DermatologicManifestations
Of InternalCancer
Bruce H. Thiers, M.D.
As the “¿monumentalfacade of the human
body,― the skin often mirrors changes in
the organism it envelops. A wide spectrum
of inflammatory, proliferative, metabolic,
and neoplastic diseases affecting internal
organs display cutaneous manifestations,
which may be the presenting signs and
symptoms of the underlying disorders. This
article will focus on the skin signs of in
ternal cancer.
internal cancer may affect the skin both
directly and indirectly. Direct involvement
may be defined as the actual presence of
malignant cells within the skin. This in
cludes tumors that are often first apparent
in the skin but eventually affect internal
organs, visceral tumors metastatic to the
skin, and tumors arising within or below
the skin that ultimately spread to the cu
taneous surface. Indirect involvement of
the skin in cancer patients implies the ab
sence of tumor cells within the skin. In
herited synd@'omes associated with skin
manifestations and an increased incidence
of systemic neoplasia are included in this
group, as are cutaneous changes resulting
from hormone secretion by tumors, and a
wide spectrum of proliferative and inflam
matory disorders occurring in conjunction
with internal cancer.
An outline of this general classifica
tion is shown in the table.
Dr. Thiers is Associate Professor of Dermatol
ogy at Medical University of South Carolina in
Charleston, South Carolina.
130
Direct Involvement
In these disorders, tumor cells are found
within the skin.
Skin Disease as an Early Sign of
Systemic Neoplasia
This group includes a number of disorders
in which skin involvement appears to pre
cede or coincide with internal spread. These
disorders may begin as indolent, perhaps
non-neoplastic, reactive processes before
undergoing malignant degeneration with
more widespread dissemination.
Cutaneous T-CeII Lymphoma
The term cutaneous T-cell lymphoma has
been used to include mycosis fungoides
and its variants, which all seem to repre
sent a proliferation of T helper cells.2 Since
certain T cells appear to routinely traffic
through the skin,3 cutaneous T-cell lym
phoma may be a primary cutaneous dis
order, at least in its earliest stages. It may
thus represent an amplification or de
rangement of a normal biologic phenom
enon.4
The issue of whether benign derma
toses can evolve into cutaneous T-cell lym
phoma has been puzzling clinicians for
years. In the earliest, or premycotic, stage
of myocosis fungoides, the diagnosis is
difficult to establish either clinically or his
tologically. Some patients have an ecze
CA-A CANCER JOURNAL FOR CLINICIANS
VOL. 36, NO 3 MAY/JUNE 1986 131

Fig. 1. Parapsoriasis en plaque.
Fig. 2. Poikiloderma atrophicans Vasculare.
132
matous or psoriasiform dermatitis that may
respond to topical corticosteroid therapy or
may even remit spontaneously. In these in
dividuals, the diagnosis of premycotic my
cosis fungoides is usually made in retrospect
after the patient has progressed to a later
stage of disease. In others, parapsoriasis
en plaque, an unusual eruption of large
flat, oval, somewhat pruritic, reddish brown
patches, develops insidiously on the trunk,
buttocks, and thighs (Fig. 1).
Patients with parapsoriasis en plaque
are often later found to have mycosis fun
goides; it is uncertain, however, whether
under these circumstances parapsonasis en
plaque was actually early mycosis fun
goides that had been misdiagnosed or
whether it was a benign dermatosis that
had evolved into mycosis fungoides.
When telangiectasia, mottled pigmen
tation, and mild atrophy are predominant
features of a suspected premycotic disor
der, the eruption is usually termed poiki
loderma atrophicans vasculare (Fig. 2).
Occasionally, mycosis fungoides may be
heralded by a universal erythroderma of
uncertain cause and benign histology. In
these patients, the presence of islands of
uninvolved skin may provide a clue to the
eventual diagnosis.
The clinical and histologic diagnosis
of mycosis fungoides can be made more
easily in the second, or plaque, stage and
the third, or tumor, stage of the disease.
In the plaque stage (Fig. 3), previously
nondescript lesions become more infil
trated and display irregular borders and
areas of partial clearing. Involvement of
facial skin may result in leonine facies and
ectropion, while involvement of hairy areas
may be associated with alopecia. With time,
the disease progresses to involve more ex
tensive areas of the skin.
In the tumor stage, tumors develop
from plaques or, less commonly, from pre
viously uninvolved skin. These may
undergo ulceration and necrosis, and sec
ondary infection is common. Regional ad
enopathy may occur at any stage and is an
unfavorable prognostic sign whether or not
malignant cells are found in the enlarged
lymph nodes.5 The incidence of visceral
spread is highly controversial; although it
CA-ACANCER
JOURNAL
FORCLINICIANS
 is most often reported in later stages of the
disease, more advanced techniques have
demonstrated that internal involvement may
occur much earlier than has previously been
recognized .“@
The three-stage sequence of mycosis
fungoides is not apparent in all patients.
Occasionally, the disease begins with the
plaque stage; in the d'embléeform, tumors
are the initial manifestation. Sézarysyn
drome, the association of large numbers of
circulating atypical lymphocytes with an
erythroderma histologically similar to my
cosis fungoides, may occur de novo or as
a late manifestation of mycosis fungoides.
Woringer-Kolopp disease probably repre
sents a particularly epidermotropic form of
mycosis fungoides. Affected patients usu
ally have a few well-circumscribed irreg
ular plaques that enlarge slowly or not at
all; histologic examination shows massive
epidermal invasion by tumor cells. Al
though internal involvement may never oc
cur, some patients have shown more
progressive cutaneous and systemic dis
ease. It is possible that only this second
group of patients should be considered to
have a variant of mycosis fungoides.
Alopecia mucinosa may occur in as
sociation with mycosis fungoides or, es
pecially in children and adolescents, as an
isolated, self-limited condition. The le
sions, which are typically located on the
face, neck, scalp, and proximal upper ex
tremities, consist of groups of follicular
papules or boggy infiltrated plaques as
sociated with hair loss (Fig. 4). Histologic
examination shows accumulation of acid
mucopolysaccharide in the outer root sheath
and sebaceous glands. Depending on the
clinical setting, the inflammatory infiltrate
may or may not show evidence of mycosis
fungoides, which can either precede or ac
company the disorder.
Patients with evidence of infection with
type I human T-cell leukemia/lymphoma
virus (HTLV- 1) may present with hyper
calcemia, lytic bone lesions, and an illness
not unlike cutaneous T-ceII lymphoma, al
though skin lesions may be absent.9 An
association of typical cutaneous T-cell
lymphoma with HTLV infection is un
likely.
