Cutaneous Signs of Paraneoplastic Disease - Dermatology Rounds ...

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DERMATOLOGY
Rounds
Cutaneous Signs of Paraneoplastic Disease
By TRACEY BROWN-MAHER, MD and LINDA MOREAU, MD, FRCPC
Cutaneous paraneoplastic syndromes represent skin conditions that herald underlying malignant disease.
Recognition of these syndromes allows earlier detection of malignancy, since they may represent the
first presentation in 1% of patients or indicate recurrence. 1 However, there is controversy regarding the
differentiation of dermatological disease in patients with malignant and nonmalignant conditions. 1
In 1976, Curth indicated that before a skin disease could be called paraneoplastic dermatosis, 6 criteria
were required:
• both skin and malignant conditions start at approximately the same time
• both conditions follow a parallel course
• in syndromes, neither the onset nor the course of either condition is dependent on the other
• a specific tumour occurs with a specific skin manifestation
• the dermatosis is not common in the general population
• a high degree of association between the two conditions is noted. 2
Currently, only 2 of the 6 criteria are needed to declare that a skin condition is a paraneoplastic
dermatosis. 2
This issue of Dermatology Rounds reviews the classic paraneoplastic dermatoses. The incidence of
the underlying malignancy varies with the specific dermatosis and the aggressiveness with which a tumour
work-up is pursued should reflect this variation. Generally, the onset of paraneoplastic cutaneous lesions
is more rapid than in benign conditions. The pathophysiology of tumours and skin disease is not always
known; in some cases, tumour-derived growth factors play a role. 1 The paraneoplastic dermatoses can be
categorized by underlying pathophysiology or malignancy or, as in this review, by clinical presentation
(Table 1).
Lesions secondary to deposition of substances in the skin
These lesions include icterus, hemochromatosis, melanosis, plane xanthoma, and systemic amyloidosis.
Icterus is usually a late manifestation secondary to an obstruction of the common bile duct or intrahepatic
obstruction. Extrahepatic obstruction may be caused by cancer of the gallbladder, pancreas, bile duct, or
adjacent bowel. 3
Hemochromatosis is a genetic disorder of increased intestinal iron absorption leading to iron deposition in
tissues, including the skin. Patients may present with infertility, arthralgias, congestive heart failure, and the
classic “bronze diabetes.” One-third of untreated patients may develop hepatocellular carcinoma. 3
Melanosis is caused by the abnormal deposition of melanin in tissue, including the skin (diffuse graybrown
pigmentation) and most organs of the body. Malignant tumours of the pituitary gland may secrete
corticotropin (ACTH), leading to a mild darkening of the skin. Diffuse melanosis and melanuria may be
caused by metastatic malignant melanoma. Melanosis presents late in the disease course and is a poor
prognostic sign. 3
Plane xanthoma is the most common type of xanthoma associated with malignant disease (usually diffuse
xanthoma and multiple myeloma). They present as yellow-brown papules or plaques on the eyelids and
periorbital skin, back, or upper shoulders, 1 with or without purpura. Xanthomas have also been linked to
other malignancies, including myelocytic/myelomonocytic leukemia, diffuse histiocytic lymphoma, and
cutaneous T-cell lymphoma. Affected patients may be normolipemic or have hyperlipoproteinemia. 3
Primary systemic amyloidosis (AL protein) exhibits cutaneous lesions that include marcroglossia, pinch
purpura, waxy or purpuric papules, plaques or nodules (often on face, neck, or scalp), or diffuse infiltration
of palms or scalp. Systemic amyloidosis may be associated with multiple myeloma. In addition, familial
cutaneous lichenoid amyloidosis (hyperpigmented papules on extensor surfaces and back) has been reported
in a kindred with multiple endocrine neoplasia 2a (MEN 2a or Sipple syndrome). 3-4 MEN 2a includes
medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. 3
Vascular and blood abnormalities
Vascular and blood abnormalities associated with malignancy include several nonspecific signs such as
palmar erythema, flushing, small-vessel vasculitis, telangiectasia, cutaneous ischemia, and thrombophlebitis.
Palmar erythema is classically seen in liver failure, but may be secondary to liver tumours.
