k e r atinocytes; they a r e
preceded by spongiosis (epidermal edema with the stretching of desmosomes) in
eczema (Fig.8.8)
o p a r enchimatous vesicles - fluid accumulates instead of destructed keratinocytes,
for example in herpes simplex (Fig.6.17), herpes zoster,as herpetic viruses are
cytopathogenic
Bulla: elevated, circumscribed collection of clear fluid with d iameter over 0.5 cm; on
histopathologic examination we can distinguish between:
o s uperficial (subcorneal) bulla (impetigo, bullous erysipela-Fig.4.5, pemphigus foliaceus)
o d eep bulla or subepidermal (bullous pemphigoid-Fig.10.7),Duhring disease
o i n t r aepidermal bulla - in the prickle cell layer, due to the autoimmune destruction
of desmosomes, called acantholysis (Fig.10.5), in pemphigus vulgaris- Fig.10.3
Pustule: elevated, circumscribed accumulation of pus (usually necrotic inflammatory
cells, with/without bacteria)
o p r i mary pustules - not preceded by any lesion
sterile pustules (pustular psoriasis-Fig.11.10)
microbial pustules (folliculitis-Fig.4.11,furuncle)
o s e condary p u stules develop f ro m v e sicles or b u l lae (superinfection of s o m e
dermatoses like herpes simplex, pemphigus)
4. B reaks of continuity of the skin
Erosion (exulceration): a loss of epidermis; it heals without a scar; impetigo, pemphigus
Ulcer.a loss of epidermis and dermis; it heals with scar (ecthyma, leg ulcer-Fig.2.5)
Excoriation: exogeneous injury of the epidermis: posttraumatic, due to scratching in
itching dermatoses like scabies, pediculosis, eczema
Fissure: a linear cleft through the epidermis or into the dermis (in skin folds like the
submammary area, between the fingers, on the tips and flexural creases of the thumbs,
fingers and toes)
Rhagades: are periorificial tears caused by stretching of s kin ( at the angles of the
mouth, at the lips, about the anus)

5. C u taneous debris
Scale: visible and palpable masses of keratin (flakes) due to rapid epidermal cell
formation or abnormal keratinization.
The scales can be fine, delicate as in tinea versicolor (Fig.3.16); coarse in eczema, ichtiosis;
stratified, micaceous, with silvery aspect given by the air trapped between the layers in
occal
psoriasis (Fig.11.4); large sheets desquamation in toxic epidermal necroiysis, staphyloc
scalded skin syndrome and scarletfever. T he l o cation of t h e s c a le o ver t h e l e s ion i s
characteristic: at the periphery of the lesion (leading scale in tinea, collarette in candida
intertrigo), over the whole lesion (eczema, actinic keratosis),leaving a peripheric rim of
nonscaly lesion (psoriasis),peripheral collarette and thin central scaling (pytiriasis rosea).
The maturation of normal epidermis is called orthokeratosis and results in flat, non-
nucleated keratinocytes in the horny layer. When the differentiation of the epidermis is

18
abnormal and/or accelerated, the outer layer will be parakeratotic, with nucleated cells.
parakeratosis is most commonly exemplified in psoriasis and in eczema.Byskeratosis is the
precocious keratinization o f individual cells w i t hi n t h e p r i c kle cell l a yer w i t h t h e
formation of round eosinophilic cells (corps ronds), with a pale halo in the prickle cell
layer and as flat, intense basophilic grains in the granular and corneal layers. Dyskeratosis
can be benign in Da r ier's disease (dyskeratosisfollicularis) or malignant in squamous cell
carcinoma.
Crust: dried exudates like serum, pus or b lood, usually mixed wi th e pithelial and
sometimes bacterial debris. Yellow crusts result from dried serum or dried pus (impetigo
contag'osa-Fig. 4.1, infected herpes) and hematic crusts result when the dermal vessels are
injured (ecthyma-Fig. 4.2, traumatic ulcers).
1Vecrotic scab (necrosis or sphacelus) results from a circumscribed death of tissue. It
may be black and dry due to arterial obstruction (ischemic necrosis-Fig.2.6) or yellow and
moist, due to necrotising bacteria (bourbillon of the furuncle-Fig.4.14).

6. Scars, atrophy
Scars are secondary type, permanent fibrous skin lesions that result from the process
of skin repair by replacement with connective tissue. Their size and shape are determined
by the form of the previous destruction. The collagen fibers are abundant and rigid, the
skin appendages and elastic fibers are absent.
Scars may be smooth (tertiary syphilis) or i r r egular (secondanj skin tuberculosis),
pliable or firm, atrophic or hypertrophic.
Scars may be preceded by ulceration (traumatic or venous ulcer) or by inflammatory
infiltrate, the latter being called interstitial scar (lupus vulgaris, chronic venous insufficiennj).
The interstitial scar that appears in chronic venous insufficiency is called Milian's white
atrophy and is due to the slow necrosis and replacement of the dermis with fibrous scar
tissue (Fig.2.8). It is localized in the lower part of the leg of varicous patients.
When the scar grows beyond the limits of the original injury, often sending out
clawlike prolongations, it is called keloid (Fig.14.12).
Sclerosis i s t h e t h i c k ening o f t h e s kin o n b e h al f o f c o l l agen f i b ers, l ik e i n
lipodermatosclerosis, morpheea, systemic sclerosis (Fig.2.3).
Atrophy of the skin is a thinning of the dermis and epidermis with loss of appendages.
In atrophic skin the dermal vessels are visible, like in old people (Fig.2.7).

The elementary lesions usually combine like in papulo-erosive or papulo-pustulous,

ulcero-crustous or ulcero-vegetant lesions.

19
 CONFIGURATION AND DISTRIBUTION OF LESIONS

Configuration or a r r angement of s ki n l esions and t h eir d i stribution pr ovides

important clues to the diagnosis.
The shape of the lesions is usually round or oval. Ring-shaped or annular lesions
result when lesions heal at th e centre w h ile p r ogressing at th e p eriphery (e.g. tinea
corporis). The confluence of several roundish elements results in p o l ycyclic lesions or
circinated lesions (e.g. tinea inguinalis). Lesions made up of several concentric circles are
called target lesions (e.g. erythema multiforma) or cocardiform. Serpiginous lesions are
snake-like, set on curved lines, e.g. in larva migrans. Clustered or grouped lesions appear in
herpetic infections (herpes simplex, herpes zoster) and herpeti
fonn eruptions. Corymbose
pattern looks like exploding bomb, with a large lesion in the center and smaller ones in the
periphery (e.g. late secondary syphilis).
Linear arrangement m a y f o l l o w B l a schko's l i n es
which reflect p a ttern of
embryonic development (e.g. epidermal nevi) or a d ermatome which is an a rea of skin
innervated by a single spinal nerve (e.g. herpes zoster). In both these situations there is
characteristic midline demarcation of the lesions. Short linear arrangement also results
from trauma-induced Koebner phenomenon (isomorphic response), as in lichen planus,
psoriasis and viti1igo or from trauma-induced autoinoculation, as in plane warts.
The anatomic distribution of the lesions may be localised, sometimes unilateral
(tinea), or symmetric (e.g. dyshidrotic eczema), disseminated (on more than 2 anatomical
areas, e.g. di s seminated stasis dermatitis), g e n eralized ( o n
all a n atomical a r eas,
e.g.exanthematous drug eruptions) or universal (the whole skin is involved, with no healthy
areas, e.g. er y throdermia). Ex tensor areas of t h e l i m b s ( e l b ows
a nd k n ees) a r e
characteristically involved in psoriasis,while flexural involvement suggests atopic dermatitis
in older children and adults.
Seborrheic areas (head, neck and the upper trunk) are favoured by acne, seborrheic
dermatitis and pihjriasis versicolor. When lesions are localized in areas exposed to ultraviolet
irradiation (phtodistribution), photodermatosis are suggested (e.g. phototoxic drug reactions,
as to doxiclicline) or diseases favoured by UV (systemic lupus erytheniatosus).

20
 Fig.2.2. Aquired acromic macules (Vitiligo)
Fig.2.1. Hyperpigmented aquired
macules (Melasma)

Fig.2.3. Hemosiderinic pigmentation (right Fig.2.4. Purpura

leg) and sclerosis (left leg)

Fig.2.5. Ulceration Fig.2.6. Ischemic necrosis

Fig.2.7. Atrophic skin Fig,2.8. Milian's white atrophy (Interstitial scar)

91
 Chapter 3

FUNGAL INFECTIONS

Fungi (Tabel 1) may cause superficial (frequent) and deep infections (very rare) of
the skin. The superficial dermatomycoses are important in medical practice.

Dermato h y t es Yeasts
S ecies Trico h t o n , E i d e rm o h y t on, Microsporum Candid a
Mycelium - w ith b r a n c he d fi l a m e n t s Pseudomycelium - c hains o f
Microscopic
( hyphae); som e w i t h c r o s s-walls, f o r m i n g r ound/oval cells t h a t d i v i d e b y
characteristics
septate hyphae. budding
Tissue inhabited Skin, hair, nails Skin, mucosa, nails
Tabel 1. Differential characters of fungi causing superficial infections.

SUPERFICIAL FUNGAL INFECTION S

Pityriasis (tinea) versicolor

This is a common superficial mycosis, caused by yeasts of the genus Malasezia (the
actual name for Pityrosporum). These yeasts are part of the normal skin flora. Because it
requires oil to grow, it occurs predominantly in seborrheic areas. Factors that lead to the
conversion of the saprophytic yeast to the parasitic mycelia form include high temperature
a nd h i g h hu m i d i t y in tr op i ca l c l i m ates w h i l e o i l y sk i n , excessive s w eating,
immunodeficiency, corticosteroid use, Cushing disease and malnutrition are involved in
temperate climates. The condition is not considered contagious because the causative
fungal pathogen is a normal inhabitant of the skin.
The lesions are usually asymptomatic. They present as i scoloured macules, with
colours ranging from white to brown, sometimes red (as the name implies, versi meaning
several) and a fine scale. The lesions occur predominantly on the trunk, shoulders, back,
abdomen and upper arms (Fig.3.1) and more rare, in children, on the face. There are two
possible explanations for depigmentation: a) light f i ltering effect by scales and fungal
layer; b) d i sturbance of m elanogenesis and/or destruction of m e l anocytes by f u n gal
metabolites.
Differential d i agnosis i n cludes p ostinflammatory h y p o pigmentation, vitiligo,
pityriasis rosea, tinea corporis and secondary syphilis.
Pityriasis versicolor is primarily treated with topical antimicotic preparations, like
shampoos and c r eams. Shampoos containing k e toconazole ( N i zoral), f e nticonazole
(Lomexine), ciclopiroxolamine, selenium sulphide 2.5%, zinc pyrithione are used for 10
minutes at the end of bath daily for 2 weeks and weekly after, to prevent recurrences.
Topical azoles and allylamine antifungal creams have to be applied also for 2 weeks on the

23
whole area of the neck, thorax, abdomen and arms. In cases of extensive disease or
frequent recurrences, oral antimicotic therapy is indicated.
Depigmentation resolves within 1-2 months after treatment has been initiated. As
endogenous factors of the patients are thought to be of g reat importance, recurrence is
common, and prophylactic therapy may help reduce the high rate of recurrence. One-monthly
dosing of ketoconazole (400 mg), fluconazole (300 mg), itraconazole (400 mg) may be used.

Dermatophyte infections
The dermatophytes are responsible for so-called "ringworm" infections or tinea (Latin: a I

gnawing worm). Dermatophytes can be acquired from different sources: people (anthropophilic
infections), animals (zoophilic infections) or soil (geophilic infections). Contact with contaminated
fomites (e.g. hairbrushes, combs, towels etc) can spread infection. Fungi spores can survive
several months in the environment (especially recreational and sport f acilities), resulting in
recurrent outbreaks. Infection is usually acquired by contact with keratin debris carrying fungal
hyphae. Dermatophytes grow only in the keratin of the skin, hair and nails(Tabel1). Animal and
geopMic fungi usually cause severe inflammatory reaction in humans.
Dermatophytes can be seen on direct examination by taking skin scrapings, nail
c lippings or plucked hair from th e affected area and mounting them on a s l ide w i t h
coverslip i n 2 0 % p o t assium h y d r o xide, which i s g e n tl y w a r m e d a n d e x a m ined
microscopically. Dermatophytes appear as branched septate filaments (mycelium). To
identify the particular species it is necessary to culture the sample for up to 3 weeks on a
suitable medium such as Sabouraud's.

1.Dennatophyte infections of the skin

Tinea pedis (Athlete's foot) is the commonest of the dermatophyte infections. It
involves the soles and interdigital web spaces of the feet. It is favoured by the m oist
environment created by occlusive shoes and is usually acquired from contact with infected
keratin debris on the floors of locker rooms, gyms, swimming-pools, showers and other
public facilities. There are three forms, with different location and clinical presentation:
• interdigital f or m - i t c h y , s c aling o r m a c erated, f issured w e b s p aces, most
frequently the tstro lateral ones (Fiff 3 2); . .

• moccasin type — diffuse hyperkeratosis, erythema, scaling and fissures on the

sole(s), extending on the lateral and dorsa of the feet (Fig.3.3).
• inflammatory (vesicular) form - on the central part of the sole, as areas of discrete
erythema with recurrent pruritic vesicles or bullae; it i s o f ten associated with
dermatophytid r eaction consisting of d y s hidrotic-like eruption o n t h e l a teral
aspects of the fingers of the hands
Tinea pedis can be complicated by allergic reactions (dermatophytids), bacterial
superinfection, cellulitis, erysipelas especially in p a tients with v enous insuficciency or
even osteomielitis in patients with chronic arterial obstruction or diabetes.
The feet are initially asymmetrically involved i n t i nea pedis, in contrast with
eczema and psoriasis, in which the involvement is symmetrical from the beginning.

Tinea cruris is m o r e c o m mon i n m e n . T h e l e s ion i s i t c h y, h a s p o l y cyclic

(circinated) erythematous margins that gradually spread down on the medial aspect of the
thighs, perineum and b u t tocks, whith central clearing (Fig.3.4). The margin t y p i cally
or presents thin scales and tiny vesicles or pustules. Tinea pedis or tinea unguium frequently
associates. The fungus is transferred to the groins on the fingers, towels or on trousers.
Tinea cruris, which starts unilaterally but might become later bilateral, should be
easily distinguished from candida intertrigo, erythrasma, flexural psoriasis or benign
pemphigus Haley-Haley.
Tinea corporis i s typ ically a nnular, sometimes arcuated or c i r c inated, wi t h
scaly, pustular, inflammatory margin that spreads centrifugally and central clearing. It
may be located on the chest, abdomen, dorsum (Fig.3.4), upper or lo wer extremities,
|:a dorsal hand or dorsal foot. In children the fungus is usually of animal origin (kitten),
ilic while in adults it is spread from the feet or groins.
:ed The differential d i agnosis includes nu m m u lar eczema, pity riasis versicolor,
ive pjtyriasis rosea, annular psoriasis, subacute lupus erythernatosus and impetigo.

Tinea manuum refers to the palmar involvement. It is often unilateral, may begin
gal
on the 4th finger, under the ring and presents as mild scaling erythema or hyperkeratosis
nd
(Fig.3.6). Tinea manum is frequently associated with tinea pedis ("two feet and one hand
syndrome" ). An important clue to diagnosis is tinea unguium of the involved hand.
ail
The differential di agnosis may i n cl ude p soriasis, irritant o r a l l ergic contact
ith
dermatitis.
ed
To Tinea faciei involves asymmetrically the glabrous skin of t he face, usually the
1a c heek. The typical aspect is annular p atch w i t h c i r cinate or a r cuate margin t hat i s
erythematous, scaling, pustular and extends peripherally (Fig.3,7).It is frequently acquired
from pets in home, but also from individuals with other forms of tinea.
Tinea faciei may r esemble systemic or c h ronic l u pus erythematosus, rosacea,
It allergic or irritant contact dermatitis or seborrheic dermatitis.
ist
ed Tinea incognito is a fungal infection with altered appearance due to inappropriate
ier treatment with topical steroid preparations that suppress the inflammatory response to the
fungus while favouring its multiplication and spreadin . The typical scaly erythematous
)st margin may disappear, leaving an ill-defined area with ustules (Fig.3.8).

2. Dennatophyte infections of the hair (pilomycosis or tinea capitis)

he Tinea capitisis the involvement of the scalp hair by dermatophyte fungi (Microsporum
and Tricophyton sp). There are non-inflammatory forms of tinea capitis (microsporosis,
'te
trichophytosis and favus) and inflammatory forms (kerion celsi and tinea barbae), depending
ith of the type of the dermatophyte and consequently the type of the hair involvement (endothrix,
ral ectothrix or favus), but also depending on the immune response of the body. Microsporosis
and tricophytosis are both very contagious in small children collectivities but are rare after
ial puberty because of the fatty acid constituents of sebum that become fungistatic.

Microsporosis capitis (caused by Microsporum sp) appears as 1-2 round, scaly patches
ith of alopecia with hair that is broken at the same level, 2-3 rnm above the surface of the
scalp. The alopecic areas have dull gray appearance due to the disposition of spores on
the exterior of the hair shaft, with destruction of the cuticle (ectotrix invasion).
11c
he Tnchophytosis capitis ("black dot tinea capitis", caused by Trichophyton sp) appears as
Lly several small round alopecic areas, with scales and hairs broken at different lengths,

25
 some at their base, causing black dots. The hair shaft is involved, with normal cuticle
(endotrix invasion).
• Favus is caused by Tr i cophyton Schoenleini and lasts even after puberty. Scarring
alopecia with some persistent greyish hairs and y ellow c u p-shaped crusts called
scutulas are characterstic features. The hair i n t h e occipital and t emporal regions
remains healthy. Hyphae and air spaces are observed within the hair shaft.
• Kerion Celsi (Kerion meaning in Greek honeycomb) is a deep, highly inflammatory
scalp infection. One or several painful, round raised, purulent and inflamed lesions
appear on the scalp. Hair fall out rather than break off or can be painlessly pulled
out. B a c t erial su p e r i n fection w ith sta p h y l o cocci is f r e q u ent . Re g i o n al
lymphadenpathy is associated. Kerion may heal with scarring and permanent hair
loss within several weeks. Immunity is developed against re-infection.
• Tinea barbae (micotic sycosis) is a dermatophytic infection of the hair-covered portion
of the face in adult men, provoked by zoophilic dermatophytes, sometimes as
professional disease, from i n f ected cattles. Tinea barbae shows agminated deep
folliculitis with sw ollen pseudotumoral purulent lesions on th e f ace (Fig.3.9) and
lymphadenopathy. This is i n c o n trast to staphylococcal sycosis, characterized by
disseminated folliculitis (Fig.3.10). In tinea barbae the infected hair is easily pulled off.
The removing of the infected hairs and a rim of healthy hairs surrounding the
inflammatory skin lesion is essential for a faster resolution in both inflammatory forms of
pilomycosis and is useful to prevent the extension of the infection.
The hair and skin scrapings should be sent for culture to confirm the diagnosis and
to identify the animal or human reservoir of infection.

3. Dermatophyte onychomycosis (Tinea unguium) ~

Tinea unguium is very common in adults and elderly, frequently associated with
tinea pedis. It has three forms depending upon the point of fungal entry into the nail unit:
o d i s t al/lateral sunungual — with i n v asion via th e h y p onychium, i t i s t h e m o st
common. The distal/lateral nail bed becomes hyperkeratotic, with yellowing and
thickening of the distal/lateral nail plate, as well as onycholysis (detachment of the
nail plate from the nail bed). The infection progresses proximally and eventually
involves the entire nail bed and plate (total dystrophic pattern).
o s u p erficial onicomycosis — with direct penetration into (and confinement to) the
nail plate; white irregular spots appear on the surface of the nail plate (Fig.3,11).
o p r o x i mal subungual — with invasion under the proximal nail fold, usually appears
in immunocompromised persons.
Trauma and other nail disorders (e.g. psoriasis) represent predisposing factors.
T oenail d e r m atophytic i n f ections a r e mo r e co m m o n th a n fingernail i n f ections.
Onicodystrophy from venous insufficiency of the legs can be very similar to onicomycosis. We
should always perform mycological exam to con6rm onicomycosis, as only the oral treatment
is efficient and this is costly, takes a long time (3-6 months) and might be hepatotoxic.

Treatment of dermatophyte infections

Topical therapy should be applied at least 2 weeks and continued for another 2
weeks after lesions resolve. Topical therapeutically agents include:

26
cle iod (Betadine = polyvidon iodide)
topical azoles: econazole, ketoconazole (Nizoral), dotrimazole, miconazole, oxiconazole,
bifonazol (Biazol), fenticonazol (Lomexin). The mechanism of action is fungistatic, by
ng inhibition of the synthesis of ergosterol, which is an important component of the fungal
ed
cell wall. Membrane damage results in p ermeability problems, in i n hibition of
ins
replication and maturation of the mold into the invasive and pathogenic form
allylamines: naftifine (Exoderil), terbinafine (~ il, Terbisil) are fungicidal agents; they
iry inhibit squalene epoxidase, which converts squalene to ergosterole, causing intracellular
ns accumulation of toxic leveL~ of squalene that lead to rapid fungal cell death
ed c iclopiroxolamine (Batrafen, Ciprox) a s l o t i ons, creams, p o w ders o r s p r ays
>al interfere with amino acid transport across the fungal cell membrane.
Mistreatment of tinea cruris with topical steroids usually results in exacerbation of
the disease, although patients note initial relief of symptoms.
Systemic therapy may be indicated for extensive or resistant fungal infections of
on
the skin, infections of the hair and nails. Use of oral agents requires attention to liver
as
enzyme levels that have to be m onitored before and throughout treatment if t h erapy
ep
extends more than 2 months. Systemic antifungal agents include:
A.d
griseofuivine — is an antifungal antibiotic that arrests the fungal cell mitosis
by
systemic azoles:
f.
o k etoconazole (Nizoral) one 200 mg tablet daily for 2-3 weeks in tinea pedis,
he
corporis, m anuum; i t i s n o t us e d f o r t i n e a u n g u iu m b e cause of
of
h epatotoxicity t h a t u s u ally r e sults d u r in g t h e n e cessary p e rio d o f
treatment (6 months for finger nail and18 months fo toenail mycosis);
md
o i t raconazole (Orungal, Sporanox) and fluconazol (Dif lucan) have less
hepatotoxic action under pulse therapy regimens:
• 300 mg fluconazole once weekly for 2-4 weeks in skin mycosis, for
.th 6 months in fingernail mycosis and up t o 18 months in toenail
mycosis;
)st • itraconazole 2x200 mg daily for 1 week/month, 2 and 4 pulses for
zd fingernail and toenail mycosis, respectively;
he terbinafine (250 mg/tb) may be used for 2 weeks for skin infections, 1-3 months for
l.ly tinea capitis, 2 and 4 months for fingernail and toenail mycosis, respectively.

he Mucocutaneous candidosis
Yeasts are unicellular round or oval fungi that typically reproduce by budding
mrs (pinching off of the mother cell). Candida albicansis the commonest member of the Candhda
genus (>150 species) and the principal infectious agent of human candidosis (Tabel1).
rs. It is a no r mal commensal of the h uman gastrointestinal tract (mouth through
anus), and vagina (13% of women) in balance with the bacterial fiora. Candida species are
Ve not part of the normal flora of the skin; however, they may colonize fingers or body folds
.nt transiently. The commensal form of candida is unicellular yeast. When pathogenic, it
multiplies resulting in budding and mycelial (pseudohyphae) forms. Pseudohyphae are
chains of pinched cells that do not separate.
Candida albicans becomes pathogenic in c e r tain f a v ourable situations: broad-
spectrum a n t i biotics, t o p i cal a n d sy s t emic steroid t h e r apy, i m m u n o defficiency,

27
hyperhidrosis, diabetes mellitus, iron deficiency anaemia, deflciencies including vitamins
B1, B2, B6, C, and folic acid, or local factors like warm and moist environment, increased
contact with invasive monitoring devices in an intensive care unit, decreased salivary flow,
use of denture.

1. Mucosal candidosis
Oral candidosis ( thrush) is c o m m on i n ne w - b o rn i n f a nts, b ecause of t h e
insufficient secretion of the salivary glands, immaturity of host defence and incomplete
establishment of the normal orointestinal flora. It may be acquired in neonates from the
infected maternal mucosa during passage of the infant through the birth canal. In adults,
candida stomatitis appears in i m m une deficiency, xerostomia, use of b r oad-spectrum
antibiotics and inhaled corticosteroids. It may also affect up to 65% of patients who wear
dentures, especially full sets. Oral infections presents as:
- white plaques that adhere to the erythematous, inflamed buccal mucosa (chronic
hyperplastic form)
- white exudates resembling cottage cheese (psudomembranous form)
- patch of erythema (chronic atrophic form)
— glossitis — painful atrophy of the dorsal tongue

Angular cheilitis (perleche) appears at the angles of the mouth where saliva
macerates the skin, especially in edentulous, denture waerers and elderly patients. It
presents with sore fissures with creamy white discharge (Fig.3.72).

Candida vulvitis and vaginitis presents with a c reamy vaginal discharge and
itchy erythema of the vulva. Predisposing factors are: pregnancy, oral contraceptives and
diabetes mellitus. Candidal colonization of vaginal mucosa is estrogen dependent and
subsequently d ecreases sharply a f ter m e n opause, but 'despread use of hormone
replacement for reduction of osteoporosis and heart disease y c a u se an increasing trend
in candidal vulvovaginitis among older women.

Candida balanitis appears as small white patches or eroded areas with creamy
satellite pustules or erosions with a collaret of ruptured skin on the foreskin and glans
(Fig.3.13). It may appear after oral antibiotics. If recurrent, diabetes mellitus is associated or
a sexual partner has Candida vaginitis.

Perianal candidosis, extended from digestive or genital candidosis, appears as itchy

erythematous swollen skin covered by small white patches or erosions with creamy discharge.

2. Cutaneus candidosis
Candid a involves i n tertriginous a reas, l ik e a x i l lae, sub-mammary, b eneath
pannus, inguinal creases or intergluteal fold. Candida intertrigois clinically suggested by
intense erythematous, erosive patches accompanied by satellite pustules. The pustules are
easily ruptured, leaving collarets of scale, with characteristic scalloped edge.
The 3'd interdigital web space is involved when hands are frequently exposed to
water. Interdigital candidosisappear as white, soft macerated skin (Fig.3.74).
Napkin candidosis is exaplined by the particular susceptibility of moist macerated
skin to invasion by C.albicans from infected stools. It presents as erythematous perianal or
perigenital plaque with polycyclic edge, collarets of scale and satellite pustules (Fig.3.75).

28
 3. Candida onixis and perionixis ('chronic paronichia)
ns
Chronic paronichia is a chroni" inflammatory process affecbng initially the proximal
d
~ f o l d and then the nail matrix(Fig.3.16).Bacteria may associate. The proximal nail fold
appears erythematous, swollen and tender, with occasional discharge and loss of the cuticle
(perionixis). The nail plate becomes dystrophic, discoloured (grey, yellow) and thick (onixis).
~o nic paronichia occurs predominantly in people who frequently submerge their hands in
he ~ater (housewife, bar staff, florists, and fishmongers). Diabetes is also a predisposing factor.
.te
4. Chronic muco-cutanous candidosis
he
Chroruc muco-cutaneous candidosis refers to a heterogeneous group of disorders
ts,
c haracterized b y r e c u rrent o r p e r sistent superficial i n f ections o f t h e s k i n , mucous

ar
mem
branes, and nails with Candida organisms, usually Candida albicans,associated with a
d efect in cell-mediated im m unity. This begins in e a rly c h i l dhood an d r e sists to t h e
conventionally topic treatments. The clinical picture consists of oral chronic candidosis
(thrush), candida intertrigo, candida granuloma (inflammatory nodules of the scalp),
candida diaper dermatitis or perionixis.
Treatment of the candida infections
Topical treatment is recommended to change the pH to a lkaline (washing with
sodium bicarbonicum 1%) because Candida prefers the acid environment. It is useful to
va
avoid contact between skin surfaces, isolating the skin folds with dry dressings and use of
It
antiperspir ants.
Topical treatment uses creams, ointments, lotions, powders in different regimens
xd and duration, depending on the clinical form of candidosis:
1d polien antibiotics: amphotericine B, nystatin (Stamicin), natamycin (Pimafucin)
ld azols: clotrimazole, econazole, miconazole, ketoconazole (Nizoral), bi n a zol (Biazol),
ze fenticonazol (Lomexin)
xd Systemic treatment:
poliene antibiotics - nystatin (Stamicin) administered orally acts only locally in the
g astro-intestinal t r act, i t i s n o t a b s orbed sy stemically; am photericin B i s u s e d
ly
intravenously in severe cases
ns
azols are recommended in cases resistant to topical therapy: ketoconazole (Nizoral)
or
200 mg/tb; fluconazole (Diflucan) 100 mg, or 150 mg/ cps; itraconazole (Orungal,
Sporanox), 100 mg/cps; voriconazole
Xy fluorocitozin is metabolized in organism to fluorouracil, a cytostatic agent that acts
inhibiting the synthesis of the fungus DNA, without acting on the macroorganism.

th
)y DEEP FUNGAI. INFECTIONS
re
The majority of deep fungal infections are tropical diseases (histoplasmosis,
to criptococcosis, coccidiosis), while others like sporotrichosis, micetoma and actinomycosis
are rarely seen in Romania.

.'d Sporotrichosisis caused by Sporotrix Schenkii which is saprophytic on plants and

can be inoculated by a puncture wound (thorns, hay, conifer needles) or seed in any
common wound. The characteristic lesion is a dermal or subcutaneous nodule that may

29
 ulcerate. After a few weeks the infection spreads along the regional lymphatic vessels and
satellite firm nodules appear, then ulcerate and open to the skin surface forming tortuous
fistulas. Sporotrix organisms can sometimes cause systemic involvement (lungs and
joints). Treatment: potassium iodide 2-4 g daily; itraconazol (Orungal) 100 mg daily, 3-4
months; amphotericin B 1-3 g daily in i.v. infusions.

Micetoma (pied de Madura, maduromycosis) is a chronic, granulomatous disease

of the skin, which sometimes involves the muscles, bones, and neighbouring organs. It is
caused by fungi (Madurella, Cephalosporium, Nocardia)or bacteria (Actinornyces)that are
inoculated in skin by a local traumatism (thorns, wood splinters or implantation with solid
objects), mostly in people who work in rural areas. The most common involved areas are
the feet and the lower legs, but also buttocks, groin area, head and neck.
Clinically, the disease begins as firm, painless, erythematous nodules that can
persist or evolve to form extensive suppurative plaques measuring up to 20 cm in
diameter and extending to the bones and joints of the feet with monstrous deformation of
the region. The exudates contain the microorganisms surrounded by inflammatory cells,
observed with the naked eye as black, white, yellow or red grains.
The treatment in my cotic mycetoma is less successful that for actinomycetoma.
High doses of ketoconazole, fluconazole, itraconazole or terbinafine can be used for 1-2
years, unless side effects warrant cessation of medication. Sometimes surgical treatment,
including amputation, remains a viable therapy.
The treatment for a ctinomycetoma is t r i m etoprim-sulfametoxazole for several
months or years, eventually associated with amikacin.

Actinomycosis is a chronic cervico-facial induration which enlarges to an abscess-

like swelling, with penetration oi th e overlying skin and the develo~pm t of draining
fistulas that discharge sulphur granules.
The term actInomycosis is misleading. Because of the term mycosis (from the Greek
mykes), some believe that actinomycosis is a fungal infection, although Actinornyces Israeli is a
filamentous Gram positive aerob microorganism. Aktino referres to the radiating organism in the
sulphur granule. The microorganism enters the tissue through a break in the oral mucosa,
favoured by poor oral hygiene and dental caries. The presence of anaerobic bacteria that
enhances the growth and propagation of actinomyces species is necessary to initiate the infection.

."-S
Uncut'- • ..
gjpjuqu~lq, .-'< ' •

v
r.

Sulphur granule
The treatment of choice includes large doses of antibiotics and prolonged therapy
coupled wit h d r a inage of th e abscesses or radical excision of th e s i nus t r acts. High
penicillin concentrations are necessary to penetrate areas of fibrosis and suppuration and
possibly the granules themselves. Intravenous penicillin G (10-20 million U/d for 2-6 wk)
followed by oral penicillin (2-4 g/d for an additional 3-12 mo) is the typical therapy for the
most deep-seated infections.

30
js

.d
4

>e
ls
.e Pig.3.1. Pityriazis versicolor Fig.3.2. Tinea pedis, interdigital form
d (brown and acromic macules)

S,

Pig.3.3. Tinea pedis-mokasin like. Onycomycosis

Pig.3.4. Tine curis extended on the buttok

.k

ie

Fig.3.5. Tinea corporis Fig.3.6. Tinea manum

h
d
')
e
Fig.3.7. Tinea faciei Fig.3.8. Tinea incognito
 Fig.3.10. Mixt sycosis
Fig.3.9. Inflammatory tinea of (tricophytic and staphylococic)
the upper lip (sycosis)

Fig.3.11 White superficial (left) and distal Fig.3.12. e (candidal angular cheilitis)
lateral onicomycosis

Fig.3.13. Candida balanitis n Fig.3.14. Candida interdigital intertrigo

Fig.3.15. Napkin candidosis Fig.3.16. Candida onixis and perionixis

 Chapter 4

BACTERIAL INFECTIONS OF THE SKIN

The skin is sterile immediately before birth and is colonized by bacteria from the
first day of life.
Resident flora is represented by harmless bacteria which permanently colonize the
to prevent infections by providing ecological competition for pathogenic organisms; there
Ne different species varying among locations of the body and individuals:
gram positive - staphylococci; corynebacteria;
anaerob bacteria — Propionibacter in the deeper part of the hair follicles, on the face
and upper trunk;
yeasts —Malassezia on seborrheic areas
Imbalances between the resident flora of the skin, vagina or intestine and other
bacteria or fungi can appear after antibiotics use or weakening of the immune system
(AIDS, cancer, corticosteroids or chemotherapy). An example is vaginal yeast infection
after antibiotic treatment.
Temporary resident flora: b acteria and fu ngi w h i r ~ s i st on t h e s k in f or a
limited period of time, multiply and cause infections (staphylococci, streptococci).
Transient flora: bacteria, fu ngi a n d v i r u s es f r om e x o genous s ources, that
contaminate the normal skin only at t i mes. In special conditions (immune deficiency,
irritated or injured skin) non-pathogenic organisms may change their behaviour, multiply
on the skin and cause infections.
Cutaneous infections are favoured by:
factors depending on the microorganism — increased virulence
factors depending on t h e h u man b od y — increased tisular glucose (diabetus
mellitus), p r eexisting d e r m atoses (eczema, s ki n p a r asitosis), m i cr otrauma,
denutrition, immunologic deficiencies (AIDS, immunosuppressive therapy)

PYODERMAS

Pyodermas are infections of the skin w it h p y ogenic bacteria (staphylococci and

streptococci, most frequently and o ther bacteria, as E.coli, pyocianic etc., more rare).
Streptococci and staphylococci can be unique etiologic agents, but they can also occur
simultaneously (impetigo, intertrigo, cheilitis, perionixis) and only the bacteriologic exam
can identify them.
Pyodermas are classified in: primary infections of the healthy skin (not preceded
by other skin disease) and secondary pyodermas that complicate previous eczema, ulcers,
herpes, pemphigus etc. Another classification refers to infections of the glabrous skin
(between the hair follicles) - caused mainly by streptococci and of the skin appendages
(pilosebaceous follicles, sweat glands) - caused mainly by staphylococci.

33
 Non-f olicular pyodermas patI
Impetigo is a highly contagious gram-positive bacterial infection of the superficial
epidermis.Staphylococcus aureus and Streptococcus beta-haemolyticgroup A (GABHS or end
Strept.pyogenes) e both implicated in the etiology of impetigo.
There are 2 forms of th e d i sease: bullous impetigo and n onbullous impetigo. ]yrr
L esions may occur anywhere on the body, but mainly on the face of children. The typical per
lesion is a rapidly enlarging bulla (superficial, subcorneal but transient and not observed
in non-bullous form) that is fragile and ruptures leaving peripheral scaly collaret and sub
yellow (meliceric) crust over th e erosion. Infection spreads to contiguous areas and are
satellite lesions appear due to autoinfection (Fig.4.1, 4.2). The lesions heal without atrophy
and scar. Rarely, poststreptococcal glomerulonephritis (pedal edema, hypertension) can 4

complicate impetigo.
While impetigo can manifest as a primary pyoderma of intact skin, it may occur as
a secondary infection of tr aumatized skin or p r e-existing dermatosis (varicella, atopic
dermatitis, m y cosis, scabies a nd l ouse i n fection), w h ic h h a s b ee n r e f erred t o as
impetiginous dermatitis.
usll
Ecthima is a streptococcal infection that extends into the dermis, being referred to
as a deeper form of i m p etigo. Streptococcimay initiate the lesion, usually on t he l egs
(primary ecthima) or may infect pre-existing wounds (secondary ecthima), in the presence
of factors like crowded living conditions, poor hygiene, immnneseppression. The initial
vesicle-pustule soon ruptures and the secretion dries to form a brown, adherent crust over
the ulcer (Fig.4.3). The dermis being damaged, ecthima heals with a round scar that is b]i,
frequently hypopigmented and peripherally hyperpigmented (Fig.4.4).
Streptococcal intertrigo appears most frequently in children and more frequent in alt~
infants, due to irritation and friction in the deep folds of the neck, axillae, antecubital and
popliteal fosae. Well demarcated fiery red erythema in an intertriginous area with foul
ap
smell and no satellite lesions differentiates clinically streptococcal from candida intertrigo.
W]'
Bacterial culture may confirm diagnosis.
gar
Erysipelas is an acute infection of the superficial dermal lymphatics of the skin.
The majority of cases are caused by Streptococcus pyogenes or Staphylococcus aureus on
the skin and its appendages that gain entry to the dermis and multiply.
The condition is most common localized on the lower legs, but any other part of
the body, like the face or ear may be involved. The portal of entry has always to be looked
for in the nelghbourlng area of the infected skin or mucosa. e g a f ssure. cut. laceration. 1Uf
insect bite, puncture wound, intravenous drug abuse, rhinovestibulitis, otitis externa - for
the erysipelas of the face or ear; tinea pedis, venous ulcers, pressure ulcers, lymphatic ap]
obstruction (after lymphadenectomy or irradiation) - for lower leg erysipelas; lymphatic
obstruction (after surgery for breast cancer) - for arm erysipelas.
After an incubation of 2-5 days, there is an abrupt onset of fever, chills and
malaise. A few h ours to a day l ater, erythematous, edematous plaque appears, with
raised and sharply d elimited m argins, associated with p ain an d t enderness (Fig.4.5,
Fig.4.6). Regional lymphadenopathy and sometimes lymphangitis are present. The
erythematous plaque with important, non-pitting edema progressively enlarges over a
few days and bullae (Fig.4.6), purpura (Fig.4.7) or necrosis (Fig.4.8) may also develop. In

34
 atjents with underlying disorders (diabetes mellitus, lymphedema, peripheral vascular
ial d>ease) complications may occur, like abcedation (Fig.4.9), acute gloroerulonephritis,
or er1docarditis and recurrences.
Repeated obstructions of the major lymphatic channels of the skin lead to chronic
go. lyInphedema and later on, to elephantiasis, characterized by hypertrophic and fibrotic
ical permanent lymphedema (Fig.4. 10).
red Cellulitis d iffers from e r ysipelas in t he f a ct t h at i t i s d e e per, involving t h e
lIld
subcutaneous tissue and not the lymphatics. The margins of the red inflammatory plaque
lxld
are not sharply demarcated.
Ihy Differential diagnosis of erysipelas and cellulitis includes deep vein thrombosis,
an
stasis dermatitis, superflcial thromboflebitis and lipodermatosclerosis.