VOL. 36, NO 3 MAY/JUNE1986
r
/11@
Fig. 4. Alopecia mucinosa.
Histiocytosis X
The three clinical patterns of histiocytosis
X—Letterer-Siwe disease, Hand-SchUller
Christian disease, and eosinophilic gran
uloma of bone—are all variations of a sin
gle pathologic process: a disseminated,
progressive, and invasive proliferation of
atypical but well-differentiated histiocytes,
which may, in fact, represent activated
Langerhans cells.― The neoplastic nature
of histiocytosis X has not been firmly es
tablished, and recent studies suggest that
it may, at least at its onset, represent a state
of altered immunity.'2'5 Thus, like my
cosis fungoides, histiocytosis X may be an
example of “¿immunologiconcogenesis,―
the evolution of an inflammatory process
into a malignant disease.
Letterer-Siwe disease occurs almost
exclusively in children three years of age
or younger. Most patients have skin le
sions, which are either localized to or ac
centuated in the seborrheic areas, including
the scalp, behind the ears, and in the ax
illary and inguinal folds (Fig. 5). Cuta
neous findings consist of an eruption similar
to infantile seborrheic dermatitis; papular
and nodular lesions may also be found. The
dermatosis is often purpuric, and papules
in skin folds may ulcerate. Involvement of
the external auditory canal may simulate
external otitis. Intraoral involvement may
cause ulceration of the buccal mucosa and
gums.
Letterer-Siwe disease is usually an
acute, fulminant, ultimately fatal disorder
associated with fever, anemia, thrombo
133

Fig. 5. Histiocytosis X.
Fig. 6. Mastocytosis (urticaria pigmentosa).
cytopenia, and multisystem involvement,
as shown by histiocytic proliferation in the
lymphoreticular organs and the lungs. Less
commonly, the disease evolves into a more
chronic form. Spontaneous remission has
been reported.
Hand-Schüller-Christian disease, a
condition that occurs usually but not ex
clusively in children two to seven years
old, follows a more chronic course than
Letterer-Siwe disease. Only 30 to 50 per
cent of affected individuals develop skin
lesions, which are similar to those of Let
terer-Siwe disease, although purpura may
134
be absent. Osteolytic defects of the cal
varia and long bones are almost always
detected. Diabetes insipidus, which occurs
in about 50 percent of affected individuals,
usually reflects histiocytic invasion of the
hypothalamus and may be accompanied by
growth retardation. Exophthalmos occurs
in 10 percent of patients.
Older children with Hand-Schüller
Christian disease have a better prognosis
than do younger children; involvement of
multiple organ systems is a poor prognostic
sign.
The peak incidence of eosinophilic
granuloma is between ages two and five
years, although older children and young
adults may be affected. The main site of
pathology is the long bones; as in Letterer
Siwe disease and Hand-Schüller-Christian
disease, the lungs and oral mucosa may
also be affected. Skin lesions are usually
absent; when they occur, they are generally
similar to those seen in other variants of
histiocytosis X.
In adults, eosinophilic granuloma is
most often a nonprogressive disease; af
fected children should be watched for evo
lution into more aggressive variants of his
tiocytosis X.
Mastocytosis (Mast Cell Disease,
Urticaria Pigmentosa)
Many similarities seem to exist between
mastocytosis and histiocytosis X, although
extracutaneous involvement is much less
common in mastocytosis. Both disorders
mainly affect children and feature prolif
erative lesions primarily composed of ma
ture elements that involve the skin and
sometimes the bones, liver, spleen, and
lymph nodes. A leukemic form with im
mature cells has been described in each.
Characteristically, only the lesions of mast
cell disease swell and vesiculate upon rub
bing (Darier's sign).
Because visceral involvement is un
usual, the prognosis is excellent for most
patients with mast cell disease. Skin le
sions in children are usually self-limited
and frequently clear spontaneously. Al
though skin lesions seldom disappear in
adults, most individuals follow a benign
CA-A CANCERJOURNALFORCLINICIANS

Fig. 7. Kaposi's sarcoma, classical type.
course. Rarely, patients with systemic in
volvement have a progressive downhill
lymphoma-like course terminating in leu
kemia.
A variety of cutaneous lesions may be
associated with mast cell disease. Solitary
mastocytomas are usually seen in children.
Multiple, small, brown, hyperpigmented
macules or slightly elevated papules are the
most common skin manifestations and can
be observed at any age (Fig. 6). In chil
dren, these often clear during the late teen
age years. With later onset, lesions tend to
persist unchanged or may become more
numerous and virtually confluent. The hy
perpigmented macules of telangiectasia
macularis eruptiva perstans (seen mostly
in adults) and the erythroderma of diffuse
mastocytosis (seen in all age groups) are
rare.
Systemic lesions occur more fre
quently in adults, can be detected in about
10 percent of affected individuals, and may
be associated with any type of skin lesion.
Kaposi's Sarcoma
Like the disorders already discussed, Ka
posi's sarcoma is of multifocal origin. As
with mycosis fungoides and histiocytosis
X, Kaposi's sarcoma may be a reactive
process that undergoes malignant transfor
mation, rather than a frank neoplasm from
its inception. It appears to represent a pro
liferation of lymphoreticular and pluripo
tential vascular cells that differentiate into
VOL 36. NO 3 MAYJUNE 1986
Fig. 8. Kaposi's sarcoma, early lesions in pa
tient with acquired immune deficiency syn
drome.
fibroblasts and endothelial cells.'4 Kaposi's
sarcoma may occur de novo, especially in
elderly persons, or may be seen in asso
ciation with states of altered immunity, such
as after renal transplantation in patients with
lymphomas or in patients with acquired
immune deficiency syndrome (AIDS). Race
Although idiopathic
Kaposi's sarcoma
is usually a slowly progressive
condition that may span
10 or more years, in
immunosuppressed patients
the disease often
follows a more
accelerated course.
and geography may affect the incidence of
Kaposi's sarcoma.
The disorder usually starts as circum
scribed red-brown or purple macules, pa
pules, or nodules on the feet or lower legs
(Fig. 7). Lesions may become increasingly
infiltrated and coalesce to involve large
areas of skin. Edema and lymphedema may
develop. Extracutaneous spread occurs
most often to the gastrointestinal tract,
where bleeding is a frequent complication.