2 0 0 6 Volume 5, Issue 2
TM
AS PRESENTED IN THE ROUNDS OF
THE DIVISION OF DERMATOLOGY,
MCGILL UNIVERSITY HEALTH CENTRE
Members of the
Division of Dermatology
Denis Sasseville, MD, Director
Editor, Dermatology Rounds
Alfred Balbul, MD
Alain Brassard, MD
Judith Cameron, MD
Wayne D. Carey, MD
Ari Demirjian, MD
Anna Doellinger, MD
Odette Fournier-Blake, MD
Roy R. Forsey, MD
William Gerstein, MD
David Gratton, MD
Miriam Hakim, MD
Manish Khanna, MD
Raynald Molinari, MD
Linda Moreau, MD
Brenda Moroz, MD
Khue Huu Nguyen, MD
Elizabeth A. O’Brien, MD
Wendy R. Sissons, MD
Marie St-Jacques, MD
Beatrice Wang, MD
Ralph D. Wilkinson, MD
Centre universitaire
de santé McGill
McGill University
Health Centre
McGill University Health Centre
Division of Dermatology
Royal Victoria Hospital
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The editorial content of
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solely by the Division of Dermatology,
McGill University Health Centre.

Table 1: Classification of cutaneous signs of
paraneoplastic disease
Lesions secondary to Icterus, hemochromatosis
deposits in skin Melanosis, systemic amyloidosis
Xanthoma
Vascular and blood Flushing, palmar erythema,
abnormalities Telangiectasia
Small-vessel vasculitis
Cutaneous ischemia,
Thrombophlebitis
Collagen vascular SLE, dermatomyositis,
diseases Scleroderma
Bullous disorders Bullous and cicatricial
pemphigoid
Pemphigus vulgaris
Dermatitis herpetiformis
Pemphigoid gestationis
Epidermolysis bullosa acquisita
Linear IgA dermatosis
Porphyria cutanea tarda
Infections and Herpes zoster, herpes simplex
infestations Scabies, bacterial, fungal
Disorders of Acanthosis nigricans,
keratinization Acquired ichthyosis
Tripe palm,
Palmoplantar hyperkeratosis,
Erythroderma paraneoplastica,
Acrokeratosis of Bazex
Skin tumours and Muir-Torre syndrome,
internal malignant Gardner’s syndrome,
disease Cowden disease, MEN 2b,
Neurofibromatosis
Hormone-related Hirsutism, gynecomastia,
changes Cushing’s syndrome
Disorders associated Basal cell nevus syndrome
with primary skin Arsenical manifestations
cancers
Other disorders Pruritus,
associated with Erythema gyratum repens,
internal malignant Sweet syndrome
disease Hypertrichosis lanuginosa acquisita,
Necrolytic migratory erythema,
Peutz-Jeghers syndrome,
Sign of Leser-Trelat,
Clubbing
Direct tumour Cutaneous metastases
involvement Carcinoma erysipelatodes and
en cuirasse,
Sister Mary-Joseph nodule,
Paget’s, extramammary
Paget’s disease
Hematologic DIC, cryoglobulinemia,
malignancy Leukemia cutis,
Adult T-cell leukemia/lymphoma
Lymphomatoid papulosis
CTCL, Sezary syndrome,
B-cell lymphoma
Adapted from 1,2,3
Flushing of central face and upper trunk when accompanied by
wheezing, abdominal pain, and diarrhea suggests carcinoid syndrome.
2 Flushing in pheochromocytoma and systemic mastocytosis
is secondary to the release of vasoactive substances.
Harlequin syndrome consists of unilateral sweating and flushing
associated with a contralateral lung cancer invading the spine.
Pancoast’s syndrome and Horner’s syndrome may also be present.
3
Small-vessel vasculitis (leukocytoclastic) can rarely be seen with
malignant neoplasms, such as bronchial squamous cell carcinoma,
renal cell carcinoma, leukemia and lymphoma. 3 It presents
as palpable purpura on the lower extremities.
Telangiectasia may be localized or generalized. Localized
grouped telangiectasia on the anterior chest may be a marker
for breast cancer. Generalized telangiectasia can be a presenting
feature of carcinoid tumour, a marker for ataxia-telangiectasia
(increased risk of lymphoma, breast cancer) or collagen vascular
diseases that are associated with an increased risk of cancer. 3
Digital ischemia, Raynaud’s phenomenon, or gangrene can be
seen with neoplasms such as carcinoma of the pancreas, stomach,
small bowel, ovary, and kidney, as well as with leukemia
and lymphoma. 3 Thrombophlebitis may be isolated or associated
with internal malignant disease; multiple migratory lesions
(migratory thrombophlebitis) are associated with occult disease,
eg, gastric carcinoma (known as Trousseau’s sign), islet cell
pancreatic tumours, or tumours of the ovary, prostate, lung,
liver, or bowel. 3
Collagen vascular diseases
Systemic lupus erythematosus (SLE) and scleroderma are
rarely associated with malignancy; SLE is associated most often
with lymphoma or thymoma, and scleroderma with lung carcinoma.
