AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Merkel cell carcinoma (MCC) is a rare, aggressive, primary skin cancer exhibiting neuroendocrine differentiation. Several synonyms exist; however, the term MCC is still most commonly used in view of the many similarities of the constituent tumor cell to the normal Merkel cell (MC) of the skin. In 1875, Friedrich Sigmund Merkel described tastzellen (touch cells) in the skin of the snouts of moles and pigs and proposed that they had a mechanoreceptor function.

In human development, MCs appear by the eighth gestational week, possibly being derived from a primitive epidermal stem cell. MCs are present in high numbers on the lip, the hard palate, the palms, the finger pads, the proximal nail folds, and the dorsa of the feet. MCs have a predilection for perifollicular areas in the skin; confirmed reports exist of MCs free in the dermis, but they are most easily identified in the basal layer of the epidermis. Normal MCs in skin have several proposed functions, including induction or stimulation of perifollicular or dermal nerve plexuses via a direct complex, stimulation of keratinocyte proliferation and maintenance of their differentiation, histogenesis of the nail, and release of various bioactive substances to the dermis. Recent studies documenting marked cyclical changes in the number of dendritic-type Merkel cells in rat skin suggest a secretory function related to the hair cycle.

Pathophysiology

The histogenesis of MCC is controversial. Possible cells of origin include the epidermal MC, a dermal MC equivalent, a neural-crest–derived cell of the amine precursor uptake and decarboxylation (APUD) system, and a residual epidermal stem cell.

Cytogenetic abnormalities are present in 30-47% of MCCs. The most frequent change is loss of heterozygosity due to translocations or deletions of chromosome 1; specifically, 2 distinct regions in the most distal band 1p36 on the short arm of chromosome 1 are implicated in MCC. Similar abnormalities near this site occur in several neurocristic tumors, including melanoma, neuroblastoma, and pheochromocytoma. Other abnormalities described in MCC include losses at chromosomes 3, 13, and 22 and partial trisomy of chromosomes 1, 11, 18, and X. Unlike neuroendocrine (small cell) carcinoma of the lung, gene amplifications are rare in cutaneous MCC.

Frequency

United States

MCC is a rare tumor, accounting for less than 1% of cutaneous malignancies. In Rochester, Minnesota, the annual incidence of MCC was reported to be 0.2 case per 100,000 residents. In a study of 1,124 cases of MCC identified in the Surveillance, Epidemiology, and End Results (SEER) database, the incidence increased over a 15-year period (from 0.15 case per 100,000 in 1986 to 0.44 case per 100,000 in 2001).

Mortality/Morbidity

Overall, the 2-year survival rate is 50-70%.

Race

Whites have a 20-fold increased age-adjusted relative risk of developing MCC compared with blacks.

Sex

The incidence reported in most studies is approximately equal for males and females, although some authors report an elevated female-to-male ratio of up to 4:1. Survival is greater in women.

Age

The mean patient age at diagnosis is about 75 years; only 5% of cases occur before age 50 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

MCC generally presents as cutaneous disease only, but some patients present with evidence of regional or distant metastasis.

• The primary skin lesion is generally asymptomatic.
• Patients with disseminated disease may have constitutional symptoms (eg, fatigue), localizing signs (eg, hemoptysis, neurologic defect, adenopathy secondary to metastasis), or both.

Physical

• Skin/primary lesion
• • MCC usually presents as a solitary, dome-shaped nodule or firm plaque (see Media File 1).
  • Lesions are most often smaller than 2 cm in greatest dimension, but may exceed 15 cm in diameter.
  • They are typically red, violaceous, or purple.
  • The epidermal surface is often shiny, and telangiectases may be seen, suggesting atrophy.
  • Ulceration is uncommon.


• Skin/distribution
• • Lesions characteristically appear on the head or the neck (about half of cases).
  • Any mucosal or cutaneous site may be affected.


• Metastases
• • Regional nodal metastases are usually the first site of dissemination.
  • They may be detectable by palpation. Sentinel lymph node biopsy is effective in predicting the risk of regional recurrence; however, lymph node dissection does not appear to convey a survival advantage.
  • Cutaneous metastatic deposits also occur.

Causes

An etiologic role for chronic exposure to solar ultraviolet radiation (UVR) is proposed, mainly due to the markedly increased risk for white patients versus black patients and the predominant location of MCC on sites of maximal cumulative UVR exposure (head and neck). The regional incidence rate of MCC increases with increasing sun exposure, measured by the UVB solar index. Both the frequency and the aggressiveness of MCC increase after immunosuppression, organ transplantation, and B-cell neoplasia. Other potential risk factors for MCC include erythema ab igne and congenital ectodermal dysplasia. MCC is not associated with infection by Epstein-Barr virus or human papillomavirus.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

B-cell lymphoma
Adnexal neoplasm

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Imaging Studies

• Radiography of the chest is indicated 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 MCC to the lymph nodes or the viscera.

