The clinical hallmark of Sweet’s syndrome is the presence of sharply demarcated, painful plaques on the face, neck, upper trunk, and extremities (Fig. 35-1). The surface of the plaques has a mammillated (nipple-like) appearance and often shows papulovesicles and pustules. Some lesions have a target-like appearance, and lesions on the lower extremities may resemble erythema nodosum. Oral mucous membrane and eye lesions can be seen. Skin lesions may develop at the site of minor skin trauma or needle-sticks in a small subset of patients. This phenomenon is called pathergy and is also seen in pyoderma gangrenosum and Behçet’s syndrome.

4. Are any laboratory abnormalities found in Sweet’s syndrome?

Leukocytosis. Ten thousand/mm³ is present in 60% of patients. Elevated sedimentation rates, increased numbers of segmented neutrophils, lymphopenia, anemia, thrombocytopenia, and increased C-reactive protein levels can be seen. A handful of cases have been reported with antineutrophilic cytoplasmic antibodies.

5. What cancers are associated with Sweet’s syndrome?

The most commonly associated malignancy is acute myelogenous leukemia, but chronic myelogenous leukemia, lymphocytic leukemia, T- and B-cell lymphomas, polycythemia, and, rarely, solid tumors also have been reported. There are no clinical or histopathologic differences between patients with and without associated cancer. Patients with persistent laboratory abnormalities, especially anemia, thrombocytosis, and thrombocytopenia, require close observation and thorough diagnostic evaluation.

Figure 35-1. Sweet’s syndrome demonstrating painful red indurated plaques on on the hand and arm.

(Courtesy of James E. Fitzpatrick, MD.)

Bae-Harboe Y-SC, Salter SA, Kimball A: Acute febrile neutrophilic dermatosis, eMedicine Online August 2009. Available at: http://www.emedicine.com.

6. Describe the clinical appearance of acanthosis nigricans.

Acanthosis nigricans appears as velvety, hyperpigmented, papillomatous, dirty-appearing skin. It is most frequently seen on the neck, axilla, groin, and dorsal hand surfaces. It is often associated with numerous skin tags and rarely affects mucosal surfaces (Fig. 35-2).

7. What clinical disease states are associated with acanthosis nigricans?

Acanthosis nigricans is a common skin finding, reported in 7.1% of children aged 11 to 16, and is frequently associated with obesity. It is commonly found in association with diabetes and other endocrinopathies with insulin resistance. Paraneoplastic acanthosis nigricans is rare and is most commonly associated with gastrointestinal cancer, especially gastric carcinoma. When associated with malignancy, it is usually abrupt in onset, severe, and may involve mucous membranes and palmar skin. Findings of tripe palms (resembling rugose bovine intestine) and the sign of Leser-Trélat, discussed later in this chapter, are often seen in patients with paraneoplastic acanthosis nigricans.

Figure 35-2. Acanthosis nigricans with hyperpigmented velvety skin lesions and small tags on the proximal thigh and groin.

Miller J, Rapini R: Acanthosis nigricans, eMedicine Online, June 2002. Available at: http://www.emedicine.com/derm/topic1.htm.

8. What is necrolytic migratory erythema?

This characteristic skin eruption is associated with an α-cell tumor of the pancreas. It presents as erythema with superficial pustules and erosions, typically involving the face, intertriginous skin, and acral extremities (Fig. 35-3). Alopecia, weight loss, glossitis, stomatitis, nail dystrophy, anemia, and diabetes are frequent associations. The eruption tends to migrate and desquamate, and most patients have elevated glucagon serum levels (glucagonoma syndrome). Skin biopsy shows necrosis of the upper portion of the epidermis and is usually diagnostic. This unique skin disease is probably related to low serum amino acid levels.

Figure 35-3. Glucagonoma syndrome. A, Erosive plaques on the leg. B, Atrophic glossitis.

Zettouni N, Harvey N: Glucagonoma syndrome, eMedicine Online, http://www.emedicine.com. May 2008.

9. What is hypertrichosis lanuginosa?

Hypertrichosis lanuginosa (malignant down) is an acquired excessive growth of lanugo hair. It usually begins on the face, neck, and ears and eventually can involve most hair-bearing skin. Glossitis is frequently an associated finding. If drug-related causes (such as minoxidil, diazoxide, and cyclosporine) can be excluded, there is a high association with internal malignancy. The most common associated cancers are lung, breast, gastrointestinal, and carcinoid. This rare cutaneous finding has also been reported in patients with anorexia nervosa.

