Dermatologic Manifestations of Merkel Cell Carcinoma Workup

Updated: Jul 14, 2020
  • Author: Meghana Agni, MD; Chief Editor: William D James, MD  more...
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Approach Considerations

Since the cutaneous manifestations can resemble a variety of other skin conditions (see DDx), a high degree of clinical suspicion is required for the expedient diagnosis of Merkel cell carcinoma. In 2018, the National Comprehensive Cancer Network (NCCN) consensus guidelines incorporated new recommendations for the use of Merkel cell polyoma virus (MCPyV) as a biomarker and the use of checkpoint immunotherapies for treatment of advanced (metastatic or unresectable) cases. [52]

During the history and physical examination, a complete skin and lymph node examination is recommended. Serologic quantitation of MCPyV oncoprotein antibodies may be considered as part of the initial workup. Seronegative patients may have a higher risk of recurrence; in seropositive patients, a rising titer may be an early indicator of recurrence. [17, 64] Skin biopsy, commonly a punch biopsy (a small core of tissue) or a shave biopsy (a portion of the lesional surface is removed using a scalpel), is required to establish a histopathologic diagnosis. Evaluation of routine hematoxylin and eosin‒stained slides, along with a panel of immunohistochemically stained slides, is necessary to differentiate Merkel cell carcinoma from other morphologically similar entities. Results of a diagnostic immunohistochemical panel would likely feature CK20+, TTF-1-, CK7-, LCA-, S100-, and positivity in a neuroendocrine marker such as insulinoma-associated protein 1 (INSM-1), chromogranin, or synaptophysin. [10, 19, 80, 81]

After pathologic diagnosis of Merkel cell carcinoma has been confirmed, another complete skin and regional lymph node evaluation with palpation for lymphadenopathy is performed. Imaging is important for evaluation for potential metastases, and the preferred imaging modalities include whole body positron-emission tomography with fluorodeoxyglucose (PET-FDG), possibly in combination with computed tomography (CT) with contrast of the neck, chest, abdomen, and pelvis, and/or brain magnetic resonance imaging (MRI) depending on the clinical scenario. Whole body PET-FDG offers improved sensitivity compared with CT alone, with an additional impact on management in 37% of patients. [82]

Furthermore, the incidence of occult nodal metastasis without clinically detectable lymphadenopathy is high (~30%). [78] Therefore, sentinel lymph node biopsy (SLNB) is recommended in all biopsy-proven Merkel cell carcinoma patients with no clinical evidence of regional lymph node involvement, unless surgery is contraindicated or declined. [52, 78] Every effort should be made to perform SLNB prior to surgical intervention. [52] The SLNB specimen should also be evaluated using immunohistochemical stains. Alternatively, patients with a Merkel cell carcinoma diagnosis who have clinically palpable or radiologically evident lymph node disease should undergo fine-needle aspiration (FNA) biopsy or core needle biopsy to enable pathologic confirmation of clinically positive nodes, again, with the help of immunohistochemical markers. [52, 78]

Finally, if metastases are suspected upon evaluation of a biopsy-proven Merkel cell carcinoma patient, a multidisciplinary tumor board meeting is recommended to discuss enrollment in a clinical trial for systemic therapy (checkpoint immunotherapy preferred over chemotherapy) and/or radiation, palliation, or surgery. [13, 52]

A detailed summary of the recommended workup and associated protocols for biopsy-proven Merkel cell carcinoma is provided in Table 1 below. [52]

Recommended workup and protocols for biopsy-proven Recommended workup and protocols for biopsy-proven Merkel cell carcinoma.