Metastases to the respiratory tract may also
occur, and other sites may be involved as
well. Idiopathic Kaposi's sarcoma is gen
erally a slowly progressive condition that
135
 9. Metastatic bronchogenic carcinoma.
Fig.10. Adenocarcinoma of stomach met
astatic to umbilicus (Sister Joseph nodule).
may span a decade or more. In immuno
suppressed individuals, however, the dis
ease often follows an accelerated course;
the initial lesions may then occur anywhere
and frequently involve mucosal surfaces
(Fig. 8).'@ Conversely, when immuno
suppressive therapy is discontinued, the
sarcomatous lesions may spontaneously
regress. 6
Cutaneous Metastases of Internal
Neoplasms
Cutaneous metastases usually occur via one
of two routes: Tumor cells may either be
transported to the skin from distant sites
via the blood vessels or lymphatics, or they
may reach the skin via extension from a
136
Fig. 11. Metastatic malignant melanoma.
contiguous primary lesion. Accidental im
plantation of tumor cells in skin may also
occur during a surgical procedure. Spread
to skin of a visceral tumor may occur at
any time and may occasionally be the pre
senting sign of an underlying cancer.
Metastatic Carcinoma
The incidence of involvement of skin in
metastatic disease is relatively low com
pared with other organs and probably av
erages about five to 10 percent. Although
any cancer can spread to skin, most cu
taneous metastases are of carcinomatous
origin. The lung is the most frequent source
of cutaneous metastases in the male; the
breast is the usual source in females. In
both sexes, metastases are most often found
on the skin of the abdomen and anterior
chest; the head and neck are also favored
sites, especially in men.
The location of the metastatic tumor
is often a clue to the site of the primary
lesion. Metastases to the head, neck, and
anterior chest often originate in lung tu
mors in men (Fig. 9) and breast cancers
in women. Metastases to the upper abdom
inal wall generally spread from gastroin
testinal lesions; the lower abdominal wall
and external genitalia are the favored site
for genitourinary cancers. Carcinoma met
astatic to the umbilicus (Sister Joseph nod
ule) is usually a sign of an underlying
adenocarcinoma of the stomach (Fig. 10).
Melanomas usually metastasize to the ex
CA-A CANCER JOURNAL FOR CLINICIANS
 tremities, while tumors of the oral cavity
often metastasize to the face (Fig. 11).
Whatever their source, tumors meta
static to the skin usually present as hard
dermal or subcutaneous masses often fixed
to the underlying tissue. Lesions may oc
cur singly or in groups, and may be flesh
colored, pink, red, violaceous, or brown
black. Ulceration is uncommon. The clin
ical picture may be unremarkable—for ex
ample, an atypical solitary nodule of
unknown etiology—or more dramatic
for example, showers of nodules that may
enlarge or even remit spontaneously. Skin
metastases are sometimes first noted along
the incision line through which the primary
tumor was removed.
Metastases to the scalp may simulate
pilar cysts and produce a scarring alopecia
(alopecia neoplastica). Carcinoma erysi
pelatoides (inflammatory carcinoma), usu
ally seen in association with carcinoma of
the breast, may be difficult to distinguish
clinically from cellulitis orerysipelas. Skin
metastases in a zostenform distribution may Fig. 12. Metastatic breast carcinoma in a
zosteriform distribution.
result from penneural lymphatic spread of
malignant cells (Fig. 12).
Any cutaneous nodule of unexplained
etiology should be biopsied to rule out the
possibility of metastatic carcinoma. Al
though rarely specific enough to pinpoint
the exact location of the primary tumor,
histologic examination of the biopsy spec
imen may provide valuable information as
to its origin. Mucin-containing glandular
tumors, for example, frequently arise from
the gastrointestinal tract. Even the discov
ery of an anaplastic metastatic nodule may Fig. 13. Histiocytic lymphoma.
have predictive value, since most of these
tumors seem to originate in the lung, as
do many metastatic squamous cell carci
nomas and some poorly or moderately dif Specific lesions are those in which tumor
ferentiated metastatic adenocarcinomas. cells characteristic of the neoplastic dis
order are found.
Lymphomas (Other Than Cutaneous The specific lesions of both Hodgkin's
and non-Hodgkin's lymphomas occur in 10
T-cell Lymphomas) and Leukemias
to 20 percent of patients and consist of
The cutaneous manifestations of lympho pink, violaceous, red-brown, or bluish der
mas and leukemias are frequently divided mal or subcutaneous papules, plaques,
into nonspecific and specific lesions. Non nodules, or tumors, often in groups, dis
specific features include pruritus, ichthy tributed anywhere on the body (Fig. 13).
osis, and exfoliative dermatitis; these are The oral cavity, nasal cavity, and other mu
seen most often with Hodgkin's disease. cosal surfaces may be affected. Skin in

VOL.36,NO.3 MAY/JUNE
1986 137

Fig. 14. Paget's disease of breast.
volvement may precede evidence of more
generalized disease; rarely, the skin may
be the primary site of involvement in pa
tients with B-cell lymphomas (cutaneous
B-cell lymphoma).'7 In Hodgkin's disease,
involvement of skin may be a consequence
of retrograde flow from involved lymph
nodes rather than active cutaneous inva
sion. Histologic examination of specific
skin lesions, while useful for establishing
the diagnosis of lymphoma, rarely allows
for more precise classification.
The types and morphology of the spe
cific and nonspecific lesions of leukemia
The cutaneous
manifestations of internal
cancer can develop
either before or after the
presence of an
underlying tumor has
been established.
are similar to those encountered in the lym
phomas. Specific skin lesions are some
what more common in monocytic than in
lymphocytic or granulocytic leukemia;
since the incidence of lymphocytic leu
kemia is relatively high, however, its der
matologic manifestations are most often
seen. There is no specific site of predilec
tion for monocytic leukemia, compared
with lymphocytic leukemia, which usually
138
affects the face and extremities, and gran
ulocytic leukemia which preferentially in
filtrates the skin of the trunk. Although
leukemia cutis occurs most often in chronic
leukemia, oral involvement, as evidenced
by gingival infiltration and hyperplasia, is
a feature of both the acute and chronic
stages of the disease, especially the mono
cytic variety.
Chloroma is a peculiar tumor of my
elogenous origin and is the sole patho
gnomonic lesion of leukemia. Its charac
teristic green color on exposure to light is
probably due to the presence of the enzyme
myeloperoxidase in the cells of the tumor,
which consist primarily of malignant my
eloblasts and myelocytes. Chloroma usu
ally affects the periorbital and cranial bones,
and is seen most often in children and young
adults with acute granulocytic leukemia.
