Merkel Cell Carcinoma

Introduction

Merkel cell carcinoma (MCC) is an uncommon and aggressive cutaneous neoplasm that lacks distinguishing clinical features. More than half of Merkel cell carcinomas (MCCs) occur in the head and neck of elderly people in areas of actinically damaged skin. The most common site of occurrence is the periorbital region. Merkel cell carcinoma (MCC) has a propensity to recur and to cause local and distant metastases. Distant metastases indicate a condition that is nearly always fatal.

The diagnosis is based on a combination of light microscopy, electron microscopy, and immunohistochemistry. Current treatment consists of wide local excision with adjuvant irradiation. Neck dissection is used for clinically positive nodes, and chemotherapy is given for advanced disease.

If the prognosis of patients with (MCC) is to be improved, early diagnoses are needed, and further understanding of the roles of neck dissection, radiation therapy, and chemotherapy must be attained.

History of the Procedure

Freidrich Sigmund Merkel, a German histopathologist, first described the Merkel cell in 1875. He fixed and stained the skin of geese and ducks and demonstrated touch cells in the snouts of pigs. These clear-staining cells at the dermoepidermal junction were near myelinated nerve fibers. Merkel postulated that these cells acted as mechanoreceptors in all animals.

Cyril Toker first described Merkel cell carcinoma (MCC) in 1972.1 On the basis of the histologic characteristics of the tumor, he named it trabecular cell carcinoma of the skin.

Subsequent studies involving immunohistochemistry and electron microscopy revealed that these tumors originate from the Merkel cell.

Problem

Merkel cell carcinoma (MCC) is a deadly disease with a poor likelihood for survival. Local recurrence occurs in 44% of patients; multiple local recurrences occur in 15%. These tumors appear as rapidly growing, painless nodules in elderly Caucasian individuals or in young adults with ectodermal dysplasia syndromes. The mean age at presentation is 68 years, and no sex bias is observed. Merkel cell carcinomas (MCCs) usually appear as indurated plaques or violaceous (red or deep purple) solitary and dome-shaped nodules. The surface is typically shiny, with telangiectasias and possibly ulceration. Most tumors measure 0.7-1.2 cm in diameter.

Merkel cell carcinomas (MCCs) usually occur in sun-damaged skin. They are often found near other lesions of actinically damaged skin, including skin involved with Bowen disease, squamous cell carcinoma, basal cell carcinoma, solar keratoses, or lentigo maligna. Merkel cell carcinoma (MCC) has also been linked to previous radiation exposure and B-cell lymphoma.

Approximately 53% of Merkel cell carcinomas (MCCs) occur in the head and neck; 35% occur in the extremities. In the head and neck, 46% of tumors occur in the periorbital region; 29%, on the cheek; 18%, on the eyelid; and 17%, on the forehead. Other sites in the head and neck include the lips (9%), ears (7%), nose and neck (5.4%), and scalp (4%; see Image 1).

Tumors have also been reported in areas not exposed to sun, such as the nasal cavity, buccal mucosa, gingiva, hard palate, and postauricular skin.

About 3% of patients with Merkel cell carcinoma (MCC) have tumors at several sites. Approximately 11-15% of patients present with clinically positive nodes. About 75-83% of patients eventually develop regional nodal and distant metastases during their illness.

The nonspecific characteristics of Merkel cell carcinoma (MCC) lead to a lengthy differential diagnosis that includes basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, epidermal cysts, lymphoma, and metastatic carcinoma of the skin. As a result, Merkel cell carcinoma (MCC) is rarely diagnosed until biopsy is performed.

Frequency

Since Merkel cell carcinomas (MCCs) were first described in 1972, more than 600 cases have been reported in the literature; 321 of these cases have involved the head and neck. The reported annual incidence of Merkel cell carcinoma (MCC) is 0.2-0.45 case per 100,000 population. Merkel cell carcinoma (MCC) is 100 times rarer than melanoma.

Recent evidence suggests that the incidence of Merkel cell carcinoma (MCC) is increasing. In an analysis of the Surveillance, Epidemiology and End Results (SEER) database, Hodgson (2005) reported that the incidence of Merkel cell carcinoma (MCC) has increased 3-fold between 1986 and 2001.

Etiology

The Merkel cell is found in the skin of fish, amphibians, reptilians, avians, and mammals. It is an ovoid or round cell in the basal layer of the epidermis, lying parallel to the surface. The cell has scant cytoplasm and a round or oval nucleus with fine, evenly dispersed chromatin. The cells cluster in areas of sensory perception, such as fingertips, the tip of the nose, and tactile hair follicles.

Ultrastructural evaluation of the Merkel cell reveals desmosomal connections with surrounding keratinocytes; intracytoplasmic aggregates of intermediate filaments; and numerous, membrane-bound, dense core granules located in short, spinous, cytoplasmic processes that synapse with adjacent terminal nerve endings.

Immunohistochemical studies of the Merkel cell have demonstrated the presence of neuron-specific enolase (NSE), an amine precursor uptake and decarboxylation (APUD) cell marker. Studies have also shown staining for cytokeratins 8, 18, and 19. The origin of the Merkel cell is still controversial. The cell has both epithelial and neuroendocrine elements. This finding has led some to hypothesize that the cell is derived from an epidermal stem cell in the basal layer of the epidermis that is capable of differentiation along either lineage. An alternative hypothesis, one stimulated by the presence of calcitonin and other hormones, suggests that the cell may be of neural crest origin. The exact function of the Merkel cell has yet to be delineated, but most believe that it acts to modulate mechanoreception.

