Merkel Cell Carcinoma (MCC) in Adults: What patients should know about

Merkel Cell Carcinoma (MCC) is a rare and aggressive form of skin cancer that primarily affects the skin‘s outer layer, or epidermis. It is known for its rapid growth and potential to spread to other parts of the body, including lymph nodes and organs, making it a life-threatening condition. Understanding MCC, its causes, symptoms, diagnosis, treatment options, and prognosis is crucial for patients and their families.

Causes and Risk Factors

Markel Cell Carcinoma originates from the Merkel cells, which are found in the top layer of the skin and are responsible for the sense of touch. The causes and risk factors of MCC are multifaceted, involving environmental exposures, viral infections, and individual predispositions.

Causes of Merkel Cell Carcinoma

• Ultraviolet (UV) Radiation – Exposure to UV radiation from the sun or artificial sources like tanning beds is a significant risk factor for most skin cancers, including MCC. UV radiation can damage the DNA in skin cells, leading to mutations that may cause cancer. MCC often develops in areas of the skin that are frequently exposed to sunlight, such as the face, neck, and arms

• Merkel Cell Polyomavirus (MCPyV) – A substantial body of research has identified the Merkel cell polyomavirus (MCPyV) as a contributing factor in the majority of MCC cases. This virus is commonly found on human skin and is generally harmless; however, in some individuals, it can integrate into the host’s DNA and trigger oncogenic processes. 

Risk Factors for Merkel Cell Carcinoma

• Immunosuppression – Individuals with weakened immune systems are at a higher risk of developing MCC. 
• Age – MCC predominantly affects older adults, typically those over the age of 50. The risk increases with age, possibly due to the cumulative exposure to UV radiation and the natural decline in immune function that occurs with aging.
• Skin Type – Individuals with fair skin, especially those who burn easily and tan poorly, are at a higher risk for MCC. This skin type is less equipped to protect against UV radiation, leading to greater damage and increased risk of skin cancers.
• Gender – Men are more likely to develop MCC than women.
• Previous Skin Cancers – Having a history of other skin cancers, such as basal cell carcinoma or squamous cell carcinoma, can also increase the risk of developing MCC.
• Genetic Factors – While specific genetic mutations have been identified in MCC, particularly in virus-negative cases, there is no clear pattern of inheritance. Most cases of MCC are not familial, suggesting that environmental factors and individual susceptibility play more significant roles.

This image is taken from “GALT Dermatology and Concierge Medicine” 

Signs and Symptoms of Merkel Cell Carcinoma

MCC typically appears as a single, painless nodule that rapidly grows over weeks or months. The nodule may vary in color, often appearing red, pink, or purple, and is usually firm to the touch. Most commonly, these nodules develop on areas of the skin that are frequently exposed to the sun, such as the face, neck, and arms. However, they can also appear on less exposed areas, indicating the aggressive nature of the cancer.

• Texture and Sensation – The nodules are typically non-tender and may feel attached to the underlying skin layers, making them less movable. Despite their aggressive nature, they are often not painful, although some patients report a sensation of tenderness or itching as the nodule grows

• Visual Characteristics –Merkel Cell Carcinoma can mimic other benign skin conditions, which can lead to misdiagnosis. It may resemble a cyst, stye, or even a common pimple, and in some cases, it can appear as a slightly raised, reddish or bluish patch that might be mistaken for a bruise or an innocuous skin lesion.

This image is taken from “Saint John’s Cancer Institute” 

Diagnosis 

The initial step in diagnosing Merkel Cell Carcinoma is a thorough clinical examination by a dermatologist or oncologist. 

1. Biopsy

The definitive diagnosis of MCC requires a biopsy of the suspicious lesion. The biopsy sample is then examined under a microscope by a pathologist who looks for characteristic cancer cells indicative of MCC.