10. What is Trousseau’s sign?

Trousseau’s sign consists of recurrent and migratory superficial thrombophlebitis, affecting both large and small cutaneous veins, which is associated with an internal cancer. Crops of oval to linear, erythematous, tender skin lesions are seen most commonly on the arms, legs, flanks, and abdomen. Thrombosis of internal veins can also occur and lead to a variety of symptoms. Men are more commonly affected. The most commonly associated cancers are lung and pancreatic carcinoma.

Superficial migratory thrombophlebitis can also be seen in Behçet’s syndrome and several coagulation factor deficiencies, including deficiencies of factor V Leiden, factor XII, antithrombin III, protein S and C, and plasminogen activating factor. Hypercoagulable states also occur in patients with anticardiolipin antibody syndrome, liver disease, nephritis, pregnancy, infection, and oral contraceptive use.

Varki A: Trousseau’s syndrome: multiple definitions and multiple mechanisms, Blood 110:1723–1729, 2007.

11. Describe the classical skin lesions of dermatomyositis.

The classic eruption of dermatomyositis is a reddish-purple erythema involving the face, typically the eyelids (heliotrope sign). The rash may be faint or quite inflamed and edematous (Fig. 35-4A).

Figure 35-4. Dermatomyositis. A, Facial erythema and heliotrope sign. B, Classic hand lesions and Gottron’s papules on the knuckles.

In addition to the facial rash, lesions on the scalp, neck, upper trunk, and extensor extremities are common. As the lesions mature, scaling and atrophy may develop. The erythema on the hands occurs over the knuckles rather than over the phalanges, as is typical of lupus erythematosus. Cuticular telangiectasias can be seen in both lupus erythematosus and dermatomyositis. Frequently, flat-topped, red-to-violaceous papules known as Gottron’s papules develop over the knuckles of patients with dermatomyositis (Fig. 35-4B).

The skin lesions of dermatomyositis may precede clinical or laboratory evidence by weeks, months, or years. A few patients may never develop muscle dysfunction. The skin lesions are notoriously resistant to topical steroid therapy.

12. Is dermatomyositis associated with internal malignancy?

The true incidence of malignancy associated with dermatomyositis is difficult to define. In 153 patients with dermatomyositis, an associated malignancy was found in 8.5% of the total and 19.2% of the men. The cancer may occur before, during, or after the development of dermatomyositis. Most of the reported cases have been in patients over age 40, although cases in children have been reported.

The type of cancer reported to be associated with dermatomyositis parallels the incidence of cancer found in the general population, though a slight increase in ovarian carcinoma has been noted. Patients newly diagnosed with dermatomyositis should have age-appropriate cancer screening, and female patients should be screened for ovarian carcinoma.

Callen JP, Wortman RL: Dermatomyositis, Clin Dermatol 24:363–373, 2006.

13. What are the three components of Sézary’s syndrome?

As originally described, Sézary’s syndrome represents a triad of findings: (1) cutaneous erythema, (2) lymphadenopathy, and (3) 10% to 15% atypical mononuclear cells in peripheral blood.

This syndrome is a subset of cutaneous T-cell lymphoma (CTCL). Erythroderma can also be associated with drug reactions, psoriasis, and other cutaneous diseases. Patients with Sézary syndrome frequently have intolerable itching, often to the point that they are suicidal. Lymphadenopathy, nail dystrophy, and hair loss are common associated features. The diagnosis is established by a skin biopsy showing CTCL, the presence of at least 15% atypical mononuclear cells in peripheral blood, and the typical clinical picture. Approximately 10% to 15% of patients with erythroderma will have an associated lymphoma or, more rarely, leukemia.

Foss F: Mycosis fungoides and the Sézary syndrome, Curr Opin Oncol 5:421–428, 2004.

14. What is paraneoplastic pemphigus?

Paraneoplastic pemphigus is a superficial blistering skin disease with a reported association with lymphoma, although a few cases are reported with solid tumors. The clinical picture may resemble pemphigus vulgaris, bullous pemphigoid, Stevens-Johnson syndrome, with significant oral mucous membrane involvement (Fig. 35-5). The disease responds poorly to immunosuppressive therapy and frequently is fatal.

