Merkel Cell Carcinoma

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Original Editor - Carina Therese Magtibay
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Introduction

Merkel Cell Carcinoma (MCC) is a rare and aggressive skin cancer typically seen on the facial skin and extremities of elderly Caucasians and immunocompromised people. This neuroendocrine carcinoma accounts for less than 1% of all cutaneous malignancies and is associated with UV exposure and infection with the Merkel cell polyomavirus (MCPyV). It frequently metastasizes to draining lymph nodes and distant organs, including liver, bone, pancreas, lung, and brain

Epidemiology

The worldwide incidence of MCC varies from 0.1 to 1.6 cases per 100,000 people annually with Australia recording the highest rate ranging from 0.82 to 2.5 . It is then followed by New Zealand (0.88–0.96) and United States (0.66–0.79). European countries such as France, Spain and Scotland report relatively similar incidence rates of 0.25 to 0.35 while Scandinavian countries have less incidence rates: 0.19 in Sweden and 0.12 in Finland.

Risk factors of MCC

Predisposing factors for MCC are as follows:

• Old age. The median age at diagnosis is documented to be 77 years with the highest incidence observed among people over 85 years old.
• UV exposure
• White skin type
• Male sex. The male-to-female ratio of MCC is over 2.5 incidence is over 2.5 in all reported studies.
• Immunosuppression. Approximately 6–12% of all patients with MCC are immunosuppressed.

Aetiology and Pathological Process

Two distinct aetiologies of MCC:

1. Viral form of MCC (Merkel cell polyomavirus)
   • Causes at least 60% of all MCC
   • Clonal integration of Merkel cell polyomavirus DNA into the tumour genome with persistent expression of viral T antigens
   • Broad exposure to this ubiquitous virus is known to occur early in life, but higher antibody levels in older individuals suggest viral reactivation with increased age
   • Two oncogenic antigens: large T (LT) and small T (ST). LT has been more extensively studied. Following incorporation of the virus into the genome of the host cell, a truncated LT antigen, with loss of its viral replicative capacity but retention of its antigenic and oncogenic roles, is produced. By binding of truncated LT to the Rb protein and by indirect ST-mediated inhibition of p53, these tumour suppressor pathways are disabled, promoting oncogenesis.
2. Nonviral form of MCC
   • Caused by UV damage leading to highly mutated genomes
   • Tumorigenesis in these cases also involves disruption of the Rb and p53 tumour suppressor pathways, but by different means. In this instance, recurrent inactivating mutations in the TP53 and RB1 genes promote oncogenesis.

Both forms of MCC are similar in presentation, prognosis, and response to therapy.

Clinical Presentation

The most common sites of MCC are the sun-exposed areas of head and neck (29–43.9%) and the extremities (36.9–45%), whereas less than 5–10% of MCCs develop on partially sun-protected areas (abdomen, thighs and hair-bearing scalp) or highly sun-protected areas (buttocks). Extra-cutaneous sites are rarely affected.

Clinically, MCC is manifested by a rapidly growing, painless, erythematous/violaceous nodule or plaque.

AEIOU acronym for MCC clinical features:

• A = asymptomatic
• E = expanding rapidly
• I = immune suppression
• O = older than50 years of age
• U=UV-exposed site.

Diagnostic Procedures

MCC is frequently misdiagnosed initially which can lead to delay in diagnosis. It may be confused with an inflammatory lesion such as acne or other folliculitis or with a benign tumour such as epidermal cyst, lipoma, dermatofibroma, fibroma and angioma. In many other cases, MCC is misinterpreted as another malignant tumour, mainly basal or squamous cell carcinoma and less frequently lymphoma, metastatic carcinoma, nodular or amelanotic melanoma or sarcoma.

A clinically useful recommendation is that any nodule with non-specific morphology, lack of tenderness and fast-growing should be biopsied rather than monitored.

Physical examination

Assessment of the primary tumour and documentation done by a dermatologist for MCC:

• Light photography
• Palpation of regional lymph node basins
• Inspection of the entire skin surface by a dermatologist.

Dermatoscopy

Dermatoscopic images of MCC reveals:

• Predominant red colour corresponding either to numerous vessels or generalised erythema
• Milky-red or pink structureless colour. It might be seen either as a pink background or as smaller roundish areas (milky red areas or globules or clods).
• Several morphologic types of vessels may be present, including dotted, glomerular, arborising and linear irregular vessels. Usually, more than one morphologic type of vessel co-exist, resulting in the so-called polymorphous vascular pattern, although lesions with monomorphous vessels have also been described.
• White areas are also frequently described.

Histological Diagnosis

Immunohistochemistry is required to distinguish MCC from its mimics. Depending on size and location, tissue sampling in suspicious lesions should be accomplished by punch, incisional or excisional biopsy. MCC generally consists of a solid nodular lesion in the dermis and subcutis

On haematoxylin eosin stains, the tumour typically exhibits:

• sheets and nests of uniform small round blue undifferentiated cells with scant cytoplasm
• a ‘salt and pepper’ chromatin pattern
• large lobulated nucleoli
• high mitotic rate
• occasional necrotic cells.

In clinical practice, a typical histology complemented with positive CK-20 and negative TTF-1 immunostaining is usually considered sufficient for the diagnosis of MCC.

Differential Diagnosis

Differential Diagnosis of MCC:

• non-neuroendocrine small cell undifferentiated carcinoma
• small cell melanoma
• cutaneous lymphoma
• poorly differentiated carcinoma metastatic to the skin (e.g. small cell lung cancer)
• Ewing sarcoma
• neuroblastoma
• leukaemia cutis
  

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