Merkel cell carcinomas that are diagnosed at earlier stages have better outcomes. Because of the rarity of this carcinoma, consulting a dermatologist might improve the likelihood of efficient, accurate diagnosis. High dermatologist density has been associated with improved Merkel cell carcinoma‒specific survival, suggesting that provider familiarity with the disease may have a positive impact on patient outcomes. [37, 43] The dermatopathologist evaluating the biopsy and excision specimens plays a crucial role in diagnosing and staging the disease. In cases with positive lymph nodes and/or distant metastases, it is recommended that a multidisciplinary tumor board be consulted to ensure high-quality, coordinated care based on the individual clinical scenario. [13, 52]


Imaging Studies

Imaging is helpful at various time points from workup to follow-up and when clinically indicated for evaluation of suspected metastasis or unresectable Merkel cell carcinoma (see Workup, Table 1). Baseline imaging is recommended soon after biopsy-proven diagnosis to identify and quantify any potential regional and distant metastasis, or it might be done after sentinel lymph node biopsy (SLNB) in cases without clinically evident lymphadenopathy. Whole-body positron-emission tomography with fluorodeoxyglucose (PET-FDG) combined with CT scanning (with contrast) of the neck, chest, abdomen, and pelvis is the preferred combination of modalities. In addition, brain MRI with contrast is recommended to evaluate for brain metastases. In the case of overt clinically suggestive lymphadenopathy with increased risk of metastasis, imaging with the same modalities may be performed to evaluate the extent of lymph node and/or visceral organ involvement. Imaging has the potential to affect staging and influence management decisions, including radiation field‒placement and dose selection. [83] However, imaging is secondary to SLNB for staging purposes because it cannot identify subclinical disease. [52, 83] Follow-up imaging studies are used as clinically indicated to ascertain treatment response and evaluate for recurrences. [52]



Sentinel lymph node biopsy (SLNB) with pathologic evaluation using immunohistochemistry is indicated for all biopsy-proven Merkel cell carcinoma patients who have local cutaneous disease without clinically apparent lymphadenopathy. [52, 78]

Fine-needle aspiration or core needle biopsy is indicated to confirm the presence of nodal metastases in those with clinically suggestive lymphadenopathy and may be helpful to assess for recurrence. [52]

Radiation therapy (RT) is an alternative approach in patients who are not surgical candidates, and it is also an option for advanced unresectable metastatic disease. Adjuvant RT is indicated in select circumstances guided by the clinical situation (see Workup,Table 1). [52] For example, in the head and neck region, there is an increased risk for false-negative results in SLNB; therefore, RT of the nodal beds is suggested after SLNB and in those cases in which SLNB is not possible, may be falsely negative, or may have been unsuccessful. [52] In addition, adjuvant RT to the primary tumor site after wide local excision is associated with improved locoregional control and disease-free survival in multiple studies. [84, 85, 86] However, in patients with small tumors (< 2 cm in greatest dimension) at low risk for recurrence, adjuvant RT may provide little additional benefit. [45, 48] The National Comprehensive Cancer Network guidelines state that clinical observation without adjuvant radiotherapy may be considered for a subset of immunocompetent patients with low-risk tumors that are small (ie, < 1 cm), widely excised, and free of lymphovascular invasion. [13, 52]


Histologic Findings

Routine hematoxylin and eosin‒stained slides, as well as immunohistochemical stains, usually are required to diagnose Merkel cell carcinoma. It is primarily a dermal tumor, with frequent extension into the subcutaneous fat. The leading edges exhibit infiltrative or pushing borders, and there is often a lymphohistiocytic infiltrate accompanying the tumor cells. [81] There is intraepidermal spread in about 10% of cases, with Pautrier-like microcollection formation (cutaneous T-cell lymphoma and superficial spreading melanoma enter the differential diagnosis). [10] Purely intraepidermal (in situ) lesions have rarely been described. The tumor is quite often accompanied by reactive epidermal hyperplasia. The epidermis may feature a coexisting actinic keratosis or squamous cell carcinoma in situ. [10]