The lesion, which can occur anytime dur
ing the course of the disease or even be its
presenting sign, carries poor prognostic
implications.
Tumors Arising Within or
Below the Skin
Paget's disease is the prototypic malignant
disease that begins below the skin and ex
tends to the cutaneous surface. While most
often noted on the female breast, the con
dition may also occur in the anogenital re
gion of both sexes and rarely in the axilla
(extramammary Paget's disease).
Paget's disease of the breast begins as
a unilateral, occasionally pruritic, ecze
matous weeping eruption of the nipple and
areola with a fairly sharp, sometimes ir
regular border (Fig. 14). Topical treatment
is ineffective. Examination of a biopsy
specimen shows numerous large, round
cells with clear cytoplasms (Paget cells)
infiltrating the epidermis. Although an un
derlying ductal adenocarcinoma is almost
always found, the traditional “¿epidermo
tropic―theory of histogenesis has recently
been challenged.―'
Extramammary Paget's disease occurs
more often in women than in men, usually
after age 50. Lesions can occur anywhere
in the genital and perianal areas, and have
been reported on the lower abdominal walls,
CA-A CANCERJOURNALFORCLINICIANS
 Fig. 15. Cowden's disease. (Courtesy of Jo
seph Bikowski, MD, Sewickley,Pennsylvania.)
inguinal region, and inner thighs. Like
@ mammary Paget's disease, the disorder
presents as a pruritic, unilateral, scaly,
sometimes weepy eruption that can easily
be confused with eczema or tinea cruris.
Microscopic examination for hyphae is
negative; histologic examination shows
features identical to those found in Paget's
@ disease of the breast.
Extramammary Paget's disease is as
sociated with an increased incidence of un
derlying cancer, but this finding is
inconsistent, and, unlike the situation with
mammary Paget's disease, an adjacent tu
mor has been found in only about 50 per
cent of affected patients. Apocrine gland
cancer is the most common associated can
cer, although tumors of the eccrine sweat
glands, Bartholin's glands, urethra, pros
tate, rectum, breast, and cervix have been
reported. Regional and distant metastases
may develop.
The uniform presence of an underlying
ductal carcinoma in mammary Paget's dis
ease suggests a glandular origin for the
Paget cell. The histogenesis of the Paget
VOL 36,NO 3 MAY/JUNE
1986
Fig. 16. Gardner's syndrome.
@“¿ .‘@‘-@@4'
ft lr',,t,
.@.J.. .“
Fig. 17. Peutz-Jeghers syndrome.
cell is less certain in extramammary Pa
get's disease, where an underlying carci
noma is not always detectable and has
occasionally been reported at a distant site.
Nevertheless, the finding of carcinoem
bryonic antigen (CEA), a marker for the
cells and secretions of normal eccrine and
apocrine glands, in Paget cells of both the
mammary and extramammary types sug
gests a glandular origin for both tumors
and implies that Paget's disease is an in
traepidermal adenocarcinoma.―' Cases of
extramammary Paget's disease without an
139

Fig. 18. Palmoplantarkeratoderma in patient
with carcinoma of esophagus.
Fig. 19. Multiple mucosal neuromas syn
drome.
identifiable underlying cancer may arise
from dermal or poral portions of sweat ducts
and may be detectable only after meticu
lous step-section examination of the pa
thology specimen. In this situation, the
tumor may spread laterally before descend
ing into the underlying glands.
Indirect Involvement
This group of disorders includes benign
dermatoses that may be associated with an
140
V
•¿s'.
.t.. .‘ 4'
.4.
L 8@
..& .‘@
...‘ .‘@‘
‘¿3..
‘¿@@1'
Fig. 20. Von Reckinghausen's disease.
increased incidence of internal cancer.
Inherited Syndromes Associated
With Internal Cancer
Cowden's disease ‘¿(multiplehamartoma
syndrome), which is inherited as an au
tosomal dominant trait, displays a variety
of cutaneous and mucosal manifestations
that can occur at any time from childhood
to middle age.2°It occurs more often in
women than in men. Small (one to four
mm) flesh-colored papules are found mainly
on the head and neck and may assume
a wart-like appearance (Fig. 15). The
histologic interpretation of these lesions
is controversial, since they have been char
acterized as either trichilemmomas or old
verrucae. Similar papules may coalesce and
produce a cobblestone appearance on the
gums. Flat wart-like papules have been
noted on the dorsum of the hands and feet,
and keratosis punctata may be present on
the soles, sides of the feet, and palms.
Lipomas and hemangiomas may also be
found.
Internal manifestations are variable.
CA-ACANCER
JOURNAL
FORCLINICIANS
 Almost all affected women have fibrocys
tic changes of the breast, and many of these
women ultimately develop breast cancer.
Thyroid tumors, both benign and malig
nant, are frequent (75 percent). Cancers of
the lung and colon have been reported.
Polyps of the gastrointestinal tract (33 per
cent) are generally benign. The signifi
cance of Cowden's disease lies in its value
as a marker for the eventual development
of thyroid or breast disease.
Extensive polyps of the gastrointes
tinal tract, especially the colon and rectum,
also occur in Gardner's syndrome, another
autosomal dominant disorder (Fig. l6).21
In Gardner's syndrome, however, the po
tential for malignant degeneration is so high
(approaching 100 percent) that prophylac
tic colectomy may be indicated for patients
demonstrating multiple polyps on radio
logic examination. Skin lesions include
large, deforming epidermoid cysts, fibro
mas, lipomas, leiomyomas, tnchoepithe
liomas, and neurofibromas. Osteomas Fig. 21. Acanthosis nigricans.
involving the membranous bones of the
face and head occur in about 50 percent
of affected patients.
In contrast to the asymptomatic pre
malignant polyps of Gardner's syndrome,
the hamartomatous polyps of Peutz-Jeghers ‘¿V.

syndrome (Fig. 17), another autosomal .,-, . ,_.al •¿@ •¿

dominant disorder, are less extensive, oc f ‘¿@f.-, ,@s'

@ cur more commonly in the small bowel,
and often cause intussusception. The in
cidence of malignant change is controver
sial, but is certainly much less than in
Gardner's syndrome.22'23 The characteris
tic cutaneous feature is freckle-like pig
mented macules on the lips, nose, buccal
mucosa, fingertips, and under the nails.