Up to 25% of cases of dermatomyositis are associated
with an internal solid organ cancer, 1-2 usually ovarian, pulmonary,
pancreatic, gastric, colorectal, or lymphoma. Dermatomyositis
may occur before the cancer; so age-appropriate
screening should be undertaken. 2 Children with dermatomyositis
do not have an increased risk of malignancy. 3
Bullous disorders
Several autoimmune and acquired blistering diseases are
associated with malignant disease. These include bullous and
cicatricial pemphigoid, pemphigus vulgaris, and paraneoplastic
pemphigus, dermatitis herpetiformis, pemphigoid gestationis,
epidermolysis bullous acquisita, and porphyria cutanea tarda.
Bullous pemphigoid (BP) presents usually in the elderly with
tense bullae on erythematous plaques or normal skin. Cicatricial
pemphigoid also presents with bullae, but has a tendency to
scar. Mucous membranes are more involved, but bullae may
also be seen on the skin, especially of the face and neck. The
association of BP with malignancy is still controversial; there are
anecdotal reports of improvement in bullous lesions with
tumour treatment, which may indicate a causal relationship. 3
Antiepiligrin cicatricial pemphigoid does have an increased risk
of solid organ tumours, with a relative risk of approximately
6.8. 3 Autoantibodies target components of the hemidesmosome
at the dermoepidermal junction: BPAG1 and BPAG2 in bullous
pemphigoid, and BPAG2, alpha6beta4-integrin and laminin 5 in
cicatricial pemphigoid.
Pemphigus vulgaris is another bullous disorder in which
autoantibodies are directed against desmoglein-3 on keratinocyte
desmosomes. It presents with flaccid mucocutaneous
bullae and erosions. It has been associated with Hodgkin’s disease,
2 but much less so with solid tumours, although lung cancer
has been reported. 3 Paraneoplastic pemphigus is clinically
and pathologically distinct from other forms of pemphigus, and
features intractable stomatitis, erythema multiforme-like

lesions, and pemphigus blisters. Reported malignancies include
lymphoma, chronic lymphocytic leukemia, Castleman’s disease,
thymoma, sarcoma, and Waldenstrom’s macroglobulinemia. 2
Dermatitis herpetiformis presents with pruritus and crusts on
elbows, knees, and buttocks. The vesicles are often not seen
because they are fragile and broken on presentation. Dermatitis
herpetiformis is associated with intestinal lymphoma of the diffuse
histiocytic type and males have a higher relative risk than
females. 3 Dermatitis herpetiformis may be seen with celiac disease,
other gluten-sensitive enteropathies, and other autoimmune
disorders. 3
Pemphigoid gestationis (antibody against BPAG2) presents as
pruritic urticarial plaques and bullae that begin on the
abdomen and usually occur in the third trimester of pregnancy.
The presentation is similar to bullous pemphigoid. The eruption
usually remits after delivery, but often requires treatment
with systemic corticosteroids. There have been reports of germ
cell tumours and hydatiform moles in association with pemphigoid
gestationis. 3
Epidermolysis bullosa acquisita (EBA) is an acquired blistering
disorder with autoantibodies against collagen VII of the fibrils
that anchor basal cells to the dermis. Blisters arise on acral areas
in response to trauma, and heal with scars and milia. Most cases
begin in middle age and are not associated with malignancy.
However, on rare occasions, EBA has accompanied multiple
myeloma, amyloidosis, and bronchial carcinoma. 3
Linear immunoglobulin A (IgA) dermatosis presents as annular
or grouped papules, vesicles, and bullae symmetrically distributed
on extensor surfaces. It is caused by antibodies against
BPAG2. Linear IgA dermatosis has been reported with lymphoma,
chronic lymphocytic leukemia, myeloma, bladder and
esophageal carcinoma, and hydatiform mole. 3
Porphyria cutanea tarda, which may be acquired or familial,
presents as skin fragility, bullae, and erosions on sun-exposed
areas. 1 It has a markedly increased risk of malignancy, particularly
hepatocellular carcinoma (7% of patients) and other
tumours such as lung, colon, and lymphoma. 1
Infections and infestations
Rarely, systemic bacterial, fungal, or yeast infections, or
severe scabetic infestation occur in profoundly immunocompromised
patients. Patients with leukemia/lymphoma are at a
higher risk of developing herpes zoster, but herpes zoster is not
a marker for malignant disease. However, disseminated herpes
zoster is frequently associated with underlying immunosuppression
or malignancy. Additionally, development of herpes
zoster in a previously treated lymphoma patient may signify
recurrence of lymphoma. While typical herpes simplex is not an
indicator of malignancy, chronic extensive, ulcerative herpes
simplex with tissue destruction warrants investigation. Generalized
cutaneous herpes simplex and disseminated systemic herpes
simplex are also associated with advanced lymphoma and
leukemia. 3
Disorders of keratinization
Several disorders of keratinization have classically been
associated with malignancy. These include acanthosis nigricans,
acquired ichthyosis, palmar hyperkeratosis, tripe palms, erythroderma,
and paraneoplastic acrokeratosis of Bazex.