Presentation

Merkel cell carcinoma (MCC) commonly appears as a painless mass on or just under the skin surface. Appropriate clinical diagnosis is often delayed because of a lack of symptoms. The tumor may take on an erythematous or violaceous appearance. Bleeding and superficial ulceration are late findings suggestive of advanced disease. Regional lymph node metastasis is common, even with tumors smaller than 2 cm.

In a representative case that demonstrates common findings, a patient was an 89-year-old Caucasian woman with a 6-month history of an enlarging painless mass involving the right side of her nose. No pain or bleeding was associated with this mass. Her medical history included no previous cutaneous malignancies or sun exposure.

Physical examination revealed a smooth violaceous discolored mass measuring 2 X 3 cm involving the right nasal ala. The mass deeply invaded the full thickness of the nasal skin, with evidence of right nasal obstruction The rest of her facial skin contained no additional lesions. The bilateral intraparotid and jugulodigastric nodes were normally sized.

The patient underwent right-sided partial rhinectomy, with at least 5-mm margins from the visible borders of the tumor. Frozen sections revealed that all margins were free of disease. Reconstruction was accomplished immediately with a nasolabial flap. The patient's postoperative treatment included radiation therapy of 45 Gy for 5 weeks. The patient was free from recurrence at 2 years after surgery, when she died from causes unrelated to this mass.

Treatment Surgical Therapy

For patients with operable disease, most agree that surgery is the treatment of choice. As with most tumors, treatment is based on the stage. The Yiengpruksawan system is used here.

Aggressive wide local excision is the treatment of choice for the primary tumor. A 2- to 3-cm margin is recommended because it is thought to decrease the risk of recurrence. All margins should be confirmed with frozen sections. The role of elective neck dissection in the absence of clinically positive nodes is controversial. Because of the low incidence of Merkel cell carcinoma (MCC), most reports are based on retrospective or anecdotal studies. Lymph node metastases develop in approximately 55% of patients; therefore, some authors recommend prophylactic neck dissection in all patients. Others recommend neck dissection after the tumor reaches 2 cm in diameter.

Silva et al (1984) recommend neck dissection for tumors with 10 or more mitoses per high-power field, for cases of lymphatic invasion, or for tumors composed of small cells.Cotlar et al (1986) recommend lymphadenectomy for tumors present longer than 6 weeks.Tumors in the midline present the problem of bilateral drainage. Goepfert et al (1984) and Hitchcock et al (1988) recommend that patients with such lesions undergo a bilateral neck dissection.

Recent studies have been conducted to investigate the efficacy of sentinel node biopsy to determine whether neck dissection is necessary. These studies have been small, but their results indicate that a negative sentinel node may obviate the need for neck dissection.

When one contemplates neck dissection, realize that no indications are universally accepted and that the effect of regional lymphadenopathy on overall survival is uncertain.

Merkel cell carcinoma (MCC) is a radiosensitive tumor, and radiotherapy is currently used as an adjuvant. Most clinical studies demonstrate better local control rates with adjuvant radiotherapy after surgery. Numerous authors have recommended postexcision irradiation of the primary site and primary areas of lymph node drainage. Adjuvant radiotherapy is routinely given by some practitioners, whereas other practitioners only give it to patients considered to be high risk, which is inconsistently defined as demonstrating any of the following: (1) primary tumor >1.5 cm; (2) positive margins; (3) margins < 2 mm; (4) evidence of lymphatic, vascular, or perineural invasion; or (5) regional lymph node involvement.

The recommended dosing schedule is 45-50 Gy for 5 weeks; this is increased to 56-65 Gy for tumors with positive margins. These doses are similar to those used to treat squamous cell carcinoma. Therapy for recurrent localized disease or extensive unresectable stage I disease is similar to that given for stage II disease because lymphadenopathy is more likely to occur in this situation than in primary disease.

A widely accepted practice is for patients with regional node metastases or local or regional recurrence to undergo excision of the primary lesion and lymph node dissection. Adjuvant radiation therapy to the primary site and regional nodes is generally recommended in addition to neck dissection.

Chemotherapy is generally not currently advocated for stage II disease.

The development of distant metastases portends a poor prognosis, with a mean life expectancy of 5 months. Many types of chemotherapeutic agents have been used with brief success in treating stage III disease, with no increase in the survival rate. Because of the morphologic and immunohistochemical similarities of Merkel cell carcinoma (MCC) to small cell lung cancer, these regimens have been used as treatment models.

Pharmacologic agents most commonly used are doxorubicin and cyclophosphamide. Other agents are cisplatin, vincristine, etoposide, methotrexate, bleomycin, and 5-fluorouracil. However, reports of these treatments to date have consisted of small studies and anecdotal evidence. Merkel cell carcinomas (MCCs) often respond to chemotherapy; however, as with small cell carcinoma, remission is brief. No chemotherapeutic protocol has notably increased survival rates.

The role of radiation therapy in disseminated disease is to achieve palliation.

Follow-up

After treatment, monitor patients closely. Recommended follow-up is every month for 6 months, every 3 months for the next 2 years, and every 6 months thereafter.

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