. as Necrotizing fasciibs (NF) is a v e ry severe, rapidly progressing necrotizing

P1C infection of the subcutaneous fat and fascia. It may follow surgery or perforating trauma
as pr may occur de novo.
In children necrotizing fasciitis is caused by group A streptococci,while in adults
IIsually it results from a polymicrobial infection with aeobic and anaerobic bacteria, like
l to
S,aureus,E.coli, Bacteroides and Clostridium sp, and rarely Pseudomona aeruginosa, or
egs H.influenzae.
nce Infection starts like erysipelas or cellulitis with red-purple hue but the pain is
tial s evere, out o f p r o p o r tion t o s k i n f i n d i ng s an d t h e p r o g ression i s r a p id , w i t h o u t
ver response to antibiotics. Within 36 hours from onset, gray-blue ill-defined patches with
t is blistering necrosis develop, the skin may become anesthetic due to necrosis of the nerve
fibers and systemic toxicity may associate with high fever, tachycardia, hypotension, and
t1n altered level o f c o n sciousness. Fascial necrosis can b e d e m onstrated, u n der l o c al
<nd anesthesia, through a 2-cm incision down to the fascia, by lack of resistance when passing
oui a probe (gloved finger) through the tissue.
.go. The most common location is the lower legs in adults and the trunk in children.
When necrotizing fasciitis involves the perineum and genital area, it is called Fournier's
gangrene.
Sepsis, renal failure and rapid death (in 20% of cases) can complicate the evolution.
on

Treatment of the streptococcal infections is both topical and systemic.

t of
Topical treatment includes wet antiseptic dressings for 15-20 minutes, especially
(ed
when bullous and eroded lesions are present (chloramin B 500mg/200ml water, boric acid
.on,
10g/1000ml water, kalium permanganicum solution 1:6000, or isotonic sodium chloride
for
solution). When crusts are p resent, antimicrobial or a n t iseptic creams/ointments are
atic
atic
applied, e.g. neom
ycin+bacitracin {Baneocin); mupirocin (Bactroban); fucidic acid
(Fucidine). Resistance to these antibiotics started to emerge and retapamulin (Altargo) is a
new option.
End
Systemic antibiotic treatment must provide coverage against both S. aureus and S.
ith
pyogenes because the two o r g anisms frequently associate. Oxacylin, erithromycin,
4.5, cephalosporins like cephalexin (Ospexin), ceftriaxon (Rocephin) are indicated.
%e
In cellulitis and erysipelas strict elevation and rest of the affected limb and the use
.r a
«c ompression stockings as soon as pain fades away are recommended. Treatment of
. In

35
 predisposing lower extremity skin lesions (e.g., tinea pedis, stasis ulcers) and long-term
prophylactic antibiotic therapy (e.g. benzathine penicillin 2.4 MU i.m. every 3 weeks for up
to 2 years) reduce the recurrences of erysipela. Renal or cardiac complications might not be
prevented by oral antibiotic treatment in streptococcal impetigo and erysipelas.
T he treatment of N F i s a n e m ergency and th e p atient is better moved in a n
intensive care unit. Immediate surgical debridment and antibiotic treatment are necessary.
Follicular pyodermas
Follicular infections are mainly determined by S.aureus,a normal inhabitant of the
a nterior nostrils i n 2 0-40% of th e a d u lts an d o n t h e h a nd s an d p e rineum i n s o m e
individuals. Nasal carriers are particularly prone to recurrent staphylococcal infections.
FolIiculitis is defined clinically by a follicular-based pustule and histologically by
the presence of in fl ammatory cells w i t hi n t h e w a l l a n d l u m e n o f t h e h ai r f o l l icle.
Perifotticulitis is defined by the p resence of inflammatory cells within the perifollicular
tissues and adjacent reticular dermis.
Predisposing factors for staphylococcal folliculitis include: occlusion of the hair
follicles by tight clothing, shaving, plucking or waxing hair, hot and humid weather, use of
topical corticosteroids, obesity, atopic dermatitis and diabetes mellitus.
Folliculitis has been classically divided into superficial deep forms; most of the
superficial forms can evolve into the deep form.

Superficial folliculitis appear as small (1-4 mm) erythematous papules or

pustules pierced by central hair, followed by a yellow crust and no scar, mostly on the face
(Fig.4.11), scalp, chest, back, buttocks or lower legs.
Deep folliculitis or staphylococcal sycosisconsists of multiple, isolated abcesses
of the hair follicles that have both a superficial and a deep, dermal component ("shirt-
button"-like abscess), explaining the inefficiency of superficial treatment. The involved
follicles are spread in staphylococcal sycosis (Fig.4.12) compared to the agminated lesions
in tinea barbae.

Furuncle (boil) develops when the entire follicle together with surrounding tissue
are infected by S.aureus haemolytic. It starts as a painful inflammatory nodule (Fig.4.13)
that becomes fluctuant and develops a central pustule centred by a velluls hair over a few
days. Staphilococcus has a necrotising toxin that induces the formation of the necrotic core
(necrotic pilo-sebaceus follicle, called bourbillon, Fig.4.14), which will be eventually
elimined, leaving a scar.
Several simultaneous boils in a patient or recurrent boils represent furunculosis.
These patients may have underlying favouring disorders (diabetes mellitus, cancer, AIDS,
etc.) or they are otherwise healthy, bnt they may he carriers of staphylococci ht the nostrils
or on the perineum, from where the organisms are transferred to various parts of the body I
on the digits.
9
The furuncle localized on the superior lip is. called "the malignant furuncle of the
face". Due to the laxity of the subcutaneous tissue at this level, the massive edema camouflages
the furuncle. The furuncle appears as lip edema with a small pustule. The name comes from
the possible complication that can appear after squeezing the lesion: septic thrombosis of the
hollow sinus, as the blood of the upper lip drain in the venous sinuses from the base of the
encephalon. This complication is i n dicated by e x treme headache, high fever (40'-42'),

36
 hptophobia, conjunctival chemosis, diplopia and coma. Death may result in 90% of cases.
up t is why th e f u runcle located on the upper lip i s t reated strictly conservatory with
be anti
bioticsand wet antiseptic dressings, while autotrauma is forbidden.
A confluence of several furuncles (agminated furunculosis) results in carbuncle,
an frequently localized on areas with t hicker skin, like nape of the neck, back, thigh in
patients suffering from diabetes or severe debility. It begins with a dome-shaped area of
tender erythematous swollen skin, and, i n a f e w d a ys, pu s d i scharge from m u l t iple
the fpiljcular orifices. A deep ulcer results that resolves with a visible permanent scar.
me Paronychia due to s taphylococcus is an acute soft tissue infection around the
fingernail that results from the breakdown of the cuticle, which prevents the inflltration of
by the infectious agent barrier u n d er t he p r o ximal n ail f o l d. T he p a tients accuse pain,
=le. tenderness, redness and swelling in the proximal and/or lateral nail folds. Pus may be
ilar expressed by slight pressure (Fig.4.15).
Acute paronychia can also be caused by other microorganisms like streptococcus,
iair pseudomonas species, gram negative and anaerobic bacteria. Favouring factors are
.of hangnails, nail biting and finger sucking, manicuring, or artificial nail placerf1ent.
Acute paronychia has to be distinguished from chronic paronychia, caused by
candida albicans, in p e ople repeatedly exposed to m o ist environment (dishwashers,
housekeepers, bartenders, swimmers).
or Staphylococcal scaled skin syndrome (SSSS) is a toxin-mediated staphylococcal
ace syndrome, given by certain staphilococcal toxigenic phag types that cause intraepidermal
splitting of the granular layer. It is more common in infants and young children, but adults
ses with renal insufficiency or immunodeficiency are also vulnerable, due to deficiency in the
elimination of toxins. SSSS originates from a focus of infection that may be impetigo, a
red purulent conjunctivitis, otitis media or nasopharyngeal infection. It starts with general
ons malaise and a rash that rapidly progresses to bullae, shedding of epidermis and
erythematous erosions. The aspect is comparable with t hat of t h e scalded skin, w i t h
c omplete recovery i n 5 - 7 d a y s . T h e t r e atment p o i nt s t o t h e e r a d ication o f t h e
sue staphylococcus focus of infection with antistaphylococcal antibiotics (cloxacillin) and
13) appropriate attention to fluid and electrolyte management.
'ew
ore Treabnent of staphylococcal infections requires local and systemic measures.
<lly Local treatment is sufficient in superficial folliculitis. One may use antiseptics
containing iod (tincture of 2% povydon iodide alcoholic solution - Betadine), chloride
S1s.
(chloramine B) or a n tibiotics (mupirocin ointment - B actroban, neomycin+bacitracin -
DS, Negamicin B, Neobasept), retapamulin 1% - Altargo.
rils Deep folliculitis is very resistant to various topical treatments because the infection
)dy of the deeper part o f t h e f o l licle is r arely r eached by t h e a ntimicrobial agents and
represents a source for reinfection.
Washes containing clorhexidine or triclosan and dilute household bleach (0.5 cup
ges of 6% sodium hypochlorid in a full bathtub) and topical antibiotic to the narines for 5-10
om days are necessary to reduce the nasal carriage of S.aureusand decolonize the skin.
the Systemic treatment is r e quired i n s e rious, painful an d f e brile i n fections like
the carbuncle or m alignant f u r uncle of th e f ace. As staphylococci secrete beta-lactamase
2'),

37
enzyme (penicillinase) that inactivates the penicillins, beta-lactamase resistent drugs have
to used, like Augmentin (amoxycilin + clavulanic acid) or other antibiotics like oxacillin,
flucloxacillin, cephalexine, or macrolides (erythromycin, azitromycin).
A ntibiotic resistance is becoming a n i m p o rtant consideration, as m ethicillin- i ~
resistant S.aureus (MRSA), former a nosocomial infection, is now a community-acquired s
s kin infection. In these situations, trimetoprim-sulfamethoxazole, doxycyline, clindamycin, ( :
minocycline (I line treatment) or oral linezolid (II-line) are recommended, and in severe
infections, intravenous vancomycin (I-line), linezolid (II-line) or t igecycline (III-line
treatment) may be necessary.
In order to strengthen the immunological resistance of the patient one may use
v accines containing e x t racts o f k il l e d s t a p h ylococci o r th e i r in a c t ivated t o x i n s 0
(staphylococcal anatoxin).
Other bacterial infections of the skin
Erysipeloid is caused by Erysipelothrix rhusiopathiae that may afflict the hands of
those handling uncooked meat, fish or poultry (farmers, butchers, fishermen, housewives).
The organism enters the skin of the hands ( Qe interdigital webs) via an abrasion and
produces a well-defined, purplish-red plaque+hich spreads gradually, usually without
systemic involvement (Fig.4.16). Very rare fever, bacteremia and endocarditis can occur. The
li
infection can be controlled by penicillin. Disinfectants are important for the working areas.

Erythrasma is a superficial infection of the intertriginous areas (axillae, groins,

t oe w e b - spaces an d s u b m a m m ar y r e g i o ns ) c a u sed b y Gr a m - p o sitiv e b a c i l l i
Corynebacterium minutissimum, members of the normal skin flora. It typically appears
as asymptomatic, symmetric, well demarcated brown-red macular patches covered by
I,'
fine scales that evolve for a long time (months-years) (Fig.4.17). The bacillus produces
a porphyrin w it h p ink f l u orescence under Wood's light. It di f fers from tinea corporis
because tinea is accompanied by p r u r i t us, i s u sually u n i l ateral and ha s an a ctive,
vesicular, red border. • i
Treatment: topical i m i d azoles (miconazole, econazole), topical f u c i di c a cid
(Fucidin), or systemic with a 2-week course of oral erythromycin.

MYCOBACTERIAL INFECTION

Cutaneous tuberculosis - Typical forms

Primary infection results from direct inoculation of Mycobacteria tuberculosis into the
injured skin or mucosa of a child who was neither previously infected with tuberculosis,
nor immunized with BCG (bacilli Calmette-Guerin). Ritual circumcision, tattooing, ear
piercing, ingestion of m il k c o ntaminated with M b o v is and a k i s s of i n f ected parent
(infected sputum) on a child's face might also result in the inoculation of the bacillus.
Two to four weeks after inoculation, an ulcer (chancre) appears at that site. It is
g
round, with necrotic, granular base and undermined edges. Lymphangitis and regional
lymphadenopaty with cold, suppurative and draining lesions follow about 6 weeks later.
Spontaneous healing occurs within one year or more, leaving irregular scars.
This primary tuberculous complex is the skin analog to the lung Ghon complex.
ave Typical secondary tuberculosis of the skin represents the inoculation of BK in the skin
colin, pf /du] ts previous ly infected with M. tuberculosis.these patients have strong del aye d-type
l ypersensitivity r e action t o t u b erculin or p u r i fied p r o tein d e r ivative/PPD i n jected
>~adermal (positive Mantoux test, Fig.4.18). Cutaneous manifestations of th e t y p ical
.red secon
dary t uberculosis a r e : w ar t y tub e r c ulosis, t u b e rculosis c u t i s gum m o s a
cin, (scrophuloderma), ulcus tuberculous and lupus vulgaris.
~ere Warty tuberculosis occurs from exogeneous inoculation of tuberculous bacilli into
line
fhe skin of a previously sensitized adult person with strong delayed-type hypersensitivity
tp M.tuberculosis (strongly positive tuberculin test). It m ay d e velop on t he f i n gers of
use <edical personal (pathologists — the prosector's wart; laboratory workers), on the buttocks
<ins pr soles as a result of direct contact with ground contaminated by infected sputum.
Infection starts as an asymptomatic warty papule with an inflammatory rim. It
enlarges reaching several centimeters in di ameter, with f l uctuant center and p u r ulent
s of discharge (Fig.4.19). Lesions usually are solitary, may evolve and persist for years.
es). Regional nodes are not affected unless secondary bacterial ' e c tion occurs.
and
Tuberculosis cutis guxnmosa (scrofuloderma) resul s from direct extension from
iout
an underlying tuberculous focus, a lymph node, infected bones or joints. The characteristic
The
lesions are gummae. These are firm subcutaneous nodules (cold abscess) that become soft
in their central part, discharge pus leaving an irregular ulcer and heal with an inesthetic,
ins, retractile scar (Fig.4.20).
cilli
Tuberculosis cutis orificialis results from autoinoculation of mycobacteria into
.ars
the periorificial skin and m u cous membranes in p atients with a dvanced pulmonary,
. by
intestinal, or genitourinary tuberculosis. It indicates impaired cell-mediated immunity.
aces
Consequently, tuberculin positivity is variable, but usually present.
311S
In orificial TB, th e ti p a n d l a t eral m argins of t h e t o n gue are affected most
ive,
frequently; however, lesions also are common on the hard and soft palate, the perianal
skin, the vulva, the urinary meatus, and the glans penis. They start as red papules that
icid
evolve into painful, soft, punched-out, shallow, persistent ulcers.

Lupus vulgaris is the most common form of t y p i cal cutaneous tuberculosis. It

results from direct extension, lymphatic or hematogeneous spread of endogeneous or
exogeneous foci of tuberculosis.
Lupus vulgaris is localized mostly on head and neck, in particular the nose, cheeks
and ear lobes. Bacilli from the infected sputum penetrate the nasal mucosa, enter the local
lymphatics and spread in the nearby — in an around the nose. The typical manifestation of
lupus vulgaris is a red-brown plaque formed of tubercles with an apple-jelly color on
diascopy. The plaque extends slowly, for years and central scaring develops with
progressive destruction of subjacent cartilage (nose, ears). The scar is irregular, results in
disfiguring and might, in time complicate with squamous cell carcinoma.
The diagnosis is based on h i stology that shows tuber cles composed of
lymphocytes, epitheloid cells and Langhans' giant cells surrounding a central caseation.
Koch bacilli are present in very small number. The Mantoux test is strongly positive.
iter.
The diagnosis in cutaneous tuberculosis is based on biopsy with acid-fast staining
(Ziehl-Nielsen) and culture of My c obacteriaorganisms from a s p ecimen on a s p e ciflc
medium (Lowenstein-Jensen). PCR testing is increasingly used to identify mycobacterial
DNA in tissue specimens. It may be positive when both stains and cultures are negative in a[
paucibacillary disease. Culture is the gold-standard and provides the means to determine
antibiotic sensitivity and response to treatment. lel
HIV testing is recommended in all patients diagnosed with tuberculosis, because
in this case longer courses of therapy are needed.
sk
Treatment o f ty p i ca l c u t aneous t u b erculosis i s s i m i l a r w i t h pul m o n ary so
tuberculosis. Multidrug therapy is recommended as drug resistance of M.tuberculosis is cP
very common. The typical anti-tuberculous chemotherapy includes 4-drug combination of nI.
rifampin, isoniazide, pyrazinamide and ethambutol (RIPE) for 3 months, then double su
c mbination isoniazide+ethambutol for 6 months. liL
Cutaneous tuberculosis - atypical forms (tuberculids) be
(pl
The tuber culids r e present a h y p e r sensitivity r e action w i t h i n t h e s k i n to
tul
M.tuberculosis or its antigens released from a distant focus of infection in individuals with
strong antituberculous cell-mediated immunity (positive test to PPD) and current or past
tuberculosis infection. Mycobacterial organisms are absent in the tuberculid lesions (nor re1
stain positive neither culture out), but mycobacterial DNA has been detected by PCR in (rr
the biopsy specimens. m1
The tuberculids are chronic, recurrent and symmetric eruptions arising in crops: of
• p a p u l onecrotic tuberculids:
red-lilaceous papules centered by a necrotic core that st
heals with pitted scars, on the superior half of the body (acnitis type,imitating gl]
acne) or on the inferior half of the body (folliclis type, imitating folliculitis of the Th
extremities).
• lichen scrofglosorum: lichen planus-like papular eruption, on the lateral trunk
• erythema indurahIm (Basin's disease): chronic nodular vasculitis that appears on be!
the posterior calves of middle-aged women; the nodules are subcutaneous, 1-2 cm
in diameter, erythematous or violaceous and resolve spontaneously over several
months with or without ulceration, with scarring.
Papulonecrotic tuberculids and lichen scrofulosorum are widely accepted as true
tuberculids, while erythema induratum Bazin may not be uniquely caused by tuberculosis.
l
The t r eatment o f t he at y p i ca l f o r m s o f the sk i n tu b e r culosis r e quires
antituberculous chemotherapy and sometimes corticotherapy with prednison.
in(
clo
LEPROSY (HANSEN'S DISEASE)
r$
Leprosy is a disease of the peripheral nerves, but it also affects the skin, eyes, tlI1I
upper respiratory tract, the bones and testes. It is caused by acid-fast, -rod-shaped bacillus hi
Mycobacterium leprae, an obligate intracellular organism with a predilection for Schwann
cells and macrophages. trel
1111
Bacilli can be identified on tissue smears using the Ziehl-Nielson acid-fast method ]
or the Fite method. The organism grows best at 27-30'C. st
The degree of infectivity of the leprosy is rather low. The incubation period is long
(4-10 years) and it is likely that most patients acquire the infection in childhood as a result thy
of aerosol spread of nasal secretions from infected parents. Leprosy is not spread by touch,

40
rial >ce the mycobacteria can not cross intact skin. Like in tuberculosis, the primary infection
sg1c
s in many persons, but the leprosy de~~lops in only 5-10'/o, who has decreased cell
iine >~djated immunity. Depending on the level of the immune deficiency, different forms of
leprosy may develop.
use Tuberculous leprosy (TL) (when the immune deficiency is minor) involves the
sldn and peripheral nerves, with sharply demarcated hypopigmented macules that are
iary spInewhat elevated, with a d r y c e nter and erythematous borders, accompanied by a
s is cha
racteristicloss of sensation, absent sweating and reduced hairs. The lesions are few in
i of >UInber (< 5) and are located on areas with lower temperature: buttocks, face, extensor
able faces of limbs. There can be palpable thickened branches of cutaneous sensory nerves,
like lnar and common peroneal nerves. Severe neuropathic pain and muscle atrophy can
be present. Skin test with antigen from killed bacilli (lepromine test) is strongly positive
(>5 mm) showing a well developed immune response, and histology in Fite stain shows
to
tUberculoid granuloma without the presence of bacilli.
with
vast Lepromatous leprosy (LL) is c haracterized by extensive skin, eyes, bones,
'nor respiratory tract and testes involvement because expressed deficiency of immune system
< in (Ininimal cellular response) and uncontrolled multiplication of bacilli. The skin lesions are
multiple (> 6) symmetric macules, infiltrated nodules and plaques causing lion-like aspect
pf the face (facies leonine: hoarsness, loss of eyebrows and eyelashes, nasal collapse
that secondary to septa perforation). Lepromin test is negative; the histology shows diffuse
ting granuloma in which acid-fast bacilli are present in greater number (multibacillary leprosy).
the This form is highly contagious.
Borderline leprosy (BLL) represents intermediate cell-mediated response to bacilli
with variable extension and severity of manifestations, between the two forms described
~ on before.
cm
The diagnosis of leprosy is established when one or more of the following are
eral
present (WHO):
hypopigmented or reddish patches with definite loss of sensation
true
thickened peripheral nerves
)S1S.
acid-fast bacilli on skin smears or biopsy material
.ires
Treatment o f l e p r osy w a s f o r m erly d o n e w i t h D a p sone, bu t a s r e sistance
increased, multidrug t h erapy w a s i n t r o duced (1981), w it h r i f a m pin, d a psone an d
clofazimine. The length of treatment ranges from 6 months to 2 years.
Sometimes antileprousy therapy i s c o m p licated b y i m m u n ological mediated
"reactional states" called leprous reactions. These are considered medical emergencies as
yes, they can result in permanent neurological sequelae, disability and deformities. Patients at
.llus highest risk are those with multibacillary leprosy (LL and BLL).
Type I reaction (type IV allergic hypersensitivity) can appear after 2-12 months of
treatment, with worsening of skin and nerve lesions, acute febrile illness. It indicates an
hod impr
ovement of the cell-mediated immunity. It i s t reated with corticosteroids and the
specific antileprosy treatment should be continued.
ong Type II reaction (type III humoral hypersensitivity) appears after a few years of
suit therapy with a systemic inflammatory response to immune complexes deposition. It shows
sch,

41
erythematous nodules on the lower legs, being also called erythema nodosum leprosum
(ENL). The elective treatment is T h alidomide, but a lso corticosteroids can be u sed.
Thalidomide can cause severe birth defects when used in pregnancy.

A TYPICAL MYCOBACTERIA INFECTION S

"Swimming pool" granuloma or fish-tank granuloma is a chronic skin infection

caused by Mycobacterium marinum. This bacterium is found in aquatic environment (fresh
or salted water) of swimming pool, aquarium, or lakes. Cutaneous infection requires a
portal of entry, e.g. when cleaning fish-tank at home or in restaurants, or swimming in
contaminated lakes, trauma of the skin may result in exposure to M .marinum. After 3
weeks a solitary indolent papule appears at the site of inoculation (fingers, hands, feet,
elbows and knees, Fig.4.21). The lesion grows to form a verrucous plaque (granuloma) and
drains over several weeks, leaving an ulcer. A succession of nodules may ascend the arm,
along the draining lymphatics.
The diagnostic is made by the culture of tissue obtained from biopsy. Sometimes
polymerase chain reaction (PCR) can aid.
Conventional anti-tuberculous chemotherapy i s o f ten n o t v e r y e f fective, but
cotrimoxazole, doxycycline, clarithromycine for 3-4 months is usual curative.

42
sum
sed..

.tion
resh
es a Fig.4.1. Impetigo Fig.4.2. Impetigo, disseminated
s- )
er 3
feet,
and

mes

but

Fig.4.3. Ectima Fig.4.4. Secondary ecthima in a patient wraith

pediculosis corporis

Fig.4.5. Erysipela of the face Fig.4.6. Bullous erysipela

Fig.4.7. Purpuric erysipela Fig.4.8. Necrotic and bullous erysipela

 Fig.4.9 Abcedated erysipela
and onicomycosis
Fig.4.10. Recurrent erysipela
and elefantiasis

' yC

cQ

s. P'
C,

Fig.4.11. Superficial foliculitis Fig.4.12. Staphylococcal sicozis

Fig.4.13. Furuncle at the onset, as an Fig.4.14. Furuncle with burbillon

in6amatory nodule

Fig.4.15. Staphilococcal paronychia Fig.4.16. Erysipeloid

 Fig.4.17. Erythrasma Fig.4.18. Positive reaction to PPD

Fig.4.19. Warty tuberculosis Fig.4.20.Tuberculous gumma with

irregular scar

Fig.4.21. Pool granuloma Fig.5.1. Dermatoscopic image of the

burrow in scabies

F.

Fig.5.2. Nodular scabies on genitalia Fig.5.3. Scabies

 L
Fig.5.4. Norwegian scabies Fig.5.5. Pediculosis capitis

Sarc
and
Infe
rnjt(
mitt
Tile
befc
e$8'
! per<
prul

Fig.5.6. Pediculus corporis Fig.5.7. Pubic lice and tinea.

epi(

rr "'
inte
$
cha,'
pab
spR
ped

Fig.5.7. a. Detail of pubic lice Fig.5.8. Tick

inf(
oftI

kE!

Fig.5.9. Erythema chronic migrans. Fig.5.10. Larva migrans

46
 ECT(3PARASITE INFECTIQNS

SCABIES

Scabies (Latin scabere = to scrach ) is a skin infection caused by the mite called
Sarcoptes scabiei var horninis, an obligate human parasite. Scabies is transmitted via direct
~d prolonged contact with an infected individual, also as a sexual transmitted disease.
Infested bedding and clothing is an alternate source of infection, as the
mite survives up to 3 days away from the human skin. The female scabies
mite burrows in the epidermis, and lays eggs in the burrow behind her.
The incubation period is 4-6 weeks if th e i n d i vidual was not i n fected
before {the time needed for the type IV hypersensitivity reaction to mites,
eggs and scybala) or 24-48 hours from reexposure in previously sensitized
persons. The hypersensitivity r e action i s r e sponsible fo r t h e i n t ense
pruritus that is the clinical hallmark of the disease. Sarcoptes scabies
Lesion distribution, intractable pruritus that is characteristically worse at night and
epjdemiologic history (similar symptoms in close contacts) are very suggestive for scabies.
The lesions are sy mmetric, located on t h e f l e xor a spects of t h e w r i s ts, th e
interdigital we b s p aces, a xillae, e l b ows, b e l t li n e a nd but t o c ks. A r e o lae a r e
characteristically involved in w o m en, scrotum and penis in men (F ig.5.2),while soles,
palms, face and all the body diffusely in children. In adults, the interscapular region is
spared of lesions. Lesions found i n t h e i n t erscapular area and n ap e s u ggest scalp
pediculosis.
The primary lesions in scabies are:
the burrow - th e d i agnostic sign of scabies, 2-10 millimetres long, tortuous, light-
brown in color, surrounded by mild erythema. Dermatoscopy can aid visualizing the
burrow (Fig.5.7).
erythematous papulo-vesicles/pustules (1-3 mm) (Fig.5.3)
Secondary changes such as excoriations, eczematization, secondary b acterial
infection (impetigo, ecthyma and cellulitis) or postinflammatory hyperpigmentation are
often seen in patients with scabies.
There are two particular clinical forms:
• nodular scabies - especially in c hildren, brownish-red papules and nodules
develop as an exagerated hyperergic reaction
crusted scabies - fu lminant i n festation, with c r u sted l esions (Fig.5.4), in
immun
ocompromised, e lderly ( i n ability t o m ou n t a n i mmu n e response),
institutionalized persons and in neurological disorders (can't perceive pruritus,
can't scratch — a m e chanism t o r i d t h e b o d y o f mi t e s), w h e n e n o r mous
multiplication mites occurs (to thousands, compared to less than 100, usually 10-15
in common forms ).
 Treatment in a d u l ts: permethrine 5% cream (Scabex), washed off a f ter 8-l.,
h ours, can be used from 2 m o n th s of age; in i n f ants and p r egnant patients: benz~ h )
b enzoate is th e c h oice. Topical su l p hu r i n c r e am s 2-10% may b e e f f ective bu t > e
f requently i r r i t a n t a nd le s s ac c e p te d b e c a us e i t s odour. G a m m a be n z e ne
hexachloride 1% ointment (Lindan) repeatedly for 3 days, washed off after 8 hours, i
u sed as a second-line therapy because of its toxicity (seizures, aplastic anemia), no f g
u nder 2 y e ars o f a ge. A l l t o p i cal t r e atments m ust b e a p p l ie d f r o m c h i n t o t o e <
including a reas under f i n g ernails an d t o enails. A n o r a l a g ent, I v e r mectin, i s a l s~
effective in one single dose of 200-250 micrograms/kg repeated in one-two w eeks i>
typical scabies, Crusted scabies may require 3 or more doses at 1-2 week interval. m
Pruritus may p ersist up t o 2 w e ek s after succesfull t r eatment, but t y p i call>
decreases after the initiation of treatment. When persistent, antihistamines or a shor
course of topical steroids are required. lie
The family members and contact persons should be simultaneously examine<
and treated, even i f t h e y h a v e n o s y m p t o ms. A l l c a r p ets sh oul d b e v a c u u m ed
clothing laundered, bed linens and tow els washed in hot w a ter in the second day o
Cg
treatment and again after 1 week. Items that cannot be washed may be professionall~
pL
dry cleaned or sealed in p l a stic bags fo r 1 w e ek . Excess scales in cr u sted scabies
should be removed to ease the penetration of topical scabicidal agents and decreas~
the burden of infestation.
ch

PEBK.'ULOSIS
CII
There are 3 types of human lice: Pediculus humanus capias •4
•

(head louse), Pediculus humanus corporis (body louse), and Pthirus Lceas.
pubis (crab louse). Head l o use i nfestations are seen i n al l
socioeconomic groups and in school children and are not a sign of
poor hygiene, as the parasites survive underwater r'or up to 6 hours.
Body lice mainly affect the homeless. Pubic lice generally are spread
as a sexually transmitted disease (STD). Head and pubic lice infest
hair, laying their eggs at the base of hair shafts. Body lice infest
clothing, laying their eggs on fibers in the fabric seams. All 3 types
take periodic blood meals by piercing the skin of the host with their
anterior mouthparts.

Head lice spread through crawling from one person's hair to another's but als(
1
through a shared hairbrush. Lice cannot jump or fly from one person to another. Seal)
pediculosis manifests by scalp p r u r i t us. It l e ads to excoriations, secondary bacterial
infections (impetigo) and regional lymph node enlargement. Head lice are found most
commonly in the retroauricular and occipital scalp. Females lay eggs and produce)
biologic clay to form nits that attach the eggs to the hair shaft. Nits (egg-cases) are sees
just above the level of the scalp (they need body warmth to incubate) but also several
millimetres from the scalp, the latter being nonviable and indicating chronic infection
1
Nits look similar to the dandruff, but have a regular ovoid form and they adhere to th(
r 8-1i
frenzy h,rs
hairs (Fig.5.5). Blacks have a lower incidence of infestation by the head louse but may
but expe
caperience
scalp infestation by P. pubis.

nzer» Body lice live and lay eggs on the seams of clothing and only moves onto the
urs, li y to take blood meals at night (Fig.5.6). Nits are also found in the seams. The adult
i), no ferna]e body louse, unlike the head louse, can survive as long as 10 days away from the
toes h~ a n body wi t h out a blood meal.
s alsi Intense itching and papulo-vesicles caused by an allergic reaction to louse bites
eks i~ are common symptoms of body lice infestation. At sites where insects bite blue-grey
il. ~acules appear, called maculae cerulea. They are pathognomonic for infestation with
iicalbl ,ce and are caused by t h e en zymes in t h e l o use saliva that b r eaks d ow n h u m a n
shorb i]jrubjn t o b i l i v e r d in . A s a result o f s c r a tching, t h e p a t i ent h a s e x c oriations,
ljchenifications and melanoderma, condition called "vagabond's disease".
nine< Body lice are vectors of epidemic typhus, trench fever.
smed Crab lice (pubic lice) are most frequently transmitted by d i r ect physical
iay o contact with an infected indivi d ual and adapted to liv ing on thick and curled hair of
snail)
p ubic, axilary, beard, and eyelash regions. Like head l i ce, the female crab lice f i x
cabiei
their eggs to hair shafts with a cement material. They appear light-brown (Fig.5.7,
ere asi
5.7a). Intense pruritus, maculae cerulae and n i t s i n t h e a f f ected areas are h i g hly
characteristic for the crab lice infestation.
Treatment of pediculosis:
Body hce: wash clothing and bed linen in hot water and dry wi th h i gh heat; dry
cleaning also effective to kill lice and nits.
Head and pubic lice:
cleaning of h a i r a c cessories, towels, bedding, clothing ar e essential t o p r e vent
reinfestation; plain white vinegar helps dissolve the cement away from the nit and aid
in mechanical removal of nit with fine-tooth combs. Removing nits after treatment is
not necessary to prevent spreading, as these contain dead eggs.
pediculicides as 1st line treatment:
o p e r m ethrin, pyrethrine — not very effective for nits and may develop resistance
o m a l a thion (solution, spray) — effective against both lice and nits
o m e r c u ric oxide ointment — useful for eyelash infestation
o b e n zyl alcohol solution 5%
o p e d i culicides as 2nd line treatment: hexachlorocyclohexane (Lindane lotion,
cream, shampoo 1%); neurotoxic for children and pregnancy
it als(
3rd line treatment (oral): ivermectin, albendazole, levamisole.
ScalI
teria
most TICKS
duce <
. seer Ticks, Ixodes species (Fig.5.8) are common in w o o ded areas and are vectors of
vera'. Lyme disease caused by the spirochaete Borrelia burgdorferi.
ction Lyme disease is divided into three stages:
to th< 1) acute illness: erythema migrans at the site of the tick bite appears 1 day-1 month after
the tick bite and develops an annular shape greater than 5 cm in diameter (Fig.5.9);
headaches, fever, myalgia and arthralgia may associate;

49
2) d i ssemination phase: secondary annular skin l e sions, migratory arthritis, cardiac
arrhythmias and meningitis; antibodies to the spirochete are developed;
3) l at e chronic phase, 2-3 years after untreated initial i n fection: destructive chronic
arthritis, acrodermatitis chronica atrophicans and neuropathy.
Treatment: doxycycline 100 mg bid or amoxiciline 500 mg tid for 3 weeks.

C UTANEOUS LARVA M I G R A N S

Larvae o f h o o k w o rms (a n aglostoma duodenale, strongyloides stercoralis) g i v e

usually
a ccidental i n fection i n h u m an s t h a t a r e d e ad-end h o sts. Th e i n f ection i s
encountered in barefoot beachgoers/sunbathers after contact with warm, moist, sandy soil
ide
etc. that contain animal feces contaminated with parasitic eggs. The larvae penetrate the
s kin and m i g rate through a t u n nel i n t h e e p i dermis and u p per de rmis, giving the a l a
dis.
characteristic sign of erythematous, slightly elevated, serpiginous (snakelike), advancing
fail
lines (2 cm/day) (Fig.5.10). Intense pruritus is associated. Erythema, urticaria plaques,
vezicles/bullae may also appear. yea
The treatment of choice: thiabendazole ointment 5-10% for early, localized lesions reg
inf i
or tablets for widespread lesions. Alternatives: mebendazole, albendazole, ivermectin as
inc
oral treatment.

im.
be1

sta

ca1

sp
ke

(F
le!
bl
lil
af

Pl
a1
s(
K

50
.rdiac
Chapter 6
.ronic

VIRAL INFECTIONS

WARTS (VERRUCAE)
give
ually ~ art s a r e b e n i g n e p i d e r ma l n e o p l asms c a u sed b y v ir u s e s o f hu m a n
y soil papillomavirus (HPV) group. Currently, more than 100 types of HPV have been
:e the >gentjfjed, with a tendency of certain HPV types to occur at particular anatomic sites.
g the +arts are transmitted by di rect or indirect contact, and predisposing factors include
ncing djsruption to the normal epithelial barrier. Treatment can be difficult, w it h f r equent
.ques, f ajlures and r e currences. Many w a r ts, h o w e ver, r e solve s p ontaneously w i t h i n 2
y ears. Probably cell-mediated immunity (CMI) p l ays a significant role in wart
.sions regression; patients w ith C M I de f i c i ency a r e p a r t i c u l arl y s u s ceptible t o H P V
tjn as i nfection and a r e n o t o r i ously d i f f i c ul t t o t r e at . A s m a l l s u b set o f H P V t y p e s,
i ncluding t y pe s 16 , 1 8 , 3 1 , 3 3 a n d 3 5 i s a s s o ciated w i t h t h e d e v e l o pment o f
rnaijgnancjes, m ost c o m m o nl y s e e n i n per s i s t en t g e n i t a l i n f e c t io n a n d i n
j~rnunocompromjsed p a tients. I n fection w i t h H P V 6 a n d 1 1 i s a s s o ciated w i t h
benign lesions and low-grade intraepithelial neoplasia.
C linial manifestation depends on th e H P V t y p e i n v o l ved an d t h e i m m u n e
status of the patient.

Common warts (verruca vulgaris) a ppear as h y p e rkeratotic, yellowish

cauliflower-like papules (verrucosities) with a rough, irregular surface, smaller than 1
cm in diameter, most frequently on the hands (Fig.6.1., 6.2, 6.3). They may resolve
spontaneously in children. Common w arts have to be di fferentiated from seborrheic
keratoses, actinic keratoses and hypertrophic lichen planus.

Plantar warts may be: a) deep, solitary or scattered over the sole of the foot
(Fig.6.4), or b) more superficial and grouped together (mosaic warts, Fig.6.5). The
lesions are round, sharply d efined, with r o ugh k eratotic surface that covers several
black dots produced by th r ombosed capillaries. Plantar warts are frequently painful
like calluses and corns, but these develop in areas of friction over bony pr ominences
and appear without capillaries, as uniformly thickened skin (calluses) or with painful
central plug of keratin (corns).