Acanthosis nigricans (AN) of malignant disease has a rapid
onset and is progressive, but otherwise, it is indistinguishable
from the benign type. AN is characterized by skin hyperpigmentation
and thickening; dark brown, velvety plaques occur in
the axilla, groin, nuchal area, and other folds. Oral papillomatosis
is also another sign of malignant AN; it is seen in 30% of
cases 5 and consists of thickening or cobblestoning of the lips and
oral mucosa. Malignant AN is secondary to adenocarcinoma,
arising from the abdomen in 90% of the cases and from the
stomach in 60%. 5 The lung is the next most common source.
When associated with tripe palms, gastric cancer is the most
likely underlying carcinoma. 2 Other reported malignancies with
AN originate from the liver, uterus, breast, ovary, or the lymphatic
tissues (lymphoma and mycosis fungoides). 2 Histopathology
reveals hyperkeratosis and papillomatosis, without
acanthosis; therefore, AN is a misnomer. 5 Etiology is related to
tumour-secreted growth factors that increase levels of insulin
and/or insulin-like growth factor-1 receptors, leading to fibroblast
proliferation. 5
Acquired ichthyosis presents as rhomboidal scales with free,
slightly elevated margins on extensor surfaces, sparing the flexural
folds. 2 An abrupt onset in an older patient is suspicious for
malignancy. Frequently, a lymphoma is to blame; however, the
ichthyosis can precede the diagnosis of lymphoma by years. 3
Palmoplantar hyperkeratosis has 2 types, diffuse and punctate,
which are associated with malignant tumours. In 1958, Howel-
Evans reported tylosis (diffuse hyperkeratosis) in members of
two families; almost all developed esophageal carcinoma by age
65 years. 3 The tylosis occurred in childhood, while the onset of
malignancy was delayed. 1 Sporadic palmoplantar keratoderma
associated with solid organ tumours consists of yellow hyperkeratotic
plaques with surrounding red erythema. The keratoderma
has varied thickness and no sharp demarcations.
Underlying solid organ tumours are breast and/or ovarian carcinoma.
1,3 The second type, punctate, manifests as discrete hyperkeratotic
papules on the palms and soles. In this type, there is a
higher than expected risk of carcinoma of the breast and
uterus. 3 Arsenic intoxication may also induce punctate keratosis,
which is linked to an increased risk of solid organ tumours. 6
“Tripe palms”: The name stems from its similar appearance to
the gut lining of bovine species, so-called “tripe.” 2 It presents as
a corrugate, rugose thickening of the palms. The most common
cancers associated with tripe palms arise from the stomach and
lung. As stated above, tripe palms may be associated with AN.
Kebria et al reported its association with AN, the sign of Leser-
Trelat, and early-stage ovarian cancer; 7 however, when not associated
with AN, the most likely cancer is lung adenocarcinoma. 2
Erythroderma is an exfoliative dermatitis characterized by
widespread erythema and skin scaling. 2 Patients may have associated
hypothermia, with protein and electrolyte imbalances.
