Dermatologic Manifestations of Metastatic Carcinomas

Cutaneous metastases from carcinoma (see the image below) are relatively uncommon in clinical practice, but they are very important to recognize. Cutaneous metastasis may herald the diagnosis of internal malignancy, and early recognition can lead to accurate and prompt diagnosis and timely treatment. However, a high index of suspicion is required because the clinical findings may be subtle.

Alopecia neoplastica due to metastatic breast cancer.

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See Cutaneous Clues to Diagnosing Metastatic Cancer, a Critical Images slideshow, to help identify various skin lesions that are cause for concern.

The recognition of cutaneous metastases often dramatically alters therapeutic plans, especially when metastases signify persistence of cancer originally thought to be cured. Some tumors metastasize with a predilection for specific areas. Recognition of these patterns can be useful in directing the search for an underlying tumor.

Primary tumors

The breast, skin, stomach, lungs, uterus, large intestine, and kidneys are the most frequent organs to produce cutaneous metastases. Cancers that have the highest propensity to metastasize to the skin include melanoma (45% of cutaneous metastasis cases) and cancers of the breast (30%), nasal sinuses (20%), larynx (16%), and oral cavity (12%). Because breast cancer is so common, cutaneous metastasis of breast cancer is the most frequently encountered type of cutaneous metastasis in most clinical practices. ^[1] See the images below.

Low-power view of breast cancer metastasis with surrounding fibrosis.

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Breast cancer metastasis with hyperchromatic cells extending between thickened collagen bundles. Dilated lymphatics are noted.

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Some common tumors, however, may not result in metastasis in a manner that parallels their incidence in the overall population. For example, prostate cancer is very common, but cutaneous metastasis from prostate carcinoma is relatively uncommon.

Unknown primary site

The term carcinoma of unknown primary site (CUPS) is used when dealing with a metastasis that occurs before primary tumor diagnosis. In dealing with cutaneous CUPS, the age, sex, and affected skin region of the patient, as well as the histology of the lesion, are useful in determining the location of the likely primary tumor. Immunohistochemistry can be invaluable in identifying the tissue of origin.

Certain attributes distinguish metastases from primary tumors. Some features include neoplastic cells in lymphatic and blood vessels, a large portion of neoplasm in the deep reticular dermis, and subcutaneous fat and neoplastic cells lined up between collagen bundles.

Metastatic tumors are usually round, discrete tumor lobules in the dermis, with a Grenz zone, and are usually unassociated with the epidermis. Physical patterns vary among different carcinomas. Fibrosis and inflammation may be present. Vascular involvement is rare. Sometimes, unusual patterns can be identified.

Paget disease typically has a distinct clinical and histologic presentation, with involvement of the nipple or the areola. Symptoms may include an eczematous patch, with intense scaling, pain, and bleeding in later stages. Paget disease may be a sign of underlying breast, genitourinary, or colon cancer, or it may be a primary neoplasm of indeterminate glands in the skin. In extraordinary situations, lesions may be pigmented and epidermotropic and simulate melanoma.

Some primary melanomas may arise in the dermis and simulate a metastasis. ^[2] On the other hand, some metastases may be epidermotropic and simulate a primary epidermal tumor. ^[3]

Primary cutaneous adnexal carcinomas may be difficult to distinguish from metastases in certain situations. Primary cutaneous apocrine carcinomas can be particularly difficult to differentiate from adenocarcinomas of mammary origin because of the identical morphological and immunohistochemical features they may exhibit. Sometimes adnexal carcinomas arise in the setting of a precursor benign adnexal neoplasm, making diagnosis straightforward. Mahalingam et al have shown that positive staining with D2-40, p63, and CK15 also favors a primary adnexal carcinoma. ^[4]

Evaluation of markers that can help differentiate metastases from primary adnexal carcinomas continues. p40, p63, and cytokeratin 5/6 are all useful in distinguishing primary adnexal carcinoma from cutaneous metastases. p63 and cytokeratin 5/6 seem to have similar sensitivity, with p40 associated with good specificity and predictive value. ^[5]

In practice, careful clinical evaluation is essential when a cutaneous adenocarcinoma is identified in the absence of a precursor neoplasm. A confident diagnosis of primary cutaneous apocrine carcinoma requires exclusion of underlying adenocarcinoma by a thorough clinical examination and imaging studies. Further work is underway to find even better immunohistochemical techniques to make this distinction ,which has important prognostic and therapeutic implications.

Metastases arise as disconnected extensions of a primary tumor. This occurs when cancerous cells break away from a primary tumor and spread elsewhere. By definition, this makes the primary tumor malignant. Determining whether a primary neoplasm will metastasize is difficult because of many factors, but, generally, the larger and faster a neoplasm grows, the more likely it will metastasize.