Plane warts (f l at w a r t s) a re t i n y , f l e s h-coloured f l a t o r s l i g h t ly e l e v a ted

papules that are smooth, usually localized on the face and dorsa of the hands. Children
»d w o men ar e m o s t f r e quently a f f ected (F ig.6.6). I n oculation o f t h e v i r u s i n t o
scratches and abrasions cause frequently disposition of these warts in l i nes (pseudo-
Koebner sign)

Viral papiloma are long, narrow, frond-like and flesh-colored elevations that
grow rapidly, usually on the face (Fig.6.7, 6.8, 6.9)

51
 Genital warts (condyloma acuminata) are one of t he m ost common sexuall~
transmitted disease (although min or). They are caused by certain types of HPV th p~
can also cause cervical and penile cancer. Among the strains in the genital area (aboq
40), 13 are high-risk (strains 16 and 18 cause 70% of all genital cancers) and the other!
are low-risk, sometimes yielding changes in pap smears but not progressing to cance!
(6 and 11 cause about 90% of genital warts).
The virus is transmitted through d i rect genital contact. Extremely unl ikely i,
transmitted through shared clothing, bed sheets etc. The incubation may be anywher!
from 1 week to more than 1 year and lesions become apparent after additional month <
or years.
Condylomata appear as d i screte small p a p u les w i t h s m o ot h s u r f ace, skin.
colored, brown or w h i t ish (w hen m acerated), that becomes papillomatous and late!
acuminated ( v egetations) w i t h w e t a s p e ct. T h e l e s ions measure on e t o s e v er<I
m illimeters diameter but t h a y m a y a l s o p r esent as p educulated papilomas, up t !
several centimeters diameter, with f oul smell (Fig.6.10, 6.11). They are located on th!
external genitalia, perineum and perianally and may extend in the adjacent cutaneous!
areas like inguinal fold, mons pubis and also mucosal areas like vagina, uretra an)
anal canal.
Giant condylomata acuminata (Buschke-Lowenstein tumor) i s a ssociated wi Q
low-risk HPV types 6 and 11 and extensive growth as large cauliflower-like tumor an<
deep infiltration. It i s b enign bu t t r a nsformation i nt o sqarnous cell carcinoma mal
occur.
High-risk HPV type (HPV-16) is associated with squamous cell carcinoma ir
situ t ha t m a y p r e sent a s m u l t i p l e b r o w n - red p a p u les o n t h e e x t e rnal g e n italia
perineum and perianally (Bowenoid papulosis)or eroded plaques on penis shaft or vulv<
(Erythroplasia of Queyrat). Biopsy is warranted to exclude malignancy.
Genital warts should no t b e c o nfused w it h c o n dyl oma l ata f rom secondary
s yphilis, a l t h ough t h e t w o di s e ases ma y a s sociate. M o l l u scum c o n t agiosum i !
frequently located in the genital area but has a different clinical aspect. fl
Oral warts results from d i g i t al or o r a l-genital sexual transmission, as small
soft, white or pink papules or plaques. Transformation in oropharyngeal cancer mal
occur.

Therapy
3
There is no specific antiviral therapy to cure HPV infection. Treatment is aime(
at destruction of the warty growths rather than elimination of the virus. HPV infectio!!
is usually self-limited but l i f e l on g subclinical infection may be also possible. Mosl
sexual partners are likely to be sub clinically infected with HPV (no exophytic lesions)
Use of condoms may, in some cases, reduce transmission of the v i rus to u n i n fecte <
partners.
Local destructive therapies
salicilic acid, tricloracetic acid, glutaraldehyde or formaldehyde
cryotherapy with l i q uid n i t r ogen, repeated every 1-4 weeks for approx.3 month(
0
(using a cryospray or a cotton bud applicator on a stick, until the lesion is frozen),
paring plantar warts is a valuable adjunct to cryotherapy

52
:ually electrosurgery requires local anesthesia
~ that l aser is an expensive treatment, reserved for l a rge or r e fractory w a rts; mu l t i p l e
about treatments may be required.
)ther' Cytotoxic therapy
ancet > odophylotoxin 0.5% solution (Condyline) - t h e m ost active constituent of t h e
plant extract p odophyllin w hich i s n o lon g e r u s e d d u e t o its tox i c i t y ;
ely i< >odophylotoxin is a self-applied treatment, more efficient that podophyllin an d
vhere contraindicated in pregnancy
onto' 5-Fluorouracil cream (5-FU)
Topical immunomodulators
skin irniquimod 5% stimulates the innate immune response to produce cytokines (IFN-
latet ~, TNF-a, IL 1 2); it w o r k s w el l o n m u c osal sites, while on c u taneous areas its
.ver al penetl ations is i n creased by s alicylic acid p r e parations or c r y o therapy; l o nger
ap ta periods of treatment are usually needed, e.g. 3-6 months
inthe s jnecathechins 15% o i n t m ent c o n t ains g r een-tea l eaf d e r i ve d c a t echins w i t h
scout immunostimulatory and antiproliferative properties
a and HPV vaccines
The new vaccines Gardasil and Cervarix are designed to elicit vi r us-neutralizing
witl antibody responses to prevent initial infection with the HPV types represented in
~1 and the vaccine, HPV 16 & 18 (that cause cervical pre-cancers) and HPV 6 & 1 1 (that
. may cause genital warts). It is recommended for w o men and men 9-26 years old, who
have not contacted HPV infection. The research continues to develop therapeutic
ma is vaccines that elicit the immune responses against established HPV infections and
italia, HPV-induced cancers.
vulvB
MOLLUSCUM CONTAGIOSUM
n.dary
im is It is caused by a pox v i r us. Hemispheric, firm, u m b i licated papules that are
flesh-colored, white or translucent, usually 2-6 mm in diameter, arranged in groups or
small, widely disseminated are very characteristic for molluscum contagiosum. The papules
may are filled with a white material containing virus-infected degenerated cells.
In children transmission occurs from nonsexual skin contact and the lesions are
frequently localized on the face, neck and trunk (Fig.6.12).In early adulthood (age 15-
30 y) molluscum contagiosum occurs as a sexually transmitted disease (minor) and is
aimed localized perigenital, on the lower abdominal wall, inner thighs, buttocks (Fig.6.13)
'ctios
The goal of the treatment is the destruction of the lesions. The central hard core
Mosl of the lesions is removed with a sharp curette or squeezed out then 1% alcoholic iod is
ions), applied. Cryotherapy, imiquimod cream or podophylotoxin can also be used.
:ected

MILKER'S NODULKS

ont The disease, caused by parapox virus, is a zoonosis in cattle. In humans, it is an

occupational disease, contracted after contact with th e u d d ers of i n fected cows. The
>zen,,
incubation takes 5-7 days and then hard hemispherical yellowish-brown or r e d dish-

53
blue nodules, 0.5 cm in d i ameter, appear on the mi l k er's fingers, hands or forearms
(Fig.6.14). The initial target aspect (a papulovesicular lesion with a r ed centre, white
ring, and red periphery) is followed by weeping (loss of epidermis over the centre),
crusts and regression. Fever, lymphangitis and r egional lymphadenopathy may
a ssociate. The c o urse i s u s u ally s e lf-limited, r u n n in g f r o m 3 - 6 w e e ks. T o a v o i d
secondary infection, local disinfecting agents can be applied.

ORE

It is t r ansmitted b y c o ntact w i t h i n f ected sheep or g o ats, causing m i l k er'8

nodule-like lesions. No human-to-human transmission occurs.

HERPES SIMPLEX

Herpes simplex viruses (HSVs) are double-stranded DN A v i r u ses that cause

acute skin infections characterized by grouped vesicles on an erythematous base. HSV
type 1 (HSV-1) is commonly known to cause herpes labialis and keratitis, whereas HSV
type 2 (HSV-2) is commonly known to cause genital herpes, but in reality these
antigenic types can locate anywhere on the body.
T ransmission of H SV can occur even d u r in g asymptomatic periods of v i r al
shedding. HSV-1 is spread through di rect contact with contaminated saliva or other
secretions, while HSV-2 is spread primarily by sexual contact. Contact must involve
m ucous m embranes o r a b r aded s k in . V i r u s r e p l i cates at m u c o cutaneous site o f
infection and then travels to the sensory dorsal root ganglia where remains latent (non-
v
infectious state) until reactivation.
t
Viral shedding an d p o s sible t r ansmission occur d u r i n g p r i m ar y i n f e ction,
during subsequent recurrences, and during asymptomatic periods.
Once a patient has become infected by herpes virus, the infection remains for
life. HSV-1 infection is acquired by early childhood, and almost 80% of adults have
positive HSV-1 serology but only a small part of them (20%) have clinically apparent
outbreaks during their lives. The seroprevalence for HSV-2 varies from 13% to 40% in
the adults worldw i de, but more than half of these do not experience clinically apparent
outbreaks, while they still have episodes of viral shedding and can transmit the virus.
The HSV-2 infection is one of the most rapidly increasing sexually transmitted disease.
Primary herpes simplex infection is c l i n i cally m o r e s e vere than r e current
outbreaks. However, most primary HSV-1 and HSV-2 infections are asymptomatic and
may never be clinically diagnosed. Incubation is 3-7 days. Clinical forms of p r i m ary
herpetic infection:
• p r i mary orolabial herpes (HSV-1 more frequently) - t he m ost common is
h erpes l a b i alis, m i g h t be sev e r e w i th f ev e r , i ntense p a i n , e r o d e d
gingivostomatitis and odynopfagia, anorexia
• p r i mary genital herpes (HSV-2 most frequently) - occurs 2 days-2 weeks after
exposure with p ainful eruption, sometimes with f ever, malaise and inguinal
lymphadenopathy
arms • pr i ~ a r y c utaneous herpes -with HSV-1 frequently on the face, or on the fingers
v'hite {herpetic w h i t l ow ) i n c h i l d ren w h o s u c k t h ei r t h u m bs, i n d e n ta l w o r k e r s
etre), (before the spread of gloves) or with HSV-2 after digital-genital contact.
may • he r p etic keratoconjunctivit is -may cause corneal ulcers
!Void • ec g eflla herpeti curn — it is a rapid, widespread cutaneous dissemination of HSV
infection in areas of dermatitis or skin b arrier di sruption (atopic dermatitis,
burns); it occurs especially in c h i l dren, usually w i t h H S V-1 and can be li fe-
t hreatening; i t a p p e ars a s m o n o m orphic, d i s crete 2- 3 m m e r o s i ons w i t h
hemorrhagic crusts
ker's • ne o n a tal H S V -2 h e r pes - m a n i f ests w i t h in t h e 2 " d w e ek f r o m b i r t h a f t e r
exposure to HSV during the vaginal delivery; the risk is higher if the mother
acquires a HSV-2 infection in the third semester of pregnancy; the infection in
newborn clinically r anges from l ocalized skin, mu cosal, or eye i n fections to
encephalitis, pneumonitis, septicaemia and death.

Recurrent herpes simplex

'.ause
About 20% of HSV-1 and 50% of HSV-2 infections are recurrent. They tend to
HSV
HSV occur at or near the muco-cutaneous site of inoculation, within the distribution of the
these sensory nerve. Stimuli that in d uce recurrences are, most frequently, febrile diseases
for herpes labialis (cold sore) (Fig.6.15) and intercourses or menses for herpes
viral genitalis (Fig.6.16). Other f a vouring f a ctors a re t r a uma, u l t r aviolet r a d iation,
other extremes in temperature, stress, immunosuppression, or h o r m onal f l u c tuations (at
rolve menses).
Recurrent clinical outbreaks are milder than the primary infection and have a
te of
',non- prodrome of pain, itching, tingling, burning, or paresthesia. A group of clustered
vesicles appear on an er ythematous base, eventually t ur n i n t o p u stules or erosions
then form a crust and usually resolve in 10-14 days (Fig.6.17, 6.18).
:tion,
Individuals exposed to HSV may have asymptomatic primary infections and
experience an initial clinical episode of herpes months to y ears after th at. Such an
is for
episode isnot as severe as a true primary outbreak.
have
Recurrent herpes simplex can trigger episodes of erythema multiforma.
arent
)% in Diagnosis of herpetic infection:
arent 1. Detecting the virus from infected cells — in symptomatic patients by
rirus. • cytologic examination (Tzank smear) — scraped cells from the base of the
.ase. erosion show i n t r anuclear inclusion bodies and m u l t i nucleated epithelial
rrent giant cells
. and • direct fluorescent antibody assay (DFA) test detects the HSU antigen and
mary distinguishes it from varicella zoster virus (VZV)
• pol y m e r a se chain reaction (PCR) — detects HSV DNA i n s p e cimens from
3n iS the skin, mucosa, cerebrospinal fluid etc; most sensitive
oded • virus culture — the gold standard, used for typing
Type- specific serologic tests — for asymptomatic or unrecognized patients with
after genital herpes wh o serve as reservoirs for H S V t r a n smission or f o r s exual
uinal p artners of p a t i ents w i t h g e n i tal h e r pes; t hese tests d etect a n t ibodies t o
glycoproteins G1 for HSV-1 and G2 for HSV-2
 Treatment
or IIl
HSV infections are usually self-limited. H o w ever, antiviral t h erapy shortertl alIl
t he course of th e sy m ptoms and m a y p r e v ent t r ansmission. Oral, i n t r avenous an) p
topical antiviral medications are available for treatment of HSV and are most effectiv< bastI
if used at the onset of symptoms (during the prodrome). Antiviral therapy is virustat>~ freQ'
blocking the virus replication; it is not viricidal and is not curative, since HSV remain~ invk
latent in sensory ganglia. the
Oral antiviral therapy with acyclovir, valacyclovir or famcyclovir can be give~ for
at the time of th e episode or as chronic suppressive therapy. Intravenous acyclovp ca
may be u se d i n s e v ere f o rm s o f h e r p e ti c i n f ections o r i n i m m u n o c ompromise]
individuals. Topical treatments are less effective than oral therapy.

Recurrent i s o des Su r e ssive thera

Dru First clinical e isode
200 mg x 5/day, for 5 days 400 mg x 2/day for up to 1 year
Acyclovir 200 mg x 5/day, for 10 days
(followed by reevaluation)
500 mg x 2/day, for 3 days 1 g /day for up to 1 year
Valacyclovir 1 g x 2/day, for 10 days
500 mg / day for up to 1 year
1 x 2/da , f or l day 250 mg x 2/da for u t o 1 year
Famcyclovir 2 50m x 3 / d a for 10da s
Table 2. Dosage recommendations for antiviral therapies in patients with genital herpes.

Imiquimod i s a t o p i cal i m m u n e r e sponse m o d i fier ( s t i m ulates th e i n n at<

i mmune r e sponse), w h il e I s o p r inosine i s a non-specific i m m u n ostimulant o r a lly
administered. Both may be used to reduce the frequency of recurrences.

HERPES ZOSTER (SHINGLES)

Zoster is a common, predominantly cutaneous and neurologic disorder causei

by the varicella-zoster virus (VZV).
VZV i s a DN A v i r us th a t i s tr a n s m i t te d t h r o u g h h i g h l y c o n t a g iouI
respiratory droplets or by direct contact. The primary infection with VZV is varicell8
usually in childhood. After the cutaneous lesions heal, the virus remains dormant h
dorsal root ganglia or cranial sensory ganglia often for d ecades. More then 90'/o 0
the adults h ave serologic evidence of V Z V i n f e ction. Because circulating specifil
antibodies develop, the person wil l no t d evelop varicella after a subsequent contac
with the vi rus, but this mi ght reactivate later on (in 10-30% of the individuals) an)
cause a localized recrudescence called herpes zoster or shingles. When reactivated
f
t he virus m i g r ates down th e sensory nerves to th e skin an d l e ads to i n j ur y o f t h
keratinocyte nuclei and subsequent intracellular edema, producing the characteristi( fa
vesicles. fr
Shingles is a dermatomal disease manifesting in 1 posterior spinal or crania s
sensory ganglia (ganglionitis) with pain (nevritis) and characteristic unilateral lesion.'
(vesiculization) on the skin innervated by this sensory nerve.
The triggers of this reactivation have not been precisely determined, but could p
be malignancies, particularly of l y m p h oreticular system, acute or chronic infection
emotional stress, or the factor remains undiscovered. Recently, a genetic susceptibilit)
to zoster has been demonstrated.

56
 Most pf the patients present prodromal sensory phenomena with pain along 1
~pre sk1n dermatomes 1-10 days before skin lesions appear. This pain may simulate
.ortegapr @lore
in pf different other etiologies and can result in incorrect diagnosis.
~s an~ pa]n 0
The clinical aspect is typical: vesicles (2-4 mm) grouped on an erythematous
fectiy<
e and associated pain confined to one unilateral dermatome (Fig.6.19, 6.20), most
usta'
frequently pn the thorax or abdomen. The eruption stops abruptly at the midline of the
.main<
;nvplved dermatome. Regional lymphadenopathy may appear. Initially the content of
the vesicles is clear, but subsequently becomes cloudy and dries up in a few d ays to
give>
fprm crusts. The condition resolves within 2 w e eks wi thout v i sible sequels. Scarring
jr clove|
can pccur if secondary infection or necrosis complicates the evolution (Fig.6.21).
)mise]
Cpmplicated forms of herpes zoster.
]. I n i m m u n osuppressed individuals herpes zoster is pluridermatomic or even
disseminated (varicelhform) with n u m e rous extradermatomal vesicles that
may be hemorrhagic or necrotic (Fig.6.23).
1 year
) postherpetic neuralgia may develop, usually in elder patients, defined as the
persistence of pain for w e eks, months, years after the cutaneous lesions
have resolved.
3. Other less common postherpetic sequels include hyperesthesia,or more
rarely, local anesthesia or in v olvement of m o tor f i b res with mu scle palsy
innatt and subsequent atrophy.
oral) 4. I n t r i g eminal zoster the ophthalmic d i v i sion is most frequently i n v o lved
(zoster o p h t almicus, Fi g .6.22). O c ular i n v o lvement wi t h co n j u n c tivitis,
keratitis and iridocyclitis is heralded by zoster rash on the tip, side or root
of the nose due to involvement of the nasociliary branch of the ophthalmic
d ivision. O p h t halmic i n v o l v ement r e q u i res i m m e diate r e ferral t o t h e
ophthalmologist innorder to prevent vision loss.
cause
5. Ra msay Hunt s yndrome defines herpes zoster infection t hat i n v o l v es the
geniculate ganglion of facial nerve (CNVII) and sometimes other nearby
agiou
cranial nerves, like CN VIII, IX, V an d V I ( i n o r der of f requency). It
ricella
presents with vesiculation and ulceration of the external ear and ipsilateral
1ant it
anterior 2/3 of the tongue and soft palate, ipsilateral facial paresis. Vertigo,
30% 0
h earing loss, ti nnitus, headaches or d y s arthria ma y a l s o d e v elop. T h e
pecifi i
'.onta( overall prognosis is good, but complete recovery of the facial nerve occurs
in less than 50% of patients.
.s) an(
ivated
Treatment
of th
Systemic treatment w i t h o r a l o r i . v . a c y clovir o r d e r i v a tives (v alaciclovir,
teristi i
famciciovir, penciclovir) has to be started as early as possible, ideally wi t hin 72 hours
«pm the onset of symptoms. It shortens the duration of zoster, prevents or reduces the
crania severity of postherpetic neuralgia. The dose for acyclovir is 800 mg x 5/day for 7-10
lesion
"ays; valacyclovir 1000 mg x 3/day for 7 days.
A cute pain du e t o d e m i elinisation of t h e n e r ves is t r eated w it h v i t a mi n 8
: coun
preparations in combination with analgesics. Glucocorticoids are sometimes used early
etio%
'« h e disease to reduce acute pain (by anti-inflammatory effect) but care has to be
tibilitI
taken in severe cases of zoster when dissemination of viral particles is possible.

57
 Postherpetic n e u ralgia can be a l l e v iated w i t h a n t i e p ileptics ( g abapenti>
carbamazepin), tricyclic antidepressants (doxepin, amitriptiline) and capsaicine crea>
(depletes neurotransmitters like P substance at involved nerve endings).
A ntibacterial treatment i s o nl y n e cessary in p a t i ents wh o ar e a t r i s k f r y >
infections to protect them against secondary bacterial infection.
Topical t r eatment u se s w e t a n t i septic d r e ssings with 1 % z i n c s u l p h at~
cloramine 8 or cyclohexidine to dry lesions and control secondary infections. After t >,
vesicles have dried up, softening antiseptic ointments are indicated.
A vaccine for p r evention of z o ster (Zostavax) was approved in 2 006 in t$,
Unites States for persons older than 60 years, including those with previous episode <
zoster or who have chronic medical conditions. It is a live, attenuated strain of VZ)
the same strain as in varicella vaccine, but much more potent.

58
senti',
crea@

; frog

mph ate
'ter th»

in th(
ode o> Fig.6.1. Common wart Fig.6.2. Diseminated common warts
E VZW

1
4

Fig.6.3. Periunghial warts Fig.6.4. Deep plantar wart

Fig.6.5. Mosaic plantar warts Fig.6.6. Plane warts

Fig.6.7. Filiform wart Fig.6.8. Filiform wart

 5 ,1 002
l ~ -j
Fig.6.9. Keratotic 61iform wart Fig.6.10. Genital warts

Fig.6.11. Genital warts Fig.6.12. Molluscum contagiosum

Fig.6.13. Molluscum contagiosum Fig.6.14. Milker's nodul

Fig.6.15. Labial herpes Fig.6.16. Genital herpes

 wc,

\
( 0 ) '4'!

Fig.6.17. Cutaneous herpes simplex Pig.6.18. Herpetic whitlow

')

Fig.6.19. Herpes zoster (initial lesions) Fig.6 20. Herpes zoster

. •

Fig.6.21.
Scarring after herpes zoster Pig.6.22. Herpes zoster ophtalmicus

' • •

p<' j c '

') •

).
I

»g 6 23. Variceliform herpes zoster Fig.6.24 Varicela

()allI
nm)
T.p(
d( t<

COIl.'
to i'
ver )

lbn

lynI
higl
P I'0

huf
h Ll I
no
ill'( i

PII

intl
t rl
infj
do
 Chapter 7

SEXUALLY TRANSMITTED DISEASES (STD)

SYPHILIS

Syphilis is a chronic systemic venereal disease caused by the spirochete Treponema

p<ilidg~ a facultative anaerobic organism of the tissue, not the blood. It is very small (5-15
coiled like a c orkscrew w it h u n i f orm t u r ns, bending and r o t atory m ovements.
T ppllidgm is difficult to s tain. Dark-field microscopy is the method of c hoice for T.p.
detection and differentiation from other saprophytic spirochetes by shape and movements.
Syphilis is t r ansmitted f ro m i n t i m ate contact w it h i n f ectious lesions (sexual
contact most common), by blood transfusions, or transplacentally from an infected mother
to her fetus. Transfer via smear infection plays only a minor part, because T.pallidum is
very sensitive to drying, temperature fluctuations and pH variations.
T.pa
llidi rapidly p enetrates intact m ucous membranes or m i c roscopic skin
abrasions and multiplies at the p ortal of entry. The infection remains localized until
regional ganglia face the multiplication of T .p., but after a few w e eks T.p. enter the
lymphatics and blood to p r oduce systemic infection. In this early phase the patient is
highly contagious, but as the disease progresses and the immune response becomes more
prominent, the patient becomes less contagious.
Antigens of T. p allidum i n d u ce a h y p e r sensitivity r e s ponse in t h e h o s t o f
humoral (synthesis of antibodies), and cellular (delayed, T-cell mediated) type. The
humoral response results in I g M a n d I g G s p ecific anti-treponemal antibodies and
nonspecific reagin antibodies. The cellular reaction results in mononuclear infiltrates
around Treponema, responsible f or t h e c u t a neous a nd v i s c eral m a n i f estations. In
primary syphilis a unique infiltrate appears at the portal of entry of treponema and
results in the chancre formation. In secondary syphilis the im m une reaction is more
intense and explains the formation of the macules and, specially, the papules. In the
tertiary syphilis, the immune reaction is exaggerated and produces giant inflammatory
infiltrates corresponding t o g u m m a . T h e t r e p onemas w i t hi n t h ese i n f i l t r ates are
d estroyed„but some persist in a l a tent state in th e l y m p h atic ganglia and m u l t i p l y
from time t o t i m e , y i el d s m al l e p i sodes of bacteriemia an d t h u s t h e r e c u rrent
cutaneous and/or visceral eruption.
The immune reaction in syphilis is incomplete, for example it may prevent the
forInation of a primary lesion (chancre) on subsequent infections with T paliidum, but it is
~ns«ficient to clear the organism. Nevertheless, there is some efficiency of the immune
«sp»se, as only 15-20% from th e i n fected and u n treated patients develops tertiary
I• yphilis Also, some heal spontaneously but they remain contagious for a number of years,
until then.
Syphiiis is characterized by episodes of active disease (primary, secondary, tertiary
'a '"'ges) interruPted by Periods of latency. The current classification of syPhilis is as follows:

63
• Acquired syphilis
o E arly syphilis
• pr i m a ry syphilis e
• secondary syphilis P
• early latent syphilis
o L a t e syphilis lab

• tertiary syphilis IW
P
• late latent syphilis t,
o P arenchymal syphilis (cardiovascular syphilis, tabes dorsalis, general paresis)
• Congenital syphilis j
o E a rly congenital syphilis lymf,
o L a t e congenital syphilis nod<
Acquired syphilis is distinguished from the congenital syphilis; the former occam
through exogenous transfer and u sually b egins w it h a p r i m ar y c h ancre (except th~
clas
transfusion syphilis, where the spirochete enters the bloodstream directly, thus the chancrt
i s lacking and secondary syphilis occurs from t h e b eginning), w h ile th e l a tter is ; ( s e r
ofT
consequence of the transfer of the spirochetes through the placenta to the foetus from @
infected pregnant mother.
ch
Known as a great imitator, syphilis can be a diagnostic challenge because of h
(tra
wide-ranging clinical presentations.
Acquired Syphilis
j
Primary Syphilis (stage I)
(sy
Primary syphilis occurs 3 weeks (incubation period) after the contact with z my
infected individual and is marked by the development of the chancre at the portal of entrI
and regional lymphadenopathy.
The chancre is usually single. It starts as a small indolent papule and in a few day,
it reaches its c h aracteristic aspect: round-oval erosion, 4-8 m m i n di a m eter, w it} asp
cartilaginous consistency on p alpation (pathognomonic character!), smooth, lacquere< Up
surface and sharply delimited edges (Fig.7.1). The classic lesion is usually painless an( ite
heals in 4-8 weeks even without therapy, leaving no scar. It differs from the chancroi( the
which has undermined margins.
Clinical forms of chancres:
giant chancre or microchancre
multiple chancres - when simultaneous entry sites occur be
air
successive chancres - when further infection occurs during the incubation time; <
soon as sufficient specific immunity develops, no other chancres appear
phagedenic chancre — with necrotic tissue extending to the depth, heals with scat
fa'
occurs when contaminating bacteria associate.
Chancres are most often located in genital regions, but extragenital chancres can b
m
encountered:
genital chancres:
sy
o i n m e n : on the glans penis and coronar sulcus, penis shaft, scrotum or pubj t
ra
area; when the chancre is on the prepuce, and the prepuce is drawn back, j:
fi
will flip over all at once, being too hard to bend (a dory-flop phenomenon)

I
 p in women, on the major and minor labia, clitoris or urethral opening; in vagina
it is often overlooked
extragenital chancres: in the oral cavity (Fig.7.2),on the lips, on the nipple, in the
perianal region, or enywhere else(Fig.7.3)
The chancre may complicate with:
ay~osis(tight prepuce cannot bedrawn over the glans penis)
paraphymosis (prepuce, after being retracted behind the glans penis, is constricted
there and can not be brought into place again)
.sis) elep
hantiasis(g iant edema).
One week after the chancre, swollen lymph nodes (syphilitic bubo) develop in the
lymph drainage region that is inguinal, if the primary lesion is genital (Fig.7.4). The lymph
nodes are hard with freely movable and of normal color overlying skin. Regression of the

occur! swollen lymph nodes occurs within 2-8 weeks.

The primary syphilis has two substages: 1) seronegative, 2) seropozitive. The
pt t4
hancrt ciassica] serum tests are nonreactive in th e f i rst 2-3 weeks after the chancre appears
r is ~ (seronegative primary syphilis). In this case the diagnosis of syphilis is based on detection
of T.pallidum by dark-field microscopy.
)m th
Syphilitic chancre should be differentiated from: genital herpes, candida balanitis,
chancroid (jagged border, yellow exudates, painful), lymphogranuloma venereum
. ofig
(transient, indurated, painless), fixed drug eruption, squamous cell carcinoma.
Secondary Syphilis (Stage II)
In secondary syphilis spirochetes flood the entire body via the blood and lymph
(syphilitic septicaemia) causing general symptoms: micropoliadenopatia, fever, malaise,
ith a!
myalgia, headache, pain in the long bones and visceral manifestation.
f entrv The cutaneo-mucous manifestations in t his stage are called syphilids. Initially
t hese are symmetrical macules, more or l ess generalized, and l ater p apules w it h a
iv de! tendency for asymmetry and grouping in cocardiform, serpiginous and corymbose
, witl aspects. The syphilids almost never itch and they commonly heal without scars or atrophy.
guerec Up to 25% relapse within the first 1-2 years. The secondary syphilis lasts 2-6 months until
ss aS it enters the latent phase. The serum tests are reactive and T. Pallidum can be detected in
incroi( the lesions, thus secondary syphilis is contagious, especially the eroded lesions.

Cutaneous secondary syphilids:

Macular syphilids (roseola) are the earliest manifestation of secondary syphilis,
beginning about 6 weeks after the chancre (9 weeks after infection), when the chancre may
.me; $ already be regressing. Roseola are discrete macules, 2-10 mm diameter, pale-red, round,
not clearly demarcated, symmetrically located on th e fl anks and shoulders. They are
h scl neither scaly, nor itching and regress spontaneously in a few days (Fig.7.5). They are so
faint that might not be observed by the patient.
Macular syphilids should be differentiated from pityriasis rosea, primary HIV
infection, drug eruption.
Papular s y p h i l i d s c a n o c cu r t o g e ther with th e
r oseola (maculopapular
p pubi' syphi»ds) or may follow them after a short latency period. The papules are round, of a
~ack,! a+-"am or coppery shade, 2-5 mm in diameter, slightly raised but with a palpable
f'™ infiltration (Fig.7.6, 7.7). Papular syphilids tend to be initially d isseminated and
)n)

65
symmetrical, but later localized, asymmetrical, hypertrophic, sometimes confluent, q
arranged in patches, rings, corymbose or serpiginous patterns. Without treatment, tg
lesions resolve over several weeks to months. Relapses occur especially in the first year, ®hll
Variations from the above described picture may be observed: coul
• len t i c ular syphilids — disseminated, with smooth, shiny surface, like in lichen planus v\Thl
• pap u l o -squamous syphilids — disseminated, covered by adherent scale, like in guttat, dev'
psoriasis mfll
• pal m a r a nd p l a n tar s yphilids — characteristic site of i n v o l vement; coppery, flat
indurated papules with squamous collarette (Biett) or hyperkeratotic surface (Fig.7,~ oth
7.9); de
• split papules at the oral comrnissures or in the crease of alae nasi
• hypertrophic papules and papulo-erosive syphilids, with their large variant condyle,sp
lata occur in intertriginous regions, especially about the genitalia and anus, sometirnq;
in axillae and g r oins; they are broad f lat (1-3 cm) p a pules wit h s m ooth, moist
s
weeping, gray-white surface and characteristic foul smell; they are highly contagiou
(Fig.7.10, 7.11, 7.12). Condyloma lata in should be differentiated from condyle;
acuminate (due to HPV) and squamous cell carcinoma.

M lcosal secondary
syphilids se
Mucous patches are the most infectious lesions of secondary syphilis. They aa fl
painless, superficial, silvery-gray erosions with red periphery, located on: an
the lips, oral mucosa, tongue (Fig.7.13), palate, pharyngs (syphilitic sore throat)
laryngs (syphilitic laryngitis with hoarsness or aphonia), tonsils (angina syphilitica);
glans penis, inner prepuce, vulva and vagina (Fig.7.14), anal canal.
]n
Other manifestations of the secondary stage:
Pigment metabolism disorders - several small hypopigrnented and depigment6
patches on the sides of the neck, also called leucoderma syphiliticum or Venus' collar 0

Disturbances of hair growth with two patterns, both completely reversible

• pa t c hy hair loss (syphilitic alopecia) with a mouth-eaten appearance on the seal~
eyebrows, beard or other parts of the body
• di f f u se alopecia
Visceral manifestations in s econdary syphilis i n clude hepatitis, nephropathI
(proteinuria, acute nephrotic syndrome), gastrointestinal involvement (gastritis, proctiti~
ulcerative colitis), p eriostitis, osteomyelitis, p o lyarthritis, ocular involvement (opti
v
neuritis, iritis, uveitis).

Latent syphilis

It is characterized by reactive serologic tests for syphilis in the absence of tb

clinical signs. The l atent period o ccurs after th e l esions of secondary syphilis has
involuted and may last for a few months or continue for the remainder of the person's lif(
Sometimes, syphilis starts as a latent form (no anamnestic chancre or syphilids).
For treatment reasons, it is important to distinguish between:
• early latent syphilis: up to 1 year from the infection
• late latent syphilis: after 1 year from the infection
II
66
 nt. ot Tertiary syphilis (stage III)
nt, tlt, Tertiary syphilis is a n o n-contagious but highly destructive phase of syphilis,
year,
h;~ usually develops within 3-10 years of infection in 15-20% of untreated patients. The
cours of syphilis is dependent on the cellular immune response. Tertiary syphilis occurs
bus
®hen a cellular hypersensitivity reaction (type IV, tuberculin type) to the treponema
plttatt
develops in th e h o st, l eading t o a s m a l l n u m ber o f o r g anisms an d a l s o t o l o c al
ammatory infiltrates in affected tissues.
The typical lesions in this phase are tubers and gumma, located in skin or any
organ. The cutaneous lesions tend to b e l ocalized and g r ouped, asymmetrical,
destructive and heal with atrophic scarring.
The nontreponemal serum tests (VDRL) are positive in about 75% of cases and the
dyioyyg specific treponemal tests (TPHA, FTA tests) are positive in all cases.
.ctime.
moist
Cutaneous tertiary syphilis
Tuberous syphilids located on the face, scalp, limbs, are firm, reddish-brown, 3-5
:agio'
Iylom; miilimeters dermal tubercles, grouped in characteristic circular, serpiginous patterns with
tendency to ulceration.
Syphilitic gumma appears as painless, single, isolated subcutaneous firm nodule or
several nodules grouped in circles or arcs. After weeks or months, central necrosis occurs, with
<ey @ fluctuation, perforation, drainage of a purulent fluid and a deep punched-out ulcer with steep sides
and gelatinous, necrotic base. It heals with smooth, white scars with peripheral hyperpigmentation.
:hr oat) It is most &equently located on the anterior shins, face, forehead and buttocks.
ica);
Mucosal tertiary sy phi lis
Nasal septum, the hard and soft palate, the tonsil region or the tongue can be
involved by tuberous syphilids and syphilitic gummata (Fig.7.15).
nente<
Tertiary lesions of internalorgans
• Eye: gummata in the iris; optic nerve atrophy; Argyll-Robertson sign: small reflex
pupil that reacts normally to accommodation but not to light.
. scalp • Gummata in bones (saber tibia), lungs, testes, liver.

Cardiovascular syphilis
opathi Occurs 10-30 years after infection and is mainly represented by aortitis resulting
tocfiti~ from thickening and hardening of vasa vasorum with consequent necrosis of elastic tissue
(optI and fibrosis of proximal aorta. This is manifested by aortic insufficiency (altered aortic
valve function), coronary disease and ultimately aortic anevrism (weakened aortic walls).

Neuro syphilis
of 8 Central nervous system involvement can occur at any stage of infection. Most
s ha>' ««n it is asymptomatic but can be detected by testing the cerebrospinal fluid (CSF) for
n's IEE~ mononuclear pleocytosis, non-specific and specific treponema tests. It is divided into early
and late forms (not directly correlated with early and late syphilis).
Early neurosyphilis
Meningeal neurosyphilis appears up t o 1 ye a r a f t er i n f e ction w i t h h e a dache,
vomiting, neck stiffness, cranial nerve palsies, seizures.

67
 Meningo-vascular neurosyphilis a ppears 5-10 years after infection with hemipares< ~ p
and hemiplegia, as a result of infarction due to syphilitic endarteritis.
Late (parenchymatous) syphilis occurs more than 10 years after infection and I, s
due to direct invasion of the cerebrum by treponemas.
Tabes dorsalis —degeneration of the dorsal roots of the spinal nerves and posterio,
c olumns of the spinal cord; it presents with the specific tabetic dissociation of pain ~ ~
tactile sensations (which are lost, resulting in deep ulcers of the feet), from temperature, in p
sensation (preserved), with ataxis wide-based gait, foot slap and areflexia. typiC
General paresis is caused by degenerative changes in the brain, corresponding to tb,
mnemonic p aresis: personality, affect, reflexes (hyperactive), eye (Argyll-Robertso>
pupils), sensorium (illusions, hallucinations), intellect (memory, judgment) and speech.
Congenital syphilis diffe
Congenital syphilis arises from intrauterine transfer of T.pallidum to th e fete, use
from the m other w it h i n fectious syphilis after the 4th m o nth o f g estation, when @
placenta becomes permeable for T.pallidum. anti
If the mother has a recent syphilitic infection (highly infective), syphilitic stillbi <
m ay result in the 7th-8th month of pregnancy, or fulminating early congenital syphib; « e p
may develop until the child reaches 2 years of age. If the mother has an old syphilitic aug
infection (low bacteriemia), the child will be apparently healthy (latent congenital syphilis)
Plas
or will develop late congenital syphilis after the age of 2 years.
bec
Early congenital syphilis manifests in the neonate or subsequently up to 2 years pi
age, corresponding essentially to the acquired secondary syphilis of the adult. There ar< neg
also specific manifestations: spo
• syphilitic pemphigus of the new-born — bullous eruption of palms and soles ind'
• rhinitis syphilitica — abundant, muco-sanguinolent nasal secretions which i m pas
sucking and can lead to the perforation of the nasal septum fals
• wit
syphilitic laryngitis — hoarse weeping of the infant
• pe r i nasal, perioral and perianal infiltrative syphilids (papular syphilids) that caus~
depressed radiating linear scars, called Parrot's grooves
• osteo-articular signs: Parrot's pseudoparalysis with immobile forearm, due to the pais
pos
caused by osteochondriti.s syphilitica with epiphisiolysis in the ulnar region
• (sy
hepatosplenomegaly, generalized lymphadenopatia, nefritis, meningitis
Late congenital syphilis m anifests after 2 years of age, in juveniles or adults, tre
corresponding essentially to the aquired tertiary syphilis of the adult, with tuberous an <
gummous syphilids. tre
Many cases (60%) of late congenital syphilis are latent (no clinical manifestation<
but reactive serum tests). In any case of unexplained seropositive latent syphilis, not only
acquired syphilis but also congenital syphilis has to be considered. In these cases, stigmas
(sequels of active syphilitic lesions) are present:
bone abnormalities:
o s y p h i l itic saddle nose (depression of the nasal root due to destruction of th<
cartilage/bone)
o s aber shins (anterior tibila bowing)
o "Olympian brow" (bulging of the frontal bone region),

68
>resjl parrot's grooves (radial periorih.cial scars at sites of previous fissures)
Hutchjnson's triad (interstitial keratitis, inner ear deafness and Hutchinson's teeth =
nd ls small, oblique, barrel-shaped upper incisors that tapper towards the tip; crescentic
„otch of jncisal edge).
teria' I,abogatory diagnosis of syphilis
l and Dark-f jeld microscopy is essential in early syphilis with moist lesions (the chancre
ature
mpfprim
jmary syphilis, the condyloma lata in secondary syphilis) where T.pa/lidum with
j cal mov'ements i s f o u nd . D i r ect f l u orescent antibody t es t ( D F A T-TP) fo r t h e
:o the ident f cat on of T. Pattldum ln lesions ls another option.
rtson Serologic diagnosis aims to identify antibodies to T.pallidum in the serum of the
h. syphilitic Patient. According t o t h eir P roPerties, antibodies against T.Paltidum are of
djfferent types: precipitating antibodies - used in VDRL test, agglutinating antibodies-
fete used jn TPHA test and immobilizing antibodies - used in TPI test.
n. the Nontreponemal or n o nspecific reactions de tect a ntibodies against l i p o i dal
antjgens (reagins) of T.pallidum. In these tests cardiolipinic antigen (extracted from ox
lbjrth heart, rich in phospholipids) is used as it cross reacts with similar phospholipids in the
treponemai wall. Antibodies in the serum of the patient and cardiolipin antigens form
Phill
hiijtic aggregates that can be directly seen in tubes.
Most widely used are Venereal Disease Research Laboratory (VDRL) and Rapid
)hilisj
plasma Reagin (RPR) tests. These are initial screening tests all over the world, as they
b ecome positive 5-6 weeks after infection, shortly b efore the chancre heals and ar e
arsof generally strongly positive throughout the secondary phase. They usually become
.e are negative during early an d e f ficient therapy. Results may also become negative
spontaneously in the third p hase of syphilis. A f o r f old decrease in the antibody titer
indicates successful treatment, while a fourfold increase indicates relapsenor reifection.
.'np all The reaction has high sensibility (rare false negative results) and low specificity (many
false-positive results). Biologic false-positive test denotes positive VDRL/RPR tests in persons
with no history or dinical evidence of syphilis and with negative treponemal tests. Most of
these tests are of low titres. Acute false-positive VDRL/RPR revert to negative in less than 6
months and can result from pregnancy, vaccinations and infections (infectious mononucleosis,
hepatitis, measles, varicella, influenza, lymphogranuloma venereum, malaria). Chronic false-
p~
positive VDRL/RPR persist more than 6 months and is found in connective tissue diseases
(systemic lupus erythematosus), chronic liver disease, rheumatoid arthritis, tyroiditjs.
Any positive nontreponemal test result should b e c onfirmed w i t h a s p ecific
treponemal test. All patients with syphilis should also be tested for HIV infection.
s ana Treponemal or specific reactions detect antibodies directed against specific
treponemal antigens:
>tlON TEA (T r e ponema pallidum h e magglutination) t est: s pecific a ntitreponemal
t onl)' antibodies in the patient's serum are agglutinated by antigen-coated erythrocytes.
~mal
7 FTA (Fluorescent treponemal antibody) test - antitreponemal antibodies are fixed on
treponemal antigens. Visualisation of this reaction is possible using fluorescein-linked
anti-human immunoglobulin (indirect jmmunofluorescence).
>f tl>e The IgM FTA-ABS test detects antitreponemal IgM antibodies that occur in congenital
and recently acquired syphilis. Treated or older spontaneously healed syphilis
produces IgG class a ntibodies. Constant t i t res o f I g M a n t i b odies i n dicate t h e
P«sjstence of T.p. in the body, thus the need of treatment.