Erythroderma has many causes: pre-existing dermatoses, drug
reactions, and malignancy. 2 Malignant causes include leukemia
and lymphoma, specifically cutaneous T-cell lymphoma
(CTCL). Solid tumours (late stage) originate from the lung,
liver, prostate, thyroid, colon, pancreas, and stomach. Erythroderma
may resolve with treatment of the primary cancer. 2
Paraneoplastic acrokeratosis of Bazex is a symmetric hyperkeratosis
that affects hands, feet, ears, and nose. It has a psoriasiform
appearance, but with a more bluish hue when compared
with the pink colour of typical psoriasis. Early and severe nail
involvement is seen in 75% of cases. 2 Subungual hyperkeratosis,
flaky white nails, and nail shedding is common; distal digits are
red, fissured, and suppurative. Bazex syndrome is seen disproportionately
in males with squamous cell carcinomas of the
upper aerodigestive tract (pharynx, esophagus, tongue, lungs). 2
It precedes the cancer in approximately 67% of patients. 3
Retinoids can be used successfully to treat the syndrome, but

they have no effect on the underlying tumour. The best
treatment is radiation of the underlying tumour; it results
in improvement of the dermatosis, but nail dystrophy is
persistent. 2 Causation of this hyperkeratosis is unknown,
but theories include antigen cross-reactivity between
tumour and skin, or tumour-derived keratinocyte growth
factors. 2
Skin tumours and internal
malignant disease
Multiple cutaneous tumour syndromes are linked to
internal cancers; the most common are discussed below,
including Muir-Torre syndrome, Gardner syndrome,
Cowden disease, Peutz-Jeghers syndrome, mucosal neuroma
syndrome, and neurofibromatosis type 1.
Muir-Torre syndrome is an autosomal dominant syndrome
that was first described in the late 1960s and features sebaceous
tumours of the skin, keratoacanthomas, and visceral
neoplasms. 3 There are often multiple sebaceous tumours
on the face or trunk, but even a solitary sebaceous tumour
of the eyelid is a marker for Muir-Torre syndrome. 3 Visceral
neoplasms are found in the colon (with polyposis), larynx,
endometrium, and lymphatic system. The defect is a
mutation in any of 4 mismatch repair genes, including
MLH1 on chromosome 3 or MSH2 on chromosome 2. 8
Gardner syndrome is also an autosomal dominant inherited
condition. The features are: intestinal polyps with a
high rate of malignant transformation; epidermoid cysts
(face, scalp, trunk); osteomatosis of the maxilla, mandible,
and cranial bones; and desmoid and other fibrous tumours
of the skin and subcutaneous tissue. 1,3,9 Aside from gastrointestinal
cancer associated with polyps, there is an
association with hepatoblastoma and nevoid basal cell carcinoma.
3 The defect is usually in the APC (adenosis polyposis
coli) gene. 3
Cowden disease is also known as multiple hamartoma
syndrome. This autosomal dominant condition features
multiple facial trichilemmomas, oral papillomatosis, and
acral keratoses and, less commonly, lipomas, hemangiomas,
neuromas, vitiligo, café-au-lait lesions, and acromelanosis. 3
There is an increased risk of breast and thyroid carcinoma,
as well as gastrointestinal polyposis and malignancy. The
mutation is in PTEN (phosphatase and tensin homolog)
tumour suppressor gene located on chromosome 10. 10
Peutz-Jeghers syndrome is another autosomal dominant
condition (mutation of STK11 on chromosome 19); 11 it
features cutaneous and mucosal hyperpigmented macules,
gastrointestinal polyposis, and carcinoma. Macules
are present at birth or infancy and fade in adolescence.
Mucosal lesions persist for life; they are grouped around
the mouth, eyes, and nostrils and found on acral areas or
periumbilical skin. The most common associated cancer is
duodenal carcinoma. 3,9 Granulosa thecal cell tumours are
also present in about 20% of females with precocious
puberty. 3
Mucosal neuroma syndrome is a variant of multiple
endocrine neoplasia (MEN) type 2, classified as either
MEN 2b or MEN 3. 3 It features oral, nasal, upper gastrointestinal
tract, and conjunctival neuromas, as well as
medullary thyroid carcinoma and pheochromocytoma.