15. Discuss the laboratory findings in patients with paraneoplastic pemphigus.

Skin and oral mucous membrane biopsy specimens reveal epidermal acantholysis, epidermal spongiosis, suprabasilar clefts, basal cell vacuolar changes, and dyskeratotic keratinocytes. Direct immunofluorescent examination reveals IgG and, less commonly, IgA with or without complement in the intracellular spaces and C3, IgG, or IgM at the basement membrane zone. Antibodies have been demonstrated against desmoplakins, proteins in keratinocyte attachment plaques (desmosomes), and a 230-kDa protein in the basement membrane (bullous pemphigoid antigen). Rat bladder is a useful substrate for indirect immunofluorescent examination and shows positive staining with serum from patients with paraneoplastic pemphigus but will be negative with serum from patients with classic pemphigus vulgaris.

Figure 35-5. Paraneoplastic pemphigus demonstrating extensive superficial blisters and erosions.

(Courtesy of James E. Fitzpatrick, MD.)

Zhu X, Zhang B: Paraneoplastic pemphigus, J Dermatol 34:503–511, 2007.

16. What is the characteristic finding in erythema gyratum repens?

This rare skin eruption is characterized by a widespread, ever-changing pattern of skin lesions resembling wood grain. The erythematous circinate lesions may have a fine scale and move up to 1 cm a day. Almost all patients with this unique dermatosis have an associated malignancy. It was first reported in conjunction with breast cancer, which remains the most common association, but has also been reported with lung, bladder, cervical, and prostate cancers. The skin lesions clear within a few weeks after removal of the malignancy and usually recur if the cancer returns.

DelRosario R, Allen K, Kaneshiro S: Erythema gyratum repens, eMedicine Online, http://www.emedicine.com. May 2009.

17. How do the lesions in Bazex syndrome (acrokeratosis paraneoplastica) progress?

This syndrome begins with acral violaceous erythema on the ears, nose, hands, and feet. Early lesions may show small vesicles. As the lesions progress, they become hyperkeratotic and psoriasiform, especially on the hands and feet. Paronychia and nail dystrophy are common. Later, the eruption may generalize, and lesions on the face may appear dermatitic or lupus-like. The syndrome is more common in men and is associated with squamous cell carcinoma of the upper aerodigestive tract.

There is another Bazex syndrome inherited as an autosomal dominant disease. This syndrome is characterized by acral follicular atrophoderma, early development of multiple facial basal cell carcinomas, and, in some patients, hypohidrosis.

Buxtorf K, Hubscher E, Panizzon R: Bazex syndrome, Dermatology 202:350–352, 2001.

18. Where does Paget’s disease most commonly occur?

On the female breast, although cases have been reported in men. It begins as a small eczematous patch on the nipple that gradually spreads onto the areola and eventually to the skin of the breast. The borders of the lesion are sharply marginated, and the surface may be crusted, moist, erythematous, and/or scaly (Fig. 35-6). Paget’s disease of the breast invariably has an underlying ductal carcinoma, although often there is no breast mass and mammograms can be normal. Any chronic eczematous lesion on the nipple or areola that is unresponsive to topical therapy should have an excisional biopsy, which includes nipple ducts and underlying breast tissue. The associated ductal carcinoma may be small and focal and is easily missed by small punch or shave biopsy.

Figure 35-6. Paget’s disease. Sharply demarcated area of erythema and scale crust that had been treated as a dermatitis, showing partial destruction of the nipple. The patient had an underlying ductal breast carcinoma.

(Courtesy of the Fitzsimons Army Medical Center teaching files.)

Extramammary Paget’s disease occurs on the axilla, groin, or anogenital skin. The disease may present with solitary or multiple lesions. It is often associated with an underlying adnexal carcinoma, and about 20% of cases have carcinoma of the rectum or genitourinary tract.

Kao GF: Paget disease, mammary, eMedicine Online November 2007.

Wilde JL: Extramammary Paget’s disease, eMedicine Online, http://www.emedicine.com. November 2007.

19. Which disorder of protein metabolism is associated with skin lesions and malignancy?

Primary systemic amyloidosis. The cause of this disease is a plasma cell dyscrasia, even though bone marrow aspiration, in some cases, may be normal. The most common associated skin lesions are purpura or ecchymoses that are seen most frequently on thin skin areas, that is, eyelids, neck, groin, axilla, umbilicus, or oral mucosa. The hemorrhagic lesions may occur on areas of clinically normal skin or in skin having waxy papules, plaques, nodules, or tumors. The intracutaneous bleeding is due to infiltration of blood vessel walls with amyloid protein. Other less common skin lesions include alopecia, nail dystrophies, scleroderma-like lesions, macroglossia, cutis verticis gyrata, bullous lesions, and dyspigmentation.

Nyirady J, Schwartz RA: Primary systemic amyloidosis, eMedicine Online, http://www.emedicine.com. April 2009.