69
 Enzyme-linked immunosorbent assay (ELISA): the visualisation of antibody+specg,
antigen complex requires an enzyme-labelled antiglobulin.
The treponemal tests become positive a bit earlier than nontreponemal tests aq,
qu
remain positive for life. Therefore they confirm syphilis even in late phases, when g, year1
nontreponemal tests tend to become negative. TPHA i s u n suitable for monitoring th,
O'P
course and treatment of syphilis. VDRL test can be used as a screening test and ii, S8
quantitative form is suitable for monitoring treatment, measuring significant falls in titer.

Treatment
Penicillin is the most effective agent in all stages of syphilis thus it remains g
drug of ch oice. It p enetrates into all b od y fl u i d s an d p asses the cerebro-spinal @g
placental barriers and kills T.palhdum by blocking the synthesis of the microbial cell wg
T.pallidum divides about every 33 hours and the treatment has to be long enough to catg
all the treponemas: at least 2 w e eks w it h c onstant penicillin serum concentration ~
recommended for early syphilis and 3-4 weeks in late syphilis. P

Early syphilis (seronegative/seropositive primary syphilis, secondary syphili~

early latent forms) and preventive treatment for sexual contacts of syphilitic patients: 2i
2.4 mil.I.U. penicillin G benzathine (Moldamin, Retarpen), that is 1.2 mil I.U. i.m. in ea6
buttock on the 1st and the 7th day of treatment.
Late latent and tertiary syphilis: 3x 2.4 mil.I.U. penicillin G benzathine divided op
the 1st, 7th, and 14th day of treatment.
In case of syphilitic patients with penicillin allergy oral tetracicline (not to be use)
in children and pregnant women) or erythromycin 500 mg every 6 h, for 15 days in earll
syphilis and 30 days in late syphilis can be used.

Herxheimer reaction
When treponemas are abundant (late I stage, II stage, early congenital syphilis), on
systemic toxic effects appear within 8 h a f ter the first dose of penicillin because hig1 ba
number of microorganisms are destroyed and fever up to 40'C, shaking chills, malaise, (b
headache and intensification of syphilitic rashes may develop. Increased inflammation i
vital structures may have serious consequences, as in aortic aneurysm (aortic rupture an)
sudden death) or CNS involvement (paralyses). Herxheimer reaction in pregnancy ma~
induce premature labor and fetal distress.
In order t o m i t i g ate the sym p t oms of H e r x heimer r eaction, small d oses 0!
penicillin G ( 2 5 000 IU ) w i l l b e a d m i n i stered ev ery 6 h o u r s i n t h e f i r s t d a y Ol
treatment, w it h w a t e r-soluble i .m . o r i . v p r e d n i solon f o r m u l a ti ons. Every p a tienl
should remain u n der m e d ical observation fo r several h o ur s after th e f i rst d ose ot
penicillin. The use of retard penicillin (benzathine-penicillin) reduces the risk ol Nu
Herxheimer reaction.
Herxheimer reaction has to be distinguished from drug reactions to penicillin. Ten

Treatment of sex partners Ulc

Sexual partners of persons with syphilis should be identified and treated, even i AP

seronegative. At-risk partners are those exposed for u p t o 3 m o n ths before plus th~ Ad
duration of the primary lesions, up to 6 months before plus the duration of the secondary
lesions, or up to 1 year before for latent syphilis.

70
specific $ggpipgicat tnpn'ttpnng
Every patient who has been treated for syphilis should be followed up u s ing a
!Sts anc
<tative
quantt a nontreponemal test (VDRL) at 3, 6, 9 and 12 months after treatment and then
hen ge arlyyfor
year or 3 years. It may take 8-12 months for four-fold decrease in titer. The longer lasting the
ing the the longer it takes for serological tests to normalize, if at all. Persistence of reactive
syp
and i(( ~
seruIyl te
eSs ts after 12 months requires retreatment with penicillin and prednisolon.
t titer,

DIPPKRKNTIAL DIAGNOSIS OI' GKNITAL ULCER DISKASKS

Iins the
Ial anc I,ymphogranuloma venereum (LGV), STD that usually occurs in tropical and
.11 wa!! subtropical countries is caused by Chtamydha trachomatis, L1-L3 serotypes and evolves in 3
to catd stages:
ation !t painless shallow, rapidly healing genital ulcer, without scarring
painful unIlateral lymphadenopathy (buboes), 2-6 weeks after the ulcer, with classical
wp~ groove sign (femoral nodes above and below the inguinal ligament); fistulae and sinus
ents: 2i tracts result with a purulent discharge and finally depressed scar;
in eacl, genito-ano-rectal syndrome occurs many years after the infection (perirectal fistulas,
abscesses, stenosis in the genital tract and rect, genital elephantiasis)
Ided otj Treatment:
needle aspiration of involved buboes, for pain relief and prevention of ulcer formation
be usee Tetracycline hydrochloride 4x500 mg/day, Doxycycline 2x100-200 mg/day, or
in ear]I Erythrom
ycin 4x500 mg/day, for 21 days
Chancroid (soft chancre, ulcus molle) is a sexual transmitted disease (STD) caused
by Haemophitus ducreyi (gram-negative coccoid-bacillary rod). Clinical picture consists of
r philis) one (or more) painful soft genital ulcer with undermined margins and yellowish-gray
se hip base, surrounded by erythema. After 1-2 weeks, painful inguinal lymph nodes enlarge
malaise (bubo) and spontaneously rupture with fistula formation.
ation!t Treatment:
ure an( Ceftriaxone 250 mg i.m. single-dose
.cy IYlst Azithromycin 1 g orally, single-dose
Erythromycin 2g/day for 7 days
oses s.' Ciprofloxacin 500 mgx2/day for 3 days.
day 0:
!! All open sores facilitate transmission on HIV.
paties
Bose 0' Disease HSV S hilis LGV Chancroid
risk 0' Nnntlrer, Clusters of erosions One or two, Ulcer lasts 2-3 weeks, One/two,may coalesce,
3, LOMtlogt on labia and enis o nva ' a a n d e n i s on labia and enis on labia and enis
Ten rter ness Little / no
Tender Painless
tenderness
Ulcer Uniform size, clean Ulcer spontaneously Can be large, ragged,
Clean, indurated
even I Appenrartce base, erythematous heals at time of necrotic base,
base
border fluctuant adeno athy undermined ed es
)lus 8
-ondar, A<em
pathy Tender
Rubbery, mildly
tender
Fluctuant inguinal
nodes, groove si
Very tender, fluctuant
in i n a l nodes
Ta hei.3• Differential diagnosis of genital ulcers of STDs.

71
 GONORRHEA (BLENORRHEA) The ce'
Qy cull
Gonorrhea is a sexually t r a nsmitted i n f ection of mucous m e mbranes th,, phase
wofneI
commonly m a n i fests a s urethritis ( i n male), cervicitis (in f emale), proctitis
conjunctivitis. If untreated, infections at these sites can spread retrogradly, leading to lo~
complications. Sometimes resistant subepithelial gonococcal "nests" can be preserved apt
urethr
with
act as starting point for relapses in patients and reinfection of partners.
Neisseria gonorrhoeaeis a Gram-negative diplococcus shaped like a coffee bean 9@ Invos
grows in pairs with adjacent concave sides seen on Gram's or methylene blue stain sm@,
uni-/bilayered epithelia, wg POStg
examination. Go nococcushas a special affinity f o r
N.gho
pavimentous and multilayered epithelia are resistant to infection.
squ
Gonorrhea is transmitted almost exclusively through sexual intercourse. Only tt
the e
exceptional cases an extragenital infection occurs, e.g. as a smear infection through da~I
towels. Infected adults can infect children sleeping in the same bed.
ostl
Gonorrhea causes asymptomatic infection (in 10% of men and 50% of worn@
folds
especially in r e ctal and p h aryngeal infection), local symptomatic mucosal infection
sometimes with complications, and systemic dissemination.
Direct mucosal infection
a. I n men.
Anterior gonorrheal urethritis is the most common clinical form of gonorrhoea i
men, involving the columnar epithelium of the urethra up to the external sphincter of th;
bladder.
The acute form has an incubation of 2-3 days, a florid stage of 2-3 weeks andI
regression stage of 4-6 weeks, when th e d i scharge diminishes. Untreated, symptom;
disappear in about 6months. First symptoms are dysuria, prickling and heat in the ureth
on urination. The next day a v iscid, creamy yellow discharge appears with numerov
intracellular gonococci at microscopic examination.
The chronic form manifests after the 6th-7th week with discrete viscous discha
rge
("good morning drops" ) and no symptom during the daytime. The morning urine is clem
but contains whitish filaments discharged from the ureflual folds, mucus, epithelial cell~
leukocytes and bacteria.
In about one quarter of infected men, the symptoms are less pronounced, simila,
to those of non-gonococcal urethritis. H ow ever the cause of urethritis is often impossibl
to differentiate on clinical grounds alone.
Posterior gonorrheal urethritis may start 10-14 days after infection and spree
distally, as the orifices of the excretory ducts of the prostate, seminal vesicles, and ducts
deferens open into the posterior urethrae. The bladder is not infected, as its transition>
epithelium is not susceptible to the gonococci.
The patient has distressing desire to urinate every 5-10 minutes,
t(1 but voids eve'
time just a few drops. Hematuria and pain at the end of micturition are characteristic.

b. I n W omen
Gonococcal cervicitis is usually symptomatic in w o m en, with m o re acute ant
intense symptoms than in chlamydial cervicitis. Increased green/yellow muco-p uruletn
vaginal discharge from the cervical orifice and dysuria are the most common symptoS-'
 The ce is red and swollen. In time, the columnar epithelium is destroyed and replaced
bycucubic
1 pr even flattened epithelium that is less favorable for gonococci, so that in chronic
> se the disease becomes less symptomatic, but gonococci are still found. Symptom-free
.s thy pl!!ase
Es omen with chronic cervical gonorrhea are a frequent source of infection.
wome
to lpq! Gonococcal urethritis u sually accompanies cervicitis. The posterior part of t h e
ethra is affected (the anterior third is coated with squamous epithelium). It manifests
ed ar!i ure
with dysuria (stinging pain or burning on urination) and scant urethral discharge.
an tQ! involvement of the trigonal region of the bladder produces tenesmus.
! sme@ Gonoc
occal v ulvovaginitis o c curs o n ly i n pr ep u b e rtal g i r l s, p r e g nant o r

wN ostrnenppausal women, wh o h av e fl at , u n i l ayered vaginal epithelia, susceptible to

N<INnorrhoeae infection. Except of t h ese situations, the v agina i s l i ned b y s t r atified
)nly ~, sqQampus epithelia. The vagina is red, edematous, with abundant purulent discharge, and
1 da+ the examination is extremely painful.
Gonococcal bartholinitis occurs occasionally due to the inflammatory ocdusion of the
vom@ ostium pf the excretory duct and manifests with painful cherry sized pseudoabsces of the labial
CtlOIg folds and purulent discharge when pressure is applied to the gland.
Local extension of gonococcal infection
of the anterior gonorrheal urethritis:
dorsal lymphangitis or thrombophlebitis: hardening and swelling of the dorsal lymph
hoeam or venous channels of the shaft of the penis
r oft' gonococcal perigrethritis: the c onnective t issue a round t h e u r e t hra i s i n v a ded,
becoming a hard and painful cord
) and ! perigtrethral abscesses: Morgagni lacunae — intraepithelial, microscopical abscesses,
nptom! observed only by u r e throscopy ; g l a nds of Li t t re —larger paraurethral abscesses,
uretIU; palpated as painful rice-sized nodules along the urethra; glands of Cowper(cherry-
merou~ sized glands behind the scrotum) — boil-like perineal abscess
phimosis and paraphirnosis(the last is a surgical emergency that can lead to the glans
s chary necrosis)
is cle8! urethral strictures —late complication, can lead to acute urine retention
al celh
of the posterior gonorrheal urethritis:
epididymitis: the gonococci migrate up to the vas deferens, reach the epididymis with
similr
unilateral tenderness and edema, high fever, high sedimentation rate and neutrophilic
iossibl!
leukocytosis. The testis itself is spared and is of normal size. The complication of the
epididymitis is oligospermia and if bilateral, azoospermia and loss of fertility.
spread
acgte orhitis: the involvement of testis
duclN
prostatitis with pain in the intestinal region and during defecation
sitio5
seminal vesiculitis with accidental ejaculations, tenesmus, blood in ejaculation

s ever of the gonococcal cervicitis:

~cute salpingitis or pelvic inflarnrnatory disease manifests usually immediately after a
menstrual period, w it h l o wer abdominal pain, abnormal adnexal mass on pelvic
examination, associated with fever, leukocytosis, elevated ESR or C-reactive protein
Jte N' level. It may result in l ong-term consequences of infertility, chronic pelvic pain or
uruler ectopic pregnancy.
>ptpS'

73
 acute perihepatitis (Fitz-Hugh-Curtis syndrome) results in women, after migration ~,
gonococci from the faloopian tubes via the peritoneal cavity to the upper abdorne<
Pain in the right upper quadrant mimics acute colecystitis.
pelvic peritonitis re sults from t he s preading of t he i n f ection to t he p elvis and I,
characterized by nausea and vomiting.
Extragenital direct gonorrhoea
Pharyngeal gonorrhea wi th r e d d ening, swelling o f t h e m u c osa an d s l igI,,
II
dysphagia occurs in men or women after oral sexual exposure. However most of the forg,
are asymptomatic and p h aringeal gonorrhoea remains undetected and r epresents @
important source of infection.
Rectal gonorrhea occurs after anal intercourse. It is asymptomatic in at least 50<,
of cases but may result in goconococal proctitis (rectal pain, pruritus, tenesmus, rectp
discharge and bleeding).
Goncoccal ophtalmia represented years ago an important cause of blindness. ],
moanifests with p u r u lent conjuctivitis and, i f l e f t u n t r eated, can rapidly p r ogess ~~
keratitis followed by permanent corneal opacification.
In newborn it is caused by inoculation of N.gonorrheaduring delivery through@ I
infected birth c anal. Prophilactical application of 1 % s i l ver n i t r ate o r e r y thromycII
ointment immediately after birth currently reduces the rate of ophtalmia neonatorum.
In adults i t r e sults f ro m s e lf-inoculation o r u n u sual sexual p r actices. Earl~
recognition and local antibiotic are essential to avoid blindness.
I

Disseminated gonococcal infection (gonococcemia)

It occurs through hematogenous bacterial spread that is favored by menstruatior
(most cases appear immediately after menses) and pregnancy. Clinical picture include
arthritis-dermatosis syndrome:
• po l y a r t hralgia with fever, pain, tenderness, decreased range of motion, usually at lary
joints: knees, elbows, wrists, ankles; erythema overlying the tendons; endocarditi<
meningitis
• skin rash: scattered necrotic pustules due to embolic septic vasculitis on the distr
portion of the extremities, but also on the trunk.

Laboratoryexamination in gonorrhea
Is based on identification of N.gonorrheaby:
Gram smear — Gram-negative (red) diplococci within neutrophils, which differer from ne
pathogen Gram-positiveNeisseriaspecies (blue); used for urethral cad 'endocervical secretion
not for pharyngeal or recto-anal exudates, where there is a large number of other bacteria
culture on special media — most specific, gold standard for gonocccal infec'tion
DNA probe — antigen detection test fromI. mucosal secretion or from u r ine sampk
C.
more sensitive than culture for extrager6tal secretion. Chlamydia can be identified fry'
the same specimen collection tube.

Treatment of gonorrhea
N.gonorheaehas a remarkable capacity to alter its antigenic structure and adapt b
chaqges of the microenvironment, thus it has become resistant to numerous antibiotic!

74
3n of S+ifpnamldes were used in 1930, penicillin until 1976, fluoroquinolones - ciprofloxacin,
meq flpxacjn, levofloxacin, since 1993 were efficient orraly as a single-dose, and also offered
or>pxa
t,~amydial activity w h e n g i ven f o r 7 d a y s, bu t n o l o n ger u sed s ince resistant
Ld ia ~ gonorrhea strains appeared. Fluoroquinolones remain an alternative treatment option
p py fp r d i s seminated g o nococcal i n fection i f a n t i m i crobial s u sceptibility c a n b e
ented. Ampicillin and Am oxicillin are also no longer reliable in the treatment of
pnprrhea. Currently 3'~ generation cephalosporines are the antibiotics of choice:
lllght
ceftriaxone 250 mg i.m as single dose (preferred);
orrrg
cefixime 400 mg p.os as single dose
:s
cefuroxime axetil 1g, single oral dose
cefpodoxine 400 mg, single oral dose
500I,
Alternatives:
ectg
ceftizoxime 500 mg, i.m. single-dose
cefotaxime 500 mg, i.m., single-dose
ss. It
Spectinomycin 2 g, i.m. single-dose — reserved for multiresistant strains
ss tp
Azithromycin 2 g, single oral dose — effective but widespread use not recommended
because rapid emergence of resistance; an option in allergy to cephalosporines
h an
Since the infection w ith Ch lamydia trachomatisi s frequently concomitant wi t h
lyQn
gpnprrhoea, doxycycline 100 mg twice a day, orally for 7 days or a single oral dose of
Azithromycine 1g has to be associated, unless Chlamydia testing excludes coinfection.
Early
Condoms, if properly used, provide effective protection against transmission and
acquisition of gonorrhoea. All p atients should be instructed to r efer sex partners for
evaluation and treatment.

ation DISEASES CAUSED BY CHLAMYDIAE

.Ud6
Chlamydiae are Gram negative bacteria that preferentially infect squamo-columnar
larg< epithelial cells. They are obligate intracellular microorganisms that need to be provided
ditla, with energy for metabolism from a host cell.
Chlamydia trachomatis is one of the 4 species (including C.puerorum, C.psittaci,
distal C.pneumoniae) in the genus Chlamydia. There are 18 serovars (serologically variant strains)
of Chlamydia trachomatis: A, B, C cause trachoma (a serious eye disease that can lead to
b lindness), D-K a r e associated w i t h g e n i ta l t r a c t i n f e ctions and L 1 -L 3 c a u se
lymphogranuloma venereum Nicolas-Favre.
non. Chlarnydia has a unique biphasic life cycle that is adaptable to both intracellular
and extracellular environments. In the extracellular milieu, it exists as an inactive spore
'e6on
called elementary body (EB). Once inside a susceptible host cell, inclusion bodies are
«need. Since only the intracellular forms of chlamydia are susceptible to antibiotics, only
drugs with good intracellular penetration will successfully combat the infection.
nplal
Chlamydial genitp-urinary infecbpns, caused by C.trachomatis serovars D-K, are
from
manifested a s c e r v i citis, salpingitis, e n d ometritis, u r e t hritis, epididymitis,
conjunctivitis, and neonatal pneumonia.
Chlamydia c auses the most common n o n-gonococcal urethritis, together wi t h
.pt ta "«aplasma urealyticum, Mycoplasma hominis and Trichomonas vaginalis.Non-gonococcal
ptiC5 "'ethritis has longer incubation period than gonococcal utrethritis, is asymptomatic or

75
 s ubacute. Th erefore, d i agnosis i s d e l a yed u n t i l p o s i t i v e screening r e sults o r ,
symptomatic p artner i s d i s covered. A s y m ptomatic p atients act a s a r e s ervoir fo,
chlamydial infections.
The clinical aspects in men include urethral discharge, urinary frequency and/0.
urgency, dysuria, scrotal pain/tenderness, perineal fullness (related to p r ostatitis); >
women mucopurulent endocervical discharge, easily i n d uced endocervical bleed~(
intermenstrual bleeding, dysuria, and abdominal pain.
Diagnosis:
• cytologic diagnosis — evaluates endocervical scrapings for intracellular inclusions, b,.
interpretation is difficult and both sensitivity and specificity are low.
• isolation in tissue culture (40-72 hours) and then detection of intracytoplasmatic inclusipg,
by Giemsa stains or immunofluorescent staining with m onoclonal antibodies; hi~~
specificity (100%) and sensitivity; expensive; swabs need to be taken invasively frog
urethra or cervix
• antigen detection —d etects the ribosomal RNA by h ybridization with a DNA p r o b f..
simpler, less expensive, high sensitivity but lower than cell culture; other technique>
direct fluorescent antibody (DFA), ELISA
• detection of chlamydial genes by DNA amplification tests — e.g. polymerase ch~
reaction (PCR) in urine or self-administered vaginal swab specimens
serologic tests are valuable in L G V, b ut n ot i n c e rvicitis, urethritis, where positivf
results reflecting a possible anterior infection, the antibody titers are low and thf.r~
may be a cross-over reactivity between C.trachomatisand C.pneumoniae
Treatment is indicated when the diagnosis is established or suspected, in sexua l
partners o f t h e p a t i ents an d f o r p a t i ents b eing t r e ated f o r g o n o coccal i n fection
Recommended drugs are:
azithromycine 1 g p.os, single dose
doxycycline 100 mg x2/day p.os for 7 days
Alternatives
erythromycine 500 mgx4/day, p.os for 7 days - in pregnancy
ampicillin 500 mgx3/day, p.os for 7 days — in pregnancy
ofloxacin 300 mgx2/day p.os for 7 days
levofloxacin 500 mg once daily for 7 days

AQUIRED IMMUNODEI'ICIENCY SYNDROME (AIDS)

This syndrome is a complex of aquired infections and tumors occuring in p atient

with T-cell deficiency due to the HIV virus.
The most common route of infection is sexual contact. Other routes of infection art
sharing of needles and syringes contaminated with blood among drog users, injuries vriII
contaminated instruments in health care workers and physicians; by transfusion of blop<
and blood p r oducts or b y t r a nsplantation of o r gans; pre- and p erinatal infection c
newborns by HIV-positive mothers.
HIV is a RNA-virus and is a retrovirus because it has an enzyme called revere
transcriptase that copies the viral RNA to the DNA in the cells of the host. Target cells fo'
HIV are CD4+ cells such as CD4+ lymphocytes, monocytes, macrophages, Langerhap'

76
 or ceIls
sI ~iia
g cells, keratinocytes and any other cells in the human body. Increased destruction
rr for of $ cells results in impaired immune response and in the proliferation of opportunistic
•sections
e and malignancies.
d/or HIV infection evolves in 3 stages after an incubation of 1-3 weeks:
rs) acute viral HIV infection starts asymptomatic or with flu-like illness (10-20% of cases):
edlQL headache, sor e thr o at , mal a ise, pe r sistent lym p h adenopathy,
hepatosplenomegaly, maculo-papular exanthema. Anti-HIV antibodies are detectable
by ELISA by 3-4 weeks.
s. but 2nd stage - starts when a specific immune response against HIV has been mounted
and has controlled the initial viremia. It may last at least 1 year but can be over 10
usrorrr years; in some patients may persist indefinitely (at least 20 years so far)
; higg o c o m p letely asymptomatic o r w i t h p r o g ressive weight l o ss, m alaise, and
frog generalized lymphadenopathy
o t h e patient is source of infection for others
robe. o C D4 positive lymphocyte counts drop progressively as they are sequestered in
.iquea the lymph nodes.
hard stage — AIDS (overt disease) — severity is directly related to the decline in CD4+ T
char'rr cells below 200/pl (normal 500-2000), which causes diminished function of T cells, B
c ells (hypogammaglobulinemia), macr ophages and N K c e l l s a n d l e ad s t o
>sitivj. opportunistic infections, neoplasms and dementia.
there Opportunistic infections are caused by microorganisms that take advantage of the
decreased immune response in order to develop:
fungal (o ral a n d oe s ophagial c a ndid osis, wid espread p i ty riasis v e rsicolor,
ction dermatophytosis, proximal white onychomycosis, deep mycoses)
viral (disseminated CMV i nfection, herpes simplex not healing after 1 m o nth,
multidermatomeric o r v a r i celliform h e r pes z oster, o r al, g e nital o r w i d e spread
cutaneous warts, mollusca contagiosa; Epstein-Barr virus induces hairy leukoplakia
that appears early in HI V i n f ection, as asymptomatic white plaques with hair-like
projections on the lateral aspects of the tongue
mycobactevia, atypical
bacterial (stafilococci, streptococci, treponema pallidum)
ectopavaziteinfections (norvegian scabies)
Non-infectious HIV-related disorders
seborrheic dermatitis with exaggerated presentation or resistant to treatment
psoriasis — severe forms; tends to worsen with decreased immunity status
atientr
Tun ol's:
on arr Kaposi sarcoma (hemorrhagic disseminated angiosarcoma) — associated with human
s wiS herpes virus type 8 (HHV-8) that can be t ransmitted by infected semen or saliva; the
blood lesions start on the upper part of the body, characteristically on the face, intraorally
ion 0< induding gingiva and the hard palate, with purple/red macules that increase in size
and become raised and tender, some of them nodular and ulcerated (Fig.8.13, 8.14). In
everI HIV-related Kaposi sarcoma, l y m p h no d e s a r e i nv o l ve d ( w i t h se c o ndary
.lls for lymphedema), gastrointestinal tract and lungs.
.rhaNr lymphomas (associated with Epstein Barr virus)

77
 squamous cell carcinomas —especially in men having sex with men and infected witI
HPV condyloma acuminatum in anogenital region

Paraclini c examination
• HIV screening should be encouraged as part of routine physical examination @g
by ELISA. Western-blot test is used for confirmation.
• Laboratory tests that help in staging HIV infection are:
o C D 4 T-cell count indicates the risk of acquiring opportunistic infectio~
The reference range for C D 4 c o unts i s 5 00-2000 cells/pL. A +
seroconversion, CD4 counts tend to decrease (around 700/pL on
average
and under 200/pL is considered AIDS-defining.
o Q u a ntitative v i ral l oad assays in p e r ipheral bl ood m easure the v i rg
replication rate (even if this occurs in the lymph nodes rather than in th<
peripheral blood), which is related to progression to AIDS and death.
The treatment of HIV infection aims to reduce viral multiplication and to treat 0~
prevent opportunistic infections. Anti-retroviral therapy suppresses viral loads to @
undetectable level so that CD 4 count r ises and the r isk o f o p p ortunistic infection g
reduced. Viral eradication is impossible as the virus is integrated in the DNA of the hog
lymphocytes.
The prognosis of HIV infection is poor. The average time from diagnosis to deaf
is one decade, with individual variability.

78
ioQs,
A.fter
rage) Fig.7.1. Primary syphilis Fig.7.2. Chancre of the soft palate

virg
n tge
L

.'at o(

3Il is
host

3.eath
Fig.7.3. Extragenital chancre Fig.7.4. Syphilitic bubo

Fig.7.5. Secondary syphilis Fig.7.6. Secondary syphilis

(macular syphilids) (papular syphilids)

Fig.7.7. Papular syphilids Fig.7.8. Plantar syphilids

79
 Fig.7.9. Palmar syphilids Fig.7.10.Secondary syphilis (condilomalag)

Fig.7.11. Secondary syphilis (condiloma lata) Fig.7.12. Intertoe condiloma lata

22 12 2002

Fig.7.13. Mucous syphilids Fig.7.14. Mucous syphilids

Fig.7.15. Soft palate perforation after guma Fig.7.16. Kaposi sarcoma

80
 Chapter 8

ALLERGIC SKIN DISORDER S

Allergic diseases are determined by hypersensitivity reactions which may be

„t body or cell-mediated. The basic immunological reactions were classified by Gell and
late)
Cpombs in four groups.
Humoral allergic reactions (antibody mediated)
IgE-dependent reactions (Type I, Gell-Coombs classification)
In the sensitization phase, antigens induce the formation of specific IgE antibodies
adhere to the surface of mast cells. When the antigen contacts again the organism,
spedfic IgE antibodies already fixed to the mast cell surface react with the circulating
antigens inducing the release of mediators from the granules of the mast cells (histamine,
prostaglandins, l e u kotriens, k i n i ns). V a so dilatation r esults, w i t h a n inc r ease i n
per
meability and exudation of serum, chemotaxis of eosinophils.
In a sensitized organism, the Ig-E dependent reaction becomes clinically manifest
within a few minutes to a few hours (immediate reaction).
Urticaria, angioedema (Quincke's edema), anaphylactic shock, reactions to insect
bites and stings are clinical manifestations of the IgE-dependent reaction and can,
sometimes, be fatal.
Cytotoxic reaction (Type II, Gell-Coombs classification)
The antigen (often drugs) is bound to a cell surface. Binding of the specific
antibody leads to activation of the complement and generation of inflammatory mediators
with cell damage. Immunohemolytic anemia, thrombocytopenia or pemphigus vulgaris
are clinical manifestations of cytotoxic reaction.
Immune-complex reaction (type III Gell-Coombs classification)
This type of r eaction involves the deposition of a n tigen-antibody complexes
oa
) mainly in the vascular walls with the activation of the complement cascade. This leads
to chemotaxis of polymorphonuclear neutrophils and release of lysosomal enzymes,
responsible for the vasculitic lesions. There are 2 types of immune-complex reactions:
Arthus type (manifested in leucocytoclastic vasculitis) and serum-sickness reactions
(manifested by widespread vasculitic lesions in skin, kidneys, joints, erythematous or
urticarial exanthem, l y mphadenopathy, p olyarthralgia, polyserositis a nd a c u t e
nephritis).

Cell mediated reactions

Cellular allergic reactions of delayed type (type IV Gell-Coombs)

Exogenous or endogenous antigens react with sensitized T ly m phocytes and a
delayed allergic reaction occurs 24-48 hours after reexposure.
a. delayed reaction of eczema type d evelops after the contact of the skin wi t h
allergens, in 2 stages:

81
 • Induction o f sensitization. Small m o l ecules (nickel, cobalt or d i c h r o mate) art,
called haptens or incomplete antigens because they have to be conjugated tto
epidermal proteins to form f ul l antigenic structures. These antigens are take<
up and processed by antigen-presenting Langerhans cells that migrate to tpe
regional l y m p h n o d e . A n t i g ens ar e p r e sented t o t h e T ly m p h o c ytes
s
conjunction with class II histocompatibility antigens (HLA-DR). As a responseI
T lymphocytes proliferate to form antigen-specific memory T cell clones, unde>
the control of the suppressor cells. The induction of sensitization to a contag
allergen takes 5 to 7 days and, once realized, it is long lasting (years, decades
or life-long).
• Reaction phase. In a sensitized person, re-exposure to very low concentrations of q
specific allergen stimulates memory T c el l c l ones that p r o liferate and r eap,
Various cytokines (IL-2, IFNs etc) will be released at the site of the contact with +
a llergen, leading to eczema type reaction w it h i n creased permeability o f + t
vessels, lymphocytic exocytosis and epidermal spongiosis followed by interstitial)
vesiculization. The clinical manifestations appear 24-48 hours after re-exposur
xpos\Q'q
and represent allergic contact dermatitis.
b. D e layed reaction of tuberculin type occurs when the antigens enter the skin
through vascular system. They r eact w i& . p r eviously sensitized ly mphocyte~
which release lymphokines and lymphotoxins, leading to an inflammatory cellul@
reaction with vasodilatation, increased permeability, edema and the clinical aspeg
of allergic exanthems (morbilliform, scarlatiniform, rubeoliform drug reactions,
fixed drug reactions).

URTICARIA

Urticaria is a h eterogeneous group of d i s eases with a c o m mon s kin r e action

pattern, i.e. the development of skin urticarial lesions (wheals/hives) and/or angioedema.
The typical features of wheal:
a central swelling of variable size, white to pink, with smooth surface, well defined'
borders, almost invariable surrounded by a reflex erythema (Fig.8.1)
associated with itching or burning sensation
a fleeting nature, with quick development (within minutes) and complete resolutios
within 24 hours (generally 2-8 hours).
There are several clinical variants of wheals, sharing the typical features:
erythematous plaques (urticaria rubra) due to the vasodilatation (Fig.8.2)
pale plaques (urticaria porcellanea) as a result of edematous compression of th<
surface blood vessels(Fig.8.3)
small, papule-like lesions (pseudo-papular urticaria)
palm size or larger lesions (urticaria gigantea)
joined wheals with policyclic borders (urticaria circinata)
annular configuration with healing of the center (urticaria annularis - Fig.8.4)
If the wheals remain fixed for longer than 24 hours, the diagnosis may be urticari a
vasculitis (Fig.8.5,type III hypersensitivity reaction) or bullous pemphigoid (autoimmune<
disease).

82
 Angioedema (Quincke's edema) is a deeper form of u r t icaria, characterized by
~den pronounced localized edema of the lower dermis and subcutis. The edema is not
en haply delimited, it is nonpitting, sometimes painful rather than itching and its resolution
he ~ fake up to 72 hours (Fig.8.6).
Angioedema is most apparent in the head and neck (face, lips, floor of the mouth,
se, „+ e and l arynx), external genital organs, hands and feet. In advanced cases it can
tongue
ler <ass to complete airway obstruction by laryngeal edema and death. It may also
proP
let ,nvo v the gastro-intestinal tract, with edema of the intestinal wall leading to colicky
nvp]Qe
les bdorninal pain, nausea, vomiting and diareea.
a
Classification of urticaria
fa
Lct, Spontaneous urticaria:
the
Acute spontaneous urticaria: up to 6 weeks of wheals/angioedema;
the
Chronic urticaria: continuous/recurrent episodes of wheals/angioedema over a 6-week
tial
period.
1re
Inducible urticaria
Q1l
tea Phisi cal urticaria (defined by the triggering stimulus):
• Dermographic urticaria (urticaria factitia) (Fig.8.7) - rubbing or writing
on the skin, induced by mechanical share forces that produce an initial red
line (capillary dilatation), followed by broadening erythema (axon-reflex
arteriolar dilatation) and the formation of a linear wheal in 1-5 minutes
(transudation of fluid/edema) termed the triple response foLewis. The
lesions are intensely pruritic.
Simple dermographism, without pruritus, appears in about 5% of
Lan healthy population and i s c onsidered an exaggerated physiological
response.
White dermographism is a misnomer (false dermographism, not
red urticaria), in f act a b l anching response to skin s troking explained by
capillary vasoconstriction. It is more pronounced in persons with atopy.
Cold contact urticaria - wh e aling w i t h in m i n u t es of rewarming after
ion cold exposure. It can be elicited by r a i ny, w i nd y w e a ther or c ontact
with cold objects; can be congenital, or associated to cryoglobulines or
cryofibrinogen. Cold u r t i caria r equires HC V d e t ermination, because
c ryoglobulins ar e i n d i r ect m a r k er s o f h e p a t i ti s C . S w i m m i n g o r
jumping into cold water may be particulary dangerous, resulting in
anaphylaxia.
• Heat contact urticaria - elicited by localized heat
• Solar urticaria — e licited by U V a n d / or v i s ible l ig ht; w h e als on s u n
exposed areas, in up to 30 minutes after exposure
• Delayed pressure urticaria —wheals within 3-12 h latency elicited by sustained
pressure under the waistband of tight clothes, under the elastic part of socks,
on buttocks sitting for a long time, feet in tight shoes, soles after prolonged
walking or climbing a ladder;
 • Vibratory urticarialangioedema - elicited by j o gging or t he u se oi
vibrating machinery e.g. pneumatic hammer, lawn mowers, motorcycles.

Special types of urticaria:

• Aquagenic urticaria - elicited by water
• Cholinergic urticaria — elicited by increased body temperature due g
physical exercise, elevated environmental temperature (warm bath), fever<
emotional stress or eating spicy f o od; i t i s d i s t inctive clinically witi
multiple, transient, small (2-3 mm) papular wheals, surrounded by @,
obvious flare
• Contact urticaria — elicited by contact with urticariogenic substances

Classification of angioedema:
• allergic angioedema —often associated with urticaria
• drug-induced angioedema (non-allergic angioedema) due to A CE inhibitors, Dpi
associated to urticaria
• aquired angioedema (AAE) - rare
o a ssociated w it h l y m p hoproliferative diseases of B ty p e ( i n creased
consumption of C1-inhibitor)
o a u t o i m mune process (auto-antibodies against the C1-inhibitor)
• heredita~ angioedema (HAE) — rare, inherited, autosomal dominant, deficiency of thy
C1-esterase inhibitor
The deficiency of th e C1-esterase inhibitor of t h e c omplement system allo<vs
u ncontrolled activation o f t h e c o m p lement cascade w it h t h e release of k i n i n-like
mediators. Increased vascular permeability results with subcutaneous and mucosal edem,
AAE and HAE are nonhistaminergic angioedema and are no longer considered subtype>
of urticaria, due to their different pathomechanisms.