Neuromas usually precede cancer, but vigilance is essential
because medullary thyroid carcinoma is the major cause of
death and has been reported in childhood. 3 Other cuta-
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neous features are marfanoid habitus, kyphoscoliosis,
lentigines, café-au-lait lesions and blubbery lips. 3
Neurofibromatosis type 1 (Von Recklinghausen) has multiple
associated tumours, including malignant schwannoma,
fibrosarcoma, rhabdomyosarcoma, Wilm’s tumour,
and acute or chronic myelogenous leukemia. There is also
an increased risk of ocular melanoma. Neurofibromatosis
is autosomal dominant and presents with some or all of
the following: café-au-lait macules, axillary freckling,
neurofibromas, Lisch nodules (iris hamartomas), and
osseous lesions. 3
Hormone-related changes
Malignant tumours can release hormones into the systemic
circulation that, in turn, can produce cutaneous
manifestations. These manifestations are not tumour-specific,
but hormone-specific, in that they occur in response
to the hormone excess regardless of etiology. For example,
increased androgens may cause hirsutism secondary to
tumours of the testes or ovaries. Gynecomastia in males
may be secondary to increased levels of estrogen produced
by tumours of the testes or lung. Signs of Cushing’s syndrome
(ie, buffalo hump, edema, truncal obesity, acne, and
striae) are secondary to excessive endogenous ACTH production,
usually from oat cell lung or pancreatic cancer,
pheochromocytoma, or medullary thyroid carcinoma. 2
Disorders associated with
primary skin cancers
Basal cell nevus syndrome (Gorlin-Goltz syndrome) consists
of multiple basal cell carcinomas, jaw cysts, palmoplantar
pitting, skeletal abnormalities, and increased risk of
other malignant disease. The most common tumour is
medulloblastoma, but others include astrocytomas,
meningiomas, and craniopharygiomas. This syndrome is
secondary to mutations in the patched gene (PTCH) on
chromosome 9. 3
Chronic arsenic intoxication has multiple cutaneous side
effects, including hypopigmentation in areas of hyperpigmentation
(“rain drops on a dusty road”), palmoplantar
keratoses, Bowen’s disease, and basal cell and squamous
cell carcinomas, often in sun-protected areas. 6 Associated
internal malignancies include bladder and lung cancers,
angiosarcoma of the liver, lymphoma, as well as nasopharyngeal,
esophageal, gastric, colonic, renal, and prostatic
carcinomas. 6
Other disorders associated with
internal malignant disease
This “catch-all” category includes both non-specific
and specific cutaneous signs of paraneoplastic disease that
do not fit easily into another category. The entities discussed
are: pruritus, erythema gyratum repens, Sweet syndrome,
hypertrichosis lanuginosa acquisita, necrolytic
migratory erythema, clubbing, and the sign of Leser-Trelat.
Pruritus is a nonspecific marker of malignant disease. It
occurs in apparently normal skin; it is usually generalized
and most commonly associated with lymphoma or
leukemia. In Hodgkin’s disease, pruritus begins on the legs
as a continuous burning. Unfortunately, pruritus is usually
a late sign and severe pruritus signifies a poor prognosis.
Severe pruritus is also seen in Fanconi’s anemia, myeloma,
pancreatic, and gastric tumours. 3
T

Erythema gyratum repens is a figurate erythema demonstrating
rapidly migrating concentric rings of erythema
with a trailing scale, found on the trunk and proximal
extremities. 2 Described as a “wood-grain” appearance, the
bands move approximately 1 cm/day. This rare eruption is
seen with carcinomas of the breast, lung, bladder, prostate,
cervix, stomach, esophagus, and multiple myeloma. Skin
changes precede the tumour 80% of the time. 2 Tumour
removal results in resolution and the disease parallels the
underlying course of the malignancy. 5
Sweet syndrome typically exhibits skin lesions of edematous
red-blue papules or nodules that coalesce to form
irregular, but well-defined plaques. These plaques appear
suddenly and have a pseudo-vesicular appearance. The
lesions are tender and painful and usually found on the face
and neck, but are also seen elsewhere. Fever and neutrophilia
are often present. 1 Sweet syndrome may be idiopathic or
associated with infection, drugs, or malignancy. Generalized,
mucosal, bullous, or pyoderma-gangrenosum-like
forms are more common in malignancy-associated forms. 3
Malignancy-associated Sweet syndrome is most likely seen
with acute myelogenous leukemia, as well as other lymphoproliferative
disorders. 1-2 Solid organ tumours have
been noted, but are rare. 3
Hypertrichosis lanuginosa acquisita or “malignant down” 1
is a rare, acquired, excessive growth of lanugo hair. The
skin, especially on the face and ears, is covered with soft,
downy hairs. Hypertrichosis lanuginosa acquisita is caused
by drugs (steroids, phenytoin, diazoxide, streptomycin,
penicillamine, cyclosporine, minoxidil), anorexia nervosa
and, most frequently, malignancy. The malignant type has
a rapid onset and progression. Causative tumours are
found in the lung (most commonly), colon, rectum, bladder,
pancreas, gallbladder, uterus, breast, and lymphatic tissues.
