Merkel''''''''s tumor: a case report

Received on: 15 January 2012
Approved on: 6 June 2012
This study was carried out at the Complexo
Hospitalar Padre Bento de Guarulhos
(CHPBG) – São Paulo (SP), Brazil.
Financial support: None
Conflict of interest: None

Abstract

Merkel cell carcinomas are highly aggressive neuroendocrine skin tumors that have a poor prognosis. The authors present a case report and emphasize the importance of early diagnosis and treatment.

Keywords: CARCINOMA, MERKEL CELL, IMMUNOHISTOCHEMISTRY, SKIN

INTRODUCTION

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that is characterized by high rates of metastasis, recurrence, and mortality.1

In the United States, its estimated incidence is 0.32 per 100,000 persons per year.1 It predominantly affects white-skinned individuals (94.9%), with a slight predominance in males (1.6:1) aged 70-80.2 An increase in the incidence of MCC has been observed in association with immunosuppression linked to HIV-positive patients, patients with transplanted solid organs, patients with leukemia or lymphoma, and those receiving immunosuppressant therapies.3

MCCs appear as a papule or an erythematous-violacious nodule, a plaque, an infiltrated nodule, or an ulcerated cystic lesion. Suspicion of lesion is difficult..2,3 In a study of 106 cases diagnosed as primary MCC, that clinical hypothesis was raised in only in 1% of cases.2 MCCs affect sun-exposed areas, such as the head and neck (29%), upper limbs (24%), lower limbs (21%), trunk (8%), and more rarely, the vulva (5%).4

This study describes anMCC case and discusses the importance of early diagnosis, the rarity of the condition,and the controversies regarding its origin and treatment.

CASE REPORT

A 72-year-old male patient, without comorbidities, presented with an erythematous, firm tumorous lesion of 2cm in diameter, with a vegetating appearance, on the lateral region of the right arm. The patient reported progressive growth during the previous eight months, without associated adenopathies (Figure 1).

The patient had an excisional biopsy, whose microscopic examination exhibited a proliferative lesion (not connected to the epidermis) that consisted of cells with marked karyomegaly, nuclear hyperchromasia, and scarce cytoplasm. Those cells sometimes present a trabecular arrangement, and sometimes appear in large solid masses that occupy the entire dermis (Figure 2). The lesion embolizes multiple adjacent blood vessels and infiltrates deep into the dermis (Figure 3). The "trabecular" aspect of the cells, associated with the marked degree of nuclear atypia and high mitotic index, point to a diagnosis of MCC (Figures 4 and 5). The material collected was sent for immunohistochemical analysis, which was positive for the markers CK-20 and chromogranin, corroborating the microscopic description.The patient was referred to Oncology for the expansion of surgical margins and follow-up.

DISCUSSION

Toker described the first MCC in 1972 as a trabecular carcinoma due to its infiltrative and reticular growth pattern. It was believed to be derived from eccrine glands.4 In 1978, after carrying out ultrastructural studies, Tang and Toker identified granules with dense nuclei in the cytoplasm of tumor cells. Those granules could only be in the skin''''''''s Merkel cells.1 There is controversy about the hypothesis that this tumor originates from Merkel cells – mechanoreceptor of the basal layer of the epidermis– or from pluripotent stem cells, which later differentiate into neuroendocrine cells.4 Due to the uncertainty of its origin, it was named trabecular carcinoma of the skin, then cutaneous neuroendocrine carcinoma, and currently MCC.1

Histologically, the tumor consists of small monomorphic cells with round basophilic nuclei, minimal cytoplasm and varying degrees of cohesiveness, with a dermal growth pattern below the Grenz zone. Typically, numerous mitotic figures and apoptotic bodies can be found. There are three histological types: intermediate, small cell, and trabecular. Most lesions present two growth patterns, the most common of which is the intermediate sub-type. Squamous cell carcinoma is present in 37% of MCC cases. In a study of 27 MCC cases, there was an association with other epithelial lesions such as squamous cell carcinoma in situ in five cases (41%), invasive squamous cell carcinoma (three cases), basal cell carcinoma (one case), and actinic keratosis (two cases). Those findings strengthen the hypothesis that their origin is in pluripotent stem cells in the epidermis that are enhanced by the mutagenic effect of ultraviolet radiation and perhaps by polyomavirus infection.5