Cutaneous and, rarely, mucosal hy
perpigmentation may also occur in the
Cronkhite-Canada syndrome; other cuta
neous features include onychodystrophy
and alopecia.24 Hamartomatous polyps oc
cur throughout the stomach and intestines,
and the incidence of gastrointestinal cancer
is approximately 15 percent. The disease
does not appear to be inheritable.
In Torre's syndrome, multiple carci
nomas, usually of the gastrointestinal tract,
are associated with numerous sebaceous
gland tumors (both benign and malignant),
:@‘:
•¿.@‘
S •¿d ‘¿â€˜â€˜!t8“¿
Fig. 22. The sign of Leser-Trélat.
primarily on the trunk;25 in contrast, soli
tary sebaceous gland tumors are not ge
netically determined, occur most often on
the head and neck, and are not associated
with visceral cancer. The diagnosis of gas
trointestinal cancer usually precedes the
onset of the cutaneous lesions, which are
not significantly aggressive even if histo
logically malignant. Similarly, the visceral
cancers behave like low grade cancers. In
heritance of Torre's syndrome appears to
occur as an autosomal dominant trait.

VOL. 36, NO 3 MAY/JUNE 1986 141


Fig. 23. Primary amyloidosis,
pura.―
r iant of malignant acanthosis nigricans.
Fig. 24. Primary amyloidosis, waxy lesions
around eyes.
An association between diffuse pal
moplantar hyperkeratosis (tylosis) and eso
phageal cancer (Howel-Evans syndrome)
has been noted in two English families.
The keratoderma usually develops during
childhood and is accentuated over pressure
sites. Onset of the esophageal carcinoma
is delayed until middle age. Rarely, ac
quired palmoplantar keratoderma, begin
ning later in life, has been associated with
cancer of the esophagus and lung (Fig.
18)26 This latter condition may
142
.4
...@,
“¿pinch
pur S syndrome.
Patients with the rare autosomal dom
inant disorder, multiple mucosal neuromas
syndrome, display a constellation of ab
normalities, including medullary carci
noma of the thyroid, pheochromocytoma,
parathyroid hyperplasia or adenomas, and
intestinal ganglioneuromatosis; the latter
may give rise to persistent diarrhea,27 Mul
tiple neuromas are present as whitish nod
ules, mainly on the lips and anterior one
third of the tongue (Fig. 19), but may also
be noted on the buccal mucosa, gingivae,
palate, pharynx, conjunctiva, and cornea.
Affected individuals have characteristic
facies, with thick, protuberant, bumpy lips;
the eyelids may be thickened and slightly
everted. Many patients have “¿marfanoid―
characteristics—long, slender extremities;
poor muscle development; sparse body fat;
laxity of joints; pectus excavatum; and dor
sal kyphosis. Although multiple mucosal
neuromas syndrome is classified as one of
the three familial syndromes of multiple
endocrine neoplasia (see below), many
sporadic cases have been reported.
In neurofibromatosis (von Reckling
be a var hausen's disease) (Fig. 20), multiple
CA-A CANCERJOURNALFORCLINICIANS
Schwann cell tumors and pheochromocy
tomas may complicate the clinical course.
The salient features of this disorder, which,
like multiple mucosal neuromas syndrome,
may be classified among the APUDomas
(see below), have been extensively re
viewed in the recent medical literature.28
Internal cancer is associated with sev
eral inherited immunodeficiency disor
ders, including ataxia-telangiectasia and the
Wiskott-Aldrich syndrome.29 Most tumors
are of lymphoreticular origin.
Skin Changes Resulting from
Hormone-Secreting Tumors
Ectopic humoral syndromes are best
understood in the context of the APUD
(normal Amino content, high amine Pre
cursor Uptake, and high content of amino
acid Decarboxylases) cell system. ‘¿Â°These
cells, which may have a common origin
from the neural crest, are capable of se
creting a variety of biologically active
amines and polypeptide hormones. Neo
plastic proliferation of these cells may re
sult in characteristic symptom complexes
associated with specific cutaneous changes.
Ectopic adrenocorticotropic hormone
(ACTH)-producing tumors cause many of
the typical signs and symptoms of Cush
ing's syndrome. Intense hyperpigmenta
tion, present in only six to 10 percent of
patients with Cushing's disease, is espe
cially common in association with ectopic
ACTH production and should alert the
clinician to the possibility of a hormone
secreting tumor. The cause of the hyper
pigmentation is unclear, but it may be
related to tumor production of the peptide
beta-lipotropin, which contains with
in its sequence of 91 amino acids the 22
amino acid sequence of beta-melanocyte
stimulating hormone (MSH). A myas
thenia gravis-like syndrome including
profound proximal muscle weakness may
be a striking clinical feature and may re
flect either underlying hypokalemia or po
lymyositis. Oat cell carcinoma is the tumor
most often associated with ectopic ACTH
production, although other cancers have
been reported.
The carcinoid syndrome is a second
VOL. 36, NO 3 MAY/JUNE 1986
Fig. 26. Oral candidiasis.
example of a humoral syndrome associated
with a nonendocnne tumor. The disorder
is probably due most often to the release
of the enzyme kallikrein from tumor cells
with subsequent conversion of kininogen
to vasoactive kinin peptides, including
bradykinin; in addition, increased blood
levels of histamine may be important in
the rare metastatic gastric carcinoid. The
most striking cutaneous manifestations are
episodes of flushing, initially lasting 10 to
30 minutes and involving only the upper
half of the body; as the flush resolves, gy
rate and serpiginous patterns may be noted.
With successive attacks, more extensive
areas may be affected and the redness takes
on a cyanotic quality, eventually leading
to a more permanent facial cyanotic flush
with associated telangiectasia, resembling
rosacea. Persistent edema and erythema of
the face may result in leonine facies. A
pellagra-like picture, noted in some pa
tients, may be due to abnormal tryptophan
metabolism. Systemic symptoms associ
ated with cutaneous flushing include ab
dominal pain with explosive watery
diarrhea, shortness of breath, and hypo
tension.
Carcinoid tumors are usually found in
the appendix or small intestine; extra
intestinal carcinoids may arise in the bile
ducts, pancreas, ovaries, or bronchi. The
carcinoid syndrome occurs primarily with
intestinal carcinoids metastatic to the liver
or with extraintestinal tumors; flushing at
tacks can be provoked by palpation of he
patic or abdominal metastases, or by alcohol
ingestion, enemas, emotional stress or sud
143
Fig.27. Dermatomyositis,
heliotrope
rash.