1-2
Necrolytic migratory erythema or glucagonoma syndrome
is a reactive erythema that is a marker for an alpha-2glucagon-producing
islet cell tumour of the pancreas. 2
Eruptions begin as erythematous patches in the groin and
spread to the thighs, buttocks, perineum, and face. This is
followed by scaling, vesicles, pustules, and bullae. These
heal over a period of 1 to 2 weeks, leaving indurated,
hyperpigmented scars. The course waxes and wanes. 2
Other clinical features are glucose intolerance, high serum
glucagon levels, weight loss, anemia, diabetes, mental status
changes, and venous thrombosis. 5 Diagnosis is made by
measuring plasma glucagon levels. Most patients have
metastatic disease at presentation. Eruptions may be treated
with octreotide that affects the somatostatin receptors
in the skin. Surgery or chemotherapy directed at the
tumour also leads to clinical improvement. 5 Median survival
is 2 years.
Clubbing involves an increased convexity of the nail and
soft tissue enlargement of the tips of the fingers and toes.
There is a loss of the 15° to 20° angle between the downward
curve of the proximal nail and the adjacent proximal
nail fold. 3 It is associated with chronic lung disease, as well
as neoplasms of the chest, such as bronchogenic carcinoma,
mesothelioma, Hodgkin’s disease of the lung, intestinal
lymphoma, and solid tumours metastatic to the
thorax. 3,5 Clubbing accompanied by subperiosteal new
bone formation is called hypertrophic osteoarthropathy. 5
Affected patients complain of bone pain, especially at
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wrists, elbows, knees, and ankles, with associated symmetrical
and firm swelling and tenderness. Epiphyses are
spared in the malignant form. On x-ray, a thin opaque line
of new bone formation is seen separated from the underlying
dense cortex by a narrow radiolucent band. 5 At least
90% of the cases of hypertrophic osteoarthopathy in
adults occur in patients who have or will develop a malignancy.
5 The most frequent tumour is non-small-cell lung
cancer. 3,5
The sign of Leser-Trelat refers to the sudden eruption of
multiple seborrheic keratoses in association with malignant
disease. The validity of this paraneoplastic dermatosis
has been contested in the literature because seborrheic
keratoses are common and so are the carcinomas reported
with this sign. 2,5,9 However, there are multiple reports of
internal solid organ tumours, and an association with palmoplantar
hyperkeratosis and AN. 3 The most frequently
reported malignancy is adenocarcinoma of the stomach or
colon. 1,2
Direct tumour involvement
Direct tumour involvement in the skin is an undeniable
sign of internal malignancy, taking the form of metastases
or a direct extension of the tumour.
The incidence of cutaneous metastases is < 10% 1 and
lesions result from lymphatic extension or hematologic
spread. A cutaneous metastasis is usually a rapidly growing,
erythematous, dermal, or subcutaneous mass. In
women, the following tumours are likely to have cutaneous
metastases: breast, melanoma, and ovarian cancer;
for men: melanoma, lung, colon, oral cavity, larynx and
kidney. 12 There are a few classic presentations of cutaneous
metastases. A Sister-Mary-Joseph nodule is a duskyred
umbilical nodule metastatic from an intra-abdominal
source (colon, stomach, ovary, pancreas, or breast). 12 Carcinoma
erysipelatoides is an erysipelas-like eruption on the
breast that represents metastatic inflammatory breast cancer.
12 Carcinoma en cuirasse is another variant of metastatic
breast cancer and consists of leather-like skin changes
that represent sclerosing breast cancer. Breast cancer can
also metastasize to the anterior chest wall as nodules. 12
Direct extension of a tumour occurs in Paget’s and
extramammary Paget’s disease. Paget’s disease presents as
an insidious unilateral nipple/areola eczema that is
indurated and well-demarcated. It is not painful, but it
may be pruritic and exudative or ulcerative. Paget’s disease
extends from an underlying intraductal carcinoma of the
breast. Extramammary Paget’s disease presents as shiny,
erythematous plaques on anogenital skin, also with an
insidious onset. Underlying extramammary Paget’s is
usually a genitourinary or gastrointestinal (rectal) adenocarcinoma.
1,3
Hematologic malignancy
There are many cutaneous signs of hematologic
malignancy, including nonspecific and specific signs. Nonspecific
signs include disseminated intravascular coagulation
(DIC) and cryoglobulinemia. DIC presents as
bleeding and clotting concomitantly in a patient with cancer,
often leukemia. The skin may show vasculopathic
changes with necrosis and there may be obvious bleeding.
Cryoglobulinemia presents as retiform purpura with or
without necrosis or ulceration, often on the lower legs.
