Cutaneous Manifestations Of Internal Malignancies

The authors identify the clinical circumstances in which it is most reasonable to suspect that a skin lesion signifies a more insidious, life-threatening disorder elsewhere.

By Stephen Schleicher, MD, and Richard Cordova, DO

Dr. Schleicher is director of the DermDx Centers for Dermatology of Northeastern Pennsylvania and a clinical instructor of dermatology at Graduate Hospital's City Line Campus in Philadelphia, Kings College in Wilkes-Barre, and Beaver College in Glenside, Pennsylvania. Dr. Cordova is chief resident, family practice, at St. Luke's Hospital in Allentown, Pennsylvania. .

The presence of cancer within the body can be signified by several dermatologic conditions. The success or failure of treatment for the disease can depend on the timely recognition of these cutaneous signs, which may or may not be benign. In this discussion, we will review the several benign skin conditions that are associated with malignant disorders and describe the characteristics of skin lesions that may suggest cutaneous metastasis. Certainly, any atypical, recently formed nodule or any dermatosis that does not respond to appropriate topical or oral therapy represents a red flag that warrants biopsy and histologic examination.

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Benign Signs of Underlying Cancer

The benign cutaneous lesions most likely to be associated with internal malignancies are those associated with dermatomyositis, acanthosis nigricans, necrotic migratory erythema, herpes zoster, multiple eruptive seborrheic keratoses, Sweet's syndrome, erythroderma, xanthoma, pemphigus vulgaris, and erythema gyratum repens. The suspicion of underlying cancer should be higher under certain circumstances: older age, failure of the cutaneous problem to respond to conventional therapy, systemic symptoms such as fever or weight loss, and personal or family history of cancer.

Dermatomyositis. Many published studies have established a link between dermatomyositis and internal neoplasia; the rate of association has been estimated at 27% of cases. The link appears to be stronger in women. Associated cancers include tumors of the ovary, breast, lung, stomach, and colon. The cutaneous manifestations of this disease are indistinguishable regardless of whether underlying cancer is present. Interestingly, among patients with polymyositis-which is clinically identical to dermatomyositis except for the cutaneous manifestations-the incidence of cancer does not appear to be increased.

Because dermatomyositis-associated ovarian cancer is most likely to appear within four to five years after the skin disease is diagnosed, many clinicians recommend gynecologic screening at six-month intervals for the first two years and yearly thereafter.

The diagnosis is indicated by a combination of muscle abnormalities and the characteristic heliotrope rash, a periorbital, reddish-purple flush that may precede the development of muscle weakness by a few weeks or months or, in rare instances, several years (see photo below, and table). Scaling and some edema may accompany this rash. Also characteristic of dermatomyositis are a violaceous erythema that appears over the knuckles, elbows, and knees-known as Gottron's sign-and raised, flat-topped papules on the knuckles, called Gottron's papules.
 

Acanthosis nigricans. A diffuse hyperplasia of the spinous layer of the skin, acanthosis nigricans is recognized clinically by areas of hyperpigmented and at times hyperkeratotic, velvety plaques, typically in a symmetrical distribution. The frequently involved areas include the locations prone to intertrigo, such as the axillae, groin, and intergluteal fold, as well as the neck and antecubital and popliteal fossae (see photo below).

Acanthosis nigricans may be either benign or malignant. Obesity is closely tied to this disorder; more than half of adults weighing more than 200% of their ideal body weight are affected. Most of these patients manifest insulin resistance in varying degrees that may be mirrored in the severity of the skin symptoms.

Acanthosis nigricans may on occasion be associated with internal cancer. This combination usually indicates a poor prognosis, as the underlying neoplasm is often aggressive. The average survival period for patients with cancer-associated acanthosis nigricans is two years. The most common underlying cancer is adenocarcinoma of the gastrointestinal tract. When associated with gastrointestinal cancer, the skin lesions are typically more widespread and asymmetric and involve oral and mucosal surfaces.

Necrolytic migratory erythema.Characterized clinically by erythematous, vesiculobullous areas with underlying erosion (see photo below), necrolytic migratory erythema is commonly found in the perianal, perigenital, and facial regions. The earliest lesions are pustules that readily rupture and leave a thin necrolytic border. Associated findings include a beefy-red tongue and angular cheilitis. A biopsy specimen taken from the edge of the rash reveals the upper epidermal necrosis typical of this disorder.

Necrolytic migratory erythema is considered a diagnostic marker for the extremely rare glucagon-secreting (alpha-cell) type of pancreatic tumor called glucagonoma. Increased levels of serum glucagon are responsible for the cutaneous manifestations of this disease. The dermatitis is unresponsive to conventional therapy and may be associated with weight loss, intermittent diarrhea, and abdominal pain. The rash usually resolves quickly after the tumor is resected.

Herpes zoster. Caused by the varicella zoster virus, herpes zoster is characterized by grouped painful vesicles on an erythematous base and usually involves one or two dermatomes. Most cases occur in persons older than 55 years. When administered early in the course of the disease, specific antiviral therapy, such as acyclovir, famciclovir, or valacyclovir, will hasten resolution of the blisters but may not prevent the dreaded postherpetic neuralgia.

In almost all older patients, herpes zoster is not an indication of underlying cancer, but several studies have shown that it may signal cancer in up to 75% to 80% of those who present with severe, ulcerated disseminated disease. The most commonly associated malignant diseases are lymphoma and leukemia. The recurrence of herpes zoster in such cases may indicate the recurrence of cancer.