Fig. 28. Dermatomyositis, Gottron's pa
pules.
den changes in body temperature. When
the syndrome is associated with bronchial
adenomas of the carcinoid variety, the
flushing is more prolonged and often
associated with fever, marked anxiety,
disorientation, sweating, salivation, and
lacrimation -
The three clinical patterns of familial
multiple endocrine neoplasia (MEN types
1,2, and 3) are examples of polyglandular
endocrine disorders involving the APUD
cell system. A carcinoid-like syndrome has
been described in MEN-2 (Sipple's syn
drome); otherwise, mucocutaneous lesions
occur only in MEN-3 (multiple mucosal
neuromas syndrome), which has already
been discussed.
The glucagonoma syndrome is asso
ciated with an APUDoma involving the
glucagon-secreting alpha cell of the pan
144
Fig. 29. Purpura fulminans in patient with
malignant lymphoma.
creas. The characteristic cutaneous erup
tion, necrolytic migratory erythema, usually
occurs on the abdomen, perineum, thighs,
buttocks, and groin. The perioral region
and the distal extremities are often af
fected. Patches of intense erythema with
irregular outlines expand and coalesce, re
sulting in circinate or polycyclic configu
rations. Superficial vesicles on the surface
rupture quickly to form crusts, but new
vesicles may continue to develop along the
active margins. An eczema craquelé-like
appearance may be noted. Pressure or
trauma may initiate or aggravate the erup
tion, which seems to share features of
staphylococcal scalded skin syndrome and
acrodermatitis enteropathica. Like the lat
ter disorder, necrolytic migratory erythema
responds to diiodohydroxyquin; zinc lev
els, however, are normal, and zinc treat
ment is ineffective.
Neurofibromatosis, discussed earlier,
is classified as an APUDoma. Malignant
melanoma is a non-hormone-secreting
APUDoma. Patients with widespread me
tastases can develop diffuse gray to blue
black hyperpigmentation of the skin and
mucous membranes.
Proliferative and Inflammatory
Dermatoses Associated with Cancer
Many of these conditions are nonspecific
and have been reported both in association
with and in the absence of underlying can
cer. Cancer is most often only one of a
number of possible provoking factors.
CA-A CANCER JOURNAL FOR CLINICIANS
 The association of acquired hypertri
chosis lanuginosa (malignant down) with
cancer is probably the most consistent.3'
The extensive growth of silky, nonpig
mented lanugo hair on the face, neck, trunk,
and sometimes the extremities may pre
cede discovery of the cancer, which usu
ally involves the gastrointestinal tract. Other
causes of hypertrichosis, such as porphyria
cutanea tarda and endocrinopathies, must
be ruled out. A painful glossitis and swol
len red fungiform papillae on the anterior
half of the tongue may accompany the cu
taneous eruption.
Acanthosis nigricans is perhaps the best
known of the cutaneous markers of internal
cancer.32 Flexural areas, especially the ax
illae, groin, and neck, are most often in
volved; the skin has a hyperpigmented
velvety appearance and in severe cases can
become quite verrucous (Fig. 21). Papil
lomatous changes may be noted in the oral
cavity, and hyperkeratosis in a rugose pat
tern may develop on the palms and dorsal
surfaces of large joints. The cutaneous
changes can occur before, coincident with,
or after the discovery of the underlying
cancer, which most often is an adenocar
cinoma, usually of the stomach. Since
acanthosis nigricans can occur in a variety
of benign conditions—for example, as a
familial lesion, at puberty, or in association
with endocrine disease and obesity—a
detailed history must be included in the
evaluation of all affected patients. The pos
sibility of underlying cancer should be
strongly considered in any nonobese adult
who develops acanthosis nigricans.
The sign of Leser-Trélat, the sudden
appearance and rapid increase in size of
multiple seborrheic keratoses (Fig. 22),
may be associated with carcinoma of the
gastrointestinal tract or female reproduc
tive system.33This condition may represent
a generalized variant of acanthosis
nigricans.
Patients with Bazex's syndrome (para
neoplastic acrokeratosis) develop a pso
riasiform eruption primarily on the face
and extremities.30'35 The ears, nose, cheeks,
hands, feet, and knees are most often af
fected; the nails are dystrophic, and the
palms hyperkeratotic. The disorder is as
VOL. 36, NO 3 MAY/JUNE1986
sociated with carcinomas of the upper res
piratory and digestive tracts.
The significance of punctate palmar
keratoses as a sign of internal cancer is
controversial,@ although they have been
reported in Cowden's syndrome. Simi
larly, the purported relationship between
Bowen's disease (intraepidermal squa
mous cell carcinoma) and systemic cancer
has been disputed.
Patients with primary systemic amy
loidosis almost always have an underlying
plasma cell dyscrasia—usually multiple
myeloma.37 The skin takes on a general
ized waxy appearance and bleeds easily
when traumatized (“pinch purpura―)(Fig.
23). Hemorrhagic lesions are especially
common around the eyes (Fig. 24). Ma
croglossia is an associated finding. Skin
lesions are not seen in secondary amyloi
dosis.38
Sweet's syndrome (acute febrile neu
trophilic dermatosis) may occasionally be
associated with leukemia, particularly the
acute myeloid or myelomonocytic vari
eties.39 Red, tender, sometimes vesicular
or pustular papules, plaques, or nodules
appear suddenly on the face, extremities,
and upper trunk (Fig. 25). Fever, malaise,
and neutrophilia accompany the cutaneous
eruption, which histologically shows a
dense dermal neutrophilic infiltrate. The
presence of moderate to severe anemia may
be helpful in distinguishing Sweet's syn
drome associated with myeloproliferative
disease from the idiopathic disorder.
Infectious disorders are frequent in
cancer patients and may either be directly
related to depressed cell-mediated immu
nity associated with the tumor or secondary
to pharmacologic immunosuppression. Oral
candidiasis, for example, can be an early
manifestation of AIDS (Fig. 26).@° The in
creased incidence of herpes zoster, either
localized or disseminated, in patients with
leukemia and lymphoma has been appre
ciated for years, although such infection
usually develops during the course of the
illness rather than as a presenting sign.@'@3
Rarely, herpes zoster may be associated
with an underlying carcinoma.
Generalized pruritus, ichthyosis, and
exfoliative dermatitis are seen as nonspe
145
 cific features of lymphoproliferative dis
orders; uncommonly, they may be
associated with solid tumors.
