Merkel Cell Carcinoma
Merkel cells are the presumed cell of origin of Merkel cell carcinoma. These cells are located in the basal layer of the skin and mucosa, present as either single cells or in clusters.1 Merkel cells, however, cannot be identified on standard H&E staining; immunohistochemistry or electron microscopy is necessary for their detection. The cells tend to be concentrated in touch-sensitive areas with close proximity to nerve terminals forming mechanoreceptors.1 Not much is known about their interaction with other epidermal cells, however, they are known to have spiked protrusions that allow them to interdigitate between the surrounding keratinocytes. Merkel cells have a unique expression pattern as they express epithelial proteins like cytokeratins as well as neuroendocrine markers.1
This tumor was originally described by Toker in 1972.2 He studied a small series of tumors that were composed of cells with large, oval nuclei with vesicular chromatin and prominent nucleoli. The tumor cells were arranged in a trabecular growth pattern infiltrating between dermal fibrous bundles. Given the histologic characteristics, he named the tumor trabecular carcinoma. In 1978, electron microscopy allowed Toker and Tang to discover neurosecretory granules within the tumor cells.3 Merkel cells are the only cells within the skin to contain dense, coarse granules, thereby suggesting the Merkel cell origin for the tumor. Despite these findings, there continues to be an ongoing debate regarding the origin of Merkel cell carcinoma. The tumor can be seen in association with an in situ or an invasive squamous cell carcinoma, with duct-like structures of eccrine type, and with basal cell carcinoma-like areas. Some researchers believe that these features support that the tumor is derived from pluripotent stems cells of ectodermal derivation.4 As a result of this dispute, this entity has been referred to by many names such as Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor and malignant trichodiscoma. Merkel cell carcinoma remains the most widely accepted and used term.
Merkel cell carcinoma is one of the most aggressive neoplasms of the skin. It usually arises in the sun-exposed areas of elderly patients, particularly on the head and neck, and the extremities, although involvement of other sites, including perianal and eyelid, has also been reported. The median age of diagnosis is 65 years, however, rare cases were reported to occur in children. Merkel cell carcinoma occurs considerably more frequently in whites than blacks and slightly greater in males than females.5 Increased incidence of this tumor has been seen in patients treated with psoralen and ultraviolet A for psoriasis and those with chronic immune suppression, especially from chronic lymphocytic leukemia, HIV, and prior solid organ transplant.6,7 Interestingly, there is a relatively high incidence of second neoplasms in patients with Merkel cell carcinoma. Clinically, the tumor may vary in its appearance, but patients typically present with a painless, solitary dermal nodule with a slightly erythematous to deeply violaceous color. Rarely, ulceration can occur. On average, the tumors are 2 cm in diameter, but both size extremes have been reported.
This tumor characteristically infiltrates local dermal lymphatics, resulting in multiple satellite lesions as well as regional lymph node spread. Regional lymph node involvement is reported in up to 75% of cases. Distant metastases occur most commonly to distant lymph nodes, distant skin, lung, brain and bone. Local recurrence has been indicated to occur in 30% of patients within 9 months of initial presentation.8
Occasionally, Merkel cell carcinoma is found in a lymph node (most often inguinal) in the absence of a primary tumor. This occurrence is most likely explained by the spontaneous regression of the primary tumor. Alternatively, the possibility that these tumors arise from nodal neuroendocrine cells has been suggested.
Clinically, the extent of disease at presentation is the best indication of prognosis.9 Female sex, limb presentation and younger age have also been suggested as positive predictors of survival. Immunosuppression and advanced age serve as two significant predictors of poor outcome. Histologically, it appears that tumors with an infiltrative pattern, tumor depth and presence of lymphovascular space invasion carry a worse prognosis. Tumor size has not been shown to be a reliable predictor of outcome.
The treatment of choice for Merkel cell carcinoma is wide resection of the primary site, regional lymph node dissection and radiation therapy. Treatment is limited for patients with recurrence or distant metastases. Surgical resection is the best option for patients with resectable recurrent disease. There are no established chemotherapy regimens for patients with distant metastases.