Several architectural patterns are recognized, but there are three main histopathologic subtypes: intermediate, trabecular, and small-cell variants. The intermediate variant is the most common, and it exhibits large, solid nodules made up of diffuse sheets of basophilic round-to-polygonal cells with characteristic round-to-oval nuclei containing powdery chromatin and inconspicuous nucleoli. The trabecular pattern consists of delicate interconnecting strands of round-to-polygonal cells with abundant cytoplasm, round centrally located vesicular nuclei with inconspicuous nucleoli, common nuclear molding, and neoplastic aggregates resembling glands or neural rosettes. [2] The least common is small-cell pattern, which consists of small, round blue cells with scant cytoplasm and oval, hyperchromatic nuclei with prominent nucleoli. The tumor cells form solid sheets and clusters with crush artifact and nuclear molding. A particular tumor often contains elements of all architectural patterns, with individual variation in the proportions represented.

See the images below.

Histopathologic appearance of nodular Merkel cell Histopathologic appearance of nodular Merkel cell carcinoma. Dermal nodule with a cohesive, expansive growth of basophilic cells.
High-power view demonstrates an open chromatin pat High-power view demonstrates an open chromatin pattern and a high mitotic index.

Regardless of histopathologic type, Merkel cell carcinoma is usually composed of small, round-to-polygonal basaloid cells with inconspicuous nucleoli and open chromatin with peripheral heterochromatin (salt-and-pepper nuclear pattern). Less commonly, Merkel cell carcinoma cells may simulate lymphoma, with a heavy lymphoid infiltrate and the presence of lymphoid follicles, or it may exhibit plasmacytoid, clear-cell, anaplastic, or spindle-cell features. Mitotic figures and apoptotic bodies are often numerous. Lymphovascular invasion is not uncommon and has been associated with a worse prognosis. [11, 51] Other histopathologic variants of Merkel cell carcinoma include the desmoplastic, epidermotropic (resembling mycosis fungoides), and pagetoid (resembling Paget disease [87] or melanoma) types, and tumors with focal true glandular or squamous differentiation. [88, 89, 90] In uncommon cases, Merkel cell carcinoma is associated with squamous cell carcinoma, basal cell carcinoma, adnexal tumors, trichilemmal or follicular cysts, or trichoblastoma. [10, 71] Combined Merkel cell carcinomas arising in association with squamous cell carcinoma seem to uniformly lack viral integration. [72]

See the images below.

Merkel cell carcinoma with a focus of squamous dif Merkel cell carcinoma with a focus of squamous differentiation.
Prominent in situ nested component of Merkel cell Prominent in situ nested component of Merkel cell carcinoma, simulating malignant melanoma.

Several tumors might have small, round blue cell morphology, so immunohistochemistry is required for distinguishing Merkel cell carcinoma from other histopathologically similar tumors, including poorly differentiated primary cutaneous malignancies and metastases to the skin. [81] Positive staining for cytokeratin (CK) 20 and neuroendocrine markers (ie, synaptophysin, chromogranin, neuron-specific enolase, insulinoma-associated protein-1 [INSM1]), along with negative staining for TTF-1, CK7, and lymphoid markers, are taken together to make the diagnosis of Merkel cell carcinoma. [19, 80, 81] Of note, small cell carcinoma of the lung can rarely express CK20 (3%); conversely, Merkel cell carcinoma can exceptionally rarely be focally positive for TTF-1 or negative for CK20 (10%), or both. In challenging cases such as this, the whole complement of markers should be used for accurate diagnosis. [10, 19]

Merkel cell carcinomas usually show positivity for CKs, including low-weight CKs (CAM 5.2, or AE1/AE3) and especially CK20, with a characteristic dotlike perinuclear pattern. Approximately 90% of Merkel cell carcinomas exhibit CK20 positivity. [81] Neurofilament is another sensitive and specific marker (positive in approximately 80% of Merkel cell carcinomas), which is particularly helpful, paired with TTF-1, in the diagnosis of CK20-negative cases of Merkel cell carcinoma. [81] Lack of S100 staining can distinguish Merkel cell carcinoma from melanoma or small-cell carcinoma, which feature 97% and 50% positive cases, respectively. [10] Leukocyte common antigen (LCA) could be helpful for differentiating lymphoma, because 98% of lymphoma cases are positive for LCA, while Merkel cell carcinoma is nonreactive. [10]

See the image below.