A search for underlying cancer is man
datory in adult patients with dermato
myositis, about 25 percent of whom will
be found to be affected; childhood der
matomyositis, however, is not associated
@ with internal cancer. Pathognomonic
clinical manifestations include an edema
tous, violaceous eruption of the upper eye
lids (heliotrope rash) (Fig. 27) and atrophic
scaly papules over bony prominences
(Gottron's papules) (Fig. 28); photosen
sitivity, malar erythema, poikiloderma and
periungual telangiectasias are important,
although less specific, findings. Derma
tomyositis is not specific for any particular
kind of cancer, although tumors of the lung,
gastrointestinal tract, and breast occur most
frequently. Raynaud's phenomenon in an
adult with dermatomyositis suggests the
connective tissue variant of the disorder
rather than dermatomyositis associated with
cancer.
Inspection of the
skin is an essential part
of the complete physical
examination.
A number of musculoskeletal disor
ders have been reported in patients with
cancer. Clubbing is noted in about 10 per
cent of individuals with lung cancer and
tumors metastatic to the lung. Subpenos
teal new bone formation in patients with
clubbing (hypertrophic osteoarthropathy)
occurs most commonly along the shaft of
the phalanges but may affect other bones
as well. Joint swelling, synovitis, pen
articular swelling, hyperhidrosis, and pal
mar erythema may be pronounced and
create a picture similar to early rheumatoid
arthritis. Hypertrophic osteoarthropathy
associated with acromegaloid features
(pachydermoperiostosis) can occur either
in association with lung cancer or as a ge
netic disease unassociated with cancer.45
Polyarthritis simulating rheumatoid
146
arthritis (in the absence of hypertrophic
osteoarthropathy), tenosynovitis, and fi
brositis have also been reported in asso
ciation with cancer.
Internal cancer may be heralded by a
number of disorders that probably repre
sent variants of disseminated intravascular
coagulation. In purpura fulminans, throm
bosis and hemorrhage occur simulta
neously (Fig. 29); purpura fulminans in
adults with cancer usually runs a chronic,
less fulminant course than the postinfec
tious disorder of the same name, although
digital gangrene has been reported. A de
fibrination syndrome, characterized by easy
bruising, purpura, and a bleeding dia
thesis, may also be a feature of internal
cancer.
Migratory superficial thrombophlebi
tis and multiple deep venous thromboses
have been noted in cancer patients, es
pecially those with tumors arising in the
pancreas, lung, stomach, prostate, or he
matopoietic system. The neck, chest, ab
dominal wall, pelvis, and limbs are most
frequently affected.
The figurate erythemas may be divided
into three groups. Erythema chronicum
migrans follows a tick bite and may be
associated with Lyme disease.@ Erythema
annulare centrifugum may be secondary to
a variety of causative factors including,
rarely, cancer. Erythema gyratum repens is
almost always associated with cancer;47no
one tumor seems to predominate. Multiple
wavy urticarial bands with a fine scale mi
grate over the cutaneous surface, giving it
an appearance similar to the grain of wood.
The eruption usually occurs within a few
months before or after the diagnosis of can
cer.
Urticaria is very rarely a manifestation
of internal cancer. Erythema multiforme,
also an uncommon sign of visceral cancer,
occurs more often after deep x-ray therapy,
presumably as a hypersensitivity response
to necrotic tumor tissue.
Blistering diseases, especially bullous
pemphigoid, have been reported in patients
with cancer.@ This probably reflects the
increased incidence of both bullous pem
phigoid and cancer in the elderly rather
than any true association. Individuals with
CA-A CANCER JOURNAL FOR CLINICIANS
dermatitis herpetiformis may have an in
creased relative risk of intestinal lym
phoma similar to that noted in patients with
sprue. Epidermolysis bullosa acquisita has
also very rarely been reported in patients
with lymphoreticular tumors. Pemphigus
is occasionally associated with thymoma.
Summary
The cutaneous manifestations of internal
cancer can develop either before or after
References
1. Comel M: Fisiologia Normale e Patologica
Della Cute Umana. Milan, Italy, Fratelli Treves
Editori, 1953.
2. Berger C, Raafat J, Edelson R: Mycosis fun
goides: Neoplasm of helper I cells. J Invest
Dermatol 70:212, 1978.
3. Tigelaar R: Lymphocyte traffic and the skin. 14. McNutt S: Kaposi's sarcoma, in Thiers B,
Dermatol Clinics 3:569—585,1985.
4. Thiers BH: Controversies in mycosis fun ease, New York, Churchill-Livingstone, 1985,
goides. J Am Acad Dermatol 7:1—16,1982.
5. Colby TV, Burke iS, Hoppe RT: Lymph node
biopsy in mycosis fungoides. Cancer 47:35 1— et al: Oral manifestations of tumor and oppor
359, 1981.
6. Bunn PA Jr, Whang-Peng J, Carney DN, et
al: DNA content analysis by flow cytometry and
cytogenetic analysis in mycosis fungoides and
Sézarysyndrome. Diagnostic and prognostic
implications. J Clin Invest 65:1440—1448,1980. immunosuppressive therapy: An appraisal. Clin
7. Scheffer E, Meijer CJLM, van Vloten WA:
Dermatopathic lymphadenopathy and lymph
node involvement in mycosis fungoides. Cancer
45:137—148,1980.
8. Whang-Peng J, Bunn PA Jr. Knutsen T, et
al: Clinical implications of cytogenetic studies
in cutaneous T-cell lymphoma (CTCL). Cancer
50:1539—1553, 1982.
9. Blayney DW, Jaffe ES, Fisher RI, et al: The
human T-cell leukemia/lymphoma virus, lym
phoma, lytic bone lesions, and hypercalcemia.
Ann Intern Med 98:144—151, 1983.
10. Solomon A: Retroviruses and lymphopro
liferative disease. Dermatol Clinics 3:615—627,
1985.
11. Basset F, Chollet 5, Ferrans V. et al: His
tiocytosis X, in Thiers B, Dobson R (eds): The
Pathogenesis of Skin Disease. New York,
Churchill-Livingstone,
1985,pp 499—515.
12. Kragballe K, Zachanae H, Herlin T, et al:
Histiocytosis X—An immune deficiency dis
ease? Studies on antibody-dependent monocyte
VOL. 36, NO. 3 MAY/JUNE1986
the presence of an underlying tumor has
been established. These signs may result
either from the physical presence of tumor
cells in the skin or from presumed meta
bolic effects of tumor cells located at vis
ceral sites. Occasionally, skin involvement
in cancer patients is biologically unrelated
to the tumor but is instead part of a well
defined inherited syndrome featuring an
increased incidence of internal cancer.
