Imaging Studies
Dermoscopy has been shown to be useful in identifying metastases. In individuals with known underlying cancer, a nodule with prominent vacular structures may indicate metastases. Pigmentation can be seen in metastases originating from breast carcinoma in addition to melanoma. [11]
Magnetic resonance imaging (MRI), computed tomography (CT) scanning, 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 proximity to vital organs makes performing a biopsy dangerous.
Determining the presence of metastases is important in staging. Fluorine 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging is useful in staging melanoma, especially in patients with American Joint Committee on Cancer (AJCC) stage III or IV cancer. [12]
Immunohistochemical Studies
Failure to perform a biopsy on a metastasis may lead to a delay in treatment. Lesions that exactly mimic cysts, dermatofibromas, pyogenic granulomas, or hemangiomas have all been reported. A high index of suspicion is needed so that tumors are not overlooked.
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 to delineate the tissue of origin.
It is important to perform a panel of immunohistochemical marker studies and to carefully correlate the resultant 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. [13]
It is important to be aware of entities such as intravascular histiocytosis that can cause diagnostic confusion on biopsy. [14] Special stains are helpful in these instances.
Immunophenotypes
Carcinoma immunophenotypes, with the location and antibody positivity/negativity, are as follows, with (+) indicating "always positive,” (-) indicating "negative but with rare exceptions," CK representing types of cytokeratin, TTF standing for thyroid transcription factor, Ber-EP4 representing an antihuman epithelial antigen, WT-1 referring to Wilms tumor protein, CEA standing for carcinoembryonic antigen, ER representing estrogen receptor, CA referring to cancer antigen, CD standing for cluster of differentiation, CAM 5.2 being a clone developed against certain keratins, DPC4 being a tumor-suppressor gene, and S100 being a family of calcium-binding proteins:
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Breast: CK7 (+), CAM 5.2 (+), vimentin (-), TTF-1 (-), Ber-EP4 (+), WT-1 (-), DPC4 (-)
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Lung adenocarcinoma: CK7 (+), CAM 5.2 (+), CEA (+), Ber-EP4 (+), WT-1 (-), DPC4 (-)
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Colorectal: CK20 (+), CAM 5.2 (+), CK17 (-), CK19 (+), CEA (+), TTF-1 (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC4 (-)
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Gastric: CAM 5.2 (+), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), WT-1 (-), DPC4 (-)
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Prostate: CK7 (-), CK20 (-), CAM 5.2 (+), CD5/6 (-), CK17 (-), CEA (-), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC4 (-)
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Pancreas: CK7 (+), CAM 5.2 (+), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC4 (+)
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Renal: CK7 (-), CK20 (-), CAM 5.2 (+), CEA (-), TTF-1 (-), CA125 (-), ER (-), CD10 (+), WT-1 (-), DPC4 (-)
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Neuroendocrine: CK20 (-), CK5/6 (-), CA125 (-), ER (-), Ber-EP4 (-), WT-1 (-), DPC4 (-)
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Squamous cell carcinoma: CK7 (-), CK20 (-), CK5/6 (+), CK17 (+), TTF-1 (-), CA19.9 (-), CA125 (-), ER (-), Ber-EP4 (-), CD10 (-), S100 (-), WT-1 (-), DPC4 (-)
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Merkel cell carcinoma: CK7 (-), CK20 (+), CK5/6 (-), CEA (-), CEA (-), CA125 (-), Ber-EP4 (+), CD10 (-), S100 (-), WT-1 (-), DPC4 (-)
Screening studies
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:
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CKAE1/AE3 and CAM 5.2 : Epidermis and appendageal tumors
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Desmin: Smooth muscle tumors
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Vimentin: Mesenchymal cells, melanoma, lymphoma, sarcoma
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CEA: Glandular or gastrointestinal tumors
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S-100: Melanocytic tumors, tumors of eccrine or apocrine glands
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CD34: Vascular tumors, dermatofibrosarcoma protuberans, angiosarcoma
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Chromogranin: Neuroendocrine cells
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Prostate-specific antigen: Prostate carcinoma
Screening immunophenotypes for undifferentiated neoplasms are as follows:
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Carcinoma: AE1/AE3 antibodies (positive), vimentin (negative), LCA (leukocyte common antigen; negative), S-100 (negative)
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Sarcoma: AE1/AE3 antibodies (negative), vimentin (positive), LCA (negative), S-100 (negative)
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Lymphoma: AE1/AE3 antibodies (negative), vimentin (negative), LCA (positive), S-100 (negative)
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Melanoma: AE1/AE3 antibodies (negative), vimentin (positive), LCA (negative), S-100 (positive)
Evaluation algorithm
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), CAM 5.2, 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. [15]
Other Tests
Recent studies indicate that it may be possible to use Augmented Intelligence (AI) to determine which cancers are more likely to metastasize. AI may identify morphological features associated with metastasis that might otherwise be missed which could help assess the risk of metastasis for primary cutaneous squamous cell carcinoma [20] .