•
Pathogeny of urticaria/angioedema
Allergic urticaria (20% of cases):
J
o I g E-dependent (type I hypersensitivity reaction)
o a u t o immune mechanism: autoantibodies against IgE or IgE receptor (iD
chronic urticaria)
• Non-allergic urticaria (80% of cases): direct mast cell degranulation by alterin[
membrane properties and secondary release of histamine, i n d uced by radiocontrast
media, drugs (agiotensin-converting enzyme i nhibitors, aspirin, AINS), fool
preservatives and food (fish, sea fruits, all types of berries, red wine)
Treatment
Patients should be informed that usually the disease has a self-limiting duration.
E tiologic therapy attempts the removal of t h e eliciting f a ctors, w h enever
identified. History should focus on medications (aspirin, NSAID, angiotensin-converting<
enzyme inhibitors), food allergens (animal proteins: meat, milk, eggs) and foo|i
pseudoallergens (fish, seafood, strawberries, nuts and food additives like tartrazin<,
sodium benzoate), contactants (latex, medication, tomato, plants), infections (bacterisi
infections of the nasopharynx, H.pylori, bowel parasites), exposure to arthropods, physicsi
precipitants (pressure, cold, sun, water), and family history. Acute spontaneous urticaria i~

84
se oI usua> ycaused by food and drugs, while chronic spontaneous urticaria may be associated
:les, tpgronune disorders (e.g., systemic lupus erythematosus).
to autoi
Symptomatic therapy is aimed at palliation of pruritus and discomfort, by:

1. First hne therapy n on-sedating anti-H1 antihistamines (compete with histamine for
histamine receptor, reduce vascular permeability): l oratadine (Claritine),
ue t0 desloratadine (Clarinex, Aerius), fexofenadine (Telfast, Allegra), cetirizine (Alerid),
feve, levo-cetirizine (Xyzal), ebastine.
Wlg Second line therapy: The dose of non-sedating antihistamine may be increased up to 4
times.
Classic, traditional anti-H1 antihistiamines may be associated in the evening, for
sedative a n d an t i c holinergic e f f ects. T h ese a r e hy d r o x y zine ( A t a rax)
promethazine, dyphenhydramine (Benadryl), c l o r pheniramine, a l k y lamine,
ethylenediamine, propylamine and phenothiazine.
I10f
3 Third-line therapy (drugs added to H1 antihistimies):
I
leukotriene receptor antagonist (LTRA) — Montelukast
Ciclosporin — in severe disease, refractory to an y d ose of antihistamine; high
ec5$$
incidence ofadverse effects
Q malizumab — IgG monoclonal antibody that inhibits IgE from binding to t h e
surface of basophils and mast cells; this removes and deactivates free circulating
of the
IgE, preventing the activation of basophils and mast cells
~liow~ oral glucocorticoids should be administered only in short course (3-7 days): for
.n-jil(e exacerbations of chronic urticaria unresponsive to H 1 a n f i histamines. Topical
den glucocorticosteroids are not indicated in urticaria.
)types Phototherapy UV-B and UV-A for 1-3 months — lowers the number of mast cells in
the upper dermis; indication: chronic urticaria and symptomatic dermographism
induction of tolerance — in cold urticaria, cholinergic urticaria, solar urticaria (UV-
A treatment), physical urticaria
4. Local treatment only achieves some symptomatic relief of pruritus using antihistamin-
containing lotions or gels, alcoholic solution with menthol 1%.

Anaphylaxis is a "serious allergic reaction that is rapid in o nset and may cause
terin) death. Anaphylaxis typically involves multiple organ systems. The signs and symptoms, in
intr@I order of frequency, are:
foo< cutaneous: flushing, pruritus, urticaria, angioedema
respiratory: nasal congestion, rhinorrhea, throat pruritus, laryngeal edema,
choking, wheeze, cough, dyspnea
ion. gastrointestinal: cramping, abdominal pain, nausea, emesis, diarrhea
weve cardiovascular: dizziness, tachycardia, hypotension, collapse
ertisf other: anxiety, mental confusion, lethargy, seizures
foo< The emergency treatment in anaphylaxis:
First line therapy:
cter>a o 0 . 5 ml of epinephrine intramuscularly in the anterior-lateral thigh; may need
to be repeated every 5-15 minutes
lysi<> v'
.ariaI' Adjunctive therapy:

85
 o i . v . soluble glucocorticoids (hemisuccinate) are indicated up to 1000 mg, 0,
metilprednisolon 60-80 mg; further oral treatment with 40-80 mg prednisoloqp
o b r onchodilator ( P2-agonist): albuterol nebulised solution every 20 minutes 0,
continuously when brochospasm appears
o H 1 a n t ihistamine(diphenhydramine) 50 mg i.v. or oral solution; alternate<
second generation less sedating antihistamine
o H 2 a ntihistamine (Ranitidine) 75-150 iv
Additonal steps
o p l a ce the patient in recumbent position if tolerated, with elevated lower legs
o o x ygen therapy
o i v fl u i d s in large volumes (volume resuscitation)
o p r o m p t transfer to an acute care facility

DERM A TITIS OR ECZEMA

Dermatitis (Anglo-American term) and eczema (in Europe) are synonyms used tp
describe e p i dermal i n t o l erance r eaction o r pru r i t i c noninfectious infl
ammatory
dermatoses. They are extremely common (in 15-25% of all patients with skin diseases).
Classification
a. Ac c ording to the clinical aspect and evolution:
o Ac u te e czema:erythematous plaques unclearly d e marcated, with o o z in~
surface and covered with vesicles (Fig.8.8). Histology shows spongiosis with
formation of interstitial vesicles.
o Su b a cute eczema:after the acute phase the oozing diminishes, the lesion i
covered by crusts. Histology shows acanthosis and parakeratosis.
o Ch r o nic eczemais c h a racterized by s c a les and l i c h enification ( F ig.8.9),
Histology s h o w s a c a n thosis, hyperkeratosis w i t h pa r akeratosis an<
inflammatory inflltrates in the dermis.
b. Ac c ording to the etiopathogenesis,
eczema can be exogenous, endogenous and mixt
Contact dermatitis/eczema (Exogenous eczema)
There are two types of contact dermatitis:
a. Irritant (toxic or orthoergic) contact dermatitis is a nonspecific inflammator)t
response of the skin to agents that cause direct skin-damage in all persons, without T-cell
immunity involvement. The lesion has sharp margins, according to the contact area and
healing starts promptly when the offending agent is withdrawn (Fig.8.10).
Clinical forms:
• acute: appears after a single exposure to corrosive agents that cause immediatt.'
death of e p i d ermal cells, destroying th e b a r r ier f u n c tion o f t h e s k in , e.g.
physical (UV, X-rays) or chemical irritants (alkaline/acid solutions, organi(
I
solvents)
chronic: a p pears by a cu mu l a t i v e e ffect o f r e p e ated e x p o sures t o l o e
concentration of contact irritants (water, soap, detergents causing "housewife'~
eczema", organic solvents, w o un d s e cretions, amm oniac i n u r i n e c a usin)
diaper dermatitis)
 p, Allergic contact eczema: is a T-cell immune response of delayed type resulting
31re
~ cutaneous contact with an allergen to which the patient has previously developed a
e<fic sensitivity. After the allergen contact the skin for the first time sensitization is
speci
.„duced
u within 5-7 days (induction phase). Lesions occur 24-48 h hours after a subsequent
ntact (reaction phase). They tend t o s p r ead ar ound th e c ontact area and a lso on
cbstant body regions (Fig.8. 1 1 ), because the contact allergen is transported through the
blood to o t her a r eas o f t h e s k in , w h e r e i t e n c o unters sensitized T - l y m p hocytes.
Memory T cells persist in the dermis even after allergic contact dermatitis clinically
resolves
The causes of contact allergic reactions include nickel (Fig.8.12; earrings, necklace,
etc)' chemicals in rubber gloves; dyes added to textiles; fragrances; topical corticosteroids;
topical antibiotics: neomycin.
Atopy and atopic eczema (Endogenous eczema)
Atopy is a t endency to develop specific allergic disorders like atopic eczema,
allergic bronchial asthma, hay fever, allergic rhinitis and allergic conjunctivitis, due to a
Btp
tory genetic predisposition to increased production of IgE immunoglobulins.
Atopy is characterized by a v ariety of i m munoregulatory and skin barrier
abnormalities:
increased serum level of IgE and specific IgE to foods, aeroallergens and bacteria
.11lg
deficient c h emotaxis o f t he ne u t r o phil s a n d ma c r o phages c ausing f r e quent

vith staphilococcal, viral (e.g. eczema herpeticum) and fungal infections;

T-helper 2 (Th2) immune response is activated, with increased type II cytokine
n lI response (IL-4, IL-5, IL-10 and IL-13) and T-helper 1 (Thl) response is inhibited with
decreased type I cytokine response (IFN-y). IL-4 and IL-5 stimulate B lymphocytes
8.9j. which produce elevated IgE levels; IL-10 and reduced IFN-y i n hibit d elayed-type
arrd cellular immune response, explaining f requent staphylococcal, viral ( e.g. eczema
herpeticum) and fungal infections
defective lipid (ceramide) production in the epidermis results in xerosis and then
deffective barier function with increased entry of antigens
Clinical signs of atopy: pale, dry skin (xerosis), dry hairs, dry and fissured lips,
tOIy keratosis pilaris, Dennie-Morgan folds (increased folds below the eye), hypersudoration,
-cell low skin temperature, recurrent keratoconjunctivitis, cataracta, white dermographism,
aIlCl poor response to i.d. histamine, irritability.
Urticaria and acute anaphylactic reactions to food (peanuts, eggs, milk, soy, fish,
and seafood) occur with increased frequency in patients with atopic dermatitis.
iate Clinical manifestations of the atopic dermatitis
e,g Intense pruritus and dry skin (xerosis) are the hallmark of all stages. The pruritus
%111C Is worse at night and the skin shows eczematous changes and lichenification with location
and morphology that change with age.
low
ife'> Infantile atopic dermatitis b egins a bout t h e 3 r d mo n t h o f l i f e w i t h pr u r i t i c
e rythematous plaques, vesicles and scales (eczematous) that are ill-defined on t h e
cheeks, scalp and extensors of the lower legs, with sparing of the napkin area. The
Itching i s v ery i n tense, interfering w i t h t h e s l e ep. Scratching i s f o l l o wed b y

87
 superinfection. The lesions may gradually heal up to 2 years or may be followed b>
atopic eczema of the childhood.

2. A t opic eczema of th e c h ildhood can e i t her d e velop f r o m t h e i n f a ntile a top<

dermatitis or appears in children after the age of 2 to puberty. As a result of chrorri<
rubbing an d s c ratching, th e l e sions become l i chenified ( t hickened) w it h l i n e@
excoriations. The distribution of the lesions changes from the extensor surfaces to th~
flexures, particular antecubital and polpliteal fossae (Fig.8.73). Eyelids, ear lobes, tir~
nape of the neck, dorsum of the feet and hands may also be affected.

3. A t opic eczema o f t h e a d u lts s t a rts a t p u b e r t y. T h e s k i n i s dr i e r a n d t h ~

lichenification is more intense. The lesions may be symmetrical or localized to sorrr<
predilection sites (circumscribed neurodermitis) (Fig.8.9). Flexural folds are aisp
involved in adult stage, along with the face, eyelids, upper arms, back, dorsa of thq
hands, fingers, feet and toes. Chronic hand eczema might be the only manifestatjprr
of adult atopic dermatitis.
The condition is worsened by sweating, contact with organic solvents and wool.

Complications in atopic dermatitis:

bacterial infections: impetiginization, staphilococcal infections
viral infections: eczema herpeticum, warts, molluscum contagiosum
fungal infections: chronic persistent trichophytosis
occupational irritant contact dermatitis of the hands (hand dermatitis) is very common
in atopic patients, favored by water, detergents, solvents; the skin of the hands is dq
and thickened
erythroderma
frequent drug sensitisation
Mixt Eczema (Exo-/Endogenous)
Some types of eczema occur in persons with a tendency to react with allergi<
manifestations to exogenous/endogenous antigens. These forms of eczema are chronir,,
relapsing, may disseminate at some distance where similar eczematous plaques appear
and may lead to erythroderma.

Nummular eczema
It i s m o r e c o m mo n i n me n , m o s tl y b e t w een 5 0-70 y ears, p r esenting @
disseminated round-to-oval, usually sharply d emarcated, "coin-shaped" erythem
atous
lesions, with overlying scaling (Fig.8.14) or oozing with crusting. The lesions art
distributed symmetrically on the legs, but they may occur on the trunk, hands or feet. Tirr,'
sharp margins make them look like psoriasis, while central clearing makes the clinic<i
differentiation from tinea corporis difficult.
Focal infection can be associated (chronic tonsillitis, chronic prostatitis, intestinal
dismicrobism, H.pylori gastritis); venous insufficiency and stasis dermatits could explaIrr
the envolvement of the lower legs.

Dyshidrotic eczema (Pompholix)

It is recurrent palmo-plantar vesiculous dermatitis.
The etiology is b elieved to b e m u l t i factorial, related to v a r i ous endogenou~
conditions (50% of c ases associated w it h a t o pi c d ermatitis) an d e x ogenous factor~

88
 drugs, bacterial o r f u n gal a n t igens through a d e l ayed t y p e c el l m e d i ated
action),
reac 1 Fungal infection of th e f eet can cause palmar p ompholyx an d a n t imicotic
~pic eatrnenf of the primary site resolves the recurrences. Emotional stressexacerbates
trea
)ltd Jyshidrotic eczema.
lQ@
It js characterized by crops of vesicles and/or bullae located strictly on the hands
thy d feet (lateral aspects of the fingers/toes, palms and soles, sometimes extending to the
p>ck of hands and feet) that will ti pically resolve with desquamation and no rupturing
(F;g 8 15, 8.16). Burning pain and intense pruritus are associated. Dyshidrotic eczema may
disseminate on the trunk or face (id reaction).
thy
)I@a Stasis dermatitis (gravitational eczema, varicous eczema)
also It occurs mostly after the age of 50 on the lower extremities in patients with venous
the hypertension and edema du e t o c h ronic venous insufficiency, heart failure or o t h er
tie conditions that cause swelling in the legs.
Stasis dermatitis starts at the medial ankle and gradually involves the lower leg up
to the knee. Itching then vesiculous, oozing erythematous plaques are the first signs
(Fig 8.17), later lichenification and hyperpigmentation secondary to scratching. Edema is
<suan p resent at the beginning, but in chronic cases of stasis dermatitis, there is gradual
tightening and sclerosing of the skin. Dermal fibrosis is the hallmark of advanced stasis
dermatitis. In severe cases, the skin breaks down with oozing, crusted areas and ulceration
which may heal with shiny scars or complicate with superintection.
non O ther ty pes o f a l l e rgic d e rmatitis ma y a s sociate, l ik e s ensitisation t o t h e
cia microorganisms present in the venous ulcer (microbial eczema) and/or to the drugs used
topically on the ulcer (allergic contact dermatitis).

Id reaction (autoeczematization)
Is a generalized acute allergic reaction to intense inflammatory diseases of the skin
caused by fungi (dermatophyte, candida, bacteria) or some antigen created during the
.rgic
inflammatory processes.
mic,
Id r eaction o c c urs 1- 2 w e e ks a f t er t h e p r i m a r y i n f e c t ion o r d e r m a t i t i s
pear
exacerbated due to infection, scratching or innapropriate treatment. The eruption has
acute onset at distant sites from the primary in fection, is symmetrical and extremely
p ruritic, with m a culo-papular o r p a p u l o -vesicular lesions. The i n f ectious agent i s
a5 absent in the id lesions. It resolves as the inflammation that initiated it resolves.
too5 Etiology of id reactions:
are stasis dermatitis — id reaction on the forearms, trunk and/or face (Ftg.8.18, 8.19)
The allergic contact dermatitis — id reaction at long distance from the contact area (Fig.8.12)
ical inflammatory tinea pedis — id reaction on the sides of the fingers (pompholyx)
kerion — id reaction as symmetrical small follicular papules on the upper trunk
final
Microbial eczema (infective eczema, paratraumatic eczema)
)laia
It is provoked by the superantigens of staphylococcus aureus and streptococcus on
t"e skin. Area of advancing erythema with microvesicles is seen around infected wounds,
Ul«rs, bacterial dermatoses, scars (Fig.8.20). Superantigens can activate multiple clones of
lymphocytes, even without prior senzitisation.
ioU5 Microbial (infective) dermatitis should be distinguished from infected eczema
tof5 ( «erna complicated by secondary bacterial or viral infection).

89
 F'

Seborrheic dermatitis
Seborrheic dermatitis needs three factors to develop: individual susceptibility
sebaceous secretion and the yeast Malasseziafurfur.
Seborreic dermatitis exhibits erythematous patches with greasy flakes on the scalp,
ears, eyebrows, nasolabial folds and the middle of the chest, with itching (Fig.8.21,8.22)
Dandruff is a m i l d f o r m o f seborrheic dermatitis, presenting with small w h ite fl akes
confined to th e scalp, w it h o r w i t h out i t ching. Seborrheic dermatitis is w orsened ~
neurological disorders (Parkinson disease, polynevritis), HIV infection, obesity, emotional
stress, myocardial ischemia.
In neonates, seborrheic dermatitis manifests with redness and greasy scaling o~
the scalp and folds during the first 3 months of life. It may complicate with erythroderrnia
desquamativa (Leiner's disease) that associates fever, diarhea and anemia.

Asteatotic eczema (eczema craquele)

It is f avored by x e rosis, decreased sebaceum and sweat secretion in e l derly
personsI excessive use of soaps that reduce the normal cutaneous hydro-lipidic film,
degreasing agents (solvents, cieansers), diabetes mellitus, hepato-renal conditions oy
cancer. Pruritus is the first clinical sign, cracks and polygonal fissures appear on the shins,
I
arms and back of the hands (Fig.8.23), redness, and scales.
Treatment of eczema
Exposure to trigger factors has to be reduced in atopic dermatitis: detergents,
soaps, toiletries containing alcohol and astringents, extreme temperature changes, stress,
infectious agents (staph.), intense activity (sweating), irritant clothing (wool), food (peanut
butter, eggs, fish and seafood, milk, soy and chocolate), aeroallergens (e.g.dust mites,
animal dander) and contact allergens.
Preventing and treating xerotic skin is important in atopic dermatitis to reduce
itching and th e f r equency between the fl ares. Restoring the cutaneous barrier with
ceramid-containing creams is particularly helpful i n i r r i t ant contact dermatitis, also.
Soaps and detergents should be replaced with syndets (like Dove, Neutrogena, Eucerin
etc) that have a pH similar to the skin (approx. 5.5). Bathing daily in lukewarm water
with mild, unfragranced cleanser should be immediately followed by application of
moisturizers/emollients (e.g. Trixera, Atoderm) to m a x i m ize m oisture retention and
provide a barrier to irritants, pathogens and antigens. I
Topical treatment
In acute eczema or acute flares of atopic dermatitis topical therapies targeting the
immune system dysfunction are the mainstays of treatment.
Wet dressings with mild antiseptics (kalium permanganicum 1/10.000, zinr
sulfate 1/1000, silver nitrate 1/6000, or in v er y sensitive patients NaCl solution) ar<
recommended for oozing lesions. Besides being antiseptic, wet dressings also reduce
inflammation b y v a s oconstriction du e t o t h e c o o l in g e f f ect an d b y m e c h anically
removing the bacteria.
Topical i m mu n o m o d u lators recommended in ec z e m a ar e topical

corticosteroids (TCSs as first-line treatment) and topical calcineurin inhibitors (TCIs).

Topical corticosteroids exert anti-inflammatory and immunosuppressive effects
through regulation of p r o i n flammatory cy t okines and cells. The potencies of TCSS

90
 <ge from very mild to very strong and they are chosen according to the severity of
rang
the d]sease and th e a r e a o f t h e b o d y t h a t i s a f f e cted. C l o betasol p r o p i onate
(perrnovate) is a potent formulation, mometason furoate (Elocom), methyprednisolon
Lp, eponat (Advantan) and hydrocortison butirate (Locoid) have medium activity and
acepo
2), hydrocortisone
h ro is th e w e akest TCS. The l o n g -use of T CSs (m ore t ha n 3- 4 w e eks
'es <ontinuously applied) is limited by the cutaneous side effects:
cutaneous atrophy — after potent formulations
ial striae, skin fragility
steroidic purpura — on the arms, legs; telangiectasia — most striking on the face,
on after fluorinated formulations (Fig.8.24)
steroid acne, steroid rosacea (Fig.8.25) and perioral dermatitis are induced or
aggravated
hypertricosis
rly microbial, viral and fungal infections are favoured through depression of the local
immune response
or healing of the wounds is suppressed by inhibition of the collagen synthesis, thus
dermatocorticoids applied on the ulcers will increase their depth (Fig.8.26)
S ystemic side effects like suppression of th e h y pothalamic-pituitary axis w i t h
ibition of growth in children may appear after potent TCSs on more than 30% of the
body surface,
for long periods.
its, Tar (coal tar, ichtiol, oleum cadini) can be associated to topical steroids as it
'.Ss, decreases inflammation, especially in t hickened, scaly plaques (e.g. Flumethasone
rut pivalat with coal tar - Locacorten tar). When lichenification appears dermatocorticoids
es, are applied u n d e r oc c l u siv e d r e s sings o r dep o t co r t i c o id s ( m i c r o cristalline
triamcinolon - Volon A, bethametasone diproprionate - Diprophos) are infiltrated
lee sublesionally.
ith Topical calcineurin inhibitors block the inflammatory cascade produced by the
SO, pathologic T cells in the skin, preventing expression of proinflammatory cytokines and
t he proliferation o f T c e l l s . T acrolimus 0 .03% an d 0 .1% o i n t ment ( P r otopic) an d
ter Pimecrolimus 1% cream (Elidel) are now available. They are indicated as continuous
of followed by non-continuos treatment in chronic eczema to reduce the incidence and
nd severity of flares and prolong the time between flares. The most common side effects
are stinging, burning or itching immediately after application.
Systemic treatment
Oral corticosteroids are used for short periods in severe flares of acute eczema if
the topical treatment is not efficient or in widespread eczema.
Systemic antibiotics are generally used in superinfected eczema, and also to
eliminate bacterial superantigens that cause the flares of the microbial eczema. Antibiotics
tee h»e no effect without the clinical evidence of infection. Only l a boratory evidence of
.lly Sa«eus without c l i nical m a n ifestation i s n o t e v i d ence of clinical i n f ection, since
«aphylococcal organisms commonly colonize the skin of patients with atopic dermatitis.
cal H1 antihistamines of sedative type reduce the pruritus.
UV light (UVB and PUVA-therapy) help reduce inflammatory activity in the skin
cd (»ibits Langerhans cells and lymphocytes).
'.Ss Ciclosporin, azathioprine, metotrexate can be recommended in very severe cases.

91
 PRURIGO

Prurigo is a severely itching skin condition characterized by dome-shaped papule,

topped with a small vesicle. The vesicle is transient because it is immediately removed p >
scratching, so that a crusted papule is more frequently seen.
I
Acute prurigo of childhood (strophulus infantum)
It appears in children of 2-8 y ears, predominantly i n s u m mer an d f a ll, as ~
recurrent reaction to insects, with severely itching seropapules of 1-2 cm on the limbs ~d
trunk. When bulla is formed, prurigo is called strophulus bullosus (Fig.8.27). Aft',
causes
s cratching, h a r d , e xcoriated a n d cr u s te d p a p u l e results. S u perinfection
impetiginization. Depigmented and hyperpigmented spots result after healing.
Treatment: adequate room desinsection or admission to a clinic will lead to heal~~
in most cases. Sedative oral antihistamines, topical powder or zinc lotion can result.

Subacute prurigo
It is a chronic inflammatory dermatoses encountered more frequently in wome~
between 20-30 years of age. Insects seem to play no role. It is frequently associated with:
diabetes mellitus (prurigo diabetica)
pregnancy {prurigo gestationis)
liver diseases (prurigo hepatica)
menses (prurigo dysmenorrheica)
hormonal influences (contraceptives)
gastrointestinal disorders (hypoacidity, chronic gastritis, enteral candidiasis)
focal infections
Clinical findings: symmetric papulo-vesiculous lesions on the extensor surfaces Of
the extremities, upper part of the anterior and posterior thorax. Atrophic scars result,
hyperpigmented or more often depigmented and surrounded by hyperpigmentation.
Chronic prurigo
It is described as multiple, intensely pruritic, excoriated nodules, erupting on thr
extensor surfaces of the limbs secondary to itching or rubbing. The individual lesions art.'
generally symmetric, 3-20 mm, firm, erythematous or brownish papules or nodules that
evolve slowly (F ig.8.28).The pruritus is characteristically p a r oxystic: i n termittent,
unbearably severe and relieved only by scratching to the point of damaging the skin, with
bleeding and scarring.
The cause of prurigo nodularis is not known, but multiple factors are supposed to
contribute: atopic dermatitis, anemia, hepatic (including l i ve r C i n f e ction) o r r ene~
dysfunction, l y m phoproliproliferative diseases, p s y chiatric c onditions, H I V
immunodeficiency conditions. The majority of patients have a positive history for atop)'
(atopic dermatitis, asthma, hay fever).
Treatment is challenging, as lesions may not heal completely. The treatment 0~
choice is i n t r alesional o r t o p i cal ( u n d er occlusive d ressing) corticosteroids. Oth«
treatments are: PUVA ( p soralen+UVA) o r c r y o therapy. Systemic treatment i n cludt'~
antihistamines, antidepressants, anxiolytics, Dapsone, Thalidomide.

92
 DRUG ERUPTIONS

The undesirable side effects of the drugs can mimic a wide range of derrnatosis. A
r eactiorl should be considered in any patient who is taking medication and wh o
drug rea
d denly
sud e develops a symmetric cutaneous eruption. Medications that are kn own f o r
sing sidn reactions more frequently are antimicrobials, non-steroidal antiinflammatory
causing
s (NSAIDs), cytokines, chemotherapeutic agents, anticonvulsivants and psychotropic
drugs
aa a
and agen s. Drug eruptions may be produced by i mmunological or nonimmunological
kfter rocesses. Immunosuppression due to HIV i n creases 10-fold the risk of d rug eruption,
process
l13ea
including severe reactions.
Immunologically mediated d r u g eru p t i on s a r e non - d os e r e l a ted and
unpredictable; they are classified in 4 groups (Gell and Coombs):
Igp dependent reactions (urticaria, angioedema, anaphylaxis). Anaphylaxis combines
(urticaria, angioedema) with systemic manifestations such as hypotension and
tachycardia and in severe cases cardiovascular shock with death. All these types of
metr
'r: reactions appear within minutes after drug administration, faster and more frequently
after parenteral drugs as compared to oral ingestion. Anaphylactoid reactions, as seen
with radiographic contrast media, may mimic clinically IgE-induced histamine release,
but are secondary to a non-immunologically release of histamine.
cjtotoxic reactions (the drug antigen is fixed on some cells, antibody-antigen reaction
activates the complement and cytolysis results) e.g. hemolytic anemia after penicillin
therapy, post-drug purpura
une complex reactions: serum sickness syndrome — caused by treatments with
heterologue serum or depot penidllin; leukocytodastic vasculitis (Fig.9.29) that appears 7-
as Ot
21 days after the onset of therapy, with red macules quiddy followed by palpable purpura
.suit,
and hemoragic vesicies associated with constitutional symptoms (fever, arthritis)
delayed hypersensitivity reactions: allergic contact dermatitis (after topical use of
neomycin, rivanol, antibiotics), exanthematous reactions, photoallergic reactions (after
doxicycline); they begin 7-20 days after medication is started.
a are
Non-immunological drug reactions are dose-related and predictable and are called
side-effects:
tent,
d yschromia: argyria — blue-gray d i scoloration o f s k i n a n d n a i l s d u e t o s i l v e r
with
treatments; brownish colour caused by antimalarics, melasma caused by estrogens
direct degranulation of mast cells (opioids, contrast substances)
anaphilactoid drug reaction after aspirine (affects the arachidonic acid metabolism
enar
resulting in synthesis of leucotriens)
imbalance of the intestinal flora (candida infections after antibiotics)
tOIrIr
m etabolic disorders (hiperlipemia and c u taneous xanthoma after t r eatment w i t h
isotrebnoin)
xt or
Herxheimer reaction due to bacterial endotoxins released from destroyed treponema;
tther
symptoms resolve with continued therapy.
ader
»opecia after retinoids, antimetabolite chemotherapeutic agents (cyclophosphamide)
hypertricosis (minoxidil, fenitoin)
skin necrosis: cumarins (warfarin, heparin)

93
 Clinical forms of drug eruptions

Acne caused or aggravated by lithium or corticosteroids

Drug-induced pemphigus: captopril and D penicillamine 4

Lupus — like eruptions: hidralazine, penicilline, griseofulvin

Psoriasiform eruptions caused by betablocant drugs
Fixed drug eruption: recurs at t he s ame s ite ( fi x) a f ter e ach exposure to d r y )
(sulphamids, AINS, analgetics). One or a f e w c i r cular, red-violaceous, edemato~
plaques (sometimes with central bu lla) t hat t u r n t o b r o w n a f ter 3-6 w eeks ar<
characteristic (Fig.8.30, 8.31). Secondary hyperpigmentation lasts for months. Han@
feet and genitalia are the most common location, but oral, perioral lesions or on tg<
trunk can also appear.
Stevens-Johnson synd.rome (SJS) and toxic epidermal necrolysis (TEN or LyeII
syndrome) presenting with disseminated, large vesiculo-bullae with atypical targetpjf
aspect (2 zones of color), significant mucous membrane involvement with p ainful
erosions and ulcerations, constitutional symptoms. Stevens-Johnson syndrome can >q
caused by drugs and infections (especially Mycoplasma) and sloughing occurs on le%
than 10% of the body surface (Fig.10.13, 10.14, 10.15). TEN is due to drugs and is <
severe skin reaction that starts with painful skin then sloughing over more than 30% o(
the body surface area (Fig.10.16).
Erythema nodosum —symmetrical, tender, bruise-like nodules, 1-10 cm diameter,
located on the anterior aspects of the legs; they last 1-2 weeks, then slowly involute
(Fig.8.32); it i s a r ea c t ive p r o c ess, often s e condary t o in f e c tion (s t reptococcu>,
M.tuberculosis), but also due to drugs (contraceptives, sulphamids), inflammatory
bowel diseases, sarcoidosis, pregnancy.
Livedo-like dermatitis (Nicolau) appears after an intramuscular injection (benzatin<
penicillin, NSAIs) that causes embolic obstruction of small arteries or arterial spasm. It
is manifested with intense pain and a livedoid patch with dendrites that ulcerates an(
heals in months.
Photosensitisation
o p h ototoxic reactions: usually predictable, appear in any persone who receive
a sufficient dose of phototoxic drug together with sufficient exposure to V~
radiation. Clinically they l ook l i k e exaggerated sunburns, limited to sun.
exposed areas, but a p pear a f ter a s h o r ter-than-expected exposure time,
Responsible drugs: tetracyclines (doxycycline), NSAIDs, fluoroquinolones,
amiodarone, phenothiazines.
o p h o t oallergic reactions: cell-mediated hypersensitive reactions due t o N
radiation that converts the drug into a photoallergen. Clinically, the lesions ar<
p ruritic and resemble eczema or lichen planus. They appear initially on st .
exposed areas, then spread on non-exposed areas and tend to be more chroni<
than ph o t o toxi c r e a c tions. R e s p onsible dru g s : thi a z id e di u r e tic>
sulphonamide antibiotics, phenothiazines.
lrug
:ous
are Fig.8.1. urticaria Fig.8.2. Urticaria rubra
nds
the

yell
toi(I
nhl
abc
less
isa
%oj

'ter,
Fig.8.3. Urticaria porcelanea Fig.8.4. Urticaria anularis
lute
'Qls,
torl

itine
n. It
anti

ives
UV
iuG'
ime, Fig.8.5. Urticaria vasculitis Fig.8.6. Angioedema
ines,

)S
onir I

k,
'.tlesi

Fig.8.7. Dermographism Fig.8.8. Acute eczema

95
Fig.8.9. Chronic eczema (neurodermitis) Fig.8.10. Acute iritant contact
dermatitis to plasture

Fig.8.11. Acute alergic contact dermatitis Fig.8.12. Acute alergic contact dermatitis
to topical NSAID to nickel with id reaction

Fig.8.13. Atopic dermatitis Fig.8.14. Nummular eczema

Fig.8.15. Dishidrotic eczema Fig.8.16. Dishidrotic eczema

96
 Ai!

i'
tT

Fig.8.17. Stasis dermatitis Fig.8.18. Id reaction to stasis dermatitis

C
f
I

Fig.8.19.Chronic id readion mith Fig.8.20. Paratraumatic dermatitis

lichenification after to stasis dermatitis

Fig.8.21. Seborrheic dermatitis Fig.8.22. Seborrheic dermatitis

/
Fig.8.24. Erythema and telangiectasia
Fig.8.23.Asteatotic eczema after fluocinolon

97
 Fig.8.25. Steroidal rosacea Fig.8.26. Superinfected steroidal ulcers

Fig 8.27. Prurigo strophulus Fig.8.28. Prurigo nodularis

Fig.8.29. Leukocytociastic vasculitis Fag.8.30. Faced drug reacbon

Fig.8.31. Fix drug reaction after Fenobarbital Fig.8.32. Erythema nodosum

98
 Chapter 9

DISEASES OI' CONNECTIVE TISSUE

The teim „collagen diseases" was created by Klemperer in 1941. He observed that
in t e connective tissue of th e p atients w it h l u p u s erythematosus, scleroderma and
derirlatomyositis an eosinophilic homogenous substance is present. He called it „fibrinoid"
because it was like fibrin. Later this group of diseases was called autoimmune, because of
the presence of autoantibodies in the serum.
Autoonmunlty is caused by loss of immune tolerance to „self" (antigens of the
b dy) due to a genetic anomaly of the i m m une system or due to autosensitisation to
tiip dified self antigens transformed in „ n o n self" af ter contact with exogenous factors
(physical, chemical, microbial, viral).

LUPUS ERYTHEMATOSUS (LE)

There are two main forms of lupus erythematosus: chronic cutaneous and acute
systemic. Cutaneous form may progress in less than 5% of the cases into the systemic form.
Cutaneous lupus erythematosus
Chronic cutaneous LE (discoid LE) is a photosensitive autoimmune dermatosis
that produces scarring and atrophy. There is no visceral involvement and the serologic
abnormalities are uncommon.
The exact pathophysiology of CLE is not well understood. It probably occurs in
g enetically predisposed individuals, where a heat shock protein is induced in t he
keratinocyte following UV light exposure or stress. This protein may act as a target for the
T-cell mediated cytotoxicity.

Clinical findings
The most characteristic elements of chronic cutaneous LE are: erythema, scales and
scarring atrophy. The disease begins with persistent erythematous papules or plaques
(Fig.9.1) that are sharply delimited and raised (with palpable infiltrate). Then adherent
thick scales appear. The scales have characteristically carpet tack aspect, that describes
multiple small keratin plugs corresponding to the follicular openings (follicular plugging)
attached to the underside of scales. The lesions progress centrifugally and may merge.
«solution of th e a c t iv e l e s ion r e s ult s i n at r o p h y a n d s c a r r ing (F i g .9.2, 9 . 3).
Hyperpigmentation, hypopigmentation (Fig.9.4) and telangiectasia may associate in old
~e»orLs leading to poikiloderma. The course is chronic, lasting for years to decades.
Most of the lesions are photodistributed on the face (often on the cheeks with
biitt«fly-shaped distribution; forehead, nose), on the ear, scalp, the V cf the chest, but they
ca»e also found on the trunk and extremities. The scalp is commonly involved and
P«iiianent alopecia may result (pseudopelade-Fig.9.5). The vermilion of the lips is often
~ffected, with epithelial thickening, erosions.

99
 There are two subsets of chronic cutaneous LE: localized —on the head and neci,
and widespread —on the trunk and limbs, regardless of whether lesions are seen on tg~
head or neck (Fig.9.6). The patients with l a t ter form o f t en have haematological any
serological abnormalities, are m o r e d i f f i cult t o t r e a t an d m o r e l i k el y t o d e v elop
systemic LE.

Clinical forms of chronic cutaneous LE:

• di sc o id LE - low number of lesions with fix dimension and thick scale
• centrifugal LE - many lesions with centrifugal spread and thinner scale
• LE t u m i d us with edematous lesions and no visible scales
• ver r u c ous LE — wartlike lesions on the extensor arms
• LE p r o fundus (lupus panniculitis) with painful nodules deep in the subcutis, th@
result in depressed scars
Complications of CLE are: inesthetic scars, mutilation (worm-eaten appearance 0~
the nose and ears), permanent alopecia and in time, squamous cell carcinoma.
Laboratory endings are usually normal, but AN antibodies can be found (10% pf
cases, mostly in disseminated forms) and anti-native DNA (dsDNA, in less than 5%, refle»f
systemic LE).
Histopathology shows vacuolar alteration of th e basal cell layer, atropN»
epidermis, hyperkeratosis and follicular plugging. Around the dilated blood vessels an<
skin adnexa dense lymphocytic infiltrate is present.
Immunhistopathology is u s e d to confi rm t he disease. Di r e »f
immunofluorescence shows positive immunoglobulin IgG and complement deposits g
the dermal-epidermal junction i n b ot h l e sional and n o n-lesional exposed skin. Th»
nonlesional and nonexposed skin i s n egative in i m m u n o histopathology in CL E but
positive in SLE (lupus band test).
Treabnent
Topical therapy is successful for small lesions. Sun-protective measures (protectiv»
clothing including hats, broad-spectrum sunscreens and behaviour changes like limi~
sun exposure to mornings and late afternoons, avoiding sunbed use, replacing fluorescent
bulb with compact bulb) are essential. Smoking appears to worsen CLE.
G lucocorticoids ( t o pical, i n t r alesional) ar e t h e standard m e d i cal t h erap~,
Superpotent drugs and occlusion are used in hypertrophic lesions, medium-potent on th»
face, foams on the scalp. The intralesional injection of corticosteroid crystalline suspensioo
(triamcinolone acetonide = Volon A, o r b e thametasone dipropionate Diprophos) t
=

effective but has the risk of cutaneous atrophy.

Topical calcineurin inhibitors are an alternative to topical corticosteroids, as thg'
do not result in skin atrophy, but the follicular plugging limits drug penetration and th»
response in chronic lesions.
Superficial cryotherapy has also proved useful.
Systemic therapy
Antimalarial drugs (hydroxychloroquin-Plaquenil 200-400 mg/day or chloroquine»
phosphate 250-500 mg/day) are recommended for several weeks to limit the effect of U>'
on the keratinocites. The most important side effects are corneal clouding and retinopath)
i
(ophtalmological checks are required before and during the treatment).
Systemic glucocorticoids are r arely e ffective, w h il e i m m u nosuppresants, lik»
metotrexate, azathioprine and mycophenolate mofetil are more successful.

