A. Incidence and pathology. Skin is not an uncommon metastatic site of solid tumors. Of patients with metastatic disease, 2% to 10% develop skin metastases. In men, the most common internal malignancies leading to cutaneous metastases are lung cancer (24%), colon cancer (19%), melanoma (13%), squamous cell carcinoma of the oral cavity (12%), and renal cell carcinoma (6%). In women, these are breast cancer (69%), colon cancer (9%), melanoma (5%), lung cancer (4%), and ovarian cancer (4%). Cutaneous involvement by cancer can occur both as a metastatic process and as a direct extension of the tumor to the skin.

B. Natural history. Metastases to the skin may be delayed 10 to 15 years after the initial surgical treatment of primary melanoma, breast carcinoma, and renal cancer or may be the first indication of an internal malignancy.

1. Breast cancer represents almost 75% of female patients with cutaneous metastases. It shows eight distinct clinicopathologic types of cutaneous involvement:

a. Inflammatory (erysipelas-resembling erythematous patch or plaque with active border, usually affecting the breast; but other skin sites can also be involved)

b. En cuirasse (a diffuse morphea-like induration)

c. Telangiectatic (papules with violaceous hue caused by accumulation of blood in vascular channels)

d. Nodular (usually multiple firm papulonodules, sometimes ulcerated)

e. Alopecia neoplastica (painless, well-demarcated, pinkish oval plaques of alopecia caused by hematogenous spread of breast carcinoma), which can occur with other neoplasms as well

f. Paget disease (a sharply demarcated, scaling plaque on the nipple or areola representing cutaneous infiltration of cancer)

g. Breast carcinoma of the inframammary crease (a cutaneous nodule that may resemble basal cell carcinoma)

h. Histiocytoid nodule of the eyelid (presents as a painless eyelid swelling with induration)

2. Lung cancer. Cutaneous metastases from lung cancer may appear on any surface, but they are most common on the chest wall and the posterior abdomen; small cell lung cancer metastasizes most frequently to the skin of the back. Between 1.5% and 16% of patients with lung cancer develop skin metastases; in half of these patients, it is a presenting sign of the disease. Lung cancer also has a rare but peculiar tendency to metastasize to the anal area, fingertips, or toes.

3. Gastrointestinal (GI) tract cancers. Skin metastases from colon cancer and rectal cancer usually develop after malignancy has been recognized. Abdominal wall and the perineal area are the most common sites. They may appear as sessile or pedunculated nodules, vascular nodules, scalp cysts, inflammatory carcinoma, or persistent fistulation after appendectomy. Cutaneous metastasis of gastric cancer is rare, and most cutaneous metastases are typically solitary, nodular, have a firm consistency, and are red or hyperpigmented but
may present as dermatitis. Anal cancer metastases to skin involve unusual sites, such as the scalp, eyelid, nose, or legs.

4. Melanoma. Both cutaneous and extracutaneous melanoma can produce skin metastasis. They usually present as multiple pigmented nodules, but they can also be erythematous or apigmented.

5. Urologic malignancies. Of all urologic malignancies, renal cell carcinoma metastasizes to the skin most frequently, but skin metastases from bladder, prostate, and testicular cancer have also been reported. These metastases are frequently the first sign of renal cell carcinoma, and they can appear very late, up to 10 years after diagnosis. Both clinically and histologically, they may resemble common dermatologic disorders, which lead occasionally to incorrect diagnosis.

6. Subungual metastases. Malignant lesions in the nail unit can be classified into three groups: metastatic lesions from a distant primary, cutaneous involvement of a hematopoietic or lymphoproliferative malignancy, and primary cancer at this location. Lung cancer is the most common type of malignancy that can metastasize to the nail bed, followed by genitourinary, breast, head and neck cancers, and sarcomas. Subungual metastases typically present as erythematous enlargement, swelling of the distal digit, or a violaceous nodule. They are frequently painful, but they can also bleed or be hot, pulsatile, and fluctuant. These lesions can be mistaken for infection or trauma; in almost half of affected persons, they are a presenting sign of malignancy.