2. Immunohistochemistry (IHC)

IHC staining is a critical tool in confirming the diagnosis of Merkel Cell Carcinoma. This technique uses antibodies that bind to specific proteins on the cancer cells. MCC cells typically express certain markers such as CK20, which stains in a perinuclear dot pattern, and neuroendocrine markers like synaptophysin and chromogranin. The absence of S100 protein can help differentiate MCC from melanoma.

3. Imaging Tests

Once Merkel Cell Carcinoma (MCC) is diagnosed, imaging tests may be conducted to determine the extent of the disease and whether it has spread (metastasized). These tests can include:

• Computed Tomography (CT) Scans
• Magnetic Resonance Imaging (MRI)
• Positron Emission Tomography (PET) Scans

These imaging modalities help identify metastases in lymph nodes, organs, and other parts of the body, which is crucial for staging the cancer.

Staging

Staging is a critical aspect of diagnosing Merkel Cell Carcinoma (MCC) as it determines the extent of the disease and guides treatment decisions. The staging system for MCC is based on the TNM system developed by the American Joint Committee on Cancer (AJCC), which considers the size and extent of the tumor (T), the involvement of lymph nodes (N), and the presence of distant metastasis (M).

Stage 0 (in situ)

• Tis N0 M0: The carcinoma is in situ, meaning it is confined to the epidermis and has not invaded deeper tissues or spread to lymph nodes or distant sites.

Stage I

• T1 N0 M0: The tumor is 2 cm or smaller in size and has not spread to lymph nodes or distant sites.

Stage II

• T2 N0 M0: The tumor is more than 2 cm but not larger than 5 cm and has not spread to lymph nodes or distant sites.
• T3 N0 M0: The tumor is larger than 5 cm but has not spread to lymph nodes or distant sites.

Stage III

• Any T N1 M0: The tumor of any size with spread to regional lymph nodes but no distant metastasis.
• T4 Any N M0: The tumor invades deep structures such as bone, muscle, fascia, or cartilage, with or without lymph node involvement but no distant metastasis.

Stage IV

• Any T Any N M1: The tumor of any size and any lymph node involvement, but with distant metastasis.

This image is taken from “iCliniq”

The stage of MCC at diagnosis significantly influences the prognosis and treatment options.

Differential Diagnosis

Merkel Cell Carcinoma must be differentiated from other skin conditions and cancers, which include:

• Basal Cell Carcinoma (BCC): BCC typically presents as a pearly nodule with visible blood vessels but lacks the rapid growth seen in MCC.
• Squamous Cell Carcinoma (SCC): SCC can appear as a scaly or crusty lesion that grows over time, but it usually develops more slowly than Merkel Cell Carcinoma .
• Melanoma: Melanoma often presents as a dark or multicolored lesion with an irregular border. The absence of S100 protein in MCC helps differentiate it from melanoma.
• Lymphoma: Cutaneous lymphoma can present with skin nodules, but these are usually not as rapidly growing as MCC nodules.
• Metastatic Carcinomas: Other cancers can metastasize to the skin, mimicking MCC. A thorough patient history and additional testing can help differentiate these conditions.

Treatment of Merkel Cell Carcinoma 

Merkel Cell Carcinoma requires a comprehensive treatment approach. The choice of treatment largely depends on the stage of the disease, the overall health of the patient, and specific characteristics of the tumor. 

1. Surgery

Surgery is often the first line of treatment for Merkel Cell Carcinoma, especially in its early stages. The goal is to remove the tumor completely along with a margin of healthy tissue to ensure no cancer cells remain. Types of surgical procedures include:

• Wide Local Excision: Removal of the tumor along with some normal skin around it.
• Mohs Micrographic Surgery: A technique that removes the cancer layer by layer, examining each layer under the microscope until no abnormal cells remain. This method helps preserve as much healthy tissue as possible.

If the cancer has spread to the lymph nodes, a sentinel lymph node biopsy may be performed to check for cancer in the lymph nodes. If cancer is found, a lymph node dissection might be necessary.