100
cia Systemic lupus erythematosus
he TMs is a heterogeneous connective-tissue disease affecting several organs and
ld
sys a ssociated w it h a u t o antibodies against n u clear a n t igens. I t a f f ects m o r e
Dp
ffrequ
equently young women (men/women ratio 1 / 1 0).
The etiology is unknown. Interactions of genetic anomalies of the immune system and
xp<npus factors (UV radiations) are responsible for the disease. It is assumed that UV
expgen
ad,at pn dters the nat ve DNA in such a way that tl is recog e d as forelg and induces the
ra
fprrnatipn pf autoantibodies. Genetic T cell defects of the suppressor cells are responsible for
the fact that the B cells form autoantibodies in an uncontrolled way. The immune complexes
that are deposited in the vessel walls of the skin and internal organs activate the complement
tat
casca
de resulting in immune complex vasculitis, nephritis, endocarditis and arthritis.

pn Clinical findings
The patient, frequently a y o un g w o m an, p r esents facial erythema, tiredness,
<eneral malaise, fever and swallen, painful joints.
Skin findings are present in only 80% of cases, the rest representing lupus sine lupo
(lupus patients without skin lesions). Symmetric diffuse erythema occurs on the face and
IUC exposed areas of the chest (I'ig.9.7). There is a butterfly-like aspect on the face, with malar
Xld ermnences and nasal bridge involvement. Morbilliform, scarlatiniform (Jig.9.8) or livedo-
like exanthems may develop on the trunk, patchy or diffuse erythema on the palms and
:ct
spies, felangiectatic blood vessels at the fingertips and along the nail folds, with subungual
at hemprrhages, even gangrene and ulcerations due to th e angiitis. Skin lesions can be
'he
transient for several days or weeks and they wax and vane in several hours with sun
)ut
exposure. The lesions are not scarring.
Joint in v olvement w i t h a r t h r algia an d p e r i p heral p o l y arthritis i s f r e quent.
Myalgias and polymyositis are signs of the muscular involvement
ive Renal involvement may exist in the form of focal nephritis, nephrotic syndrome,
Jlg nephrosclerosis with hypertension, ending in renal insufficiency.
.nt Involvement of other organs: pericarditis, endocarditis, polyserositis, polyneuritis,
uveitis, pneumonia, hepatospelnomegaly, aseptic bone necrosis.

Laboratoryfindings
ion non-specific changes:
o a n e mia, leukocytopenia, thrombocytopenia
o t h e ESR is significantly raised (100 mm/more in the 1s~ h)
tg o e l ectrophoresis sh ow s h y p o albuminemia, i n c reased a l ph a 2 gl o b u l ins,
the hypergammaglobulinemia with polyclonal IgG
o t h e C-reactive protein and RF are frequently positive, immune complexes and
cryoglobulins can be present; the complement level is usually low
o p r o t einuria, hematuria and urine casts reveal nephritis
|ne o f a l se positive serological syphilis reactions (VDRL, RPR) — in 10% of cases, due
'JV to antophospholipid antibodies responsible for thrombosis, fetal loss
immunological changes:
o a n t i n uclear antibodies (ANA) — positive in m ore than 95% of patients, but
non-specific for SLE; may be positive in 10-15% of healthy persons;
o a t b . anti-native double-stranded DNA (anti-dsDNA) — very specific for SLE

101
 o Sm a n t igen, which is part of the RNAse-resistant fraction of the extractable
nuclear antigens (ENA) — strongly specific for SLE
are neutrophili<
o L E - cell p h e n omenon and L E -cell t e st . T h e L E ce l l s
granulocytes containing phagocytosed basophilic nuclear material resulted
from th e d e struction o f t h e n u c l eus b y t h e a n t i nuclear factors. LE-cell
material is ',
phenomenon is rosette formation, when th e a l t ered n u clear
surrounded by neutrophils
o l u p u s band test is specific for SLE and demonstrates the deposition of IgG @
the basement membrane in unaltered skin which is not exposed to sunlight. g
diseased skin the test is positive in both systemic and chronic LE.
Course and prognosis
L
The formerly very poor prognosis, often with fatal outcome within a few weeks up
to 2 years, has improved since the introduction of corticosteroids.

Treatment
Systemic
Advise patients to avoid exposure to the sun.
Systemic corticosteroids are the mainstay of therapy for systemic disease. Initial]y
high doses are given (over 1g/kb/d, usually 100-150 mg prednisolone). After cutaneous,
clinical and paraclinical response (ESR) is obtained, the dose is carefully reduced to
individual maintenance dose that must be continued for years. Adverse effects of systemic
osteoporosis,
corticosteroids must b e a d d r essed: d i abetes mellitus, o steonecrosis,
hypertension, stigmata of Cushing syndrome, gastritis, gastric ulcer.
Additional immun o s uppressives a re u s e d (azathioprine = IMURAN,
cyclophosphamide) because of steroid-sparing effects.
Antimalarial drugs (hydroxichloroquine) also have steroid-sparing effects and are
used as first-line therapy especially in patients with skin lesions.
Intravenous IgG (0.5-1 g/kb/d for 4 days) have recently become important in
controlling recalcitrant disease.
Topical
creams or
UV sunscreens, topical c alcineurin i n h i bitors, c orticosteroids i n
ointments are used as an adjunct to systemic therapies.

DERMATOMYOSITIS

D ermatomyositis (DM) i s a systemic a u t oimmune d i s order with s evere,

inflammatory myopathy and characteristic cutaneous involvement, but also with frequent
involvement of i n t ernal organs, mainly t h e p u l m onary, gastrointestinal and c ardiÃ
systems. It occurs more often in 30-60y females.

Clinical findings
The skin symptoms are accompanied by muscle disease. In the absence of the s
>
involvement one speaks of polyrnyositis.
The pathognomonic skin lesions in D M a r e t h e h eliotrope rash and Gottro~
papules. The heliotrope rash is a periorbital violaceous erythema with or without
ed'~
of the eyelids (Eig.9.9). Gottron papules are violaceous-red, flat-topped papules an

102
)Ie ues located over bony p r o m inences, particularly th e m etacarpophalangeal joints,
terphalangeal joints, wrists, elbows and k ees
irtterp
4c Other characteristic but not pathognomonic cutaneous findings include:
symm
etric violaceous-red or h y p erpigmented macular p atches: in a d i s t ribution
'lar to that of Gottron papules (Gottron sign-Fig.9.10), on the nape of the neck,
ell
upper back and shoulders (Shawl sign), on the V of the neck and upper chest (V sign),
on the latera] thighs or hips (Holster sign), linear extensor erythema on the legs, thighs,
upper arms and forearms, hands and feet, facial erythema in a malar distribution or
at
In more extensively with perioral sparing
poikilodermia results from chronic evolution of macular violaceous erythema in sun-
exposed areas and consists of mottled hyperplgmentatlon and h y p opi g e n t atlon.
telangiectasia and skin atrophy with or without scale
LlP
periunghial erythema, nail-fold telangiectasia, cuticular overgrowth
caicinosis cutis (dystrophic calciflcation) - firm, yellow or flesh-colored nodules in the
subcutis {Fig.9.11) and muscles
photosensjtlvlty
• pr u r i tus
lly Muscle findings are characteristic: increased fatigability, proximal symmetrical
Ila, tnUscle weakness and tenderness of the limbs. Patients may have difficulty in r a ising
to hands (combing), squatting or rising from this position and climbing. Involvement of the
respiratory muscles leads to dysphagia and dyspnea.
Inc
Systemic findings include interstitial pneumonia, arthralgias and o p ortunistic
ns,
infections.

Laboratory findings
mildly raised ESR, leukocytosis with l y m p h openia and eosinophilia; occasionally
ire positive rheumatoid factor; negative LE factor, ANA and syphilis serology
muscle enzyme levels are increased and m easure the l evel o f d e struction: CPK
(creatine phosphokinase), GOT (glutamate-oxalate transaminase), LDH ( l actate
dehydrogenase), ALD (aldolase); serum creatine is raised and excreted in urine
electromyogram (EMG) demonstrates fibrilation and small polyphasic potentials
musde biopsy shows inflammatory infiltrates in the connective tissue between muscle
fibers and degenerative lesions with l oss of t h e c r oss striations in t h e m u scles,
homogenization and destruction of the muscle fibers, resulting in sclerosis.
An evaluation for a possible malignancy should be performed, as dermatomyositis
may be a paraneoplastic disorder (carcinomas of t h e d i g estive tract, l u ngs, female
genitalia).
re,
Evolution, prognosis
iac DM can be acute in more than half of the cases in children but rarer in adults; it
«rt have a polycyclic evolution i n 1/ 3 o f t h e cases or i t can b e c hronic. In case of
Paraneoplastic disease, dermatomyositis improves after removal of the tumor, but recurs
with recurrence of tumor or metastases.

Treatment
'On S ystemic glucocorticoids (0.5-1 mg/kb/d t apered t o 5 0 % o ve r 6 m o n th s a n d
"'scontinued in 2-3 years) are the treatment of choice. Steroid-sparing immunosuppressants
trta
I an be associated, like Metotrexate {weekly low dose), Azathioprine (2-3 mg/kb/d), pulse
g(l

103
Cyclophosphamide, Cyclosporine, recently biologics and intravenous immunoglobulin
Sun avoidance and sunscreens are recommended.

SCLERODERMAS

Sclerodermas are chronic diseases in which, after an inflammatory phase, sclerosis

of the skin develops. There are two groups of sclerodermas: localized or circumscribed
scleroderma and progressive systemic scleroderma.
Localized. or circumscribed scleroderma (morphea)
Localized scleroderma is characterized by excessive collagen deposition leading to
thickening of the dermis, subcutaneous tissue or both. Different clinical f orms of localized
scleroderma may be distinguished according to the size, form and depth of the sclerotic
changes in the skin.

Morphea (plaque form)

One or several lesions, 1 cm to more than 20 cm in diameter are found on the trunk
or limbs. The lesions start as erythemato-violaceous plaques and enlarge slowly. The
typical mature lesion is a sclerotic, firm plaque, shiny, waxy or ivory, without hair and
sweat glands, surrounded by a blue-violet erythema, called „lilac ring" that later becomes
hyperpigmented (Fig.9.12, 9.13). The plaque softens and the dermis becomes atrophic,
sometimes hyperpigmented after months/years.

Guttate morphea
It is characterized by small (<1 cm in diameter) scattered yellowish-white sclerotic
lesions (white spots disease).

Linear scleroderma
Is characterized by unilateral, linear, band-shaped lesions along the length of an
extremity, causing restricted movement; circumferentially on a finger or a limb, leading to
I
amputation of a digit; or paramedian on the frontoparietal region, from the eyebrows up
into the scalp. The latter is also called „coup d e sabre" because the linear, atrophic
depression with permanent alopecia resembles the stroke from a sw o rd. This form is
deeper than the plaque and guttate forms, involving the underlying tissue (muscles or
bones or even the cerebral substance).

Etiology may be l i n ked to i n f ections like Borrelia burgdorferi (after tick bite),
Epstein-Barr virus, varicella etc at least in some cases.
Course. Morphea typically has a benign, self-limited c o urse, with sp ontan
resolution over 3-5 years. Unlike systemic scleroderma, morphea lacks sclerodactily,
Raynaud phenomenon and internal organ involvement.
Treatment
Topical treatment is based on glucocorticoids that can be applied as ointments or
injected intralesionally (triamcinolone acetonide suspension) in early lesions to reduce
inflammation. Topical calcipotriene, tacrolimus or i m i quimod can also be used under
oclusion. Physiotherapy with heat treatment and massage is useful.
Systemic treatment with penicillin is recommended in extensive and active forms
Systemic corticoids might be helpful in the inflammatory phases of morphea, but they

104
have l'ttle
itte benefit for established sclerosis. Broadband UVA (320-400 nm), or better UVA1
0 400 nm) penetrate deeper into the dermis than UVB and is particularly eHective in the
(340-4
treatment of morphea.
progressive systemic scleroderma (systemic sclerosis)
T his i s a chronic systemic a u toimmune d i sease o f t h e c o n n ective t i ssue
characterjzed
er by cutaneous and systemic manifestations. The pathogenesis of the disease
inclu es unologic system disturbances and vascular changes that lead to increased
collagen
ag deposition in skin and other tissues.
Clinical findings
Skin lesions
The disease starts slowl y w i t h v a s omotor d i s o rders - ac r ocyanosis',cutis
rrnorata 2 and the most characteristic Raynaud syndrome. The Raynaud syndrome
marmor
ecedes
prece e the development of skin and systemic sclerosis by 1-15 years, it is caused by
episodic vascular spasm i n t h e f i n g ers an d i t e v o l ves i n a t y p i cal t h r ee-stage
sequence of painful ischaemia, local cyanosis, and arterial vasoplegia. The skin color
changes from white to blue and red, and intense pain associated through the spastic
crisis (15-30 min).
Skin sclerosis is acral at the beginning. Sclerodactily appears progressively as
sbght erythematous swelling of the fingers and turns into extremely tight, stretched and
~ax-like skin. The mobility of th e hands and feet is greatly restricted because of the
sc}erotic shrinkage of t h e s ki n r e sulting i n b en t an d c o m pletely i m m ovable fingers
(Fig.9.14).Small painful necroses at the fingertips are often found (rat-bite necroses), with
mutilated terminal digits.
The face shows loss of facial expression, the nose becomes pointed, the lips are
narrow, the mouth becomes small and r ound ( m i crostomia) with r a dial grooves. The
mobility of the face is restricted. Sclerosis may slowly become generalized, on the trunk
and limbs (Fig.9.15).
Involvement of internal organs:
• digestive tract: the esophagus (most frequently involved) looses peristalsis and shows
atonic dilatation in scintigraphic examination
• lungs: massive fibrosis
• heart: diffuse, interstitial, myocardial fibrosis and cor pulmonale
• kidneys: fibrosis of the interlobular arteries and atrophy. The first sign is proteinuria,
and then progressive insufficiency with malignant hypertension develops.
CRESTsyndrom
e is a particular form of scleroderma manifested with calcinosis,
Raynaud, esophagus involvement, sclerodactyly and telangiectasia (Fig.9.16).

Laboratory f'indings: increased ESR, hypoalbuminemia, hypergammaglobulinemia

and C reactive protein. Antinuclear antibodies are positive in over 90% of cases, and
anticentromere antibodies in 70-80% of cases.

1
> «aii symmetric, permanent blue-red color of the skin in cold environment due to reduced oxygenation
reticulated blue color of the skin due to obstruction of superficial vessels and secondary stasis in other vessels
t»t are compensatory dilated; it does not blanch on pressure

105
 Treatment
The therapeutic approach depends o n t h e p r e sentation o f t h e d i sease and
complexity of symptoms. In systemic sclerosis the treatment is symptomatic
in Raynaud syndrome - v a soactive drugs: calcium-channel blockers, vasodilators I

(pentoxifyllin, xantinol n i cotinate, intravenous prostaglandins), and i n h i bitors o{'

thrombocyte aggregation (aspirin); smoking cessation is adviced II
glucocorticosteroids (antiinflammatory and immunomodulatory action) in moderate
dosage (40 mg p r ednis oneevery second morning), cytostatics (azathioprine,
cyclophosphamide)
antisclerotic drugs: D-penicillamine can arrest the disease in early inflammatory forms
Side effects: drug-induced pemphigus, renal d a mage, h ematological c h anges,
P enicillin i n fusions are better t olerated, and t h e a ction ma y o c cur t h r ough t h e
degradation product (penicillamine).
Topical treatment r efers t o p h y s iotherapy, ointments w it h n i t r o glycerin or
heparinoids to promote circulation.

106
Fig.9.1. Chronic lupus erythematosus Fig.9.2. Chronic lupus erythematosus

Fig.9.3. Chronic lupus erythematosus Fig.9.4. Atrophic scar after chronic LE

Fig.9.5. Scarring alopecia in chronic LE Fig.9.6. Diseminated chronic LE

>>g 9.7. Systemic lupus erythematosus Fig.9.8.Systemic LE

107
 Fig.9.10. Gottron sign in dermatomyositis
Fig.9.9. Heliotrope rash in dermatomyositis

Fig.9.12. Morphea
Fig.9.11. Calcinosis cutis in dermatomyositis

Fig.9.13. Morphea Fig.9.14. Scierodactily with vasculitis

in systemic sclerosis

Fig.9.16. CREST syndrome

Fig.9.15. Systemic sclerosis
 Chapter 10

BUI.GUS DISEASES

PEMPHIGUS VULGARIS

Pemphigus vulgaris (PV), the most severe and frequent autoimmune bullous
disease, is mediated b y c i r culating autoantibodies directed against k eratinocyte cell
surface.The disease usually affects people between 40 and 60.

Pathogenesis:
IgG a u t oantibodies t o de s m osomes ( i n f a c t to des m o g lein I and III,
transmembranar proteins that belong to d esmosomes) are produced. Desmoglein-
autoantibody complexes initiate an immunologic inflammatory reaction that destroys the
d esmosomes resulting i n l o s s of cell-cell adhesion, a p rocess called acantholysis.
lntraepidermal acantholytic blisters are formed in the lower part of the prickle cell layer
(medium blisters) within a few hours.
1 Clinical findings:
Mucous membranes are typically affected first in PV, preceding cutaneous lesions
for about 4 months. Blisters develop most often in the mouth. These soon rupture and
painful, slow-healing erosions result with peripheral extension and epithelial shedding
(Fig.10.1,10.2).
On normal appearing skin flaccid blisters filled with clear fluid arise. They
are fragile an d s o o n p r o d u c e p a i n fu l e r o s i on s w i t h p e r i p h e ra l e x t ension and
shedding of the epithelium. Crusting develops while the margin o f t h e b l ister
advances (Fig.10.3). T he lesions have litt le tendency to epithelisation but w h e n t h i s
happens, characteristic hyperpigmented macules result (Fig.10.4). As new lesions
a ppear, the e r u p t ion b e comes p o l y m o r p h ous, w i t h b l i s t ers, erosions, crusts an d
hyperpigmented macules.
The skin fragility might be revealed in two ways: a) firm and repetead sliding
pressure with a f i nger separates the upper layers of normal-appearing epidermis,
producing bulla (Nikolskysign); b) pressing on the top of a blister may spread the content
into clinically unaffected skin (Asboe-Hansen signor blister's migrating sign).

Lab tests
Blister smear cytology (Tzank test): acantholytic cells are found on a smear taken from
the base of a freshly opened blister, in May-Griinwald-Giernsa stain; these are
epidermal cells with a round shape because they lost desmosomes
Histopathology: suprabasal cells separate from t h e b a sal cells t o f o r m b l i sters;
acantholytic cells are found in the blisters (Fig.10.5).
Immunology:

109
 o d i r ec t i m m u n o fluorescence (DIF) o n p e r i l esional s ki n d e t ects Ig G a r i d
complement on the surface of keratinocytes, resulting in a fluorescent networl,
aspect throughout the epidermis
o i n d i r ect imm unofluorescence(IDIF) using the patient's serum and m o nkey
esophagus demonstrates circulating antibodies IgG against desmosomes. The
titre of the circulating antibodies correlates with the disease activity.

Pemphigus vulgarls
IgG 8, C3 blister urlthin the epidermis
floor lined by basal cells
acantholybc cells in blister fluid
intercellular IgG & Ca by direct
immunofluorescence

Pemphigoid
subepidermal blister
eosinophil infiltrate in underlying dermis
basement membrane IgG & Ce by
•

•
• ••
•
•
~ • IgG 8 C3 direct
immunofluores cence

Dermatitis herpetlformh
f subepidermal blister
neutrophil infiltrate in underlying dermis
dermal papillary Ig A by direct
•

• Immunofluorescence
IgA

Graphic 10.1. Diagram showing histology of typical bullous autoimmune dermatosis

Course
The untreated disease usually leads to death within 1-3 years because of cachexy,
as water, electrolytes and proteins are lost and oral erosions hinder feeding or because of
superinfections.

Tfeatfnent
The aim of th e treatment is to i n duce disease remission by reducing antibody
production. ail]
Since the introduction of glucocorticosteroids and imunosupressive drugs, over'
mortality has been reduced by more than 50 %. Most of the mortality is now linked to the
side effects of therapy. Minimal drug doses required for disease control should be used in
order to minimise side effects.
T reatment o f pe m p h i gu s i s started wit h h i g h s t eroid d o ses (1-2 r ng
prednisolone/kg) in order to in duce rapid remission. After remission of cutaneous and
mucous lesions is achieved (4-8 weeks), the dose is slowly tapered to a sufficient
maintenance dose (5-15 mg prednisolone daily) that will be for life. If the dose is reduced
too fast, recurrence can occur. As the treatment is in many cases for life, side effects such as
diabetes rnellitus, g a stric h y p e rsecretion or u l c eration, h y p e rtension, t i e ombosis
l

osteoporosis and activation of tuberculosis or candidosis may occur. Although steroid-

dependant, this treatment prolongs these patients' life with 20-25 years.

110
 Immunosuppressants should be considered early in the disease, as steroid-sparing
ents when complete remission is attained. Azathioprine and mycophenolate mophetil
are first-line agents.
~ o un d ca r e i nc l u d e s g e n t l e c l e a n sin g w i th anti s e p ti c a g e n t s a n d
n onadherent dressings to p r o m ote healing, m i n i m iz e t r a um a t o s u r r o u n d in g s k i n
and Prevent scarring.

OTHKR FORMS OF PKMPHIGUS

Pemphigus vegetans
Is a rare form of pemphigus that involves predominantly skin folds (axilla and
;Aghinai regions, the lip commissures, vulva and anal areas), scalp and face. In these
areas the blisters are rapidly b r o ken, thus barely seen, and v egetations and crusts
develop. The target is desmoglein 3 (lower epidermis, suprabasal). This form is more
resistant to therapy.
Pemphigus foliaceus
Is a benign variety of pemphigus characterized by acantholysis in the upper
layers of the epidermis resulting in s uperficial blisters (Fig.10.6). The target is
desmoglein 1. The blisters are not evident but extensive scales, crusts and erosions on
an erythematous base are observed mainly i n t h e s o -called seborrheic areas (face,
scalp, upper part of the trunk). Mucosal areas are respected and the N i k olsky sign is
positive.
Pemphigus erythematosus
It is a v a r i ant o f t h e p e m p h i gu s f o l i aceus that can be p h o t oactivated. The
target i s d e s m o g l ei n 1 . It has ov e r l a pe d f e a t u r e s o f lu p u s e r y t h e m atosus
( circulating AN A a n d I g G d e p o sits a t t h e d e r m o-epidermal j u n ction) a n d
pemphigus (superficial a catolysis an d I g G d e p o sits i n t h e i n t e r keratincyte
substance). Prognosis is favorable.
Paraneoplastic pemphigus
Is a rare form o f p e m p h igus, associated wit h c ancer elsewhere in th e body,
most commonly l eukemia or l y m p h oma. The most common cl i nical presentation is
intractable erosive stomatitis that can be confused with severe herpes simplex infection
O r erythema m u l t i f o rma. Systemic t h erapy p r o v i des t e m p orary r e l ie f u n l ess t h e
primary tumour is not treated.
Drug-induced pemphigus
Thiol-drugs (D-penicillamine, captopril, enalapril, piroxicam) and non-thiol
«ugs (penicillin, cefalopsporins, quinolones, carbamazepin) may i n duce bullous
eruption similar to pemphigus.

BULLOUS PKMPHIGOID

Bullous pemphigoid i s an autoimmune, subepidermal blistering disease that

f«cts people over 65 years and rarely involves mucous membranes.

111
 It is characterized by IgG autoantibodies directed against the hemidesmosorrtg pe>
prtl
antigens (minor and major bullous pemphigoid antigens - BPAG1 and BPAG2)
Subepidermal bullae result when hemidesmosomes are destroyed (Graphic 10.1, 10.2). mI
Bullous pemphigoid may have a paraneoplastic character.
orI
Clinical findings coI
Tense, large bullae with clear content associated with i n t ense pruritus arise CO'
or m or e o f t e n o n s y m m e tric
spontaneously e i t h er o n apparently n o r m a l s k i n
erythematous plaques, slightly elevated (urticariform). The lesions appear mostly 0>
the flexural areas: neck, axillae, inghinal fold, and upper abdomen. Later the blisters
may show hemorrhagic content and bloody crusts (Fig.70.7, 10.8). Nikolsky apd
Asbboe-Hansen signs are negative. Oral l e sions rarely occur. The general state of
health is good. it

gsset e4rg eytrrytesrs trrterrrrrergerte gterrtertts

rtK6 f Kt4 tgt

p
igry/y .r/y'- r r ,'.',,Pr.~gz •
'

. ~- — — irtsrtrre ~gPAG t~
L
f rl~ r r
rtrerrrbrsrre -
'hertsrrrerrrbterre trrroteirrs
grrg Q trttegrlrr y
Arrretrrtstrrgtitemerrts -.,
tttgltgI r.r t t.. l l i tt :~ :: "'; , ",. " : ~r, l igg l
grsset terrrrrre
f4e8rttrr tf'f

Arrrehcrr irrg fibrils

f@rrttagerr Vltt
g.rrtreeetltrrirr r
rrretrisef gre
rter'Irr le

Arretrrrrrflrrgr trtsrtrre
tCottsgerr tV, Usrrrtrrrrirr'f

Graphic.10.2. Connections between basal keratinocytes, basement membraneand

derm1s.

Lab exufns
Tzank test is negative. The histopathology shows deep subepidermal bulls
without a cantholysis (G raphic 10.7). DIF f r o m n o r m a l -appearing p e r i lesional sknt
shows deposits of I g G an d c o m p l ement C 3 i n a l i n ear b an d a t d e r m al-epidermal
junction. IDIF and ELISA techniques show circulating autoantibodies in the patient' s
serum that target the bullous pemphigoid antigens (BPAG) 1 and 2 i n t h e skin
basement membrane.
The course of b u l l ous pemphigoid i s u s u ally c h r onic w i t h r e m issions over
months an d y e a rs. W i t h ou t t r e atment t h e m o r t a l it y r a t e i s l o w e r t h a n t h a t Ut
pemphigus vulgaris.
As in o t h e r autoimmune d i s o r d ers, t r e atment i s d i r e c ted a t r e d u c irt
<
ed
infla
mmatory r esponse and a u t oantibody p r o d u c tion. Th e m o s t c o m m o nl y u s e
medications are antiinflammatory dr ugs (glucocorticosteroids in lower doses than irt

112
 ernphigus vu l garis, are u s u ally s u f f i cient t o i n d u c e r e m ission, e.g. 0.5-1 m g / k b
rednisolon) an d i m m u n o s u p p ressants ( a zathioprine, mycophenolate m o p h e t il,
®etotrexate, cyclophosphamide). As compared to pemphigus vulgaris, patients with
bulious pemphigoid ar e n o t c o r t i co-dependent, systemic steroid b e in g n e cessary
only in recurrences. Recent evidence shows that strong topical corticosteroids may
c ontrol cases wit h l o c alized l e sions w h i l e a v o i d in g s y stemic s id e e f f ects o f o r a l
corticosteroids.

HERPES GESTATIONIS (PEMPHIGOID GESTATIONIS)

Is the bullous pemphigoid of the late pregnancy. The original name is a

misnomer, as it is not a herpetic infection but somehow the clinical aspect resembles
;t The immune response seems to be t r i g gered by I g G a u t o antibodies to p aternal
antigens in amniotic basement membrane.
The eruption resembles bullous pemphigoid and appears periumbilical in the
2nd or 3rd tr imester of pr egnancy. Sometimes neonates from these mothers show a
similar eruption. The d i sease heals spontaneously bu t i t m a y r e cu r i n s u b sequent
pregnancies.

DERMATITIS HERPETII'ORMIS DUHRING-BROCQ

Dermatitis herpetiformis is a n a u t oimmune blistering disease associated with

gluten-sensitive enteropathy. Gluten is found i n w h eat, barley, rye and k a muth. This
autoimmune disease occurs in genetically predisposed individuals whose immune system
mistakenly perceives gluten as a foreign invader and attacks it. IgA antibodies to gliadin (a
protein in gluten) are formed. They cross-react with enzymes normally present in the gut,
tissue transglutaminase (tTG), and in the skin, epidermal transglutaminase (eTG). IgA-
eTG complexes deposit at the tips of papillary dermis to cause endothelial cells activation
and accumulation of n eutrophils w it h subsequent lesions of dermatitis herpetiformis.
These deposits may resorb after 10 years of gluten-free diet.
Gluten-sensitive enteropathy is asymptomatic in m ost patients, but 90% show
abnormalities at the endoscopic examination (villus athrophy, lymphocyte infiltration in
the jejunum).

Clinical findings
The symptoms of dermatitis herpetiformis appear in early adulthood (20-30
years old).
Intense itch and burning sensation located tipically symmetric on the extensor
arms, knees and buttocks are followed by erythematous, pseudo-urticarial plaques with
herpetiform vesicles (small, clustered) or bullae. The pruritus is so intense that often
patients present with erosions or crusts in the absence of vesicles which have ruptured
due to excoriation (Fig.10.9). The oral mucosa is usually not involved. The Nikolsky sign
i»egative
Symptoms of celiac disease may be associated (abdominal p ain, l oose stool,
fatigue).

113
 L,ab exams
Tzank test is negative.
Biopsy taken from the edge of the lesion shows neutrophil deposits in the
derma
l
papillae and deep, subepidermal bulla, without acantholysis (Graphic 10. 1).
• DI F of normal-appearing perilesional skin shows granular deposits of IgA and C3 ~
the dermai papillae, the standard criterion for the diagnosis ot herpettform dermatitis
• ID I F or ELISA of the patient's serum shows the presence of IgA autoantibodies against
gliadine or the endomysium in smooth muscle tissue.

Course
Dermatitis herpetiformis is a benign disease with recurrent eruptions and periods
of several months with few or no symptoms, related to the amount of ingested gluten.

Treabnent
Gluten-free diet ( i ncluding m a ize, rice, mi llet, teff, sorghum, bu ckwheat) is
necessary in p atients with g l uten-sensitive entheropathy. Oats are also generally not
recommended, as they induce symptoms in a small minority of celiac patients. N o n-
cereals as amaranth, quinoa are allowed. I o d inated salts, sea fish and drugs containing
iodine have to be avoided, as they may exacerbate the disease.
Sulfones (DAPSONE, 100 mg daily) are the primary drugs in the treatment pf
dermatitis herpetiformis. They act b y i n h i b ition o f n e u trophil m i g ration. Immediate
(within a few hours) improvement of pruritus and skin lesions after first dose of treatment
is another diagnostic criterion. Side effects: methemoglobinemia, anemia, hemolysis. Other
sulfonamides that can be used: sulphapyridine, sulphametoxypyridazine.
Absolute gluten restriction in the diet is the best treatment, making the reduction
of Dapsone dosage possible or even eliminating the disease from the skin and gut mucosa.
Topical t r eatment a i m s t o relieve th e b u r n in g i t c h in g s e nsation. T o pical
corticosteroids could be apllied.

EPIDERMOLYSIS BULLOSA AQUISITA

Epidermolysis bullosa aquisita (EBA) is a very rare disease with tense blisters
at sites of trauma and IgG autoantibodies to type VII collagen (anchoring fibrils).
These fibrils attach th e b asement m e mbrane t o t h e u n d e r l y in g d e r mi s an d t h eir
destruction results in subepidermal blisters, within lamina densa.
EBA is not inherited and usually presents in adult life (50-60 years old), unlike
epidermolysis bullosa (EB) which is inherited blistering disease that is present from birth.
Clinically is characterized by blisters, scars and millia at trauma-prone areas such
as the hands, feet, knees, elbows and buttocks. Mucus membranes may also be involved
(oropharyngeal, nasal, ocular) with possible sequels — esophageal strictures, conjunctival
scarring, blindness). The scarring nature of EBA can lead to nail destruction and hair loss.
Skin biopsy shows subepidermal blister and direct immunofluorescence detects
linear C3 and IgG deposits along the basement membrane, like in bullous pemphigoid
Indirect immunofluorescence detects in the patient's serum IgG circulating autoantibodies
to type VII collagen, on of the skin basement membrane component. Split skin technique i~

114
„ed to differentiate EBA (IgG autoantibodies are located in the lower part of the basement
>embrane, that is lamina densa and sublamina densa) from bullous PemPhigoid (IgG
utpantibodies to the hemidesmosome are localized in the upper lamina lucida).
The treatment is similar with that in bullous pemphigoid.

PORPHYRIA S

Porphyrias represent a group of disorders caused by inborn defects in the haem

Qjpsynthetic pathway. This causes elevation of certain porphyrins or their precursors in the
tissues, urine, or stool. The principal sites of porphyrin synthesis are the erythropoietic
system, liver and kidney.
Porphyrin b iosynthesis starts with th e c ondensation of s uccinate and g lycine
resulting in delta aminolevulinic acid (dALA) and porphobilinogen. Four molecules of
pprphpbjlinogen form th e p orphirins. After decarboxilation and oxigenation processes
pprphpbilinogen transforms i n pro t o porphyrin v ia uro p o rphyrinogen and
cpprpporphyrinogen. The heme is formed by incorporation of iron into protoporphyrin,
catalyzed by ferrochelatase (Grapht'c 10.3). The individual steps in heme biosynthesis are
catalysed by specific enzymes. Enzymatic disturbances in porphyrin metabolism lead to
porphyrias.
Sectittyl CeA

Rttt Z'041$

ALA ttyttthaee

ALA de'r ytlrare re O'A dehydro'eee-detit:ier«y perphyria

Acttte itttertrtittertt ttartthyrie

Vreiterphyrittegett I

Ureprtrphy..inegen Il strnti:are Cnrrteniinl erythrnpeietie porpLyrig [Cfpj

Uraparphyrirtalett ttt

Urepnrphyrinegendeertrhnxy'nte perphyrtn eetenee tncen

Cattrattertehyrlttegelt

Cep&pe'phy':rtegen ex ciJK Hereditary eettrettertthyria

ttretetttartthyritteeett

Vrelepe"phyrineger. err c'ate

ttr@letpertthyt ta

ter.rrri:.elntnte prntnporphyrn'.

Haettt

Graphic 10.3. Biosynthesis of haem and the porphyrias

115
 There are two main groups of porphyrias:
manifested with abdominal pain and neurological signs due to superproduction of
porphyrin precursors (dALA and porphobilinogen)
photosensitization due to accumulation of porphyrins in the skin that are activated by
UV light resulting in free radicals which induce blisters.
Porphyria Cutanea Tarvia
elbo
h e p a t i c deficiency of deIIl
Porphyria c u t a n ea tarda ( PCT) r e sults f rom
of cc
uroporphyrinogen decarboxylase. This is the most common form of porphyria seen by the
dermatologist. Types of PCT:
• fa m i lial PCT - autosomal d o minant d i s order w here more t h a n 9 0 % o f t h e
uroporphyrinogen decarboxylase is deficient
• sporadic PCT —the deficiency of uroporphyrinogen decarboxylase is about 50% and is
usually compensated, but becomes manifested when hepatic disease is associated
(ethanol, oral contraceptives, hepatitis, hepatic tumors, and environmental exposure to
polyhalogenated aromatic hydrocarbon compounds).

Clinical ff.'ndings
The first manifestations usually occur after th e age of 30, m ore frequent in
males.
The most common presenting sign of PCT is fragility of skin exposed to sun and
mechanical trauma, leading to erosions and bullae typically on hands and forearms,
occasionally on feet, face, and ears. Crusted lesions heal with hypopigmented atrophic
scars, milia (keratotic cysts-Fig.10.10) and patchy hyperpigmentation. Hypertrichosis pre(
appears over m a la r a n d t e m p oral a r eas an d t h e f a c e b ecomes hy p erpigmented. by I
Sometimes extensive sclerosis and t h i ckening o f t h e s k i n o n t h e c h est an d b a ck invl
develops.
Laboratory findings
The excretion of urinary porphyrins is massive and urine appears beer-brown with tarl
red fluorescence in UV light (Wood's light). Evaluation of the iron profile (serum ferritin pur
level), liver enzymes (transaminases, AT) and screening for hepatitis viruses are required. (Fig
Treatment epi(
Systemic
Sun, alcohol, estrogen and hepato-toxic agents must be avoided. Treatment of clas
chronic hepatopathy has to be associated.
Therapeutic phlebotomy reduces iron levels (250-500 ml blood weekly and
then every 2-4 weeks until haemoglobin drops to 10 microgm/dl or until the serum
iron drops t o 5 0 m i c romg/dl). H ig h l e vels of i ro n i n h i b i t u r o p o r p h i r i n ogen-
decarboxylase and disturb haem synthesis. In patients in w h o m p h l ebotomy is not
convenient or is contraindicated, alternatives for iron mobilization are: Chloroquine
hy
i n l o w d o ses 125 m g t w i c e w eekly f o r 8- 1 8 m o n t h s or c h el atin g a g ents
SllII
(desferrioxamine).
8, i
Topical
ha
I
Superinfected blisters are treated with antiseptics.

116
 ERYTHEMA MULTIFORME

It is an acute self-limited eruption with iris or target lesion as a hallmark. It occurs

s type IV hypersensitivity reaction characteristically induced by herpes virus infection.
The typical target lesions have symmetric acral distribution (hands, forearms,
elbows, knees and feet) and mild or n o m u cosa involvement. They are round, sharPly
dejnarcated, palpable, expanding to maximum 2 cm over 1-2 days, bright red with 3 zones
af colour {Fig.10.11). The lesions subside in 2-3 weeks without scarring but usually recurr.
According to the aspect of the target, there are two clinical forms:
• erythemato-papulous
form (erythema-iris): small papule in t h e c e ntre, raised
edematous and pale intermediate ring, and violaceous periphery
• ve sicuto-buttous
form (herpes iris): central vesicle, surrounded by a cyanotic zone
and a margin of small herpetiform vesicles.

Treatment
Recurrent EM is typically related to episodes of recurrent herpes simplex infection
and can be prevented by continuos antiviral therapy.

STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL

NECROLYSIS

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and
present as dermatological emergencies, potentially life-threatening. They are characterized
by targetoid lesions with full-thickness epidermal necrosis and with mucous membrane
involvement.
Oral, genital and ocular mucosa involvement precedes the cutaneous lesions and is
manifested by painful erosions, ulcerations and crusts in almost all the cases.
The cutaneous lesions begin on the face and upper trunck and differ from classic
target lesions of EM by a) having only 2 zones of color (targetoid lesions): central dusky
purpura or central bulla, w it h s u rrounding macular erythema that is p o orly d e fined
{Fig.10.12); b) typicall flat aspect, with the exception of central bulla. Areas of denuded
epidermis are dark red with oozing surface.
D epending o n t h e e x t ension o f t h e e p i d ermal d e tachment, th e f o l l o w i ng
classification has been proposed:
SJS - less than 10% of the body surface detachment (Fig.10.13, 10.14)
overlapping SJS/TEN — confluent lesions, epidermal detachment of 10-30% of the
body surface
TEN — more than 30% epidermal detachment (Fig.10.15); the mortality rate can
approach 40%
C learing o f the les i on s t a k e s 3 - 6 w ee k s, with s ubsequent h y per-or
hypopigmentation. Nearly al l c ases of SJS/TEN are d r ug-induced (trimetoprim-
supfamethoxazole, NSAID, allopurinol, carbamazepine etc), but viral infections (hepatitis
~. influenza), microbial infections (streprococcal, mycoplasma), autoimmune disease (LES)
"ave also been reported.

117
 Treahnent
TEN should be treated in an intensive care unit. Principles of management of
SJS/TEN:
withdrawal of the causative drug
r esulting i n fl u i d s h i f t s and
fluid r e placement because of epidermal loss
dehydration
nutritional supplementation — because massive protein loss through denuded s~
wound care — debridement of necrotic epidermis, application of antiseptics and
biologic dressings, avoiding silver sulfadiazine as sulfonamides are frequent
inciting drugs; broad-spectrum antibiotics are not recommended.
Systemic glucocorticoids are controversial, as some believe they may predispose to
superinfections. Intravenous Ig and cyciosporine have shown some benefit in reducing the
mortality rate.
Because the high mortality rate in TEN and treatment arrest progression when
administered early enough, the early recognition of this entity is very important.