7. Umbilical metastasis (Sister Mary Joseph nodule) is encountered in 1% to 3% of patients with abdominopelvic malignancy. The term Sister Mary Joseph nodule was assigned to the Mayo brothers’ surgical nurse who recognized that umbilical metastasis denoted incurable disease when the patient underwent laparotomy. The most common origins are GI (52%), gynecologic (28%), stomach (23%), and ovarian (16%) cancer. Survival in these patients, which depends on the type of tumor and treatment modalities, can range from 2 to 18 months.

C. Prognosis. Skin metastases usually indicate advanced disease and carry a poor prognosis. The average survival time from the recognition of skin metastases is 3 months, but it can be years for lymphomas, melanoma, and breast cancer.

D. Diagnosis is based on biopsy results, especially in patients who have not previously been diagnosed with malignancy.

E. Management. Most skin metastases are treated symptomatically, and they tend to regress when the primary tumor responds to systemic therapy. Occasionally, these lesions require treatment with local radiation therapy, surgery, cryotherapy, or photodynamic therapy. Intralesional injections of thiotepa (30 mg), bleomycin, or cisplatin, or electrochemotherapy (in which the effect of intralesional chemotherapy is enhanced by electroporation) have also been utilized.

Cutaneous paraneoplastic syndromes comprise a heterogeneous group of dermatologic syndromes describing skin lesions that do not contain malignant cells, but they appear in the presence of underlying malignancy.

A. Acanthosis nigricans is characterized by hyperpigmented, velvety plaques on the neck, in the axilla, groin, and antecubital fossa. In most cases, it reflects metabolic disturbances seen in patients with obesity, metabolic syndrome, or diabetes. If the lesions appear abruptly and progress rapidly, or they are associated with tripe palms or mucous membrane involvement, they can reflect underlying malignancy, mainly adenocarcinoma of the GI tract (in >50% of cases, gastric cancer). Benign causes of acanthosis nigricans include

1. Acromegaly, gigantism

2. Adrenal insufficiency

3. Hyperthyroidism, hypothyroidism

4. Lipodystrophy

5. Diabetes mellitus

6. Syndrome with hirsutism, obesity, and amenorrhea

7. Inherited abnormality in humans (and Swedish dachshunds)

B. Amyloidosis secondary to nonmalignant disease rarely involves skin. Patients with multiple myeloma or, less commonly, Waldenström macroglobulinemia may develop “pinch purpura” (ecchymoses or purpuric patches occurring spontaneously or with minor trauma). The lesions are primarily in flexural areas, paranasal skin, anogenital regions, the neck, and around the eyes.

C. Bazex syndrome (acrokeratosis paraneoplastica) consists of psoriasiform lesions in the acral areas (ears, nose, nails, hands, feet, elbows, knees). In 18% of cases, lesions can be pruritic. This syndrome is universally associated with malignancy, mainly carcinoma of the upper aerodigestive tract, but also prostate carcinoma, hepatocellular carcinoma, lymphoma, and bladder carcinoma. In nearly two-thirds of cases, cutaneous lesions precede the diagnosis of malignancy.

D. Dermatomyositis and polymyositis belong to a group of idiopathic inflammatory myopathies. Between 15% and 25% of cases of dermatomyositis and about 10% of polymyositis are associated with malignancy. Almost any type of malignancy has been reported in patients with dermatomyositis, but ovarian carcinoma and lung and breast cancer are the most common. Dermatomyositis may precede development of the neoplasm for up to 5 years. Treatment of the malignancy results in symptom improvement, and worsening of symptoms may herald tumor recurrence.

These myopathies are typified by proximal muscle weakness with or without tenderness. Patients typically report that they are not able to brush their hair. Flat-topped erythematous papules over the phalangeal joints (Gottron papules) and pinkish-purple discoloration around the eyes (a heliotrope rash) are pathognomic signs of dermatomyositis. Other signs include periungual telangiectasias; patchy discoloration of the skin; red, scaly scalp rash; and photosensitivity. Laboratory work commonly reveals elevated creatinine kinase level, although the cases with normal level of creatinine kinase have been reported, and possibly they are more frequently associated with malignancy.

E. Ectopic Cushing syndrome is caused by the secretion of an adrenocorticotrophic hormone (ACTH) prohormone or ACTH, most commonly by small cell lung carcinoma and bronchial carcinoids, and occasionally by thymoma, islet cell tumor, non-small cell lung carcinoma, and pheochromocytoma. It presents as proximal muscle wasting, hypertension, hypokalemia, usually weight loss (not weight gain), and, because an ACTH prohormone contains pro-opiomelanocortin, frequently with hyperpigmentation.

