Metastatic Disease

Epidemiology

Studies regarding cutaneous metastases vary greatly in methodology (case reports, series, meta-analyses) and in the patient populations investigated (autopsies, cancer registries). Furthermore, some studies exclude particular cancers, such as melanoma or hematopoietic malignancies, while others exclude tumors with local extension or direct invasion, including only local or distant metastases. The incidence of cutaneous metastases in the literature ranges from 0.2% to 10%. In a retrospective study of 7316 patients with carcinoma (excluding melanoma, leukemia, lymphoma, and sarcoma), 5% of patients developed cutaneous metastases. In the follow-up study of 4020 patients that included melanoma, 10% of patients had cutaneous metastases. The average age of patients with locally invasive and/or cutaneous metastases in one study was 62 years.

Skin metastases were the presenting sign of an internal malignancy in 0.8% of patients, and were the presenting sign of extranodal metastatic disease in patients with a known underlying malignancy in 7.6% of patients (6.4% if melanoma was excluded).

The most frequent neoplasm associated with cutaneous metastases varies by study and inclusion of particular cancers. In most studies, breast cancer has the highest incidence of skin metastases. However, some studies include direct extension, while others include only local or distant metastases. In one series, metastasis occurred in 6.3% of patients with breast cancer and was the presenting sign in 3.5% of patients. In another study, skin involvement occurred in 23.9% of patients with breast cancer and was the presenting sign in 8% of patients. In patients who developed cutaneous infiltration or metastases after the diagnosis of breast cancer, it was a late finding, occurring an average of 101 months after diagnosis. In another study of 1287 patients with internal malignancy, hematologic cancers were the most frequent source of cutaneous metastases, while in another that included melanoma (but excluded hematologic malignancies), melanoma was the most frequent. Cancers of the upper respiratory tract metastasized to the skin at a high incidence as well. Lung, colon, and rectal cancers uncommonly metastasize to the skin, but given the high prevalence of these cancers, they are a common cause of metastases. Cutaneous metastases are often the presenting sign in lung cancer, and it is proposed that this type of malignancy spreads more quickly to the skin than many other cancers. Based on gender, breast, colon, and ovarian cancer are the most common causes of cutaneous metastases in women, whereas lung and colon cancer are the most common causes in men. However, if melanoma is included, it has been reported to be the most frequent source of cutaneous metastases in men, and second in women (preceded by breast cancer). The primary malignancies for cutaneous metastases based on percentage and gender are shown in Table 19-1 . Prostate cancer has a very low incidence of cutaneous metastases even with its high prevalence. Neuroblastoma and leukemia are the most frequent cause of cutaneous metastases in children. In neonates, leukemia, multisystem Langerhans cell histiocytosis, and neuroblastoma, in order of rank, were the most frequent cause of cutaneous metastases.

Pathogenesis

Cutaneous metastases may result from hematogenous and lymphatic spread, direct tissue invasion, or iatrogenic implantation. Metastatic cells may be produced from a minor specialized subpopulation of cells, be clonal, and be genetically less stable than the nonmetastatic tumor cells. These cells must develop a blood supply through angiogenesis and cross a basement membrane to reach the extracellular space. Through cell motility, they invade lymphatics or vasculature while evading apoptosis, attach to and invade target tissues through matrix degradation, and proliferate. Chemokine expression by tumor cells has been implicated in organ-specific metastases. Melanomas can express the chemokine CCL27, which is site-specific for skin and could explain the high incidence of cutaneous metastases in this cancer. Other factors may be related to locations for metastases as well. In one study, the face and scalp were involved preferentially in distant metastases, possibly secondary to the high vascularization of these sites.

Clinical Manifestations