More recently, Chang and Moore identified a polyomavirus, designated as Merkel Cell Polyomavirus (MCV), clonally integrated into the MCC''''''''s genome in eight out of ten cases. Other studies have confirmed that association, which was found in 24% of samples in Australia and in over 85% in North America and Europe. Fourteen polyomavirus have been described so far, two of which (JCV and BKV) have been demonstrated to induce tumor formation. Little is known about that virus, with seroprevalence above 80% observed in patients over 50. The JCV and BKV polyomavirus remain latent in the kidneys and become active following severe immunosuppression – which is in line with the observation that MCCoccurs more frequentlyin imunocompromised patients.1

Immunohistochemistry is essential in the diagnosis in order to differentiate MCCs from other tumors. The low molecular weight cytokeratins 8, 18 and 20 were positive with a sensitivity of over 90%. The cytokeratin CK20, an intermediate protein filament with an expression restricted to gastric and intestinal epithelium, urothelium, gustative papillae of the tongue, and Merkel cells, has been proposed as a marker to differentiate MCC from lung small cell carcinoma and other cutaneous carcinomas. Bobos and colleagues showed that in 391 MCC cases, 87% were CK20-positive. Another marker, such as chromogranin- A, which confirms the neuroendocrine origin, was present in 52% of cases in one of the series. Neuron-specific enolase is found in 50% of cases. Positivity can also be found for somastatin, neurofilament, CD56, and synaptophysin.5

MCC''''''''s staging is the most important prognostic indicator, which also influences the treatment type.The American Joint Committee on Cancer classified MCCs into four stages: Stage 1 (primary tumor <2cm), Stage 2 (primary tumor = 2 cm), Stage 3 (regional lymph node disease), and Stage 4 (distant metastases). Chest radiography and sentinel node biopsy must be per- 270 Rossoe EWT, Fernandes KKML, Prado IDF, Bazzo ILMS, Tebcherani AJ, Santos TC formed, especially in patients with clinically negative lymph nodes, for in 30% of cases the lymph nodes were positive. It is also desirable to perform immunostaining of lymph nodes with pancytokeratin to help detect micrometastases.3,4

In the SEER study, Agelli and others reported five-year survival rates of 75% for localized MCCs, 59% for regional involvement, and 25% for distant CMM. In a study of 346 MCC cases, Stokes and colleagues presented clinically negative lymph nodes at diagnosis in 71% of cases; 24% had regional metastases, and 5% distant metastasis. They also reported that no patient with a tumor =1cm hidden lymph node metastases, and that 5% of 1-2 cm tumors presented hidden nodes (12% of those over 2cm).6 High-risk factors were described as: recurrence after initial therapy involving lymph nodes, residual disease after surgery, primary tumor of 1cm or larger, or primary hidden lymph nodes.7

Surgical excision is the mainstay of treatment, and 1.1cm margins present low recurrence rates.4 As MCCs are radiosensitive, radiation therapy is also an important treatment option. There is a consensus that radiation therapy is beneficial for unresectable or recurrent tumors. Chemotherapy is a palliative option for patients in Stage 4 of the disease; two-thirds of tumors respond to chemotherapy, however they generally recur after a few months.8

The authors conclude that the clinical diagnosis of MCC is difficult, however early diagnosis and prompt treatment of the disease is crucial.

ACKNOWLEDGEMENTS

We thank Dr. Roberto Paes Pinto, a pathologist at Instituto Adolfo Lutz, for conducting the immunohistochemistry analysis.

References

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4 . Lien MH, Baldwin BT, Thareja SK, Fenske NA. Merkel Cell Carcinoma: Clinical Characteristics, Markers, Staging and Treatment. J Drugs Dermatol. 2010; 9(7):779-84

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6 . Stokes JB, Graw KS, Dengel LT, Swenson BR, Bauer TW, Slingluff CL Jr, et al. Patients with Merkel Cell Carcinoma Tumors <= 1.0 cm in Diameter are Unlikely to Harbor Regional Lymph Node Metastasis. J Clin Oncol. 2009;27(3):3772-7

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8 . Fernandes KKML, Bazzo ILMS, Tebcherani AJ, Rossoe EWT. Tumor de Merkel: Relato de Caso. 65o Congresso Brasileiro de Dermatologia; 2010 Set 4-7; Rio de Janeiro, RJ (Brasil). Poster, PC 398