Histologic Findings
A biopsy of the skin helps in confirming a diagnosis of tumor. The pattern and 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.
High-powered microscopic examination reveals tubules composed of clear cells, hemorrhage, and a prominent vascular pattern characteristic of metastatic renal cell carcinoma.
Biopsy of a nodule on the scalp revealed a precocious metastasis from renal cell carcinoma. Cutaneous metastases are sometimes the first presentation of internal disease. Histologic examination reveals a spherical tumor in the dermis with no connection to the overlying epidermis. Hematoxylin and eosin‒stained sections; original magnification 20x.
Biopsy of metastatic melanoma reveals a well-circumscribed tumor in the dermis with no connection with the overlying epidermis. Hematoxylin and eosin‒stained sections; original magnification 20x.
In some cases, such as in patients with renal cell carcinoma, the cancer can be identified through characteristic histologic findings, but metastases usually are classified only broadly as adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma. (See the images below.)
Breast cancer metastasis with hyperchromatic cells extending between thickened collagen bundles. Dilated lymphatics are noted.
A well-circumscribed metastasis of renal cell carcinoma is surrounded by compressed collagen, which is indicative of rapid growth.
Pleomorphic clear cells with prominent vasculature are characteristic of metastatic renal cell carcinoma.
Metastatic squamous cell cancer typically does not involve the epidermis, allowing for differentiation of metastases from primary cutaneous squamous cell cancer.
High-powered examination reveals a nest of atypical melanocytes with enlarged and pleomorphic nuclei. Melan-A and S-100 stains were positive and helped confirm the diagnosis. Hematoxylin and eosin‒stained sections; original magnification 200x.
High-power examination reveals neoplastic epithelioid cells within dilated lymphatics. Hematoxylin and eosin‒stained sections; original magnification, 400x.
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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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Alopecia neoplastica due to metastatic breast cancer.
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Close-up view of patient with alopecia neoplastica due to metastatic breast cancer shows telangiectases and nodularity. The plaque was markedly indurated on palpation; in contrast, patients with alopecia areata would exhibit normal skin texture.
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Breast cancer with an Indian file pattern of metastasis.
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A well-circumscribed metastasis of renal cell carcinoma is surrounded by compressed collagen, which is indicative of rapid growth.
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Pleomorphic clear cells with prominent vasculature are characteristic of metastatic renal cell carcinoma.
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Metastatic squamous cell cancer typically does not involve the epidermis, allowing for differentiation of metastases from primary cutaneous squamous cell cancer.
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Biopsy of metastatic melanoma reveals a well-circumscribed tumor in the dermis with no connection with the overlying epidermis. Hematoxylin and eosin‒stained sections; original magnification 20x.
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High-powered examination reveals a nest of atypical melanocytes with enlarged and pleomorphic nuclei. Melan-A and S-100 stains were positive and helped confirm the diagnosis. Hematoxylin and eosin‒stained sections; original magnification 200x.
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High-power examination reveals neoplastic epithelioid cells within dilated lymphatics. Hematoxylin and eosin‒stained sections; original magnification, 400x.
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Inflammatory breast carcinoma.
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High-powered microscopic examination reveals tubules composed of clear cells, hemorrhage, and a prominent vascular pattern characteristic of metastatic renal cell carcinoma.
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Biopsy of a nodule on the scalp revealed a precocious metastasis from renal cell carcinoma. Cutaneous metastases are sometimes the first presentation of internal disease. Histologic examination reveals a spherical tumor in the dermis with no connection to the overlying epidermis. Hematoxylin and eosin‒stained sections; original magnification 20x.