Metastatic pathways

The mechanism for metastasis varies, and several different pathways are thought to be important. Regional spread by way of tissue most often occurs through body cavities, especially the peritoneal cavity. Transplantation can be caused, albeit rarely, by mechanical transport of tumor fragments by instruments during surgery or other invasive procedures.

Lymphatic and vascular routes are the most common pathways, although differentiating the routes is difficult because they are interconnected. Lymphatic spread is the most common pathway for the initial spread of carcinoma. Hematogenous spread is commonly associated with metastasis from sarcomas, although carcinomas may also use this pathway.

Cells may have a predictable metastatic spread, but unusual sites of metastasis may be encountered. The use of sentinel lymph node studies is an attempt to define likely paths of metastasis to identify whether metastasis has occurred. Unfortunately, for some tumors (such as melanoma), there is as of yet no clear evidence that lymphatic spread is the predominant mode of metastasis. Although sentinel node studies may provide useful information on prognosis, this does not enhance overall survival.

Establishment of metastases

Many steps have to be met for metastasis to occur. The primary tumor has to be large enough to release a sufficient amount of neoplastic cells into the circulatory or lymphatic system. These cells need certain properties, such as cell suspension and mitotic rate, to survive while in circulation. Most single neoplastic cells released are destroyed by the immune system, whereas clusters of 6 or 7 cells have a better chance of metastasis.

To establish metastases once the neoplastic cells are in the circulatory system, the neoplastic cells need to attach and penetrate vessel walls. The circulatory path influences the location of the most common attachment sites, but the neoplastic cells also have affinities for certain target tissues.

Once attachment occurs, a thrombus forms around the neoplastic cells through endothelial cell injury. This thrombus serves as protection for the neoplastic cells. The new metastasis establishes itself and obtains nutrition initially through diffusion; it then forms its own vessels.

The incidence of cutaneous malignancy varies. In some autopsy studies of patients with metastatic carcinoma, as many as 9% of individuals were noted to have cutaneous metastases. Other studies suggest a range of 3-4%. A 2003 meta-analysis ^[6] estimated a rate of cutaneous metastasis of 5.3%. A recent large study shows that the incidence of cutaneous metastases due to melanoma is increasing. ^[7]

Sex-related demographics

The most common sources of cutaneous metastases in woman are the breasts (69%), the colon (9%), melanomas (5%), the ovaries (4%), and the lungs (4%). In men, the most common sources are the lungs (24%), the colon (19%), melanoma (13%), and the oral cavity (12%).

Age-related demographics

Cutaneous metastases are very rare in children. Rhabdomyosarcoma, leukemia, and neuroblastoma are the most frequent causes in children.

In men younger than 40 years, the most common sources of cutaneous metastases (in decreasing order of frequency) are melanoma, colon cancer, and lung cancer. In men older than 40 years, the most common sources of cutaneous metastases (in decreasing order of frequency) are lung cancer, colon cancer, squamous cell carcinoma in the oral cavity, and melanoma.

In women younger than 40 years, the most common sources of cutaneous metastases are breast cancer, colon carcinoma, and ovarian carcinoma. In women older than 40 years, they are breast carcinoma, colon carcinoma, lung cancer, ovarian carcinoma, and melanoma.

The mortality rate is high in patients with cutaneous metastases. The appearance of these neoplasms signals widespread metastatic disease, resulting in a poor prognosis. Patients often survive for a short period, depending on the type of carcinoma, but this is changing. Exciting advances in chemotherapy have greatly increased survival in recent years; many patients now survive for a number of years with directed therapy.

In a retrospective study, Song et al found that 2.8% of patients with advanced non-small cell lung cancer (NSCLC) initially presented with cutaneous metastases and that these metastases were indicative of a poor prognosis. In the study, 60 out of 2130 patients with advanced NSCLC had an initial diagnosis of cutaneous metastases. (Fifteen patients had only cutaneous metastases, and 45 patients had a combination of cutaneous and noncutaneous metastases.) The overall length of survival for patients with cutaneous metastases was 3.9 months, compared with 10 months for patients who did not present with cutaneous metastases. ^[8]

The serum TA90 immune complex assay, developed at M.D. Anderson Cancer Center and licensed through Quest Diagnostics, can predict the likelihood of melanoma recurrence with 70% sensitivity and 85% specificity. ^[9] Similar studies are being developed for other types of cancer to help identify patients at high risk for metastasis.

For patient education information, see the Cancer Center, as well as Skin Cancer and Skin Biopsy.