What Is Merkel Cell Carcinoma?

Have you heard of this rare, and not-so-well-known yet an aggressive kind of skin cancer known as Merkel Cell Carcinoma (MCC)? Although it is a rare form of cancer, MCC cells have a higher potential for growth, meaning the tumour can spread from one site of the body to other at an early stage of cancer with poor prognosis.¹

Merkel cell carcinoma is an uncommon neuroendocrine tumour  which causes less than 1% of skin cancer cases.²  MCC was initially referred as “trabecular carcinoma of the skin” by Toker in 1972.³ Though MCC coincides with Merkel cells, they are not derived from Merkel cell lineage. Although still a matter of some debate the origin of MCC is likely to be from B-cell, dermal and epidermal stem cells.⁴ 

Merkel cell carcinoma usually appears on the sun-exposed regions including the head, neck and extremities. However, tumours can also appear on the trunk and limbs as well. MCC most commonly affects people in old age and immunosuppressed patients.⁵

Overview

Merkel cell carcinoma is a rare kind of cancer which was previously thought to have derived from Merkel cell, a cell found abundantly on the top layer of the skin and are in close proximity with the nerve endings of neuroendocrine cells. But the actual cell of its origin remains unidentified. Merkel cell carcinoma are of two types: UV radiation-induced MCC and viral-induced MCC. MCC tumours appear as fast-growing red or bluish nodules..The treatment strategy employed are surgical excision with additional radiotherapy. In advanced Merkel cell carcinoma, immunotherapy or chemotherapy is more commonly utilised.

Causes of merkel cell carcinoma

• Chronic exposure to sun or ultraviolet (UV) rays on bare skin, inducing genetic mutations and activation of tumour promotion genes (oncogenes) which can transform normal cells to cancerous cells
• The majority of Merkel cell skin cancer patients (75%) are at an advanced age (> 65 years) 
• Fair skinned or light skinned people areat greater risk
• Merkel cell polyomavirus
• History of other skin cancers previously such as basal cell carcinoma or squamous cell carcinoma
• Immunocompromised states that include, HIV patients, organ transplantation, chronic inflammatory diseases or other cancer conditions such as leukaemia are at high risk of developing Merkel cell carcinoma even at a young age⁶

Signs and symptoms of merkel cell carcinoma

Merkel cell cancer appears as red-violet, firm, dome-shaped nodules on sun-exposed regions of the skin. Sometimes the MCC tumours can appear as flesh coloured nodules arising from the subcutaneous layer of skin which is just beneath the skin. These tumour cells are singular, rapidly growing, distinct shapes at times (pleomorphic), asymptomatic, raised plaques, bumps or raised patches that appear on the skin. Due to the innocent appearance and found in different shapes, these lesions are interpreted mistakenly as benign tumour cells, basal cell carcinoma, acne, cysts, and lipomas ⁷

Merkel cell carcinoma is staging is based on the AJCC 8 (American Joint Committee on Cancer) system and the size and diameter of the tumour. This may be followed by assessing the lymph node involvement through clinical, radiological and sentinel lymph node biopsy. The final parameter involves the identification of metastatic (moving) Merkel cell carcinoma, evaluating the spread of the primary tumour to other local sites such as distant sites including skin, lymph nodes, lungs, and all other visceral sites.

• Stage 0: the top layer of the skin contains abnormal cells and may have the potential to become cancerous and spread onto nearby tissues
• Stage 1: The tumour size is less than 2cm
• Stage 2: Stage 2 is divided further into stages 2A and 2B
  • 2A: The MCC tumour size is greater than 2cm
  • 2B: The cancer has spread onto the nearby tissues, fascia, cartilage, bone or connective tissues

• Stage 3: Stage 3 is divided into Stage 3A and 3B
  • 3A: The MCC tumour is of any size which has spread onto the localised area.   The nearby lymph node is either palpable or non palpable in patients but sentinel lymph node biopsy shows positive signs of cancer. The site of cancer origin is not known.
  • 3B: The MCC tumour could be of any size which has spread to lymph nodes from the primary tumour

•  Stage 4:  The tumour has spread to distant tissues and organs such as bone, liver and lungs

Management and treatment of merkel cell carcinoma

The following guidelines are set up in accordance with National Comprehensive Cancer Network (NCCN) on treatment, diagnosis and follow-up of Merkel Cell Carcinoma. 