Merkel cell carcinoma is characterized by a monotonous round cell infiltrate within the dermis of the skin, sometimes with involvement of the subcutaneous tissue. The overlying epidermis is usually uninvolved. The cells have round nuclei, vesicular chromatin and multiple nucleoli. The tumor cells have scanty cytoplasm. Mitotic figures and apoptotic bodies are frequent. Necrosis may be seen and sometimes accompanied by the Azzopardi phenomenon (hematoxyphilic staining of vessel walls and fibrous septa). The surrounding stroma demonstrates proliferative blood vessels with plump endothelial cells. Merkel cell carcinoma can be classified into three distinct subtypes: trabecular, intermediate/solid patter (most common) and small cell (second most common). Numerous staging systems have been suggested over the years. Merkel cell carcinoma used to be included in carcinoma of the skin. However, the 7th edition of the AJCC cancer staging manual published in 2010 contains a new chapter dedicated to the staging of this tumor.10 It includes 4 stages as follows:
Stage I - primary tumors ≤ 2 cm in size
IA - pathologically proven node negative disease
IB - clinically evaluated node negative disease
Stage II - primary tumors > 2 cm and < 5 cm in size
IIA - pathologically proven node negative disease
IIB - clinically evaluated node negative disease
IIC - presence of extracutaneous invasion and negative node status pathologically or clinically
Stage III - primary tumors ≥ 5 cm
IIIA - microscopically positive and clinically occult nodes
IIIB - macroscopic nodes
Stage IV - extracutaneous invasion by primary tumor into bone, muscle, fascia, or cartilage
CK20 expression has been regarded as a highly sensitive and specific marker for Merkel cell carcinoma.11 The tumor cells express cytokeratin as "dot-like" paranuclear globules, present in both the dividing and interphase cells. CK20 and CAM5.2 immunostains will demonstrate this pattern of positive expression. Neuron-specific-enolase (NSE) and neurofilament protein (NFP) expression have also been considered to be specific markers for Merkel cell carcinoma. Additionally, tumor cells show reactivity for chromogranin (less than 50% of cases), synaptophysin, VIP, calcitonin, somatostatin, PAX-5, Tdt, glypican-3 and CD117.
CK20, NSE and NFP expression aid in distinguishing between Merkel cell and small cell lung carcinoma as both are morphologically similar. However, it has been established that approximately 5% of Merkel cell carcinomas lack CK20 expression.12 In addition, it has been demonstrated that up to one-third of small cell lung carcinomas are positive for CK20.13 As a result, TTF-1 and CK7 negative staining in Merkel cell carcinoma has become a valuable tool in distinguishing Merkel cell from small cell lung carcinoma. Lymphoma, another malignancy in the differential diagnosis, can be excluded due to the positive expression of LCA and negative expression of CK20, CK7, TTF-1, NSE and NFP.
Merkel cell carcinomas are known to contain genetic alterations. The most common alterations observed are chromosome 1p abnormality (loss of heterozygosity at 1p35-36 in 70% of cases)14, trisomy 6 (approximately 50% of cases)15, and promoter hypermethylation of P14/ARF (42% of cases).16
In 2008, researchers suggested a link between Merkel cell carcinoma and a new polyomavirus, named the Merkel cell polyomavirus (MCV).17 This virus's sequence was found to be clonally integrated in 80% of the Merkel cell tumors studied. It was concluded that the virus may be a contributing factor to the pathogenesis of the tumor. Polyomaviruses encode for large and small T-antigens which bind to host proteins facilitating viral replication and inactivation of tumor suppressor proteins, p53 and pRb. Since these pioneer studies, numerous studies have been performed looking at MCV T antigen expression in Merkel cell carcinoma. MCV T antigen expression has been found to be less in Merkel cell carcinomas of the head and neck as compared other anatomical sites.12 In addition, it has been elucidated that MCV T antigen can reliably be detected by the mouse monoclonal antibody, CM2B4, in tumors that lack CK20 expression.18
Despite these discoveries, the significance of the new Merkel cell polyomavirus remains uncertain. The virus has also been detected in normal skin distant from the tumor primary, in patients with skin disorders not related to Merkel cell carcinoma, and in normal appearing individuals. Also, not all cases of Merkel cell carcinoma appear to be associated with infection. The prognostic significance of the viral load, antibody titers, and role of underlying immunosuppression are still currently being investigated.
Contributed by Stacey Barron, MD, Amal Kanbour-Shakir, MD and David Dabbs, MD