118
 • '

. ['I

Fig.10.1. Pemphigus vulgaris Fig.10.2. Pemphigus vulgaris

4i-'"

*
I

Fig.10.3 Pemphigus vulgaris Fig.10.4. Hyperpigmented macules after

pemphigus vulgaris
~ ~ ' RCF
+
cb ' g ~•Q
OQO • gg ~

'6 e~ ~ ~ O Oy Q ~ ®
,~,'I

0 l

• l

~P a~~ ~ 0ea ~~g •• p

Fig.10.5 Acantholytic bulla
Fig.10.6.
Pemphigus foliaceous
(hematoxylin-eozin stain)

Fig.10.7. Bullous pemphigoid Fig.10.8. Bullous pemphigoid

119
 r •

Fig.10.9. Dermatitis herpetiformis Fig.10.10. Milium cysts in porphyria

cutanea tarda

Fig.10.11. Erythema multiforma Fig.10.12. Stevens-Johnson syndrome

after Didofenac

Fig.10.13.Stevens-Johnson syndrome Fig.10.14. Stevens-Johnson syndrome

il
h

Fig.10.15. Stevens-Johnson syndrome Fig.10.16. Toxic epidermal necrolysis

120
 Chapter 11

ERYTHEMATO-SQUAMOUS SKIN DISEASES

PSORIASIS VULGARIS

Psoriasis is a common, chronic, relapsing inflammatory disease with a strong genetic

basis. Kith a morbidity of 1-2%, psoriasis vulgaris is one of the most common skin diseases.
The disease is much less common in the tropical and subtropical climates than in temperate
zones. The white races are most frequently affected, while psoriasis is practically nonexistent
in red skinned people (Eskimo and American indians).
Pathogenesis
The inflammatory mechanisms are most probably initiated and maintained by the T
cells and cytokines (interferon y, TNFa) in the dermis. These result in increased epidermal
pro
liferation( increased mitotic activity and DNA synthesis in the basal cells) and increased
djfprentiation (decreased epidermal transit time from 30 to 7 days, increased and defective
keratinisation, named hyperkeratosis and parakeratosis).
Both genetic and environmental factors are involved in th e pathophysiology of
psoriasis:
' f '
g %6 i& i i ld ph d dp 8
probability of a child having the disease if one parent has psoriasis is about 16%, about
50% if both parents have psoriasis and only 7.8% when neither parent has psoriasis
o H L A -Cw6 antigen is associated to type I psoriasis with early onset (<40 years)
and increased familiar occurrence, but not to type II psoriasis with late onset
(>40 years)
o p s o r iatic arthropathy is frequently associated with HLA-B27 antigen
environmental factors (non-genetic):
o l o cal factors:
• t rauma: p h y sical, c h e mical, e l e ctrical, s u r g ical, i n f e ctive a n d
inflammatory types of injury, even excess scratching
• sun/artificial light: generally considered beneficial for p soriasis,
however, a small minority find aggravation due to summer sunlight
o s y s temic factors:
• infections: streptococcal infection is linked to guttate psoriasis (throat
culture in patients with pharyngitis is recommended); HIV increases
psoriatic activity
• drugs: beta-blockers, lithium, withdrawal from systemic corticosteroids
• psy c h ogenic/emotional factors: stress increases severity of the disease
• alcohol, smoking
o e n d o crine: hormonal changes influence the evolution — improves during
pregnancy, flares after parturition; peaks at puberty and during menopause

121
 Clinical findings
The primary lesion in psoriasis is a red and sharply marginated palpable plaque
that soon becomes incompletely covered by multilayered, dry, silvery-white or micaceous
scales. The number of the lesions can range from a few to many at any given time and the
s ize varies from one to several centimetres (Fig.11.1). The lesionsmacules
' mented are symmetric an t e y
result (Fig.11.2j
usually do not itch. After regression, temporary hypopigmented ma
and then the skin becomes completely normal.
Clinical signs:
: 'f h 1 scraped off they detach from the lesion as small
candle phenomenon: i t e sca es are scrape
flakes, like wax flakes scraped from a candle
g off the scales, a
last cuticle phenomenon: if one continues scraping, after removin
moist sheet appears (the lowest layer in the epidermis above the dermal papillae)
focal bleeding phenomenon (Auspitz sign): after removing the last epidermal layer
spotty bleeding occurs, as enlarged dermal capillaries within unequally elongated
dermal papillae are eroded
Kobner phenomenon: psoriatic lesions often appear after injuries (surgical scars-
) thi' s sign is specific for psoriasis, but also for lichen
Fig.11.3, burning, insect b't
i es et c);
planus (where lichen lesions appear)
The psoriadc lesions are frequently localized on the scalp, knees, elbows (Fig.11.4),
'
sacra1region an d trunk.. Ps oriasis is generalized or universal when lesions are spread over all
. ). Mucous membranes
are left ((Fi'g..11.5).
anatomical regions and just some areas or normal skin
(ips,
(li s, glans
anspenis with circinate erythematous plaques) are rarely affected. 'p
o atica. The nail l ate might
.

T he nails are more frequently affected in psoriasis arthr p '

inhea
d size
' (ps
ps o riatic pitted nails), yellowish patches (psoriatic oil
present depressions up to p'
spot) or hyperkeratosis with irregular thickening resembling onychomycosis (psoriatic
dystrophic nails) (Fig.11.6).
Particular morphologicalforms ofpsoriasis: common in
uttate soriasis: disseminated d r o p -sized p s oriatic l e sions; q ui te
.)
streptococcal infections, particularly in children and young adults ( ig.
psoriasiswi'th several
se aspects: coin-sized (nummular psoriasis-Fig.11.8), arge,
' '

plaque
l ular
h ' 1 p soriasis) lesions with a clear centre ( annu ar
(
irregular lesions (geograp ica p
rs
pso riasis)I with polycyclic margins (gyrate psoriasis) surfaces and aaffects
spears the ty pically
e p ' i n v o l ved e x tensor
psoriasis inversa: ma a nd/or
intertriginous areas with minimal scales (axillae, inguinal folds, inframammary and or
intermammary creases -Fig.11.9)

Histopathology
Hyperproliferation of keratinocytes leads to irregular thickening of the epidermis
(acanthosis), with elongated rete ridges and dermal papillae. Above the tops of the papillae, the
nl fe 11 1 ers thick. Abnormal differentiation of the keratinocytes is

manifested as parakeratosis in the thickened corneum layer and loss of the stratum granulosum.
with p e r i vascular chronic in fl ammatory
The d ermis shows v asodilatation
infiltration. Neutrophylic leukocytes migrate from the dermis (exocitosis) and extend up to
form microabscesses in the horny layer (Munro abscess).

122
 Special forms of psoriasis
a. Pustular psoriasis

I s an uncommon f or m o f p s o riasis consisting of w i d espread pustules on a n

erythematous base. It results from the confluence of the Munro microabscesses into the
rnacropustule Kogoj. Culture from the pustule's content is negative (sterile pustules).
Clinical forms of pustular psoriasis:
pustular palmo-plantar psoriasis (Fig.11.10) — aggravated by smoking, it is commonly
resistant to treatment
acroderrnatitis continua H allopeau — involves the f i ngers and t o es, causing nail
destruction and atrophy of the distal falangs (Fig.11.11); it may remain confined to the
original site up to many years or spreads proximally to the hand, feet, limbs.
generalized pustular psoriasis (Fig.11.12) - can be pustular from the beginning, or it can
complicate other forms of psoriasis. The eruption is often triggered by infections, drugs
(antimalarials, lithium and w i t h drawal of systemic glucocorticoids), strong irritating
topicals (tar, anthralin, steroids under occlusion), or it is idiopathic. Generalized pustular
form may have a poor prognosis, especially in older patients.
b. Psoriatic arthritis

Psoriatic arthritis is a chronic inflammatory arthritis that is commonly associated with

psoriasis (10-15% of the patients with psoriasis). It is most frequently a seronegative (negative
rheumatoid factor) oligoarthritis with asymmetrical distal joint involvement. Joint findings
may include dactilitis (painM swelling of the distal interfalangeal joints of the fingers and toes
with the aspect of „sausage digits" — Fig.11.13); enthesopathy (inflammation of the insertion
point of tendon into bone); tendonytis and spondylitis. The bone is severely destructed in
advaced stages with osteolysis and erosions that cause restrictions in movement.
In the absence of overt psoriatic skin lesions, a careful examination of the scalp, the
gluteal crease, the umbilicus, the axillae and the nails may aid diagnosis of psoriatic arthritis.

c. Erythrodermic psoriasis

This is a severe form, characterized by the extension of the psoriatic lesions over
the entire skin („red man"), which shows deep inflammatory reddening with scaling and
slight lymph node enlargement (Fig.11.14). Pruritus can be intense. Water, protein and
heat loss is an aggravating factor. These cases require appropriate fluid and protein
supplements. Erythroderma can be triggered by drugs or excessive UV exposure.

Course
The guttate psoriasis is an acute form in w h ich the cutaneous lesions disappear
spontaneously in a few w e eks without treatment, or represent the initial stage of the
chronic plaque-type psoriasis. Once cleared, patients with guttate psoriasis usually have
hmited or no evidence of psoriasis for prolonged periods.
Plaque psoriasis is a chronic disease with a relapsing course. It is impossible to
predict the duration of the active disease, the time or the frequency of relapses, or the
duration of a remission. The disease is rarely life-threatening, but often is intractable to
treatment, with relapses occurring in most patients. With age, the relapses are more and
~ore frequent, becoming annual, and then the lesions are permanent.
Psoriasis is linked to other disorders, particularly to cardiovascular disease (long-
standing psoriasis is a risk factor for coronary arterial disease) and metabolic syndrome

123
(obesity, dyslipidemia, high blood pressure, increased glucose tolerance) but also to
rheumatoid arthritis, diabetes, Crohn's disease and streptococcal infections.
The quality of life is very much affected in psoriatic patients, related to dry and
peeling skin, fissuring (especially at the fingers), embarrassment about appearance, the
adverse effects and high cost of therapy. The mortality rate in psoriasis is low, related tp rom
associated disorders (cardiovascular disease) or to its therapy: liver and lung fibrosis f
metotrexate, PUVA-induced skin cancers with metastasis.

Treatment
Psoriasis is a chronic skin condition w it h a n i n h erited predisposition, so the
treatment is not curable and must be considered for long term.
Experience shows that low-calories diet can be favourable. Alcohol is considered a
risk factor for psoriasis and smoking aggravates palmo-plantar pustular psoriasis.
Three basic treatment modalities are available for the management of psoriasis.
These can be used alone or in combination.
1. Topical therapy
is generally suitable for plaque psoriasis. Many topical agents are used
sequentially over t i m e o n t h e s ame p atient ( a r o t ational therapeutic approach),
lowering the adverse effects of each drug. Clearing of th e scale is observed first,
followed by the flattening of the plaque. Sometimes perilesional white ring precedes
psoriatic lesion regression (Fig.11.16). Resolution of erythema may take 6-8 weeks and
then transitory hypopigmented macules result before the skin turns to normal.
Kerutolytics (5-10% salicylic acid, 5-10% urea) are recommended alone at the
beginning of the treatment to remove the thick scales. As scales continuously reappear,
keratolytics will be combined after a few days with anthralin, corticosteroids or other
drugs that reduce the turnover of th e k eratinocytes. Keratolytics are followed by
prolonged bathing for a soaking effect. Sea bathing is even more favourable.
Anthrulin (dithranol) reduces oxidative metabolic processes, decreasing the rate of
epidermal cell proliferation. It is one of the most effective topical reductor, but irritates and
stains the skin, cloths and bedding. The desirable irritant effect is confined to slight
reddening of the skin (crisophanic erythema, Fig.11.15). Increased irritation (vesicles,
oozing) may favor evolution of plaque psoriasis into erythroderma or pustular psoriasis.
Because it is irritating, it should not be applied on the face, scalp and folds. There are two
different methods of application: a) prolonged contact method — 0.5% preparations, for 2-4
hours; b) short contact method -1-2% preparations, for as much as 1 hour.
Topicul corticosteroids in creams, ointments, foams, sprays and lotions are the
eks
most used topical agents. High potency steroids can be used for maximum 4 wee
(Clobetasol/Dermovate) and continued with medium potency preparations (Elocom,
Advantan). If stopped abruptly, they have a rebound effect. Topical steroids are
quickly effective but psoriasis usually recurs rapidly after the end of treatment. Sid<
effects: skin atrophy, purpura, hypertrichosis, telangiectasia, striae distensae, steroid
acne and pyoderma. To reduce the incidence of adverse local effects, two weeks of
continuous treatment can be followed by pulse therapy on weekends. d
Culcipotriene is synthetic vitamin D3 a nalogue that in hibits proliferation an
promotes differentiation of the keratinocytes and has immunosuppressive effects on
lymphoid cells. For best results it is combined with strong topical corticosteroids, e.g
with betamethasone in Daivobet, with fewer side effects and steroid sparing effects.

124
 Tazarotene (Tazorac) is a topical retinoid derivative, available as 0.05 and 0.1%
gels, particularly useful for scalp lesions. It modulates keratinocyte proliferation and
differentiation and su pp."esses inflammation. M a y b e c o m b i ned w i t h t o p i c al
corticosteroids to increase effects and decrease irritation that commonly occurs when
used alone.
Tacrolimus and pimecrolimus are topical calcineurin inhibitors (macrolactams)
and can be u sed w h en c orticosteroids are contraindicated (thin l e sions prone to
atrophy or s teroid acne). The burning sensation associated with t h e ir u se can be
avoided by prior treatment with a corticosteroid.
Crude coal tar (pix lithantracis) and tar extracts have antimitotic effect. Bath oils
and shampoos are available, often combined with salicylic acid. They are effective but
have an o f fensive odour. C oal ta r i s a s sociated w it h f l u m ethasone pivalate in
I.ocacorten Tar formulation. It can be used in occlusive dressings.
Phototherapy is now frequently used in extensive and widespread disease and if lesions
are resistant to t o p ical therapy. UV r a d i ation r educes DNA sy n t hesis, decreases
cellular proliferation and induces local immunosuppression. While sunlight usually
improves psoriasis, burning o f t h e s k i n m a y c a use K oebner p h enomenon and
e xacerbation o f p s o r iasis. Climatotherapy combining sea b athing w i t h U V a r e
especially effective.
Artificial UV light is produced by fluorescent bulbs in short-wave UVB (280-320
nm) or long-wave UVA spectrum (320-400 nm). The whole body can be exposed to UV
in special phototherapy cabins but there are also small devices for limited affected
areas (scalp, palms, and soles). There are different types of phototherapy:
narrow-band UVB of 311 nm, more effective than broadband UVB
PUVA photochemotherapy combines the oral administration of a photosensitizing
agent (8-methoxypsoralen Oxoralen) with UVA irradiation
excimer laser UVB therapy delivers high-dose light to limited plaques
Systemic therapy is i n d i cated when t o p ical t herapy a nd p h o t otherapy have b een
unsuccessful or in complicated forms (erythrodermic psoriasis, generalized pustular
psoriasis, psoriatic arthritis):
Methotrexate is a folic acid antagonist with immunosuppressing effects through
inhibition of DNA synthesis in tissues with high rates of turnover (such as psoriatic
plaques); the weekly dose is 10-20 mg orally, divided in 3 doses at 12h interval.
Methotrexate can induce anemia, leukopenia, liver (elevated transaminases) and lung
fibrosis or aggravate kidney disease. Methotrexate has to be stopped when leukocytes
are under 3000/mm', haemoglobin is under 10g% or transaminases rise above normal
values.
Retiwoids are vitamin A d e r i v atives that control t he a bnormal keratinisation.
Etretinate (Tigason) was first used and t hen i t ' s m or e active derivative acitretin
(Neotigason). Side effects: transitory hyperlipemia and teratogenity. Contraception is
m andatory i n f e r t ile w o men fo r t h e t r eatment p eriod an d o n e m o r e y e ar. Th e
combination of retinoids with PUVA (Re-PUVA) is very efficient.
Cyclosporin inhibits the activity of T h e lper lymphocytes and proinflammatory
epidermal cytokines. Side effects: renal toxicity. It i s v ery expensive. It can not be
combined with UVA, as it enhances the risk of cutaneous carcinogenesis.

125
 Biological therapies are relatively new systemic therapies that provide selective
intervention at key steps in the pathogenesis of the disease:
inhibit the initial cytokine release and the Langerhans cell migration
prevent further T-cell activation and eliminate pathogenic T-cells (alefacept)
block cell-to-cell interactions that lead to T -cell activation and m i gration into
tissues (efalizumab, a humanized monoclonal antibody)
alter the balance between T-cell types
inhibit the proinflammatory cytokines: infliximab, adalimumab (both anti TNFg
monoclonal antibodies) and etanercept (TNFa Ig-receptor protein) inhibit alfa-
tumour-necrosis factor (TNFa).

PARAPSORIASIS

Parapsoriasis is a group of erythematosquamous diseases that clinically resemble

psoriasis, but are different in respect to pathogenesis, histopathology and response to treatment.
There are two types of parapsoriasis with different variants:
Pytiriasis lichenoides (Guttate parapsoriasis, Mucha-Haberman disease)

Is a rare disorder of unknown etiology with two clinical presentations:

pityriusis lichenoides et variolifonnis aclta (PLEVA): sudden onset of multiple
reddish-brown or purpuric papules that rapidly progress to pseudovesicles with
central necrosis and heal with varioliform scars. Sometimes high fever is associated
with coalescent necrotic ulcerations (Fig.11.17).
pityriasis lichenoides chronicu (PLC): small, benign-appearing papules, covered by
fine scales, similar to frosted glass
In both presentations, the lesions appear symmetrically on the trunk, buttocks and
proximal extremities. Lesions of PLEVA and PLC are often found together. They may self-
involute over weeks or have an ondulatory evolution for m o nths or y ears. Pytiriasis
lichenoides is considered a self-limited self-healing lymphoproliferative disease.
Treatment
Phototherapy (sun exposure, PUVA, UVB) may result in clearing. Oral antibiotics
like tetracycline and erythromycin may have an immunomodulatory activitiy.
Parapsoriasis en plaques

Large plaque parapsoriasis and small plaque parapsoriasis are 2 diseases caused
by T-cell infiltrates in the skin. They differ in respect to the capacity of progressing to
mycosis fungoides (MF), a form of cutaneous T-cell lyrnphoma (CTCL).
as well-circumscribed, slightly scaly,
Small plaque purapsoriusis manifests
elongated fingerlike patches, with less than 6 cm in diameter on the lateral thorax
are asymptomatic,
and abdomen, f o l l owing t h e d e r m atomes. Th e l e sions
occasionally slightly itching. Small plaque parapsoriasis is a benign disease that
can last for several months to years and rarely if ever progresses to malignancy.
Large plaque parapsoriasis manifests as faint erythematous patches > 6 cm ®
diameter with arcuate geographic borders, on the proximal extremities and trunk
The lesions show thin scales and central cigarette-paper-like atrophy. Large plaque
parapsoriasis can progress in 10% of cases in CTCL. Controversies exist in tb<

126
 terminology, as some consider large plaque parapsoriasis to be equivalent to the
early stage of CTCL, the patch stage.

Treutment
In small plaque parapsoriasis, emolients and mild topical corticosteroids reduce
scaliness and pruritus. Phototherapy (UVB, PUVA) can induce remission.
In large plaque parapsoriasis, treatment may prevent progression to MF (CTCL).
Beside mid-to potent topical corticosteroids and phototherapy, chemotherapeutic agents
g<e nitrogen mustard and topical carmustine can be used. Follow-up every 6 months is
recommended. Possible progression should be considered when lesions grow in number
and size, induration or epidermal atrophy develops. These situations suggest a need for
reevaluating by skin biopsy.

LICHEN PLANUS

Lichen planus is a pruritic subacute or chronic papular dermatosis localized on the

skin and mucous membranes.

Etiopathogeny
It is most likely a cell-mediated immunological reaction with u n k n ow n o r igin.
Viral infection (HCV hepatitis), stress, drugs (antimalarials, gold salts, isoniazid) have
been suspected to elicit the disease. Autoimmunity has also been suspected, based on the
presence of „lichen planus antigens" detected by immunofluorescent methods.

Clinical f'indings
The name of lichen derives from the typical appearence of aggregated papules that
resembles that of lichen growing on rocks and trees.
The lesions appear first on wrists and anterior calves and then they spread on the
whole body (Fig. 11.18). The typical lesions of lichen planus are violaceous, poligonal
(delimited by the natural skin lines) papules 1-3 mm in size, with shiny and plane surface
that reflects light. Adjacent papules can coalesce to form p l aques. After healing
characteristic hyperpigmented macules remain (Fig.11.19). Pruritus is common. Sometimes
the papules located especially on the anterior shins become extremely pruritic, brown-red
to blue-red, larger and thicker, hyperkeratotic (hypertrophic lichen planus — Fig.11.20).
This form is very resistant to treatment.
Characteristic fine, milky-white network can be observed on the surface of the
papules, called Wickham stria and representing focal thickening of the statum granulosum
(Fig.11.21). On sites of skin injury new lichen papules appear (Kobner sign-Fig.11.22).
M ucous membrane i n v olvement i s c o m mo n a n d m a y o c c u r w ithout s k i n
involvement. On the buccal, genital and anal region striated, reticular, arborizing, or
ramifying whitish lesions appear, called leukoplasia, explained by aberrant thickening of
granular layer (Fig.11.23). They are asymptomatic but erosions that may add are painful.
Some of the mucous membrane lesions may develop in carcinoma (facultative precancer).
The nails can be involved and also the scalp, with permanent hair loss.

127
 Histopathology epidermal changes are
The papule i n l i c hen p l a nu s i s d e r m o-epidermal:
a band-like
acanthosis, orthokeratosis and hypergranulosis. Beneath the epidermis
inflammatory infiltrate can be seen. Degenerated basal cells release melanin that is taken
up by dermal macrophages resulting in hyperpigmentation.

Course
Lichen planus is a self-limited disease that usually resolves within 6-12 months.
Recurrences after healing are quite often, even after years. Oral lichen has a mean duration
of 5 years. Hypertrophic lichen planus is usually chronic.

Treatment
Topical steroids with high activity are the first-line therapy of lichen planus. In
hypertrophic forms corticosteroids can be applied under occlusion (covered by plastic
sheets) or, as intralesional injections (triamcinolone acetonide suspension).
Systemic steroids are used for e xtensive disease and m ore r apid r e gression.
Prednisolone 20-40 mg is administered daily for about 3 weeks with slowly reduction of
the doses. Other options are retinoids, such as acitretin (Neotigason), PUVA, UVB.

PITYRIASIS ROSKA

Pityriasis rosea is a common, acute but benign, self-limited inflammatory disease

that appears on the trunk in adolescents and young adults (18-35 years). Pityriasis denotes
fine scales and roseatranslates as rose colour or pink.
The etiology is probably viral, linked to herpes virus type VII. Others consider it
an allergic reaction to a viral respiratory tract infection. It is more frequent in the spring
and autumn. It is not contagious and a single outbreak tends to elicit lifelong immunity.

Clinical findings
The disease begins with a typical, single plaque („ medallion" or herald plaque)
usually on the trunk. It is pink, oval, 2-7 cm in diameter, with pseudoatrophic, slightly
depressed centre, like cigarette paper and with a collaret of fine scale just inside the well-
demarcated border. The herald patch is mistaken as ringworm or psoriasis (Fig.11.24).
Within the next 1-2 weeks, symmetrical round to oval scaly patches appear, that
resemble the primary plaque but are smaller. They are found on the trunk, with the long
axes following the rib lines, like a fir tree, but also seen on the neck, upper third of the
arms and thighs. Facial involvement is rare, except in African Americans. The palms and
soles are not i n v o lved an d t h ere i s n o l y m p h adenopathy, w h ich d i stinguishes the
condition from secondary syphilis. The eruption gradually resolves within 6-8 weeks.
Pruritus is commonly m il d an d b ecomes moderate severe with i n appropriate
treatment. The disease is very irritable under some physical factors: frequent hot baths,
rubbing, exercise, leading to atypical forms that have to be differentiated from psoriasis,
urticaria, eczema, secondary syphilis.

Treatment
Topical corticosteroids, antihistamines and UVB can be used to reduce the itching
Systemic treatment is not necessary, because of the spontaneous tendency to regression.

128
 Fig.11.1. Psoriasis vulgaris Fig.11.2. VA6tening psoriatic lesion (1)

3$

Fig.11.3. Koebner sign in psoriasis Fig.11.4. Typical location of psoriatic lesions

Fig.11.5. Gener~ psor i a sis Fig.11.6. Nail psoriasis

Fig.11.7. Guttate psoriasis Fig.11.8. Nummular psoriasis

 Fig.11.9. Psoriasis inversa Fig.11.10. Palmo-plantar pustular psoriasis

"'4. *

>I

!sE.W

Fig.11.12. Generalized pustular psoriasis

Fig.11.11. Acrodermatitis continua Hallopeau

Fig.11.14. Erythrodermic psoriasis

Fig.11.13. Psoriatic arthritis

Fig.11.16. Perilesional white halo of Vorono~

Fig.11.15. Crisophanic erythema
 Fig.11.17 Acute guttate parapsoriasis Fig.11.18. Lichen planus

Fig.11.19. Hyperpigmented macules Fig 11.20. Hypertrophic lichen planus.

after lichen planus

Fig.11.21. Wickham striae Fig.11.22. Koebner sign in hchen planus

Fig.11.23. Leukoplasia in lichen planus Fig.11.24. Pytiriasis rosea

131
 Chapter 12

G ENOI3ERM A T O S E S

Genodermatoses are skin diseases caused by gene mutations or, more rarely by
chromosomal anomalies. Sex-linked genodermatoses result when a gene from a sexual
chromosome is involved. Autosomal genodermatoses result when the mutation involves a
gene from an autosomal chromosome.
The recessive inheritance is caused by genes that are capable of exerting their full
effect only in homozygous state (the patient has mutated genes from both mother and
father). The recessive diseases are rare. The parents do not have the disease, but they have
affected relatives.
The dominant inheritance is caused by a gene that is capable of exerting its full
effect when present on only one chromosome in the pair (heterozygous state). In this case
the mutated gene comes from only one parent, who has the disease. Mutations de novo
can also exist.
T he probability fo r a m u t ated gene to p r o d uce the d i sease depends on t h e
expression of the gene. The frequency with w h i ch a g e ne produces a disease is called
penetrance.

DISORDERS OF KERATINIZATION

ICHTHYOSIS
The Greek w ord ic h thys m eaning " f i s h" i s c o n s idered the r o ot o f t h e t e r m
ichthyosis that encompasses a heterogeneous group o f d i seases with a bnormal
differentiation of the epidermis presenting with excessive scaling.

Ichthyosis vulgaris is the most common form of ichthyosis. Most of the cases are
inherited as autosomal dominant genetic disorder but acquired forms also exist, secondary
to systemic diseases, including malignancy (leukemia, lymphoma, multiple myeloma,
hypervitaminosis A, pellagra, chronic renal failure, hypothyroidism, sarcoidosis, leprosy,
dermatomyositis etc) o r t o c e r t ai n m e d ications ( cimetidine, i soniazid, allopurinol,
retinoids). Inherited form appears in early childhood, intensifies up until puberty and then
decreases with age, while acquired form appears at adult age and follows the severity of
the associated systemic disease.
Ichthyosis vulgaris is caused by a defective synthesis in f'Ellagrin, an epidermal
protein responsible for the skin barrier function. Genetic mutation that causes ichthyosis
vulgaris is a major predisposing factor for atopic dermatitis, thus the two diseases are
frequently associated.
T he clinical aspect i s s i m i lar i n b o t h f o r m s o f i c h t h yosis v u l garis an d i s
characterized by symmetrical dryness and scaling of the skin of v ariable severity. The
scales are small (1mm-lcm), polygonal, curled at the edges and more expressed at the
lower a nd e x tensor e x t r emities (F ig.12.1). Palms and s oles ar e i n v olved w i t h

133
hyperkeratosis and accentuated skin m arkings while the flexural areas (neck, axillae,
antecubital and popli
tealfolds) are spared. Keratosis pilaris (follicular hyperkeratosis) is
associated on the cheeks, neck, dorsum of the upper arms, buttoks and thighs. Pruritus,
caused by dry skin leads to scratching and erythema. Symptoms improve during summer
and with age.
Biopsy shows moderate orthokeratosis and reduced or absent granular layer.

X-linked ichthyosis i s t h e s e cond m o st c o m m on t y p e o f ic h t h y osis. It i s

transmitted only to m ales by heterozygous mothers as an X-linked recessive trait. The
cause is a deficiency of steroid sulfatase, leading to delayed dissolution of desmosomes in
the stratum corneum.
Onset is usually before 3 months of age with a "dirty" appearance of the posterior
and lateral neck, upper trunk and extensor surfaces of the extremities due to dark, large
and prominent scales. The flexures, palms and soles are spared. Corneal opacities (which
do not affect vision ) and cryptorchidism predisposing to testicular cancer are frequent
associations. Unlike vulgar ichthyosis, the extent and severity gradually worsen with age.
Skin biopsy demonstrates normal granular layer with hyperkeratosis.
The diagnosis can be established by: a) genetic studies done prenatally; b) the
assessment of the reduced activity of steroid sulfatasein the placenta or after birth in the
peripheral leukocytes; c) l i p oprotein e lectrophoresis w h er e L D L s migrate f aster
demonstrating increased cholesterol sulphate (a substrate of the steroid sulfatase enzyme )
in the blood.
Treatment of ichthyosis is continuous and includes hydration of the skin (alpha-
hydroxy acids, urea) and application of an ointment to prevent evaporation.

There are other forms of ichthyosis that are rare, are apparent at birth and continue
throughout life, showing dramatic aspects:
epidermolytic hyperkeratosis — autosomal dominant, with wi d espread denuded
areas and bullae and later development of hyperkeratosis; it improves with age
congenital ichthyosiform erythroderma — autosomal recessive; the new-born is
enclosed in a tough, firm membrane collodion-like or "baked-apple"-like which
fissures when stretched; this peels of within 2 weeks, followed by red skin and fine
scales that generalize, including the face and large folds
lammelar ichthyosis — autosomal recessive, with collodion-like membrane that
peels of within 2 w e eks, followed by l arge scales with free edges and central
adhesion
Harlequin fetus — autosomal recessive; the m o st s evere form w i t h m a s sive
hyperkeratotic plates, limb deformities, rudimentary ears, ectropion and eclabium,
leading to death usually within a week.

DARIER'S DISEASE (KERATOSIS FOLLICULARIS)

Darier's disease is a dominantly inherited disorder of keratinization characterized
by early keratinization (dyskeratosis) and acantholysis mainly at the hair follicles.
It usually appears in young adults as greasy, brown keratotic papules that coalesce
in plaques in seborrheic areas (behind the ears, about the nose, on the forehead, scalp,
1
neck, shoulders, groin, chest and midline of the back). The eruption is symmetrical an

134
 becomes worse during summer, especially after sunburns, with malodorous vegetating
growths (Fig.12.2, 12.3). Flat, wart-like papules may be seen on the dorsa of the hands
(Fig.12.4) and shins and punctuate keratosis may be present on the palms and soles. Nails
are fragile, with i r r egular ni cks of t h e f ree edges. Oral and r e ctal m u cosal surfaces
demonstrate s m all , c o b blestone-like p a p u les. H e r pe s s i m p le x i n f e ction b e c omes
widespread and severe in these patients.
Biopsy shows acantholytic dyskeratosis. Acantholysis results from the detachment
at the desmosome/tonofilaments level and is seen as a suprabasal cleft. Dyskeratotic cells
appear as round eosinophilic cells (corps rounds) in the lower layers of the epidermis and
flat, deeply basophilic cells (grains) in the upper layers of the epidermis.
Treatment is not able to cure the disease, but reduces the flares. Moisturizers
containing urea, lactic acid, salicilyc acid or t o pical corticosteroids reduce scaling and
irritation. Oral retinoids (Neotigason) are the drugs of choice for more severe cases, but
toxicity (teratogenicity) limits their use.

BENIGN FAMILIAL CHRONIC PEMPHIGUS (HAILEY-HAILKY

DISEASE)
This form o f p e m p h i gus i s a n a u t o somal d o m inant i n h erited s ki n d i sease
characterized by acantholysis due to d efective formation of t o nofilaments-desmosome
complexes. In addition to the primary gene defect, contributing factors like sun exposure,
friction and infection (microbian or micotic) are known to exacerbate the disease.
I tching erythematous plaques with v e sicles that break and f o r m c r u sts w i t h
peripheral spread are formed especially in the intertriginous areas (neck, inguinal-Fig.12.5,
axillae-Fig.12.6 and p e r i anal r e gion). Th e e v o l ution i s c h r o ni c w i t h r e l a pses and
remissions.
Treatment includes soothing compresses followed by intermittent use of topical
antibiotics, animicotics and mild corticosteroids.

INHERITED KPIDERMOLYSIS BULOSA

This group of diseases, also called "Mechanobullous disorders" represent rare,
I gene t i cally determined disorders that have in common blister formation after trauma of
the skin or m u cosa. They usually appear at b i rth o r i n i n f ancy bu t c ause problems
throughout life.
The cause is defective formation of structural proteins responsible for dermo-
I
epidermal adhesion. Depending on the level of the cleft, there are 3 main varieties (each
with numerous subtypes) of inherited epidermolysis bulosa (EB):
1. EB s i m p l ex — autosomal d o minant; t ra uma r e sults in e p i d e rmal b u l l ae d ue t o
production of defective tonofilaments in the basal cells.
Blisters may be present at birth, but more often when the child starts to crawl and
walk. Sometimes the disease is not diagnosed until increased pressure is generated on
skin surfaces, like marching in the military. Mild blisters and desquamation develop
on hands, knees, feet or other sites subject to repeated trauma and h eal w i t hout
scarring, sometimes with milia (keratin cysts) formation. Usually the mucosa and nails
are not involved.

135
2. Junctional EB — autosomal recessive; the bullae appear between the epidermis and
dermis, at the level of lamina lucida due to alteration in laminin 5.
The blisters form l a rge denuded areas with l i t tl e t endency to h eal, m u cous
membranes are severely involved and the teeth are abnormal. A high proportion of
these children die in infancy.
3. Dy s trophic EB — both autosomal dominant and recessive; subepidermal blisters result
due to defective anchoring fibrils (collagen VII) that connect the basement membrane to
the dermal collagen.
The dominant variant is not very severe, showing a tendency to become localized
and less severe with age (Fig.12.7). Bullae heal with scars and milia, while hair and
teeth develop normally.
In the recessive variant hemorrhagic blisters appear at birth and heal with scarring
and formation of w ebs between fingers. Eventually a useless fist results (Fig.12.8),
conjunctival s ynechia), h a i r
Mucous m e mbranes ( esophageal strictures,
abnormal an d s q u amous ceQ
( pseudopellade-type alopecia) and teeth may be
carcinoma may develop over the scars.

As the clinical and histological picture is not specific to one form o f EB, the
electron m i c r oscopy and
diagnosis is e s t ablished by im m u n o f iuorescence,
immunomapping. Th e l a tter t echnique i n v olves antibodies directed against k n own
pro
roteins oca e at specific sites in the skin i n o r der t o d etect the level of the blister
eins located
formation.
There is no specific treatment for t hi s group o f d i sorders. Trauma has to be
minimized to prevent new blisters (soft shoes, for infants padded trousers). Emollients
minimize shearing forces. Occupational therapy may d elay th e d evelopment of
contractures. Specialist dental care is needed. Antiseptic treatment of the wounds prevents
superinfection.
Parents of children with EB should benefit for genetic counselling and should be
informed about the possibility of prenatal diagnosis by fetal skin biopsy at around 9 weeks
of gestation.

136
 Fig.12.1. Ichtyosis vulgaris Fig.12.2. Darier's disease

a 4P
lb

Fig.12.3. Folicular keratosis Fig.12.4. Wart-like papules in Darier's disease

in Darier's disease

Fig.12.5. Hailey-Hailey disease Fig.12.6. Hailey-Hailey disease (axila)

Fig.12.7. Dystrophic epidermolysis bulosa Fig.12.8. Dystrophic epidermolysis bulosa

137
 Fig.13.1. Epidermal nevus Fig.13.2. Sebaceous nevus

Fig.13.3. Nevus Hammeus Fig.13.4. Nevus anemicus

Fig.13.5. Congenital nevus Fig.13.6. Aquired melano

ticnevi;
histopathologically compound type

Fig.13.7. Aquired melanocytic nevi Fig.13.8. Dermatoscopical image of

traumatized nevus from Fig.13.7

138
 Chapter 13

NEVI (moles, birthmarks}

Nevi are circumscribed malformations during embryonic development.

Classification:
• depending on the time they appear
o c o n genital nevi — are present at birth or appear later in life
o a c q uired nevi — appear after later in life, usually until early adulthood
• depending on the type of the dominant cells
o o r g anoid nevi
o n e v ocytic nevi
Organoid nevi
Epidermal nevus ( often zoniform) s hows v e rrucous, skin-coloured or b r o w n
papules that coalesce to form a serpiginous plaque (Fig.13.1). It appears at birth or in the
first 10 years of life and persists indefinite.
Nevus sebaceous of Jadassohn(Fig.13.2) occurs preferentially on the scalp as a
congenital, alopecic plaque that is yellow, soft, elevated and flat, measuring from several
mm to cm. The lesion persists through life. N evus sebaceous can develop into basal cell
carcinoma.
Vascular nevi are represented by:
nevus fl ammeus (F ig.13.3) — c ongenital m a l f ormation o f t h e d e r m al b l o o d
capillaries which are dilated; it is present at birth, grows commensurate with the
child and has no tendency to involute; it is unilateral, initially pink-red to purple,
flat (macule) and later evolves into deep-red to purple, raised, thickened plaque,
studded with vascular papules prone to bleeding; treatment: pulse-dye-laser
nevus anemicus (Fig.13.4) —congenital disorder characterized by a pale macule
that looks like vitiligo but cannot be made red by trauma, cold or heat and the
number of melanocytes is normal; the vascular structure is also normal but there is
an increased sensitivity to cathecolamines.
Melanocytic nevi (nevocytic nevi)
Nevus cells or nevocytes are round, nondendritic cells that are closely related to
the melanocytes. Melanocytes and nevocytes both originate from the neural crest and are
capable of melanin synthesis, but melanocytes are scattered within the basal layer of the
epidermis, while nevocytes form small groups, known as nests, at the dermoepidermal
junction or in the dermis.
Melanocytic nevi are benign proliferations of m elanocytes, arranged in nests,
either in the form of a congenital, circumscribed malformation / hamartoma (congenital
melanocytic nevi) or a benign tumor (acquired melanocytic nevi). An increased number
of melanocytes, like in lentigo, without arrangement in nests, is not enough to define a
nevus.
The prevalence of nevi is lower in dark skin, where they are specially located on
acral areas, while light-skinned individuals not uncommonly have large nevi (> 1 cm), in

139
high number (> 50), located mostly on the trunk. The number of nevi is high in children with poor
sun intolerance.
Congenital nevi (Fig.13.5)are subdivided into large (> 20 cm), medium-sized (1.5
19.9 cm) and small {( 1.5 cm). They are present at birth (especially the large and medium-
sized) or appear during childhood and puberty (small congenital nevi). Sometimes,
congenital nevi have terminal hairs. The melanocytic nests extend down to the reticular
dermis. Their occurrence is independent of exposure to UV r ays. The high number of
congenital nevi correlates with a higher risk of melanoma.
Nevus Spilus is a variant of congenital nevus with variously pigmented dots that
are rised or flat on a light brow macule.
Sutton nevus (halo nevus) occurs mainly in ch ildren and adolescents as small
congenital nevi with a hypopigmented halo. This is more likely due to an immune reaction
that sometimes leads to complete disappearance of the nevus.
B oth Miescher nevus and U n n a n evus h ave similar h i stopathologically w i t h
congenital nevi presenting with dermal melanocytic nests. Both appear around puberty.
Miescher nevus is a dome-shaped nodule on the face, skin-colored or light brown, rarely
dark-brown and sometimens with terminal hairs. Unna nevus appears usually on the
trunk as papillomatous, soft, occasionally pedunculated skin-colored or brown papule.
Acquired nevocytic nevi, called Clark nevi (Fig.13.6,13.7) appear after the age of 2
until 35-40 years, with increasing numbers throughout childhood and early adulthood and
slowly involute towars advanced years. Their pigmentation is related to the skin color, so
that light-skinned persons have less-pigmented and non-pigmented varieties. The clinical
s pectrum varies from small m acules of fe w m i l l i m etres to p l aques up t o 1 c m , o f
symmetrical aspect. Acquired nevi typically have less than 1 cm in diameter. Clark nevi
appear on the trunk and the proximal parts of the extremities, not on the face or acral
areas. Ultraviolet radiation favors the appearance of acquired melanocytic nevi especially
in children with poor sun tolerance.
Atypical moles or dysplastic nevi are acquired nevocytic nevi that usually appear
after puberty an d a r e c onsidered t o h a v e a h i g h r a t e o f m e l anoma d evelopment.
" Atypical" r e fers t o t h e a b n ormal c l inical aspect, according t o t h e A B CD E r u l e -
asymmetric, irregular borders, mottled color, diameter > 6m m a n d e l evated surface.
"Dysplastic" refers to the abnormal histological aspect (atypia of melanocytes). But
atypical mole is sometimes difficult to be clinically distinguished from melanoma and, on
the other hand, histological "dysplasia" in nevi can not predict melanoma development.
Thus the terms "atypical" an d " d y splastic" are controversial and t h ere are opinions
sustaining that they should no longer be used.