On possible suspicion, a biopsy taken from the tumour cell is recommended. A positive diagnosis of MCC tumour is obtained by immunohistochemistry staining of 2 biological markers (positive Cytokeratin 20 (CK20) and negative Thyroid transcription factor-1 (TTF-1)). 

Dissection of lymph nodes is preferred on positive signs of cancer. A palpable lymph node also needs to be monitored for possible spread of tumours to distant sites. This is performed through Computerized Tomography (CT) or Positron Emission Tomography (PET) scan.

The treatment strategy is based on the staging and severity of the cancer on diagnosis. Surgical excision of the tumour remains the mainstay treatment followed by adjuvant radiation therapy in high-grade Merkel cell cancer (to remove the cancer cells left within the primary site). The recommended radiation is 50-66 gray depending on the tumour size and grading, this aims to prevent the reoccurence of carcinoma at the primary site. 

Chemotherapy is used for metastatic Merkel cell carcinoma patients to irradicate the cancer cells at distant sites of the body. Immunotherapy mainly targets the checkpoint proteins that are present on the cancer cells which prevents the attack from our immune cells (T-cells). Some of the immune drugs include Pembrolizumab, Avelumab and Nivolumab.⁹

Targeted therapies that are available for various cancers are being researched for use as a treatment for Merkel cell carcinoma -  the clinical trials are ongoing.

Merkel cell carcinoma has a higher chances of recurringwithin 2 years of treatment. Thus, frequent follow up appointments (every 3-6 months) may include skin and radiological examinations, e.g., CT or PET, or testing of tumour markers, e.g., neuron-specific enolase (NSE) specific for Merkel Cell Carcinoma,in the blood sample.¹⁰ 

FAQs

How is merkel cell carcinoma diagnosed?

To make a proper diagnosis, the previous history, pathology, radiology and clinical findings of the patient have to be studied by the respective healthcare professionals. Some of the tests include: MCC tumour biopsy, immunohistochemistry staining of biological tumour markers (e.g., CK20, TTF-1).

How can I prevent merkel cell carcinoma?

• Try to avoid sun exposure as much as possible
• Use sunscreen with high SPF liberally on the skin when outside
• As soon as you see any changes in the colour and size of moles, freckles or bumps on the skin, consult the doctor.

Who are at risk of merkel cell carcinoma?

The immunocompromised , older persons, and individuals who are frequent exposed to UV radiation are at higher chances of developing Merkel cell carcinoma.

How common is merkel cell carcinoma?

Merkel cell carcinoma: Epidemiology, . Merkel cell carcinoma is very uncommon. Globally, 0.1 to 1.6 cases per 100 000 people are reported annually

When should I see a doctor?

When a bluish-red or flesh-coloured nodules appear on any sun exposed regions of skin. These small lumps may increase in size, if so, consult the health care provider. Identifying at an early stage of cancer is really important.

Summary

• The article summarizes the pathology, causes, diagnosis, treatment and management of Merkel Cell Carcinoma
• Merkel Cell Carcinoma is a rare and aggressive type of skin cancer
• Advanced age, exposure to UV radiation, previous incidence of cancer, Merkel Cell Polyomavirus and immunosuppressive patients are at higher risk of developing Merkel Cell Carcinoma
• Merkel Cell Carcinomas often appears as red-violet bumps or raised patches on the skin which can be misinterpreted as benign tumours or acne, which may delay the diagnosis of MCC
• Merkel Cell Carcinoma is diagnosed through biopsy and immunohistochemical staining of cancer associated proteins and through lymph node biopsy
• The treatment strategy involves surgical resection of the tumour and adjunct radiotherapy to prevent relapse and clear the primary tumour. Chemotherapy and immunotherapy are used in cases of advanced Merkel Cell Carcinoma
• Management involves following up appointments every 3-6 months to prevent MCC relapse