Dermatologic Manifestations of Merkel Cell Carcinoma Workup

Updated: Nov 07, 2018
  • Author: Christopher R Shea, MD; Chief Editor: William D James, MD  more...
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Workup

Imaging Studies

Radiography of the chest is indicated in Merkel cell carcinoma (MCC) to rule out the alternative diagnosis of cutaneous metastasis from a primary small cell neuroendocrine carcinoma (oat cell carcinoma) of the lung.

Staging CT or MRI studies are needed to assess the possibility of dissemination of primary Merkel cell carcinoma to the lymph nodes or the viscera.

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Procedures

Fine-needle aspiration may be helpful to assess recurrence or metastatic spread.

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Histologic Findings

Tumors cells are usually located intradermally; an intraepidermal component may also be present, and a purely intraepidermal (in situ) Merkel cell carcinoma rarely may be encountered. Reactive epidermal hyperplasia is frequent.

Several architectural patterns of intradermal tumor are recognized. The classic trabecular pattern consists of interconnecting strands of tumor cells in the dermis, with formation of cellular aggregates resembling glands or neural rosettes. [29] The intermediate pattern is the most common, and it exhibits large, solid nests of neoplastic cells. The least common, diffuse pattern consists of an infiltration of tumor cells among dermal collagen bundles, without the more distinctive organoid appearance of the trabecular pattern. A particular tumor often contains elements of all architectural patterns, with individual variation in the proportions represented.

Histologic appearance of nodular Merkel cell carci Histologic appearance of nodular Merkel cell carcinoma. Dermal nodule with a cohesive, expansile 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.

The tumor is usually composed of round, small, dark cells with conspicuous nucleoli and open chromatin with peripheral heterochromatin (salt-and-pepper pattern). Less commonly, Merkel cell carcinoma cells may simulate lymphoma, or may exhibit plasmacytoid, clear cell, anaplastic, or spindle-cell features. Mitotic figures and apoptotic bodies are often numerous. Vascular or lymphatic invasion is not uncommon. Histologic variants of Merkel cell carcinoma include the desmoplastic, epidermotropic (resembling mycosis fungoides), and pagetoid (resembling Paget disease [30] or melanoma) types, and tumors with focal true glandular or squamous differentiation. [31, 32, 33] Merkel cell carcinoma has been associated with squamous cell carcinoma, basal cell carcinoma, adnexal tumors, and trichilemmal cyst.

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.

Immunohistochemistry is very helpful. Cytokeratin 20 is expressed in a dotlike paranuclear or crescentic pattern; other low molecular weight (MW) cytokeratin antibodies (eg, CAM5.2, MNF116), while less specific, react in a similar localization pattern. Neurofilament is also expressed in the cytoplasm of most Merkel cell carcinoma. The above findings support the diagnosis of primary Merkel cell carcinoma of the skin and tend to rule out metastatic neuroendocrine carcinoma, as from a pulmonary primary. The CK20 expression is so sensitive and specific that it has largely replaced traditional markers of neuroendocrine differentiation (ie, synaptophysin, chromogranin) as the initial antibody panel of choice; however, the latter may be helpful adjuncts in difficult cases. [34]

Fluorescence in-situ hybridization studies of MCV in the tumors can differentiate a punctate pattern, indicating viral integration, correlated with moderate viral load, versus a combined punctate and diffuse pattern, associated with very high viral load. [35]

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

Electron microscopic findings are characteristic, revealing a lobulated nucleus that may contain 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 cytokeratin distribution visualized by immunohistochemistry. [36] Desmosomes may be present. Most diagnostic is the dense core granule (80-120 nm in diameter), the source, and the locus of the neuroendocrine peptides.

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 aspirates (FNAs) 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. [37]

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

A consensus staging system based on analysis of 5823 cases from the US National Cancer Database was been adopted for use by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer in 2010. [38] This staging scheme has been updated in the current classification of the AJCC (8th edition). [39] The 4-stage system is summarized in the Tables below.

Table 1. (Open Table in a new window)

 

Clinical Stage Groups (cNM)

 

Pathological Stage Groups (pNM)

Tumor (T)

Node (N)

Metastasis (M)

Tumor (T)

Node (N)

Metastasis (M)

0

Tis

N0

M0

0

Tis

N0

M0

I

T1

N0

M0

I

T1

N0

M0

IIA

T2-3

N0

M0

IIA

T2-3

N0

M0

IIB

T4

N0

M0

IIB

T4

N0

M0

III

T0-4

N1-3

M0

IIIA

T1-4

N1a(sn) or N1a

M0

       

T0

N1b

M0

     

IIIB

T1-4

N1b–3

M0

IV

T0-4

Any N

M1

IV

T0-4

Any N

M1

Table 2. (Open Table in a new window)

Tumor (T)

Node (N)

Metastasis (M)

Tx, primary tumor cannot be assessed

T0, no primary tumor

Tis, in situ primary tumor

T1, primary tumor ≤2 cm

T2, primary tumor >2 cm but ≤5 cm

T3, primary tumor >5 cm

T4, primary tumor  invades fascia, muscle, cartilage, or bone

cNx, regional lymph  nodes cannot be clinically  assessed (eg, previously removed  for another reason, body habitus)

cN0, no regional lymph node metastasis by clinical or  radiological evaluation

cN1, clinically detected regional nodal metastasis

cN2, in-transit metastasis without lymph node  metastasis

cN3, in-transit metastasis with lymph node  metastasis

pNx, regional lymph nodes cannot be  assessed (eg, previously removed for another  reason) or not removed for pathological evaluation

pN0, no regional lymph node metastasis  detected on pathological evaluation

pN1a(sn), clinically occult nodal  metastasis identified only by sentinel lymph node biopsy

pN1a, clinically occult regional lymph  node metastasis following lymph node dissection

pN1b, clinically or radiologically detected regional lymph node metastasis, pathologically confirmed

pN2, in-transit metastasis without lymph  node metastasis

pN3, in-transit metastasis with lymph  node metastasis

M0, no distant  metastasis

M1, distant  metastasis

 M1a, metastasis to distant skin, distant subcutaneous  tissue, or distant lymph  nodes

 M1b, lung

 M1c, all other distant sites

Sentinel lymph nodes may be examined by breadloafing and subsequent analysis of keratin expression with an antikeratin cocktail. Because dendritic cells in the lymph nodes may express keratin, in case of doubt anti-CK20 antibodies may be useful to rule out metastatic Merkel cell carcinoma. As in other solid tumors, positive sentinel lymph nodes correlate with impaired prognosis. [38]

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