T

Type I consists of a monoclonal cryoglobulin (IgM or IgG),
while Type II has a mixed picture with monoclonal IgM and
polyclonal IgG. Both types may be associated with lymphoproliferative
disorders; Type I is associated with macroglobulinemia
and myeloma and Type II with leukemia and lymphoma. 3
Leukemia cutis is a specific sign of leukemia; that is, biopsy of a
lesion will demonstrate a leukemic infiltrate. It presents as multiple,
yellow-pink, infiltrated papules and nodules, scattered on
the body. 1 They are abrupt in onset, extremely pruritic, and
resistant to treatment. An affected patient will also have signs
and symptoms of pancytopenia, such as infections, bruising, or
dyspnea. Treatment of the leukemia with chemotherapy or total
body electron beam irradiation may relieve the symptoms.
Acute myelogenous leukemia and hairy cell leukemia are the
most common leukemias to present in this manner. Leukemia
cutis is a poor prognostic sign. 3 Adult T-cell leukemia/lymphoma
is a neoplasm of CD+4 cells; it also presents as violaceous
papules, which are located mainly on the trunk. Similarly,
lymphomatoid papulosis, a low-grade T-cell lymphoma, presents
as recurrent, polymorphous crops of brown papules that
remit spontaneously over 2-to-8 week periods.
Cutaneous T-cell lymphoma (CTCL) is usually insidious in
onset, with psoriasiform plaques that persist for years. These
patients are usually older and the lesions occur first in nonexposed
areas; later, nodules may develop. Sezary syndrome is a
rare leukemic variant of CTCL that presents as an erythroderma
with lymphadenopathy or “red man syndrome.” Patients
appear ill, with fever, rigors and red, thick skin. 3 B-cell lymphoma
often presents as a solitary, plum or dusky-colored, infiltrated
nodule. It may be asymptomatic or associated with
constitutional symptoms. Solitary cutaneous lesions are usually
treated with radiotherapy alone. 3
Conclusion
There are many specific and non-specific cutaneous signs of
paraneoplastic disease. As physicians, it is important to recognize
these in order to institute prompt investigations for occult
malignancy. 2 This can be accomplished by a thorough history
and physical examination, with age- and symptom-appropriate
screening. Failure to identify these cutaneous clues will delay
diagnosis and treatment of cancer, and have an impact on
patient morbidity and mortality. Therefore, it is always important
to consider paraneoplastic dermatoses in the differential
diagnosis of eruptive or treatment-resistant dermatoses. 2
References
1. Sabir S, James W, Schuchter LM. Cutaneous manifestations of cancer
(melanoma and other skin neoplasms). Cur Opin Oncol 1999;11(2):139-
48.
2. Boyce S, Harper J. Paraneoplastic dermatoses. Dermatol Clin 2002;20(3):
523-32.
3. McLean DI, Haynes HA. Cutaneous Manifestations of Internal Malignant
Disease: Cutaneous Paraneoplastic Syndromes. In: Freedberg IM,
Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, eds. Fitzpatrick’s
Dermatology in General Medicine, Vol 2. 6th Ed. New York: McGraw-Hill;
2003:1783-96.
4. Black MM, Albert S. Amyloidosis. In: Bolognia JL, Rapini RP, Jorizzo JL,
eds. Dermatology. Vol.1. London: Mosby; 2003:659-67.
5. Kurzrock R, Cohen PR. Cutaneous paraneoplastic syndromes in solid
tumours. Am J Med 1995;99:662-71.
6. Maloney ME. Arsenic in dermatology. Dermatol Surg 1996;22:301-4.
7. Kebria MM, Belinson J, Kim R, Mekhail TM. Malignant acanthosis nigricans,
tripe palms, and the sign of Leser-Trelat, a hint to the diagnosis of
early stage ovarian cancer: A case report and review of the literature.
Gynecol Oncol 2006; January 26, Epub ahead of print.
8. Horenstein MG, Prieto VG. Muir-Torre Syndrome. eMedicine 2005;
http://www.emedicine.com/DERM/topic275.htm. Accessed: March 31,
2006.
9. Braverman IM. Geriatric Dermatology, Part II. Skin manifestations of
internal malignancy. Clin Ger Med 2002;18(1):1-19.
10. Miller, C. Cowden Disease. eMedicine 2005; http://www.emedicine.
com/derm/topic86.htm. Accessed: March 31, 2006.
11. Carethers JM. Peutz-Jeghers Syndrome. eMedicine 2003; http://www.
emedicine.com/med/topic1807.htm. Accessed: March 31, 2006.
12. Ahmed I. Cutaneous Metastases. In: Bolognia JL, Rapini RP, Jorizzo JL,
eds. Dermatology, Vol.2. London: Mosby; 2003:1953-56.
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