Merkel Cell Carcinoma

 

 

Merkel cell carcinoma (MCC) is a rare, aggressive, primary skin cancer exhibiting neuroendocrine differentiation. Several synonyms exist; however, the term Merkel cell carcinoma is still most commonly used in view of the many similarities of the constituent tumor cell to the normal Merkel cell 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, Merkel cells appear by the eighth gestational week, possibly being derived from a primitive epidermal stem cell. Merkel cells are present in high numbers on the lip, hard palate, palms, finger pads, proximal nail folds, and dorsa of the feet. Merkel cells have a predilection for perifollicular areas in the skin; confirmed reports exist of Merkel cells free in the dermis, but they are most easily identified in the basal layer of the epidermis. Functions proposed for normal Merkel cells in skin include 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. 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.

Also see Merkel Cell Tumors of the Head and Neck and Skin Malignancies, Merkel Cell Carcinoma and Rare Appendageal Tumors.

The histogenesis of Merkel cell carcinoma is controversial. Possible cells of origin include the epidermal Merkel cell, a dermal Merkel cell 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 Merkel cell carcinomas. 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 Merkel cell carcinoma. Similar abnormalities near this site occur in several neurocristic tumors, including melanoma, neuroblastoma, and pheochromocytoma. Other abnormalities described in Merkel cell carcinoma include losses at chromosomes 3, 13, and 22 and partial trisomy of chromosomes 1, 11, 18, and X.^2,3,4,5,6 Unlike neuroendocrine (small cell) carcinoma of the lung, gene amplifications are rare in cutaneous Merkel cell carcinoma.

Merkel cell carcinoma is a rare tumor, accounting for less than 1% of cutaneous malignancies. In Rochester, Minnesota, the annual incidence of Merkel cell carcinoma was reported to be 0.2 case per 100,000 residents. In a study of 1,124 cases of Merkel cell carcinoma 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).

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

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

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.

The mean patient age at diagnosis is about 75 years⁹ ; only 5% of cases occur before age 50 years.

Merkel cell carcinoma 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.

• Skin/primary lesion
  • Merkel cell carcinoma 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 Merkel cell carcinoma on sites of maximal cumulative UVR exposure (head and neck). The regional incidence rate of Merkel cell carcinoma increases with increasing sun exposure, measured by the UVB solar index. Both the frequency and the aggressiveness of Merkel cell carcinoma increase after immunosuppression,14 organ transplantation, and B-cell neoplasia. 

Other potential risk factors for Merkel cell carcinoma include erythema ab igne and congenital ectodermal dysplasia. Merkel cell carcinoma is not associated with Epstein-Barr virus or human papillomavirus.15 However, DNA sequences of a previously unknown polyomavirus (Merkel cell polyomavirus, MCV or MCPyV) have been detected in 80% of Merkel cell carcinomas but only 16% of healthy skin.16 The frequent finding of clonal integration of viral DNA within the Merkel cell carcinoma genome sugge Treatment

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 Merkel cell carcinoma (MCC) remains unclear. Merkel cell carcinoma 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 Merkel cell carcinoma 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

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 Merkel cell carcinoma, but any effect on survival is unclear.³¹ Prophylactic complete lymph node dissection, combined with wide local excision and adjuvant radiotherapy, reportedly may improve survival.

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

sts that viral infection and integration may contribute to the pathogenesis of Merkel cell carcinoma.