Merkel Cell Carcinoma

Overview

Merkel cell carcinoma is a rare neuroendocrine malignancy originating from skin Merkel cells, first reported by Toker in 1972. This disease is more common in the head, face, and limbs of middle-aged and elderly people, and is clinically characterized by rapidly growing purple red nodules with a high misdiagnosis rate (up to 87.1%), often misdiagnosed as ordinary masses or lymphomas. Pathological features show that tumor cells are small blue circular in shape, with obvious nuclear lobulation, and immunohistochemical characteristic expression of CK-20 and neuroendocrine markers. As of 2024, treatment options include expanded resection, radiotherapy, chemotherapy, and new immunotherapy such as PD-L1 inhibitors, but the overall 5-year survival rate is still below 7%, and the prognosis for advanced cases is extremely poor.

Overview

Merkel cell carcinoma is a skin neuroendocrine tumor, which means it originates from cells that share common characteristics with nerve cells and hormone secreting cells. Cancer is named after Merkel cells, which are located in the deepest layer of the epidermis (the outermost layer of the skin). Merkel cells are a part of the body's sense of touch, connected to nerve endings. Although it has been historically believed that MCC originated directly from Merkel cells, recent research suggests that this may not be the case. Scientists now believe that cancer may be caused by other types of skin cells, but the exact origin of the cells is still under investigation.

Causes and Risk Factors

The exact cause of Merkel cell carcinoma is not fully understood, but there are two main factors closely related to its development: a common virus and ultraviolet radiation.

Merkel cell multitumor virus (MCPyV): Approximately 80% of MCC tumors are associated with this virus. This virus is very common, and most people have been exposed to it throughout their lives without any adverse effects. In the vast majority of cases, it is still harmless. However, in certain individuals, especially those with weaker immune systems, the virus can integrate into the host's DNA. This integration is considered a key event in the development of cancer.
Ultraviolet (UV) radiation: Long term exposure to sunlight is an important risk factor for MCC, just like other skin cancers. Most tumors occur in areas exposed to sunlight, such as the head, neck, arms, and legs. Ultraviolet radiation can cause DNA damage in skin cells, coupled with immune system damage and the presence of MCPyV, leading to malignant transformation of cells.
Weakening of the immune system: The immune system plays a crucial role in preventing and combating cancer. People with suppressed or weakened immune systems have a higher risk of developing MCC. This includes people who have received organ transplants and are taking immunosuppressive drugs, people with HIV/AIDS or people with other diseases that affect immune function. The body is unable to effectively monitor and destroy abnormal cells, which allows cancer to be controlled and grow.

Diagnosis

Diagnosing Merkel cell carcinoma typically involves a multi-step process, starting with physical examination and medical history.

Physical examination: Doctors will examine suspicious lesions and check for lymph node enlargement, as MCC usually spreads to nearby lymph nodes first.
Biopsy: The final diagnosis of MCC is made through biopsy. A small portion of tissue samples were taken out and sent to the laboratory, where pathologists examined them under a microscope. Special tests, such as immunohistochemistry, are used to confirm the diagnosis and distinguish MCC from other 'blue round cell' tumors.

Staging

Staging: Once diagnosed, using the American Joint Committee on Cancer (AJCC) TNM system for staging to determine the severity of the disease is crucial for prognosis and treatment planning.

Stage 0: In situ disease.
Stage I and II: Localized disease (only primary tumor, no spread).
Stage 3: Regional diseases (spreading to nearby lymph nodes or skin).
Stage 4: Distant metastatic diseases (spreading to other organs such as lungs, liver, brain, or bones).

Installment inspection usually includes:

Imaging: PET/CT scanning has become the preferred method for evaluating lymph nodes and distant metastatic diseases due to its high sensitivity.

Sentinel lymph node biopsy (SLNB): It is strongly recommended that all patients with clinically lymph node negative diseases undergo this procedure to detect microscopic spread to regional lymph nodes, which can greatly alter staging and treatment.

Treatment of Advanced Diseases

Treatment	Details
Immunotherapy	This completely changes the treatment of advanced MCC. Immune checkpoint inhibitors, especially Avelumab (PD-L1 inhibitor) and Pembrolizumab (PD-1 inhibitor), have become first-line therapies. Their function is to 'release' the brakes on the patient's immune system, allowing T cells to recognize and attack cancer cells. These drugs have shown significant response rates and improved survival rates.
Chemotherapy	Previously the standard for metastatic diseases, chemotherapy (such as platinum based drugs containing etoposide) is now mainly used for cases where immunotherapy is not feasible or has failed. Although it can initially shrink tumors, the response is often short-lived.
Palliative radiation therapy	can effectively control symptoms at the site of metastasis, such as bone pain or brain metastases.

Future Directions

MCC's research focuses on addressing unmet needs, including improving the response rate of immunotherapy, developing targeted therapies for non responders, and preventing MCPyV infection. The main areas of investigation include:

MCPyV vaccine: Preclinical studies of MCPyV large T antigen vaccine have shown that it has the potential to induce antiviral immune responses. Clinical trials are currently underway to evaluate the primary prevention (high-risk population) and secondary prevention (MCC survivors) of the vaccine.
Combination immunotherapy: The trial is testing ICI (such as anti-PD-1+anti-CTLA-4) or a combination of ICI and targeted therapy (such as PI3K inhibitors) to improve response rates.
Molecular targeting: Genomic research is identifying new targets in virus negative MCC, such as mutations in the NOTCH pathway or fusion genes, which may be targeted by small molecule inhibitors.
Liquid biopsy: Circulating tumor DNA (ctDNA) testing is being evaluated for early detection of recurrence and monitoring of treatment response, which may aid in early intervention.

Conclusions

Merkel cell carcinoma is a terrible skin malignancy, and its treatment has undergone a transformation due to advances in virus discovery, sensitive imaging, and most importantly, immunotherapy. Although its incidence rate is rising, the key to early diagnosis is to improve clinicians' and the public's awareness of its typical manifestations (the rapidly growing red nodules on the sun exposed skin of the elderly). The prognosis of this once spreading cancer patient is steadily improving through a multidisciplinary approach that utilizes surgery, radiation, and novel immunotherapy. The ongoing research continues to focus on improving treatment plans and developing new strategies for those who do not respond to current therapies.

Reagent Solutions

Antibodies

Cat. No.	Product Name	Host	Isotype	Application
DPABH-08513	Anti-CD37 (aa 104-134) polyclonal antibody	Rabbit	IgG	WB, FC	Inquiry
DPABH-22346	Anti-CD37 (aa 126-175) polyclonal antibody	Rabbit	IgG	WB	Inquiry
CABT-ZB180	Mouse Anti-Avelumab monoclonal antibody, clone 23I8	Mouse	IgG1,	ELISA(cap)	Inquiry
CABT-ZB181	Mouse Anti-Avelumab monoclonal antibody, clone 23H0	Mouse	IgG1,	ELISA(det)	Inquiry
CABT-Z203R	Recombinant Rabbit Anti-Human KRT20 Monoclonal Antibody, clone CQ7141	Rabbit	IgG	IHC-P	Inquiry

ELISA Kits

Cat. No.	Product Name	Size	Species Reactivity	Application	Detection Method
DEIASL160	Anti-polyomavirus JC (JCV) IgG ELISA Kit	96T	Human	Quantitative	iELISA	Inquiry

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