Multiple eruptive seborrheic keratoses. Seborrheic keratoses are benign neoplasms characterized by hyperkeratosis and hyperpigmentation. The lesions appear to be "stuck" on the skin. Extremely common, they are most frequently found on the trunk and face. Both a genetic predisposition and exposure to sunlight have been implicated in their pathogenesis.

The abrupt onset of seborrheic keratoses associated with an underlying cancer is called the sign of Leser-Trélat. The average age of onset is 60 years, and lesions may be found on the trunk, face, and extremities. The most common associated cancer is adenocarcinoma of the stomach; others include leukemia, mycosis fungoides, hepatoma, and carcinoma of the lung and breast. The seborrheic keratoses may arise either concurrently with, before, or after the associated cancer.

Definitive evidence supporting the relationship of seborrheic keratosis to underlying cancer has been elusive, given the significant incidence of both the skin disorder and the associated cancers in the general population.

Sweet's syndrome. Also referred to as acute febrile neutrophilic dermatosis, Sweet's syndrome is characterized by the rapid onset of numerous bright- to dusky-red, well-demarcated, tender plaques. The initial lesions are inflamed papules or nodules that coalesce to form inflamed annular or arcuate lesions with clear centers. The most commonly involved areas are the face, neck, chest, and upper extremities (see photo below). Fever and peripheral leukocytosis are usually present. The lesions resolve within three months.

Most episodes of Sweet's syndrome occur in younger patients and are drug induced or follow a viral illness. However, in approximately 10% of cases an underlying cancer is the cause-most often acute myelocytic leukemia, but other types of nonmyelocytic leukemia and lymphoma have been reported.

Erythroderma. Defined by diffuse erythema and scaling in a generalized distribution, erythroderma usually is a manifestation of psoriasis, atopic dermatitis, or drug-induced allergic reactions (see photo below). In about 15% of cases, however, an underlying malignant disorder such as Sézary syndrome or mycosis fungoides is identified. In these instances, biopsy will confirm direct involvement of the malignant cells in the skin. The prognosis varies with the extent of the involvement in the skin and internal organs.

Xanthoma. Most commonly linked with abnormalities of cholesterol and triglyceride metabolism, xanthoma is marked by cutaneous lipid eruptions and has been associated with the presence of multiple myeloma and other hematologic cancers. Xanthoma planum is a specific type of xanthomatous disease that appears clinically as yellow to tan, well-defined, slightly elevated plaques spread diffusely over large areas of the skin (see photo below). In most cases, serum lipid and lipoprotein profiles are normal. Because xanthoma planum is frequently associated with myeloma, all patients who have the disease should undergo serum immunoelectrophoresis testing.

Pemphigus vulgaris. An autoimmune disease of the skin and mucous membranes, pemphigus vulgaris produces bullous lesions that arise on normal skin, are flaccid, and rupture easily, leaving denuded patches called Nikolsky's sign (see photo below). Rarely, pemphigus vulgaris is associated with thymoma and myasthenia gravis.

Paraneoplastic pemphigus, first described in 1990, is invariably associated with an underlying cancer-most commonly non-Hodgkin's lymphoma-and is clinically characterized by painful mucosal lesions accompanied by a vesiculated skin eruption. The mean age at onset is 60 years, and the disease proves fatal in up to 90% of cases, typically owing to sepsis or respiratory failure.

Erythema gyratum repens. A rare cutaneous marker of cancer, erythema gyratum repens is characterized by annular, erythematous plaques surrounded by areas of fine desquamation in a distinctive and striking wood-grain pattern (see photo below). The lesions expand rapidly in concentric rings after initial onset and are usually pruritic. Skin biopsy produces nonspecific results. Approximately 90% of cases are associated with internal cancer, most commonly of the lung and less so of the esophagus and the breast.

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Metastatic Skin Involvement

Skin involvement has been reported as the first sign of cancer in approximately 1% of patients who have internal neoplasms. Involvement of the skin can occur as a result of direct extension of the tumor or of local or distant metastasis. Direct extension is most commonly associated with breast and oral cancer, local metastasis is usually linked to breast and pelvic cancer, and distant metastasis can be caused by cancer in any location (see photos below). Metastatic skin lesions caused by renal carcinoma will appear mostly on the scalp.

Malignant cutaneous lesions that are indicative of systemic cancer are typically nodular, have a firm consistency, and are red, plum-colored, or hyperpigmented. Ulceration and increased vascularity of the lesions also suggest an underlying cancer. In all cases, biopsy is necessary for a definitive diagnosis.

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Other Superficial Signs of Cancer

In addition to the previously mentioned skin conditions, other, less complicated cutaneous signs may be linked to cancer (see table below). Flushing, usually evident in the face and upper chest, most commonly accompanies carcinoid tumors of the intestine. Palmar erythema, usually associated with advanced liver failure, may also accompany primary or metastatic malignant liver disease. Direct extension of breast cancer to the skin may be accompanied by telangiectasia. Purpuric lesions may be a manifestation of disseminated intravascular coagulation induced by cancer. Thrombophlebitis, when associated with cancer, is usually migratory.

Suggested Reading Binnick AN, et al.: Glucagonoma syndrome: Report of two cases and literature review. Arch Dermatol 113:749, 1977. Kurzrock R, et al.: Cutaneous paraneoplastic syndromes in solid tumors. Am J Med 99:662, 1995. Meszaros L: Internal cancers revealed by cutaneous signs. Dermatology Times 24:6, March 24, 1999. Schwartz RA: Acanthosis nigricans. J Am Acad Dermatol 31:1, 1994. Schwartz RA: Sign of Leser-Trélat. J Am Acad Dermatol 35:88, 1996. Zantos D: The overall and temporal association of cancer with dermatomyositis and polymyositis. J Rheumatology 21:1855, 1994.

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