Skin Cancer - Merkel Cell Carcinoma Workup

Updated: Mar 27, 2023
  • Author: James M Pearson, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Approach Considerations

Guidelines on the diagnosis and treatment of Merkel cell carcinoma were released in 2015 by a collaborative group of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and Treatment of Cancer (EORTC). Diagnostic guidelines included the following [4] :

  • Clinical features of the cutaneous/subcutaneous nodules contribute little to the diagnosis of Merkel cell carcinoma

  • The diagnosis is made by histopathology, and an incisional or excisional biopsy is mandatory

  • Immunohistochemical staining contributes to clarification of the diagnosis

  • Initial work-up consists of ultrasonography of the locoregional lymph nodes and total body scanning examinations

  • In patients without clinical evidence of regional lymph node involvement, sentinel node biopsy is recommended, if possible, and will be taken into account in a new version of the American Joint Committee on Cancer classification


Laboratory Studies

Baseline laboratory studies should include a complete blood count (CBC), a chemistry profile, and liver function tests.


Imaging Studies

See the list below:

  • No optimal imaging algorithm has been defined.

  • Because of the difficulties in distinguishing metastatic oat cell carcinoma from Merkel cell carcinoma (MCC), chest radiography should be performed.

  • Obtain CT scans of the chest, abdomen, and pelvis to rule out metastases.

  • Some have suggested that obtaining octreotide scanning may also be helpful for ruling out metastases. However, this study is not part of the standard evaluation.

  • The role of [18 F]2-fluoro-D-2-deoxyglucose (FDG) positron emission tomography (PET) remains undefined.

    • Recent reports indicate that FDG-PET may aid in the staging and following up Merkel cell carcinomas (MCCs).

    • Yao et al (2005) reported that pretreatment FDG-PET scans revealed metastatic disease in subcentimeter lymph nodes that were not appreciated on initial CT images. [15] Likewise, posttreatment FDG-PET scans revealed responses to therapy, with the level of FDG uptake correlating with complete responses to treatment and with residual disease.


Histologic Findings

Diagnosing Merkel cell carcinoma (MCC) is difficult and requires a high degree of suspicion. Light microscopy, electron microscopy, and immunohistochemistry may be needed to confirm the diagnosis.

Light microscopy

On occasion, Merkel cell carcinomas (MCCs) may be diagnosed with histology alone, but confirmation with immunohistochemistry and/or electron microscopy is always encouraged. Diagnosis by means of light microscopy alone is difficult because the appearance of Merkel cell carcinomas (MCCs) is similar to that of many other undifferentiated small-cell neoplasms, especially other APUD tumors, such as metastatic oat cell carcinoma. In fact, 66% of Merkel cell carcinomas (MCCs) are misdiagnosed when studied with light microscopy alone.

These points emphasize the need to consider Merkel cell carcinoma (MCC) when small cell tumors are being diagnosed with light microscopy. Light microscopy reveals round-to-polygonal neoplastic cells that are compactly arranged. Rare fusiform cells are also observed. A ball-in-mitt arrangement of cells is often described, where 1 or 2 crescentic tumor cells wrap around a round tumor cell. A grenz zone usually separates the tumor from the epidermis. As a result, the epidermis is commonly spared because the Merkel cell carcinoma (MCC) alternatively extends into the subcutaneous tissues, vessels, and lymphatics.

Gould et al (1985) described a widely accepted histologic classification of Merkel cell carcinoma (MCC). [16] The classification details 3 specific cellular patterns.

The most common pattern is the intermediate cell type; observed in over 50% of patients with Merkel cell carcinoma (MCC). These tumors display a large nest of cells without organoid architecture or recognizable palisading. A distinct disassociation exists between cells. Areas of focal necrosis and lymphocytic invasion are typical. Cytoplasm is moderate, nuclei are vesicular, and mitoses are abundant.

The trabecular cell type is observed in 25% of Merkel cell carcinomas (MCCs). It is believed to be the original tumor Toker described (1972). [7] In this class, the cells are arranged in organoid clusters with interconnected trabeculae separated by strands of connective tissue. Clusters may show glandlike organization. Individual cells are compactly arranged round-to-polygonal cells. Cytoplasm is abundant, and the nuclei are round, centrally located, and vesicular. Pleomorphism and mitotic activity is mild to moderate.

The final and least common class is the small cell variation. This pattern consists of solid sheets and clusters of cells separated by abundant stroma, with large areas of necrosis. The cells are small with scant cytoplasm and hyperchromatic nuclei. Pleomorphism and mitoses are common.

Electron microscopy

Because of the difficulty in diagnosing Merkel cell carcinoma (MCC) with light microscopy, electron microscopy plays an important role in the diagnosis of Merkel cell carcinoma (MCC). The ultrastructure of the tumor is similar to that of the normal Merkel cell. The cells are round to ovoid and intimately apposed to adjacent tumor cells, with desmosomal junctions to surrounding keratinocytes. One of the most consistent findings is the aggregation of intermediate filaments in a paranuclear location. Other characteristic findings are membrane-bound, dense core granules. The granules are usually concentrated in the periphery or in dendritelike processes.


Immunohistochemistry is often used to confirm Merkel cell carcinoma (MCC). Merkel cell tumors stain positively for NSE, as would any APUD cell tumor. They also demonstrate perinuclear staining with antikeratin antibodies to low-molecular-weight cytokeratins 8, 18, and 19. These 2 markers are the most constant immunohistochemical markers and are often said to be present in 100% of Merkel cell carcinomas (MCCs). A third marker, neurofilament protein, is used to distinguish Merkel cell carcinoma (MCC) from oat cell carcinoma. Neurofilament protein is seen in nearly all Merkel cell carcinomas (MCCs) but few oat cell carcinomas.

Other markers present with variable frequency are chromogranin, synaptophysin, vasoactive intestinal peptide (VIP), calcitonin, bombesin, corticotropic hormone (ACTH), met-encephalon, gastrin, and somatostatin.

Finally, the absence of certain markers also helps in the diagnosis of Merkel cell carcinoma (MCC) by ruling out other tumors. S-100 is seen in melanoma, whereas leukocyte common antigen is present in lymphoma. Neither of these is found in Merkel cell carcinoma (MCC).



No universally accepted staging system for Merkel cell carcinoma (MCC) exists. Some have used the American Joint Committee on Cancer Staging System for skin cancer to stage Merkel cell carcinoma (MCC). Others use a staging system developed by the Memorial Sloan Kettering Cancer Center. This article uses the widely-used system suggested by Yiengpruksawan et al (1991), as follows: [17]

  • Stage I - Absence of lymphadenopathy

    • Stage IA - Tumors < 2 cm

    • Stage IB - Tumors >2 cm

  • Stage II - Positive regional lymphadenopathy

  • Stage III - Evidence of distant metastases

At presentation, most patients have stage I disease (55%), followed by stage II (31%), and stage III (6%).