Dotlike paranuclear pattern of cytokeratin immunol Dotlike paranuclear pattern of cytokeratin immunolocalization.

A 2018 study of 52 cases demonstrates that the classic or expected immunohistochemical profile (CK20+, NF+, Chromo+,TTF-1-, CK7-) is observed more often in Merkel cell polyoma virus (MCPyV)‒positive Merkel cell carcinomas than MCPyV-negative ones (75% vs 25%, P=.002). Additionally, MCPyV-negative carcinomas less frequently express neurofilament (66.7% vs 100%, P=.001) and more often express TTF-1 (37.5% vs 3.6%, P=.003). [91]  Fluorescence in-situ hybridization studies of MCPyV in the tumors can differentiate a punctate pattern, indicating viral integration correlated with moderate viral load, versus a combined punctate and diffuse pattern, which is associated with very high viral load. [92]

Electron microscopic findings are also characteristic, revealing a lobulated nucleus that may contain proteinaceous filaments called rodlets. The cytoplasm is electron-lucent and contains a prominent Golgi apparatus and numerous ribosomes. Intermediate filaments are numerous and often assume a parallel or whorled arrangement near the nucleus, accounting for the dotlike pattern of CK distribution visualized by immunohistochemistry. [93] Desmosomes may be present. Also characteristic are the dense core granules (80-120 nm in diameter), the source and the locus of the neuroendocrine peptides.

See the images below.

Electron micrograph of Merkel cell carcinoma showi Electron micrograph of Merkel cell carcinoma showing a dense core granule (arrow).
Electron micrograph of Merkel cell carcinoma showi Electron micrograph of Merkel cell carcinoma showing whorled bundles of intermediate filaments (arrow) near nucleus in Merkel cell carcinoma.

Cytologic preparations from fine-needle aspiration demonstrate a loosely cohesive pattern of small-to-intermediate‒sized cells with round nuclei, finely granular chromatin, a thin rim of cytoplasm, and, infrequently, pseudorosette formation. Immunocytochemistry may be helpful. [94]

See the image below.

Pseudorosette formation in Merkel cell carcinoma. Pseudorosette formation in Merkel cell carcinoma.


In patients with a biopsy-proven Merkel cell carcinoma diagnosis, further workup including physical examination, with complete skin and lymph node evaluation, imaging, and surgery is required to establish the American Joint Committee on Cancer (AJCC) stage. Prior to 2010, up to five different staging systems contributed variable criteria for Merkel cell carcinoma staging, which made it difficult to compare research results. The first consensus staging system, based on analysis of 5823 cases from the US National Cancer Database, was adopted for use by the AJCC in 2010. [50] A 2017 update based on analysis of 9387 Merkel cell carcinoma cases, from the same database, comprises the current AJCC (8th edition) staging classification. [27]

Accurate staging provides important information on prognosis, guides management strategies, and can determine eligibility for clinical trials. Patients with similar 5-year survival outcomes are grouped together, forming the basis for staging using the TNM (tumor, node, metastasis) system. The TNM system is based on the size and extent of the primary tumor (T), the extent of spread to regional lymph nodes (N), and the presence of metastases to distant sites (M). The T, N, and M stages are combined, and these are stratified into an overall numerical stage of I to IV, increasing with worsening severity and prognosis.