Dermatoscopy (epiluminiscence microscopy) is a non-invasive optical method that

allows the o bservation o f p i g m ented structures in t h e e p i d ermis, d ermo-epidermal
junction and upper dermis. These colors and structures are otherwise not visible to the
unaided eye and have specific histopathological correlates. Thus, dermatoscopy improves
the clinical diagnostic accuracy (Fig.13.8).
Histopathology is the gold standard in the diagnosis of melanocytic nevi, thus
only the pathologist is able to establish the correct pathological diagnosis, while 'el th<'

clinician just predicts it, based on the clinical presentation. The nevi cannot be definite y

140
distinguished only upon clinical aspect. The nests of melanocytes can be located at the
dermoepidermal junction or in the dermis (papillary or reticular dermis). In interpreting
the behaviour of a nevus, the morphopathological aspect plays a leading role, so that we
will use this criterium to classify nevi.
Malignant transformation of nevi is more frequent in patients with positive family
history of melanoma (inherited risk) or can be triggered by exogenous factors like trauma
Qf the nevi and brutal sun exposure (sun burning).

Clinical features suspicious of malignant changes in a nevus are:

sudden increase in surface area;
borders become irregular, notched and ill-defined
pigmentation increases, different colors (pink, brown or black) appear
signs of focal regression
) p r u r i t us, pain
inflammation
) e r o sion and bleeding
irregular surface with macular and papular areas („fried-egg appearance")

Treatment
Patients with multiple nevi need to be educated about the importance of self-skin
examination, watching for new and changing lesions. The entire cutaneous surface should
be examined every year. Not all melanomas will exhibit the classic ABCDE rule (e.g. they
may be less than 6 mm), therefore always be suspicious about changing nevi and consider
an excision and a biopsy to rule out the dev lopment of malignant melanoma.
Intensive sun exposure and UV tanning beds have to be avoided and sunscreens
with SPF at least 30 are to be used on skin areas exposed incidentally to sun. Sun has to be
avoided and/or protective clothing has to be used between 12 a.m. and 4 p.m.
Because melanoma may develop de novo on the skin (on healthy skin, without
previous nevi) and because the risk of any one atypical mole to progress to melanoma is
low (considering the immense number of nevi in the general population ), prophylactic
excision of all atypical moles does not prevent melanoma and is not recommended. The
nevi that must be removed and examined histologically are the ones that change along a
few months and are clinically worrisome for melanoma.

141
 Chapter 14

B ENIGN TUM O R S

BENIGN EPITHELIAL TUMORS

B enign ep ithelial t u m or s ca n a r ise f r o m t h e i n t e r f ollicular e p i d ermis, t h e

epithelium of hair follicles, or the epithe
liumof the ducts of the sweat glands.
Seborrheic keratosis (seborrheic wart)
Seborrheic keratoses are the most common benign tumors in older indivi duals.
They usually appear after the age of 40, on the trunk and face. The early lesion appears
as a sharply defined yellow-brown macule (Fig.14.1) which develops a velvety to
verrucous surface, covered by a greasy brown scale, with comedo-like black keratotic
p lugs (Fig.14.2). W it h t i m e , t h e l e s ions b ecome t h i cker an d h a v e a "s t u c k o n "
appearance. Sudden occurrence of a large number of seborrheic keratosis may indicate
development o f a v i s c eral m a l i gnancy, especially a d enocarcinoma o f t h e g a s tro-
intestinal tract (paraneoplasic syndrome Leser — Trelat, Fig.14.3).
The lesions do not need to be removed unless annoying or become irritating.
Keratolytic agents can be used (ammonium lactate lotion 12 or 15%, tricloacetic acid
100%), cryotherapy w i t h l i q u i d n i t r o gen o r e l e c trodessication. I f h i s t o pathology
confirmation i s n e e de d t o di f f e r entiate a s e b o r r heic k e r atosis f r o m m a l i g n ant
m elanoma, basal c el l c a r cinoma o r s q u a m ou s c el l c a r cinoma, s u r gery p r o v i d es
histological material and removes the lesion.
Keratoacanthoma
Originates in the pilosebaceous follicle and represents tumor characterized by
the proliferation o f a t y p i c al, h i g hl y d i f f e r entiated s q u amous c e lls. I t r e s embles
clinically and pathologically squamous cell carcinoma (SCC), but it is characterized by
a benign c o urse an d s p o n taneous regression w i t h i n 1 y e a r . K e r atoacanthoma i s
characterized by a rapid growth, within 2-3 weeks, of a dome-shaped nodule of 1-2 cm,
with smooth shiny surface and central crateriform ulceration or keratin plug that may
project like a horn (Fig.14.4).It usually occurs on uncovered sun-exposed areas, like
face, neck, dorsum o f t h e u p per extremities. To d i stinguish keratoacanthoma fr om
SCC, deep excision of the whole lesion is necessary, to observe the symmetric aspect of
the whole lesion. After shave biopsy, keratoacanthoma might look similar to SCC.
Treatment: surgical excision, laser therapy or cryotherapy can be used in small
lesions and radiotherapy i n l a rge and n u m erous t u m ors. Injection of m e thotrexate,
bleomycin under the lesion is another option in inoperable tumors.
Syringoma (hidradenoma)
Are benign neoplasms considered to differentiate along the ducts of the eccrine
sweat glands. They appear as skin-colored, round or flat-topped, small (3 mm) papules
{often mistaken for xanthelasmas or milia), sometimes with cystic aspect. The lesions

143
 b>
are multiple symmetrical distributed, on the upper cheeks and lower eyelids (Fig.14.5),
cosmetic reason an d c o n sists of bt
c hest, l o w er a bdomen, p e n is. T r e atment h a s
cl
electrosurgery, laser therapy or cryotherapy.
hi
Epidermal and pilar cysts re
Keratinous cysts have been incorrectly named as sebaceous cysts. There are
p(
two types of keratinous cysts: a) epidermal cysts that result from t he i m p l a ntation of
epidermal elements in the dermis, more frequently from the infundibular region of the re
o cysts arise from the outer root sheet of the
hair follicle (Fig.14.6a);b) pilar (trichilemma T(
hair follicle at or distal to the level of sebaceous duct (Fig.14.7). fh
The cysts appear as hemispherical, skin-colored, painless nodules. Epidermal Si
cysts occur on any part of the skin (face, trunk, scalp scrotum, extremities, fingers),
while pilar cysts occur mostly on th e scalp. A central pun ctum exists in epidermal
cysts, from w h i c h a t h i c k f o u l - smelling cheesy m aterial i s s o m etimes expressed,
while in p i la r cy sts there is no p u n ctum. They are asymptomatic but ma y b ecome
ot
inflamed (Fig.14.6b) or secondarily infected, resulting in pain and tenderness.
Histologically the two variants differ: the epidermoid cyst is characterized by
cornified epithelium with well-defined granular layer and multiple lamellae of keratin; of
the pilar cyst has a trichilemmal keratinisation pattern that lacks the granular layer. er
Very rarely, malignant transformation can occur (BCC, SCC).
Treatment: surgical excision. p(
eI
BENIGN MESENCHYMAL TUMORS
d<
h<
13ermatof ibroma
cO
This is a c o m mon t u m o r o f t h e e x t r emities, particularly th e l o w e r l e gs. It
(e
usually occurs as a solitary nodule that hardly exceeds the size of 3-8 mm and is firm,
uz
grey-brown, slightly raised, usually set into the skin like a lens or a pastille (Fig.14.8).
Dermatofibroma are characteristically asymptomatic but i t c hing an d p ai n ar e often
noted. A useful clinical sign for diagnostic is the dimple sign: the overlying epidermis
tethers to the underlying lesion with lateral compression.
Treatment: excision, for symptomatic lesions.
Fibroma pendulum (acrochordon, skin tag)
These are small, skin-colored to dark-brown, sessile or pediculated papilomas
that commonly occur on th e n eck, axillae, eyelids and l ess often on th e t r un k an d
groins (Fig.14.9, 14.10). Occasionally, as a result of twisting the pedicle, the lesion
becomes inflamed, tender or even gangrenous. Fibroma pendulum o ften increases in
size with age (Fig.14.11) but mostly with gaining weight or pregnancy. Histologically,
they are characterized by epidermis enclosing a dermal fibrovascular stalk. without
Treatment: cryotherapy, electroexcision, l a ser t h e r ap y w i t h or
anesthesia, depending on the size of the lesion.
Keloid
of scar t i s s«
Keloids and h y p ertrophic scars ar e e xagerated g r o w t h s
surgery
developing after a deep (dermal) skin injury that can be physical (piercing,

144
bruns etc) or pathological (acne scars, chickenpox). Keloids usually extend beyond the
borders of th e o r i ginal w o u nd , w i t h c l a w - l ike aspect (the Greek chete, mean crab's
claw) and have no tendency to regress spontaneously (Ftg.14.12). They differ from
hypertrophic scars that d o n o t e x t end b eyond th e i n i t ial i n j ur y a n d m a y p a r t i ally
regress spontaneously within 12-24 months. Both are erythematous and may be tender,
painful and puritic.
Keloids are t r eated w i t h i n t r a lesional i njection o f t r i a m cinolon su spension,
repeated at 4-6 weeks, as required. Other treatment is p u lse dye laser. Both reduce
TGF-P, know n t o b e i n v o l v e d i n k e l o i d f o r m a t ion. C r y o therapy, i n t r alesional 5-
f luorouracil an d c a l c i u m-channel b l o ckers ( V erapamil) a l s o h a v e some efficacy.
Silicone sheeting and pressure are adjunctive methods to reduce recurrences.

Hemangioma s
These are benign tumors of blood vessels of the skin, mucous membranes and
other organs, characterized by the proliferation of the endothelial cells.

Infantile hemangioma is present at birth or appears in the first several weeks

o f life. It c h aracteristically g r ow s r a p i dl y d u r i n g t h e f i rst 6 m o n th s o f l i f e d u e t o
endothelial cell p r o l i f eration an d t h e n s l o w l y b u t s p o n t aneously i n v o l u tes ( 70%
completely involute by the age of 7). The skin may return to normal but in most cases
permanent skin changes remain in the form of t elangiectasia, dilated venes, scarring,
epidermal atrophy or hypopigmentation.
It appears as a vascular proliferation of different size (0.5 — 20 cm) and depth,
d ome shaped, bosselated, plaquelike or t u m o r al. The color i s b r i gh t r e d w h e n t h e
hemangioma is s u perficial (Fig.14.13), a nd purple o r b l u ish w h e n d e ep. T h e
consistency i s f i r m , r u b b er y a n d t e n s e an d e x p ands w i t h i n t r a v ascular p r essure
( e.g.when th e b ab y c r i es). R arely, i n f a n til e h e m angioma ca n b e a s sociated w i t h
underlying congenital anomalies.
Treatment: laser surgery with pulsed dye laser is effective in both proliferating
and residual v e ssels f ro m h e m a n giomas; i n v o l uted h e m angiomas with r e si dual
cutaneous defects can be surgically excised. Propranolol works w ell i n l a rge infantile
hemagioma that compress vital organs (eyes), cause high-output cardiac failure or
result in deformation of the face.

Cherry angiomas (late angioma) appear as round, slightly elevated, 0.5-6 mm

ruby-red papules in a d ult p ersons (Fig.14.14). The number of c h erry angiomas
increases with age.
T reatment: e l e ctrodesication, l a s e r ablation, but m os t p at i e n t s a c c ept
reassurance and do not request removal.
Pyogenic granuloma (lobular capilary hemangioma)
Pyogenic granuloma i s a b e n ign v ascular t u mo r t ha t r esembles granulation
tissue. It is a misnamed entity, being neither inflectious, nor granulomatous. It occurs
in children and y o ung a d u lts as a gl istening red p apule or n o d ul e t hat g r ow s f ast,
within a few weeks, and is prone to bleeding and ulceration. The head (face, lips), neck
and distal extremities (fingers) are sites of predilection, but lesion can occur anywhere

145
(Fig.14.15, 14.16). The cause of the p y o genic granuloma is n ot k n o w n, b ut t r a u m a ,
hormonal influences, topical and systemic retinoids are implicated.
Clinically, acromic melanoma must be excluded.
Treatment: excision, electroexcision, laser therapy. It i s i m p o rtant to r emove
t he angiomatous pedicle w h ich e x tends deep i n t o t h e d e r m is, since i f i t i s o n l y
removed superficially, recurrence may occur.

146
Fig.14.1. Seborrheic keratosis on the back Fig.14.2.Seborrheic keratosis

I»

,I
' 0
•

jt

II
•

Fig.14.3. Leser-Trelat sign Fig.14.4. Keratoacanthoma

Fig.14.5. Syringoma Fig.14.6 Epidermal cyst (b. inflamed)

Fig.14.7. Trichilemmal cyst Fig.14.8. Dermatofibroma

147
 Fig.14.10. Fibroma pendulum of the neck
Fig.14.9. Axillary fibroma pendulum

Fig.14.12. Presternal keloid

Fig.14.11. Fibroma pendulum of the groin

Y.
Fig.14.14. Cherry angioma (red) and
Fig.14.13. Infantile angioma
seborrheic keratosis (brown)

Fig.14.16. Pyogenic granuloma

Fig.14.15.
Pyogenic granuloma
 Chapter 15

PRE CANCEROSES

Precanceroses are skin conditions which pose a risk to malignant transformation.

Actinic keratosis (solar keratosis, keratosis senilis)
Actinic keratosis is a thickened scaly growth (keratosis)induced by UV (actinica)
that may progress to squamous cell carcinoma. It appears in fair-skinned persons after
long-term sun exposure, on any chronically sun-exposed area, but mostly on the forehead,
bald scalp, nose, earlobes, dorsal forearms and hands (Fig.15.1). Immunosuppression after
organ transplantation is another risk factor for actinic keratosis. However, actinic keratosis
does not occur without sun exposure.
Initially it is a well delimited thin keratosis that is easier felt, like sand-paper, but
later it enlarges, becomes thicker, with hard, dirty-brown surface. If the adherent horny
layer is tried to be removed, bleeding occurs. Many lesions can appear on one anatomical
area. Sometimes the keratinization is so prominent that a horn-like projection develops,
known as cutaneous horn (Fig,15.2).
After years of e v olution th e b ase of t h e l e sion ma y b e come infiltrated and
squamous cell carcinoma develops.
Actinic keilitis
Actinic keilitis usually develops on the lower lip, related to cumulative life-time
sun exposure. It is characterized by continuously dry an d f issured lip (Fig.15.3), white
patches (leukoplakia) t hat m i gh t p r o g ress t o s q u amous cell c a rcinoma. M a lignant
transformation is announced by infiltration, erosion and ulceration of the lesion.

Treatment of both actinic keratosis and actinic keilitis is warranted as they can be
cured and malignant progression prevented:
sun avoidance between 10 a.m. and 3 p.m., protective clothing, sunscreens
i medi c al therapies:
o t o p i cal 5-fluorouracil (EFUDIX cream) — 2x/day for 4 weeks has cytostatic
effect; it results in temporary intense erythema and erosions over the areas
of actinic keratosis (Fig.15.4)/ actinic keilitis
o i m i q u i mod — 2-3 times/week for up to 4 months; immunoregulator
o t o p i cal diclofenac sodium gel 3%, 2x/day for 3 months
o p h o t odynamic therapy (PDT): application of delta-aminolevulinic acid, a
photosensitizer that accumulates preferentially in dysplastic cells of actinic
keratosis, is followed by exposure to light; this will generate oxigen free
radicals and cell death
surgical care
o c r y o therapy with liquid nitrogen or solid carbon dioxide
o e l ectroexcision or electrocauterisation
o s u r g ical excision — for cutaneous horn

149
 Radiation keratoses
Following prolonged X-ray therapy or p r ofessional exposure (radiologists)
atrophic skin l e sions w it h t e l agiectasia and h y p opigmentation w i t h i n c reased focal
h yperpig
perpigmentation ma y a p p ear. Six-twelve m onths after i r r adiation, f i brotic, t hick,
adherent erythematous plaques are formed, characteristic for chronic radhodermabbs.
Radiation keratosis presents with f i r m ly a d h ering keratosis that cannot be r e moved
without pain and bleeding and that can transform 20-40 years later into squamous cell
carcinoma.
Treatment: excision.
Xeroderma pigmentosum
Is an autosomal-recessive disorder characterized by a) defective DNA repair after
UV insult; b) sun sensitivity and lentigines before the age of 2; c) actinic keratoses and skin
cancer before the age of 10. Basal cell carcinoma, squamous cell carcinoma, melanoma
often results in an early lethal outcome.
Bovren disease (sqamous ce11 carcinoma in situ)
Bowen disease or squamous cell carcinoma in situ is an intraepidermal carcinoma
with potential lateral spreading. Usually the lesion is unique, asymptomatic with very
slow progression, over months or a few years. The initial erythematous scaly patch may
become hyperkeratotic, crusted, fissured (simulating psoriatis plaques), or ulcerated. After
removing the crust, a red, eroded surface appears (Fig.15.6).
Bowen disease can also occur on mucosa. On the glans penis and foreskin is called
erythroplasia Queyrat. It appears as a persistent sharply delimited red patch without
crusts and scales(Fig.15.7).
Histopathology shows a full-thickness anaplasia of the epidermis with atypical
and disorderly keratinocytes (windblown appearance), under the hyperkeratotic or
are atypical epithelial cells, with i n d i v i dual
p ar akeratotic k e r atin l a y er . T h e r e
keratinization (dyskeratosis), and atypical mitoses.
Course: chronic, with malignant transformation after some years.
Treatment: 5-flourouracil cream (EFUDIX), cryotherapy with liquid nitrogen,
excision, electroexcision, laser therapy.
Paget disease of the nipple
Paget disease occurs almost exclusively in w omen. It is no longer considered a
precancerosis but a retrograde extension into the overlying
epidermisof an underlying
intraductal carcinoma of the breast.
The initial presentation of mammary Paget disease is typical for a long standing
eczema of the nipple with itching, recurrent small vesicles and excoriations, but unlike
eczema, Paget disease is located unilaterally and th e er ythematous patch is sharply
demarcated and infiltrated. Retraction of the nipple and palpable nodules indicate the
underlying breast cancer.
Histopathology: Paget cells are found in the thickened epidermis (large cells
devoid of desmosomes, with edematous cytoplasm and large oval nuclei).
Treatment: mastectomy with removal of the axillary lymph nodes. ands
occurs in a r eas w i t h a p o crine s w eat g i an
Extramammary P aget d i sease
(anogenital and axillary region).

150
 Fig.15.1. Actinic keratoses Fig.15.2. Cutaneous horn

L'

Fig.15.3. Actinic keilitis Fig.15.4. Erythema after 5-FU

treatment for solar keratoses

Fig.15.5. Radiation keratosis Fig.15.6. Bomen disease

Fig.15.7. Eritroplasia Queyrat Fig.15.8. Malignant lentigo

151
 Lentigo maligna (melanosis Dubreuilh)
Lentigo maligna is melanoma in situ, characterized by the proliferation of atypical
melanocytes within th e epidermis that can p r ogress to melanoma when th e atypical
melanocytes reach the dermis. Lentigo m aligna is i n d uced by l o n g-term cu mulative
ultraviolet injury. It occurs mainly on the face or lower leg, as brown-black macules and
plaques that increase very slowly in size and change both the contour (extension of one
margin and regression of another) and the colors (from pale and dark-brown to black
colors) (Fig.15.8). Lentigo maligna can be present for 5-15 years before invasion occurs.
Invasion is suggested by slight infiltration and elevation of the surface.
Other precanceroses
o C h r o nic ulcers
o B u r n scars
o L u p u s vulgaris
o C h r o nic lupus erithematosus
o E p i d ermolysis bullosa dystrophica

153
 Chapter 16

M A LIG N A N T EPITHELIAL TUM O R S

B ASAL CELL CARCIN O M A

Basal cell carcinoma (BCC) is the most common malignant tumor, characterized by
dermal proliferation of cells that closely resemble normal epidermal basal cells. It occurs in
persons aged 50-80 years, with fair skin, especially on the sun-exposed skin regions (face,
ears, scalp, neck, upper trunk). Chronic exposure to UVB radiation is more involved. Basal
cell carcinoma usually arises from clinically normal skin w i thout precursor changes, in
contrast to squamous cell carcinoma, which is preceded by precancerous lesions.
The initial basal cell carcinoma is often a small, grayish-white induration wi t h
telagiectases. At the very beginning, patients observe a small hemorrhagic crust, always in
the same l o cation a f te r r e p eated t r auma ( scratching o r s h a v i ng). T h e t u m o r i s
asymptomatic, without pain, neither spontaneously, nor upon palpation.

Clinical forms:
solid BCC: waxy, translucent papules that grow slowly (in months, years) to nodules
with telangiectases over the surface (Fig.16.1)
ulcerating BCC (ulcus rodens): persistent erosion or ulceration surrounded by a hard
pearly border formed from confluated tiny emisferic nodules with shiny surface (so
called basalioma pearls) (Fig.16.2, 16.3)
superficial BCC (pagetoid) occurs frequently on the trunk as red-brown, fine scaly
patches with pearly nodules at the periphery (Fig.16.4)
pigmented BCC is a brown or black aspect of any type of BCC (Fig.16.5). Distinction
from melanoma, pigmented nevocytic nevi, and seborrheic keratosis is very important
morpheaform and i n f i l t rating BCC are sclerotic (scar-like) plaques with ill-defined
borders that s u rpass the cl inical m argins. I t i s a n a g g ressive for m a n d r e c urs
frequently after excision (Fig.16.6)
basalioma terebrans leads to deep tissue destruction that can affect the cartilage and
the bone (Fig.16.7). This tumor can be life threatening due to erosion, hemorrhage, and
meningeal complications

Histopatho
logy
The tumoral cells resemble normal basal cells with t h eir l arge oval basophilic
nuclei and appear as nodular aggregates in the dermis with a palisade-type arrangement
of the cells at th e p eriphery. The epidermis over the basal cell carcinoma is usually
atrophic and frequently eroded.

Course
BCC has a slow course, over a few years, with tendency to ulcerate. Metastases do
not occur, but the terebrant form may be life threatening or mutilating. The tumour can

155
recur within a treated area because of basal cell carcinoma residues that were not removed,
but new basal cell carcinomas can also arise in predisposed patients. Treated patients
should be followed up l ong enough (5 years) in order to detect recurrences as soon as
possible.
Treatment
Surgical treatment
excision of the tumour with 4 mm margins of normal tissue is the treatment of choice;
plastic surgery methods can be used in large tumours
Mobs chemosurgery method involves histological monitoring of all the outer edges of
the excised tissue. The sections are frozen and examined while the patient is still in the
operating room. Tissue is mapped microscopically, so if any t u m oral nests persist,
further excision is directed to only those areas to spare the normal tissues, repeatedly,
until no malignant cell is found.
radiation therapy i n s e lected patients: elderly o r d e b ilitated patients, aggressive
tumours that have already been treated surgically, patients who refuse surgery
electroexcision and laser therapy are not recommended as no tissue for biopsy can be
provided
Medical treatment
topical cytostatic treatment w it h 5 - f luorouracil o r i m u n o m odulating agents like
imiquimod are used only in very superficial tumours or in patients who refuse other
treatments
Avoidance of exposure to UV is strongly recommended, with protective clothing,
road-brimmed hat and sunscreen during outdoor activities.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma (SCC) is a malignant tumour of epidermal keratinocytes that

develops on both skin and mucosa, also on both normal skin and precancerous lesions.
Risk factors associated with SCC are:
o f a ir-skin (burs easily and never tans); SCC can also appear on black skin, usually on
the scalp and is more aggressive, probably because delayed diagnosis
o h i gh cumulative dose of UV (natural or therapeutic-PUVA) or X-ray radiations
o p r e m alignant lesions: actinic keratosis, cutaneous horn, actinic keilitis, leukoplakia,
chronic ulcers, chronic scars or some forms of carcinoma in situ (Bowen disease,
erythroplasia Queyrat).
o e x p osure to chemical carcinogens (tar, arsenic)
o c h r o nic immunosuppression
o v i r a l infection with certain subtypes of HPV.

Clinical findings
SCC starts with a small, slightly raised, firm and painless warty hyperkeratosis
that grows slowly until 1 cm di ameter, then quickly larger. It can express sometimes a
yellowish paste-like material, like little worms which consist of cornified tumour cells.

Clinical forms:
Nodular squamous cell carcinoma (Fig.16.8)

156
 Ulcerated squamous cell carcinoma (Fig.16.9)
Ulcero-vegetant squamous cell carcinoma (Fig.16.10, 16.11)
E xtensive u l c er at iv e n e c r osis occurs af ter m o n t h s an d t h e t u m o u r i n v a d e s t h e
soft tissues, bones, and cartilages. It develops faster (within a few m o n t hs-one year)
than BCC and metastasizes, first in the regional lymph nodes and later on, after years
in internal organs (lungs etc). The lymph nodes are enlarged and hard, then fixed to
the neighbouring tissues, with possible central ulceration and fistulisation (Fig.16.12).
In advanced stages, SCC affects the general state of health, producing haemorrhagia,
anemia, and death.

Histopatho
logy
While SCC in situ i s c onfined to th e epidermis, SCC is characterized b y t h e
proliferation of atypical keratinocytes that invade the dermis. The tumoral cells resemble
those in the prickle cell layer (plasma-rich, large nuclei and visible intercellular bridges),
but they have varying degrees of differentiation and atypia (atypical dyskeratosis, atypical
mitosis, nuclear atypia), with the formation of concentrically layered cornified spheres
within the tumour, so-called horny pearls. Marked stromal reaction with h istiocytes and
mast cells, lymphocytes and plasma cells are present.
Staging of the squamous cell carcinoma
according to the TNM classification system, based on the characteristic of the primary
tumor and on the presence or absence of regional lymph node and metastasis:
o T x : p r imary tumor cannot be assessed
o T O : no evidence of primary tumor
o Ti s : c arcinoma in situ
o T l : t u mor < 2 cm in greatest diameter
o T 2 : tumor 2-5 cm in greatest diameter
o T3 : t u m o r > 5 cm in g r eatest diameter (+metastases in lymph nodes)
o T 4 : destructive tumor invading the cartilage, muscle, bone
o N x: regionallymph nodes cannot be assesed
o N O : No regional lymph node metastasis
o N l : r e gional lymph node metastasis
Broders classification according to the degree of differentiation
• gra d e I — under 25% undifferentiated tumor cells
• gr a d e II — under 50%;
• gr a d e III — under 75%;
• gra d e IV — more than 75% undifferentiated tumor cells.

Prognosis
The prognosis depends on the a) localization: SCC of the tongue, vulva, and penis
have a relatively poor prognosis, b) dimension: up to a size of 2-3 cm can be cured in about
90% of cases and c) the degree of differentiation: greater differentiation, lower tendency to
metastasize.

Treatment
Surgical methods
radical removal of t h e t u mo r m ass w it h a m a r gin o f 4 - 6 m m o f n o r m a l t i ssue,
depending on the TNM stage

157
 5.
Mohs micrographic surgery is the treatment of choice with reconstruction by plastic B
surgery s
electrodessication in low-risk cases
Nonsurgical methods are used in inoperable tumours and metastasizing forms:
radiotherapy
systemic chemotherapy node
Patients with a history of SCC should be carefully examined every 6-12 months as bone

there is an increased risk to develop another carcinoma.

• s

MALIGNANT MELANOMA • s

Melanoma is a malignancy of the pigmented cells (melanocytes) that are

located predominantly in the skin, but also in other organs (eyes, ears, nervous system,
oral and genital mucosa). It is one of th e m ost severe malignant tum ors w it h early
lymphogenous and/or hematogenous metastases, and lethal outcome. The incidence of
melanoma has increased in recent years (more than tr i pled in th e w h i t e p opulation The h
during the last 20 years in the US). epidh
Risk factors in the development of melanoma include fair skin, intermittent and meta
intense sun exposure with blistering sunburns in childhood, large number of nevi (more
than 10 atypical/dysplastic nevi; more than 100 common nevi; large congenital nevi), • )
p revious melanoma o r m e l anoma i n f i r s t-degree relatives. Melanoma occurs m o re
frequently on the trunk in men and on the legs in women. For dark-skinned individuals,
the most common sites are the plantar areas, followed by nail plate, palms and mucosa.
Melanoma develops in precursor melanocytic nevi, but more than 60% appear
de novo (with no preexisting pigmented lesion). It is very rare before puberty.
Clinical forms of primary cutaneous melanoma
1. Superficial spreading melanoma (SSM) usually occurs in middle-aged people.
Initialy it is a sharply lim ited, flat or slightly elevated patch with variegate colors
(grayish-bluish-black-pink-white) and irregular asymmetric borders (Fig.16.13).
The lesion grows horizontally, and later it becomes infiltrated with p a p ules and
thre i
nodules (vertical growing). The prognosis is favorable in early phases. mar
2. Nodular melanoma manifests as a dark brown to black papule or dome-shaped 2 CII
nodule with rapid growth over weeks or months (Fig.16.14); it may ulcerate and defe
bleed with minor trauma; it may be clinically amelanotic! (Fig.16.15)
3. Le n t igo maligna melanomaoccurs in 10-20% of melanoma cases; it develops mostly mar
in older individuals (over 65 y) from lentigo maligna which has often been present
for decades with varicolored patches ranging from light to dark or blackish brown,
dela
on the face or arms. It grows slowly over 5-20 years. Dermal invasion (progression to
Lyrr
invasive melanoma) is announced by i n f i l trated changes or small b l ack n odules of tl
(Fig.16.16). The prognosis is more favourable than in other types
4. A c ral melanoma occurs on the palms, soles, and beneath the nail plate, sometimes rs u<
in the mouth and g enital region; on th e n ail p l ate it m a n ifests as a dif fuse nailal
discoloration or a nail band; the spreading of the pigment to the proximal or latera useh
nail fold (H u t chinson sign) is a hallmark for m elanoma and differentiates it from
subungual hematoma;

158
5. Ac r o mic melanomais a nonpigmented variant that looks like pyogenic granuloma,
BCC or SCC, but grows faster; it occurs more often as a nodular melanoma or as
skin metastasis of the melanoma or visceral carcinoma.

Course and prognosis

Early metastases appear in the surrounding skin (in transit) and regional lymph
nodes. Later, blood-borne metastases occur, particularly to the lungs, liver, heart, brain,
bones and skin.
Clinical staging and 5-year survival rates:
• stage I: primary tumor without clinically detectable regional lymph node metastase; >
90%,
• stage II: primary tumor w ith clinically detectable in-transit or regional lymph node
metastases;80-40%
• stage III: primary tumor with distant metastases; < 20%

Histopathology
The histopathological examination is the criterion standard for melanoma diagnosis.
The epidermis is invaded by large atypical melanocytes, arranged haphazardly at the dermo-
epidermal junction, with upward migration. Dermal invasion by atypical melanocytes confers
metastatic potential. The stromal inflammatory reaction is pronounced.
Histology offers also important prognostic information:
• Levels of invasion (Clark) — measure anatomical tumour invasion
o s t age I: epidermal invasion
o s t age II: discontinuous invasion of the papillary dermis
o s t age III: continuous invasion of the papillary dermis
o s t age IV: invasion of the reticular dermis
o s t age V: invasion of the subcutis
• Breslow index: tumour thickness in mm, measured from the stratum granulosum to
the deepest tumoral cell

Treatment
Malignant melanomas should be treated by surgery. As far as possible, extensive
three dimensional surgical removal of the primary tumor is performed with a resection
margin that depends on the Breslow index (e.g. 1 cm margins for up to 1 mm thickness or
2 cm margins for 4mm thickness) into the healthy tissue and down to the fascia. The skin
defect must be covered by plastic surgery. Mohs micrographic surgery has also been used
in melanoma with the advantage of providing visualisation of 100% peripheral and deep
margins microscopically.
Prophylactic lymph node excision might confer a survival advantage, compared to
delayed removal of the lymph nodes when lymphadenopathy became clinically apparent.
Lymphatic mapping and sentinel node biopsy were developed to identify the localisation
of the first-draining nodal metastasis (sentinel node).
In extensive lymph node metastases and distant metastases palliative radiotherapy
is used for pain relief.
Cytostatic drugs used in melanoma: dacarbazine (DTIC), vinca alcaloids, cisplatin
used in monotherapy or polychemotherapy.

159
 s pecific i m m u n otherapy w i t h
Interferon alpha an d i n t e rleukins and al so
melanoma vaccines (based on tumor cell associated antigens) have been used in clinical
trials.

Pro phy laxi s

Early detection and treatment of malignant melanoma are of vital significance for
melanoma (lentigo maligna,
t he patient. Premalignant conditions that ca n l ea d t o
dysplastic nevi) have to be early treated. As great percent of melanoma appears on normal
skin, the pigmented nevocytic nevi shouldn't be all prophylactically excised. If, however,
pigmented patches appeared after the age of 30 and developed over the course of a few
months, or a mole changes (in diameter, colour, symmetry, elevates) it is advisable to
perform
p rophylactic excision.
Patients should be f ollowed regularly after a d i agnosis of m elanoma because
m etastasis or recurrences occur mostly in t h e f i rst 3 y ears after the treatment of t h e
primary tumor. Annual skin examination is recommended for life, as a new melanoma can
appear.

160
 Fig.16.1. Solid basal cell carcinoma Fig.16.2. Ulcerated basal cell cardnoma

Fig.16.3. Ulcus rodens Fig.16.4. Superficial (pagetoid)

basal cell carcinoma

; • , '

Fig.16.5. Pigmented basal cell carcinoma Fig.16.6. Morpheaform basal cell carcinoma

Fig.16.7. Basalioma terebrans Fig.16.8. Nodular squamous cell carcinoma

161
Fig.16.9. Ulcerated squamous cell carcinoma Pig.16.10. Ulcero-vegetant SCC
and actinic keratoses

(*

Fig 16 11. Ulcero-vegetant SCC Fig.16.12. Necrotized lymph node metastases

on chronic leg ulcer from SCC of the right cheeck

Fig.16.13. Superficial spreading melanoma Pig.16.14. Nodular melanoma

. '
'" + • t

.P
P !-
r •

'J
Q(

Fig.16.1S. Nodular melanoma (acromic) Fig.16.16. Melanoma on lentigo maligna

16'2
 SELECTED REI'ERENCES

1. Benedek F,Sarac Floarea et al.B azele Dermato-Venerologiei. Ed. Treira, ed.a II-a,2003.
2. Badulici Sonia, Berila I. Dermatoze profesionale. Ed.Tehnica, Bucuresti, 2004.
Bucur Gh, O p ri y D ana A n g ela. Boli D e rmatovenerice, Enciclopedie. Ed.Medicala
Nationala, 2002.
Buxton P, Morris-Jones R. ABC of D ermatology, Ed.Wiley-Blackwell, fifth edition,
2009.
5. Cawson RA, Odell EW. Cawson's Essentials of Oral Pathology and Oral M edicine.
Eight edition. Churchill Livingstone Elsevier, 2008
6. Cheryl M.Burgess. Cosmetic Dermatology. Springer-Verlag Berlin, 2005
7. Diaconu JD, Coman OA , Bendea V. Tratat de Terapeutica Dermato-Venerologica.
Ed.Viata Medicalh Romaneasca, 2002.
8. Fitzpatrick B.Thomas et al. Dermatology in General Medicine. McGraw-Hill, Inc. 1993.
9. Fitzpatrick JE, Aeling JL. Dermatology secrets in color. Second ed., 2001.
10. Forsea D, Popescu R, Popescu CM. C o mpendiu d e d e rmatologie yi v enerologie.
Ed. Tehnica, 1996.
11. Graham-Brown R, Burns T. Dermatology. Seventh edition. Blackwell Science, 1996.
12. James W D, B e r ger T G , E l s ton D M . A n d r e w 's D i s eases of t he S ki n. C l i nical
Dermatology. Tenth edition. Saunders Elsevier, 2006.
13. Kaplan AP, Greaveas MW. Angioedema. J Am Acad Dermatol 2005; 53(3):373-88
14. MacKie M R. Clinical Dermatology. Fourth edition. Oxford University Press, 1997.
15. Naylor F M , F a rmer C K. Sun Damage and Prevention. The Electronic Textbook of
Dermatology, The Internet Dermatology Society, 1995-2000.
16. Sarac Floarea, Benedek Francisc et al. Dermatologie yi Patologie cosmetica. Editura
Treira, Oradea, 2003.
17. Sauer's Manual o f S ki n D i seases. Hall C.John Editor. Ed.Lippincott W i l l iams 6
Wilkins, ed.a 8-a, 2000
18. Vulcan P, Barsan Simona, Georgescu Simona Roxana. Semne yi simptome in patologia
cutanata. Editura National, 2004.
19. wv w.medscape.corn/ dermatology
20. Wolf K, Johnson RA. Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology.
Mc-Graw-Hill, 6th edition, 2009
21. Zuberbier. T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Gimenez-
Arnau AM, Grattan CEH, Kapp A, M erk HF, Rogala B, Saini S, Sanchez-Borges M,
Schmidt-Grendelmeier P, Schunemann H, Staubach P, Vena GA, Wedi B, Maurer M.

163
 classification an d d i a gnosis of
EAACI/GA'LEN/EDF/WAO g u i d eline: d efinition,
urticaria. Allergy 2009:64:1417-1426
22. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Gimenez-
Arnau AM, Grattan CEH, Kapp A, Maurer M, Merk HF, Rogala B, Saini S, Sanchez-
Borges M, Schmidt-Grendelmeier P, Schunemann H, Staubach P, Vena GA, Wedi B.
EAACI/GA'LEN/EDF/WAO guideline: management of urticaria. Allergy 2009:64:1427-
1443
23. The Electronic Textbook of Dermatology. 1995-2000 The Internet Dermatology Society,
Inc.

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