Dermatologic Manifestations of Metastatic Carcinomas Workup

• The diagnosis of metastatic carcinoma hinges on histopathologic evaluation of involved skin. Tumors may show characteristics of the underlying tumor, or they may have a more anaplastic appearance. In the situation of an anaplastic tumor, immunohistochemical marker studies and ultrastructural examination may help delineate the tissue of origin. It is important to perform a panel of immunohistochemical marker studies and to carefully correlate the immunohistochemical findings with light microscopic findings and clinical information. As with any test, false-positive and false-negative findings may occur. Clinicians should look at the overall clinical situation when making therapeutic decisions.
• Punch or excisional biopsy usually provides sufficient tissue for diagnosis. Fine-needle aspiration cytology can also be useful in certain circumstances.^[3]
• Carcinoma immunophenotypes, with the location and antibody positivity/negativity, are as follows, with (+) indicating "always positive" and (-) indicating "negative but with rare exceptions." Additionally, CK represents types of cytokeratin, TTF stands for thyroid transcription factor, Ber-EP4 is an antihuman epithelial antigen, WT-1 is Wilms tumor protein, CEA is carcinoembryonic antigen, ER is estrogen receptor, and CA is cancer antigen.

  • Breast: CK7 (+), CAM 5.2 (+), vimentin (-), TTF-1 (-), Ber-EP4 (+), WT-1 (-), DPC4 (-)
  • Lung adenocarcinoma: CK7 (+), CAM 5.2 (+), CEA (+), Ber-EP4 (+), WT-1 (-), DPC4 (-)
  • Colorectal: CK20 (+), CAM 5.2 (+), CK17 (-), CK19 (+), CEA (+), TTF-1 (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC4 (-)
  • Gastric: CAM 5.2 (+), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), WT-1 (-), DPC4 (-)
  • Prostate: CK7 (-), CK20 (-), CAM 5.2 (+), CD5/6 (-), CK17 (-), CEA (-), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC4 (-)
  • Pancreas: CK7 (+), CAM 5.2 (+), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC 4 (+)
  • Renal: CK7 (-), CK20 (-), CAM 5.2 (+), CEA (-), TTF-1 (-), CA125 (-), ER (-), CD10 (+), WT-1 (-), DPC4 (-)
  • Neuroendocrine: CK20 (-), CK5/6 (-), CA125 (-), ER (-), Ber-EP4 (-), WT-1 (-), DPC4 (-)
  • Squamous cell carcinoma: CK7 (-), CK20 (-), CK5/6 (+), CK17 (+), TTF-1 (-), CA19.9 (-), CA125 (-), ER (-), Ber-EP4 (-), CD10 (-), S100 (-), WT-1 (-), DPC4 (-)
  • Merkel cell carcinoma: CK7 (-), CK20 (+), CK5/6 (-), CEA (-), CEA (-), CA125 (-), Ber-EP4 (+), CD10 (-), S100 (-), WT-1 (-), DPC4 (-)
• Immunohistochemical screening studies can be used in cases in which no clues point to a particular type of underlying cancer. Immunohistochemical markers and the cellular tissue of origin are as follows:

  • Cytokeratins AE1/AE3 and CAM 5.2 : Epidermis and appendageal tumors
  • Desmin: Smooth muscle tumors
  • Vimentin: Mesenchymal cells, melanoma, lymphoma, sarcoma
  • Carcinoembryonic antigen: Glandular or gastrointestinal tumors
  • S-100: Melanocytic tumors, tumors of eccrine or apocrine glands
  • CD34: Vascular tumors, dermatofibrosarcoma protuberans, angiosarcoma
  • Chromogranin: Neuroendocrine cells
  • Prostate-specific antigen: Prostate carcinoma
• Screening immunophenotypes for undifferentiated neoplasms are as follows:

  • Carcinoma: AE1/AE3 (positive), vimentin (negative), LCA (leukocyte common antigen) (negative), S-100 (negative)
  • Sarcoma: AE1/AE3 (negative), vimentin (positive), LCA (negative), S-100 (negative)
  • Lymphoma: AE1/AE3 (negative), vimentin (negative), LCA (positive), S-100 (negative)
  • Melanoma: AE1/AE3 (negative), vimentin (positive), LCA (negative), S-100 (positive)
• Recent advances in immunohistochemistry have led to recommendations regarding a logical algorithmic approach to the immunohistochemical evaluation of a poorly differentiated neoplasm from an unknown primary source. Pancytokeratin (AE1/AE3 antibodies), CAM5.2, CK7, and CK20 represent tests that can be performed first. Depending on the results additional choices in a "decision tree" can lead to specific diagnoses.^[4]

• MRI, CT, and ultrasonography can be used in select cases to gauge the extent of metastases or to identify metastases if biopsy samples are inconclusive. Imaging studies are also of value when performing a biopsy is dangerous because of proximity to vital organs.
• Fluorine 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging is useful in the staging of melanoma, especially for American Joint Committee on Cancer (AJCC) stages III and IV.^[5]
• Exciting recent developments include serologic testing for immune complexes. 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.^[6] Similar studies are being developed for other types of cancer to help identify patients at high risk for metastasis.

• A biopsy of the skin helps in confirming a diagnosis of tumor. The pattern noted and the microscopic appearance often suggest the likely tissue of origin.

The initial diagnosis can be made by examining frozen sections, but the final diagnosis should be reserved until permanent sections are included. Generally, the histologic features of the metastases are similar to the primary tumor, although metastases may be more anaplastic and exhibit less differentiation. Cases, such as renal cell carcinoma, can be identified through characteristic histologic findings, but, usually, metastases are only classified broadly as adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma. Note the images below.

Certain attributes distinguish metastases from the primary site. 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. Some primary melanomas may arise in the dermis and simulate a metastasis.^[7] On the other hand, some metastases may be epidermotropic and simulate a primary epidermal tumor.^[8]

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.

Determining the presence of metastases is important in staging. FDG-PET scanning may be particularly helpful in the staging of cutaneous malignant melanoma for AJCC stages III and IV to identify soft tissue metastases.