F. Erythema gyratum repens is characterized by an extensive eruption of erythematous, scaly, rapidly progressing, ring-forming, wood-grain-resembling lesions over most of the body, sparing the hands, feet, and face. It is frequently accompanied by severe pruritus. It is almost always a representation of underlying malignancy, and it precedes the detection of malignancy by 1 to 24 months. Lung cancer is most commonly reported, followed by esophageal and breast cancer. The treatment consists of surgical removal of the primary tumor, but some improvement can sometimes be observed after therapy with systemic steroids, radiotherapy, and azathioprine.

G. Exfoliative erythroderma syndrome is a generalized erythema of the skin accompanied by a variable degree of scaling. It is frequently accompanied by severe pruritus and generalized lymphadenopathy. Malignancy accounts for 5% to 12% of cases, and it is most frequently associated with cutaneous T-cell lymphoma, rarely with solid tumors or acute myelogenous leukemia.

H. Hypertrichosis lanuginosa acquisita (“malignant down”) refers to the development of fine, unpigmented hair predominantly localized to the head and neck. It has been associated with lung and colon cancer, but it can also occur in conjunction with shock, thyrotoxicosis, porphyria, and cyclosporine, minoxidil, phenytoin, and penicillin ingestion. Treatment should be directed toward the removal of malignancy.

I. Ichthyosis. Acquired ichthyosis is manifested by symmetric scaling ranging in severity from minor roughness and dryness to dramatic desquamation of white-to-brown scales. The diameter of the scales can range from <1 mm to >1 cm. It primarily affects the trunk and limbs. The lesions are usually more accentuated on extensor surfaces. It should be differentiated from the late-onset ichthyosis vulgaris, xerosis, and Refsum disease. Hodgkin lymphoma is the most common malignancy associated with acquired ichthyosis, but it can also occur in patients with a cutaneous T-cell lymphoma or carcinomas of the breast, lung, or bladder. It may be also a result of nonmalignant disease (e.g., autoimmune syndromes, endocrinologic disorders, nutritional abnormalities, infectious diseases, and finally a drug reaction).

J. Multicentric reticulohistiocytosis is characterized by pink, brown, gray papules appearing initially on the hands and then spreading to the face. The lesions can be also present on the knees, elbows, ankles, shoulders, feet, or hips, and they may have pathognomic coral-bead appearance. Approximately 20% to 25% of multicentric reticulohistiocytosis cases are associated with malignancy, including hematologic, breast, ovarian, gastric, and cervical neoplasms.

K. Necrolytic migratory erythema (NME) is an uncommon inflammatory dermatosis usually associated with glucagonoma and rarely with nonneoplastic conditions, such as liver disease, inflammatory bowel disease, pancreatitis, and malabsorption disorders. The postulated mechanism for NME involves a combination of zinc, amino acid, and fatty acid deficiencies. The clinical features of NME include transient eruptions of irregular erythematous lesions in which a central bulla develops, subsequently erodes, and heals with hyperpigmentation. The lesions follow a periorificial distribution, or they are located in the areas subject to greater pressure and friction (i.e., the perineum, buttocks, groin, lower abdomen, and lower extremities).

L. Necrotizing leukocytoclastic vasculitis is a rare representation of malignancy. It appears as a palpable purpura, typically in dependent areas. This vasculitis is more common with hematologic malignancies than with solid tumors. Occasionally, it can also be a complication of antineoplastic therapy.

M. Pachydermoperiostosis exhibits thickening of skin and creation of new skin folds (leonine facies). The scalp, forehead, lids, ears, and lips are the typical sites. The tongue, thenar and hypothenar eminences, elbows, and knees may be enlarged. The fingers are clubbed. Biopsy shows thickening of the horny layer and hypertrophy of the sweat and sebaceous glands.

The familial form of pachydermoperiostosis is not usually associated with malignant tumors. The acquired variety occurs almost exclusively in patients with undifferentiated lung cancer. Clubbing and hypertrophic osteoarthropathy are also associated with a variety of nonmalignant disorders.

N. Paget disease. Extramammary

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