Whatever the association, inspection of the
skin remains an essential part of the com
plete physical examination.
mediatedcytotoxicity.
Br J Dermatol 105:13—
18, 1981.
13. Nesbit ME Jr, O'Leary M, Dehner LO, et
al: The immune systems and the histiocytosis
syndromes. Am J Pediatr Hematol Oncol 3:141
149, 1981.
Dobson R (eds): The Pathogenesis of Skin Dis
pp 459—474.
15. Lozada F, Silverman S Jr, Migliorati CA,
tunistic infections in the acquired immuno
deficiency syndrome (AIDS): Findings in 53
homosexual men with Kaposi's sarcoma. Oral
Surg 56:491—494,1983.
16. Gange R, Jones E: Kaposi's sarcoma and
Exp Dermatol 3:135—146,1975.
17. Burg 0, Kaudewitz P, Klepzig K, et al:
CutaneousB-celllymphoma. DermatolClinics
3:689—704, 1985.
18.LagiosMD, WestdahlPR, Rose MR, etal:
Paget's disease of the nipple: Alternative man
agement in cases without or with minimal extent
of underlying breast carcinoma. Cancer 54:545—
551, 1984.
19. Nadji M, Morales AR, Girtanner RE, et at:
Paget's disease of the skin: A unifying concept
of histogenesis. Cancer 50:2203—2206, 1982.
20. Salem OS, Steck WD: Cowden's disease
(multiple hamartoma and neoplasia syndrome).
A case report and review of the English liter
ature. J Am Acad Dermatol 8:686—696,1983.
21. Gardner E, Richards R: Multiple cutaneous
and subcutaneous lesions occurring simulta
neously with hereditary polyposis and osteo
matosis. Am J Hum Genet 5:139—147,1953.
22. Perzin KA, Bridge MF: Adenomatous and
carcinomatous changes in hamartomatous
147
polyps of the small intestine (Peutz-Jeghers
syndrome): Report of a case and review of
the literature. Cancer 49:971—983,1982.
23. Burdick D, Prior JI: Peutz-Jeghers syn
drome: A clinicopathologic study of a large
family with a 27-year follow-up. Cancer
50:2139—2146, 1982.
24. Daniel ES, Ludwig SL, Lewin KJ, et al:
Cronkhite-Canada syndrome: An analysis of
clinical and pathologic features and therapy in
55 patients. Medicine 61:293—309, 1982.
25. Housholder MS, Zeligman I: Sebaceous
neoplasms associated with visceral carcinomas.
Arch Dermatol 116:61—64,1980.
26.Parnell DD, JohnsonSA: Tylosis palmaris ciency syndrome. N EngI J Med 311:354—358,
et plantaris: Its occurrence with internal malig
nancy. Arch Dermatol 100:7—9,1969.
27. Khairi MR. Dexter RN, Burzynski NJ, et
al: Mucosal neuroma, pheochromocytoma, and population-based study. N Engl J Med 307:
medullary thyroid carcinoma: Multiple endo
crine neoplasia type 3. Medicine 54:89—112,
1975.
28. Riccardi VM: Von Recklinghausen neuro
fibromatosis. N Engl J Med 305:1617—1627, 43. Weller TH: Varicella and herpes zoster:
1981.
29. Rosen FS, Cooper MD, Wedgewood RJP:
The primary immunodeficiencies. N EngI J Med
311:235—242,300—310,1984.
30. Pearse A, Welbourn R: The APUDomas.
Br J Hosp Med 10:617—624,1973.
31. Kassis V. Sondergaard J: Hypertrichosis
lanuginosa. Scm Dennatol 3:282—286,1984.
32. Andreev V: Malignant acanthosis nigricans.
Scm Dermatol 3:265—272,1984.
33. Curry SS, King LE: The sign of Leser
Trélat.Arch Dermatol 116:1059—1060,1980.
34. Witkowski JA, Parish LC: Bazex's syn
drome: Paraneoplastic acrokeratosis. JAMA
248:2883—2884, 1982.
35. Pecora AL, Landsman L, Imgrund SP, et
al: Acrokeratosis paraneoplastica (Bazex's
syndrome). Arch Dermatol 119:820—826, et al: Bullous diseases and malignancy. Semin
1983.
Bibliography
Braverman IM: Skin Signs of Systemic Disease,
ed 2. Philadelphia, WB Saunders Co, 1981.
148
36. Cuzick J, Harris R, Mortimer PS: Palmar
keratoses and cancers of the bladder and lung.
Lancet 1:530—533, 1984.
37.KyleRA: Amyloidosis: Part2.mt J Der
matol 20:20—25,1981.
38. Kyle RA: Amyloidosis: Part 3. Int J Der
matol 20:75—80,1981.
39. Cooper PH, Innes DJ Jr, Greer KE: Acute
febrile neutrophilic dermatosis (Sweet's syn
drome) and myeloproliferative disorders. Can
cer5l:1518—1526, 1983.
40. Klein RS, Harris CA, Small CB, et al: Oral
candidiasis in high-risk patients as the initial
manifestation of the acquired immunodefi
1984.
41. Ragozzino MW, Melton U III, Kurland
LT, et al: Risk of cancer after herpes zoster: A
393—397,1982.
42. Riegelman R: Cancer and herpes zoster
(Letter to the Editor). N Engl J Med 307:1706—
1707, 1982.
Changing concepts of the natural history, con
trol, and importance of a not-so-benign virus.
N Engl J Med 309:1362—1368, 1434—1440,
1983.
44. Callen JP, Hyla JF, Bole GG Jr, et al: The
relationship of dermatomyositis and polymyo
sitis to internal malignancy. Arch Dermatol
116:295—298,1980.
45. Amin R: Hypertrophic osteoarthropathy
without radiographic evidence of new bone for
mation. Postgrad Med J 59:54—56, 1983.
46. Myerhoff J: Lyme disease. Am J Med
75:663—670, 1983.
47.Gammel JA:Erythema gyratum repens: Skin
manifestations in a patient with carcinoma of
the breast. Arch Dermatol 66:494—505, 1952.
48. Jablonska 5, Chorzelski T, Blaszczyk M,
Dennatol 3:316—326,1984.
Callen JP: Cutaneous Aspects of Internal Dis
ease. Chicago, Year Book Medical Publishers,
Inc. 1981.
CA-A CANCER JOURNAL FOR CLINICIANS