20. List the autosomal dominant diseases that have prominent skin findings and internal cancer.

See Table 35-1.

21. Describe the cutaneous features of Gardner’s syndrome.

The cutaneous hallmark of the syndrome is epidermoid cysts, which often appear before puberty, frequently on the extremities. These cysts may be many or few. The syndrome is also characterized by osteomas (typically on facial bones), fibrous and desmoid tumors, abnormal dentition, lipomas, hypertrophy of retinal pigmented epithelium, and leiomyomas of the gastrointestinal tract. The syndrome is characterized by the early onset of colonic polyposis and has a very high incidence of colon cancer.

22. What are the clinical findings in Cowden’s syndrome (multiple hamartoma syndrome)?

This syndrome is characterized by a triad of findings: (1) small keratotic facial papules (Fig. 35-7A), (2) cobblestoning of the oral mucosa (Fig. 35-7B), and (3) acral keratotic skin lesions. These patients also have benign tumors of neural, fibrous, vascular, and epithelial origin. Multiple small tumors of facial hair follicles (trichilemmomas) are pathognomonic of this syndrome. Fibrocystic disease of the breast is common, and 30% of women will develop breast cancer. Many other associated cancers have been reported, with thyroid cancer being the second most common malignancy.

23. When do the characteristic skin lesions of Peutz-Jeghers syndrome appear?

Brown to blue-black macules (lentigines) are present at birth or early infancy on the lips, oral mucosa, nasal mucosa, palms, soles, dorsal hand surfaces, central face, and elbows. Polyps of the small intestine develop in 90% of patients; polyps may also occur in the stomach, colon, and rectum. There is an increased incidence of gastrointestinal malignancy, but it is not nearly as common as in patients with Gardner’s syndrome. In one series, 16 fatal malignancies were seen in 72 cases, with an average age at death of 36 years. Intussusception occurs in about 50% of cases.

24. How does multiple mucosal neuroma syndrome typically present?

As the name implies, this syndrome is characterized by the development of multiple flesh-colored papules on the tongue, lips, and, occasionally, other mucosal surfaces early in life. These patients have a characteristic appearance with thick prominent lips and a marfanoid habitus. Ninety percent of these patients develop medullary thyroid carcinoma, and half will suffer from pheochromocytoma that is often multifocal and/or bilateral.

25. What is Torre’s syndrome (Muir-Torre’s syndrome)?

This syndrome includes cutaneous sebaceous neoplasia and a high incidence of low-grade colon cancer. The sebaceous tumors include sebaceous adenomas, epitheliomas, and carcinomas. In addition, about one third of patients develop keratoacanthomas. The sebaceous skin tumors may be few or many, but even one sebaceous adenoma should alert the clinician that the patient may have this syndrome.

Table 35-1. Autosomal Dominant Diseases with Skin Findings and Malignancy

Figure 35-7. Cowden’s syndrome. A, Typical small keratotic papules on the face. B, Characteristic cobblestone papules on the mucosal surface of the lower lip.

Winship IM, Dudding T: Lessons from the skin-cutaneous features of familial cancer, Lancet Oncol 9:462–472, 2008.

26. Is the sign of Leser-Trélat (eruptive seborrheic keratoses) associated with internal malignancy?

This association remains controversial. Seborrheic keratoses are common in older patients, and so is cancer. There have been many skin lesions and skin diseases reported to be associated with internal malignancy, but these associations are difficult to prove and probably are spurious. Examples include dermatitis herpetiformis, bullous pemphigoid, pemphigus vulgaris (excluding paraneoplastic pemphigus), persistent erythemas (excluding erythema gyratum repens), cutaneous vasculitis, pruritus, scleroderma, and ichthyosis.

Schwartz R: The sign of Leser-Trélat, eMedicine Online May 2009.

27. Is dry scaly skin associated with internal malignancy?

Yes. Acquired ichthyosis was first reported to be associated with Hodgkin’s disease in the 1940s. In 32 patients with acquired ichthyosis, Hodgkin’s disease was reported in 80% of the cases and was the presenting symptom in a few patients. This association is also reported with T-cell lymphoma, leukemia, Kaposi’s sarcoma, malignant histiocytosis, leiomyosarcoma, and multiple myeloma.

Moore RL, Devere TS: Epidermal manifestations of internal malignancy, Dermatol Clin 26(1):17–29, vii, 2008.

28. Which recessively inherited diseases have skin findings and associated internal malignancy?

See Table 35-2.