This image is derived from “The National Cancer Institute”

2. Radiation Therapy

Radiation therapy is commonly used in Merkel Cell Carcinoma treatment, either as an adjuvant therapy after surgery to eliminate any remaining cancer cells or as a primary treatment when surgery is not feasible. It can also be used palliatively to relieve symptoms in cases of advanced disease. Radiation is particularly effective for Merkel Cell Carcinoma due to the cancer’s high radiosensitivity. It may be directed at the primary tumor site or the regional lymph nodes to prevent recurrence.

3. Chemotherapy

Chemotherapy is generally reserved for advanced stages of Merkel Cell Carcinoma or when the cancer has recurred or metastasized. Common chemotherapeutic agents used include platinum-based drugs like cisplatin or carboplatin, often combined with etoposide. While chemotherapy can be effective in reducing tumor size and controlling symptoms, it is not typically used as a first-line treatment due to its temporary effects and significant side effects.

4. Immunotherapy

Immunotherapy has emerged as a highly effective treatment for advanced Merkel Cell Carcinoma, particularly with drugs targeting the PD-1/PD-L1 pathway. The FDA has approved drugs such as pembrolizumab (Keytruda) and avelumab (Bavencio) for the treatment of advanced Merkel Cell Carcinoma . These drugs have shown promising results in improving survival rates and are generally well-tolerated compared to chemotherapy. Immunotherapy works by enhancing the body’s immune response against cancer cells. It is particularly suitable for patients who have not responded well to chemotherapy or those with recurrent disease.

Watch this video about “Beating Merkel Cell Carcinoma With Immunotherapy” from American Association for Cancer Research

Survival Rates and Prognosis

General Survival Statistics

The overall five-year relative survival rate for Merkel Cell Carcinoma is approximately 64%. However, this rate varies widely depending on the stage of the cancer at diagnosis:

• Localized Disease (no spread beyond the primary site): The five-year survival rate can be as high as 78% when the cancer is localized.
• Regional Disease (spread to nearby lymph nodes): The survival rate drops to about 52%.
• Distant Metastasis (spread to distant organs): The prognosis worsens significantly with a five-year survival rate of around 18%.

Factors Influencing Prognosis

Several factors influence the prognosis of Merkel Cell Carcinoma:

• Stage of Disease: Early-stage disease generally has a better prognosis compared to advanced stages where the cancer has spread to lymph nodes or distant organs.
• Lymph Node Involvement: Negative lymph node status at diagnosis is associated with a better prognosis.
• Patient’s Immune Status: Immunocompromised patients, such as those with HIV/AIDS or those on immunosuppressive medications, generally have a poorer prognosis.
• Tumor Size and Location: Smaller tumors and those located on the limbs tend to have a better prognosis than larger tumors or those on the head and neck.

Recurrence and Monitoring

Merkel Cell Carcinoma is known for its high recurrence rate, which significantly affects prognosis. Regular follow-up and monitoring are crucial for early detection of recurrence, which can be managed with further treatment.

The prognosis for Merkel cell carcinoma varies widely based on the stage at diagnosis, lymph node involvement, patient health, and response to treatment. Advances in immunotherapy have opened new avenues for treatment, particularly for advanced stages of the disease, improving the overall survival rates and quality of life for many patients. However, MCC remains a challenging cancer to treat, necessitating ongoing research and specialized care.

Resources

1. American Cancer Society – cancer.org
2. Cancer Research UK – cancerresearchuk.org
3. American Society of Clinical Oncology (ASCO) – Cancer.net 
4. Penn Medicine Abramson Cancer Center  – pennmedicine.org
5. Merkel Cell Carcinoma: Therapeutic Update and Emerging Therapies-PubMed
6. National Cancer Institute – cancer.gov
7. Johns Hopkins Medicine – hopkinsmedicine.org
8. Canadian Cancer Society – cancer.ca
9. Diagnosis and treatment of Merkel cell carcinoma: European consensus-based interdisciplinary guideline – Update 2022 – PubMed
10. OncoDaily