Stage I and II Merkel cell carcinomas are localized to the skin. Stage III of Merkel cell carcinoma includes metastases to the lymph nodes close in proximity to the primary tumor (regional lymph nodes), or in the unusual case of positive lymph nodes when no primary tumor is detected (unknown primary). Stage IV includes metastases to distant sites, other than the regional lymph nodes. The stages are each further subdivided into A and B categories to, again, reflect groups of patients with similar prognoses. Previously, the TNM staging system based its categories on clinical and imaging findings, but the 2017 updated 8th edition AJCC staging incorporates staging categories based on pathologic staging of lymph nodes. Pathologic staging provides more accurate information than clinical examination and/or imaging. Pathologic examination is required to detect micrometastasis in sentinel lymph node biopsy specimens or to confirm the presence of metastasis. [13, 52, 78]

The current, AJCC 8th edition, four-stage system is summarized in Table 2 below. [27, 95]

Summary of Merkel cell carcinoma AJCC, 8th Edition Summary of Merkel cell carcinoma AJCC, 8th Edition, Staging. Courtesy of with permission.

Components of the pathology report

The pathology report contributes significantly to staging. However, at the present time, consistent histopathologic synoptic reporting for Merkel cell carcinoma is not widespread, which limits retrospective analysis of diagnostic and potentially prognostic parameters. Consequently, the AJCC strongly encourages synoptic reporting for Merkel cell carcinoma beyond that which is required for determination of T-stage. The College of American Pathologists (CAP) provides a complete synoptic protocol for cutaneous Merkel cell carcinoma. [52, 96]

There are two elements required to ascertain the T-stage: (1) maximum tumor diameter (tumor size) and (2) tumor extension (invasion of the fascia, muscle, cartilage, and bone). [52] The tumor should be measured clinically before resection to avoid underestimation of size due to shrinkage of formalin-fixed tissue. Evaluation by a pathologist is needed to determine extracutaneous extension. Although not required for staging, the AJCC strongly encourages the reporting of primary tumor thickness (measured microscopically), tumor site, peripheral and deep margin status, and lymphovascular invasion, all included in the CAP protocol. Primarily owing to possible prognostic potential, other recommended parameters include specimen laterality, mitotic rate, infiltrating lymphocytes (present/absent, brisk/nonbrisk), growth pattern (nodular/infiltrative), and presence of second malignancy. [11, 51, 52, 96]

Staging SLNB

Sentinel lymph node biopsy (SNLB) specimens should be cut by serial sectioning, or “bread-loafing,” the node to increase observable surface area available for microscopic evaluation. [81] Analysis of immunohistochemically stained slides is highly recommended. [81] Because dendritic cells in the lymph nodes may express keratin and even microscopic tumor deposits are considered positive, cytokeratin (CK) 20 immunopositivity is useful to locate any nests of metastatic Merkel cell carcinoma [labeled N1a(sn), if detected via SLNB]. [94] A typical immunohistochemical panel of stains would include CK20 and/or NF, TTF-1, CK7, S100, and a neuroendocrine marker such as INSM-1, chromogranin, synaptophysin, or CD56. [80, 81, 91] As in other solid tumors, positive sentinel lymph nodes correlate with impaired prognosis. [50]


Laboratory Studies

The most recent National Comprehensive Cancer Network guidelines (2018) introduce a role for serology for Merkel cell polyomavirus (MCPyV) antibodies when performing the initial skin biopsy and, subsequently, at follow-up visits for comparison. [52] Low baseline values of antibodies to the major MCPyV capsid protein (VP1) correspond with a higher risk of recurrence and increased mortality, but do not vary with disease burden. [64] Additionally, rising MCPyV T-antigen antibodies can predict and sometimes precede clinical detection of recurrent disease. In newly diagnosed Merkel cell carcinoma, the condition of rising T-antigen antibodies is associated with a 66-83% positive predictive value for increasing tumor burden, but falling titers have a negative predictive value of 97%. [17] Therefore, baseline titers for both the MCPyV VP1 and T antigens may be helpful for patient risk stratification and prognostication. [15, 52] Determining the viral status of a Merkel cell carcinoma may have prognostic value, in and of itself, because MCPyV-negative tumors might be more clinically aggressive with higher risk of recurrence, progression, and death from the carcinoma with putatively less immunogenicity than the virus-positive counterpart. [60]