29. Can pyoderma gangrenosum be associated with internal malignancy?

Yes. Pyoderma gangrenosum (PG) is an ulcerative skin disease of unknown etiology. The lesions are painful, may rapidly enlarge, and are characterized by an erythematous or violaceous undermined border with a necrotic center (Fig. 35-8). The most common diseases associated with PG are inflammatory bowel disease, rheumatoid arthritis, and a small subset may have monoclonal IgA gammopathy. In a review of several studies, PG was associated with internal malignancy in 7.2% of patients. Leukemia is the most frequently reported malignancy with myelocytic and myelomonocytic leukemia accounting for the majority of cases. Other reported hematologic cancers are multiple myeloma, polycythemia vera, and lymphoma. In two thirds of the cases associated with myelocytic leukemia, the PG preceded or was concurrent with the diagnosis of the leukemia. There are rare sporadic reports of PG associated with solid tumors.

Table 35-2. Recessively Inherited Diseases with Skin Findings and Malignancy

Figure 35-8. A young woman with acute-onset pyoderma gangrenosum.

Callen J, Jackson JM: Pyoderma gangrenosum: an update, Rheumatol Dis Clin N Am 33:787–802, 2007.

30. What is erythromelalgia?

Erythromelalgia is a rare skin disease characterized by erythematous, painful, burning of the feet, ankles, and lower extremities. The disease is aggravated by heat exposure and relieved by cooling. Many patients can find relief only by soaking their legs in ice water. The incidence of associated malignancy has been variably reported as between 3% and 65% of cases. Some authors subdivide the disease into two subtypes: the idiopathic type, which frequently begins in childhood, and the secondary type associated with hematologic malignancies, usually polycythemia vera or essential thrombocythemia.

Nardino RT, Silber AL: Erythromelalgia, eMedicine Online, http://www.emedicine.com. August 2009.

31. Can pruritus be a sign of malignancy?

Generalized pruritus without skin lesions has been reported as a symptom of internal malignancy. Pruritus is reported as an initial symptom of Hodgkin’s disease in 5% to 10% of patients and in 3% of those with non–Hodgkin’s lymphoma. The relationship of this symptom to visceral solid cancers is far less clear.

Lober CW: Pruritis and malignancy, Clin Dermatol 11:125–128, 1993.

Key Points: Cutaneous Manifestations of Internal Malignancy

1. Patients with biopsy-proven Sweet’s syndrome should have a complete blood count to evaluate for an underlying hematologic malignancy.

2. Acanthosis nigricans is a common condition, and most cases are associated with insulin resistance. Paraneoplastic acanthosis nigricans is rare, may be of explosive onset, and associated with tripe palms and the sign of Leser-Trélat.

3. Patients with refractory oral pemphigus vulgaris should be evaluated for paraneoplastic pemphigus.

4. Patients with dermatomyositis should have age-appropriate cancer screening, and women should be screened for ovarian carcinoma.

5. Any refractory eczematous eruption on the breast should be biopsied to exclude mammary Paget’s disease.

32. Is vasculitis associated with malignancy?

Vasculitis is rarely associated with internal malignancy. In one large review of 200 patients with vasculitis and cancer, 77.5% had a hematologic malignancy.

Paydas S, Zorludemir S, Sahin B: Vasculitis and leukemia, Leuk Lymphoma 40:105–112, 2000.

33. What is multicentric reticulohistiocytosis?

Multicentric reticulohistiocytosis is a rare disease characterized by multiple skin papules and nodules in patients with severe arthritis. Skin biopsy shows characteristic histology of a diffuse histiocytic cellular infiltrate with large multinucleate giant cells with ground-glass cytoplasm. Associated malignancy was reported in 28% of the patients in 82 cases reported in the literature. The disease preceded the development of cancer in 73% of the patients. This association is controversial, there was no consistent cancer reported, and there are no careful prospective studies.

Rapini RP: Multicentric reticulohistiocytosis, eMedicine Online, http://www.emedicine.com. March 2008.

34. What is carcinoid syndrome? Does it have prognostic significance?

Carcinoid syndrome is a systemic manifestation of neuroendocrine carcinoid tumors that manifest most commonly by flushing that progresses to persistent telangiectasia (Fig. 35-9) and diarrhea. Less common findings include bronchospasm, cardiac valvular dysfunction, and pellagra-like skin changes (photodistributed dermatitis). It is estimated that 10% of patients with carcinoid tumors will develop this syndrome. Development of this syndrome has prognostic significance, as liver metastases underlie most cases, and thus it signifies metastatic, unresectable disease.