Procedures

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

Histologic Findings

Tumors cells are usually located intradermally; an intraepidermal component may also be present, and a purely intraepidermal (in situ) MCC 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. 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.

The tumor is composed of round, small, dark cells within conspicuous nucleoli and a generally open chromatin with peripheral heterochromatin (salt-and-pepper pattern). Mitotic figures and apoptotic bodies are often numerous. Vascular or lymphatic invasion is not uncommon. Histologic variants of MCC include the desmoplastic, epidermotropic (resembling mycosis fungoides), and pagetoid (resembling Paget disease or melanoma) types, and tumors with focal true glandular or squamous differentiation. Cases of MCC have been associated with squamous cell carcinoma, basal cell carcinoma, and trichilemmal cyst.

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 MCC. The above findings support the diagnosis of primary MCC 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.

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. 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.

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.

Staging

According to the American Joint Committee on Cancer guidelines, carcinoma of the skin is staged by the status of T (primary tumor), N (lymph node), and M (metastasis). The definitions are as follows:

Table 1. Tumor Status

Table 2. Node and Metastasis Status

Table 3. Stage Grouping

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 MCC.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Various chemotherapeutic regimens have been used, but none has been proven to result in improved survival; the role of chemotherapy in the management of MCC remains unclear. MCC is chemosensitive but only rarely chemocurable in patients with metastasis or locally advanced tumors. Moreover, a high incidence of toxic death occurs due to chemotherapy.
• The role of radiation therapy (RT) in managing MCC remains controversial. RT may help control unresectable primary or metastatic lesions, and it may also be useful for local control when administered postoperatively to the primary site and the regional draining lymph node basin. Adjuvant RT reportedly reduces the local and regional recurrence rate but may not lead to improved overall survival.

Surgical Care

• Wide local excision (eg, with margins of 3 cm) is usually indicated if clinically feasible. Some have recommended Mohs micrographic surgery for its tissue-sparing effects and possible superior control of local disease; however, tumor deposits may be noncontiguous histologically, rendering this modality less effective in such cases.
• Selective lymphadenectomy (sentinel lymph node procedure) has reportedly been feasible in small series of patients with MCC, but any effect on survival is unclear. Prophylactic complete lymph node dissection, combined with wide local excision and adjuvant radiotherapy, reportedly may improve survival.

Consultations

Early referral to a surgical oncologist, a medical oncologist, and a radiation therapist is indicated.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention:

• Photoprotection (eg, sunscreen, behavioral prevention) may help prevent MCC, but this is not proven.

Complications:

• Complications secondary to metastasis depend on the anatomic sites of involvement.

Prognosis:

• Partial or complete spontaneous regression (reminiscent of that sometimes seen in melanoma) is a well documented but rare phenomenon in MCC and may be more common in women than in men. Even some metastases may remit spontaneously. Regression is accompanied by dense lymphocytic infiltrates, primarily of the CD8 phenotype, and proceeds via apoptosis (as documented ultrastructurally and by the in situ DNA nick end labeling [TUNEL] technique).
• Local cutaneous recurrence occurs after wide excision in 30-40% of patients with clinical stage I MCC; local invasion of contiguous organs (eg, intracranial) is also possible. Regional lymph node metastasis occurs in 50-79% of patients, and distant metastasis occurs in more than 30% of patients; major sites include liver, bone, central nervous system, lung, and skin.
• Overall, the mortality rate is 30-50% in 2 years; few studies include longer-term follow-up. Women appear to have a better survival rate than men. Histopathologic features associated with a lower survival rate include small cell size, high mitotic rate, subcutaneous invasion, diffuse growth pattern, heavy lymphocytic infiltrates, and tumor size greater than 5 mm.

Patient Education:

• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Skin Cancer and Skin Biopsy.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Misdiagnosis of MCC pathologically as basal cell carcinoma is a pitfall; adjunctive techniques, including immunohistochemistry and electron microscopy, can be helpful in questionable cases.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Large, violaceous nodule of Merkel cell carcinoma on the antecubital fossa. Courtesy of Dr. Jonathan Cook.
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Media file 2:  Histologic appearance of nodular Merkel cell carcinoma. Dermal nodule with a cohesive, expansile growth of basophilic cells.
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Media file 3:  High-power view demonstrates an open chromatin pattern and a high mitotic index.
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Media file 4:  Pseudorosette formation in Merkel cell carcinoma.
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Media file 5:  Merkel cell carcinoma with a focus of squamous differentiation.
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Media file 6:  Prominent in situ nested component of Merkel cell carcinoma, simulating malignant melanoma.
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Media file 7:  Electron micrograph of Merkel cell carcinoma showing a dense core granule (arrow).
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Media file 8:  Electron micrograph of Merkel cell carcinoma showing whorled bundles of intermediate filaments (arrow) near nucleus in Merkel cell carcinoma.
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Media file 9:  Dotlike paranuclear pattern of cytokeratin immunolocalization.
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REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Jun 21, 2007