Merkel cell carcinoma is a rare, aggressive form of skin cancer. The condition is most common among fair-skinned people of European ancestry, but can also affect individuals with a darker complexion. It is frequently diagnosed in adults—men, more commonly—aged 65 and older. It usually appears in sun-exposed areas of the body, but can present in sun-shielded areas, too. Younger people are occasionally diagnosed with Merkel cell carcinoma, but they typically have health conditions that have compromised their immune systems, such as organ transplantation or HIV. Patients with chronic lymphocytic leukemia (CLL) and other forms of lymphoma are also at higher risk of developing Merkel cell carcinoma.

Although Merkel cell carcinoma is one of the most dangerous forms of skin cancer, the majority (75%) of people survive five years or more after diagnosis when the cancer has not spread. But those numbers worsen if the cancer spreads regionally or to distant locations in the body, underlining the importance of early detection and treatment.

“As radiation oncologists at Yale Cancer Center, we work as part of a collaborative, multidisciplinary team to care for each of our patients with this rare disease,” says Yale Medicine therapeutic radiologist Thomas Hayman, MD, PhD. “Using state-of-the-art technology in radiation oncology, we devise custom treatment plans for each patient to improve outcomes or reduce symptoms in a patient-centered manner.”

In the past, once the cancer spread beyond its original site in the skin and beyond the draining lymph nodes, the prognosis was very poor, adds Yale Medicine oncologist Harriet Kluger, MD. However, promising new research, including studies of newer drugs conducted at Yale and partnering institutions, has yielded benefits for patients. “With contemporary immunotherapy, many patients with metastatic Merkel cell carcinoma are living for years, and some might have complete, durable responses,” she says.

Merkel cell carcinoma is a type of skin cancer that appears as a hard, raised, rounded, reddish-purplish bump, or nodule, that grows quickly over the course of several weeks or months.

Nodules caused by Merkel cell carcinoma often develop on parts of the skin that are exposed to the sun, particularly the head and neck. However, they can also occur on the arms, shoulders, trunk, and other areas, including those that have not been exposed to the sun. Nodules usually do not cause pain or discomfort, but they tend to grow rapidly and may spread to other body parts.

Merkel cell carcinoma is a rare form of cancer. In the U.S., approximately 2,500 people are diagnosed with the condition each year. However, the number of cases is rising, and is predicted to reach nearly 3,300 in 2025. The increasing incidence is likely due to an aging population in which the proportion of people over age 65 is rising, though improvements in the detection of the condition may also play a role.

Cancer, in general, occurs when cells grow and multiply uncontrollably. However, doctors and researchers do not know the type of cell that gives rise to Merkel cell carcinoma. Historically, it was thought that the condition began in Merkel cells, a type of cell found at the base of the top layer of the skin. Today, however, most doctors and researchers do not believe the condition begins in Merkel cells. Specialists have hypothesized other potential cells of origin for Merkel cell carcinoma, though at present, the cell of origin remains unknown.

Doctors don’t yet know the exact cause of Merkel cell carcinoma. Researchers have identified two causes of the condition:

• Merkel cell polyomavirus infection. Around 80% of cases of Merkel cell cancer in the U.S. are caused by infection by a virus called Merkel cell polyomavirus (MCPyV). MCPyV is a common virus; roughly 60% to 80% of people have been infected by it. The virus often infects the skin, though it can also infect other organs. In rare cases, the DNA of MCPyV can become integrated into a person’s genome (the set of DNA instructions in a cell), leading to the production of two proteins involved in tumor formation. Merkel cell carcinoma attributed to MCPyV infection may be referred to as MCPyV-positive or viral-associated Merkel cell carcinoma.
  
  
• Exposure to ultraviolet radiation (e.g., sunlight) in people with certain genetic factors that predispose them to Merkel cell carcinoma. In the U.S., around 20% of cases are attributed to exposure to ultraviolet radiation. Ultraviolet radiation damages DNA, resulting in mutations in certain genes involved in suppressing tumor formation and DNA repair. These mutations disrupt the function of these genes and lead to the development of Merkel cell carcinoma. Merkel cell carcinomas attributed to exposure to UV radiation may be called MCPyV-negative or non-viral-associated Merkel cell carcinoma.

People who have Merkel cell carcinoma may notice a new bump on their skin that has some or all of the following qualities:

• Reddish-purple color (sometimes pinkish or bluish)
• Raised and rounded, like a dome
• Hard to the touch
• Painless
• Shiny, smooth skin
• Expanding in size over a short period of time

People with fair skin who are of European ancestry are at a greater risk of Merkel cell carcinoma.

Other risk factors for Merkel cell carcinoma include:

• Increasing age (it is most common in people over age 65)
• Male sex
• A history of chronic exposure to ultraviolet light (sun exposure)
• Suppressed immune system, which may be due to other medical conditions or medications, including:
  • HIV, which may suppress the immune system
  • Use of immune-suppressing drugs after organ transplantation or for autoimmune diseases
  • Cancer treatments, which suppress the immune system
  • Other types of cancer, including melanoma, multiple myeloma, or chronic lymphocytic leukemia, that may suppress the immune system

When doctors suspect Merkel cell carcinoma, they will examine the area, obtain a health history from the patient, and perform a biopsy to diagnose the condition.

Merkel cell carcinoma has a distinct look, but when the tumor is small, it can be confused with other skin conditions, such as acne, firm cysts, or other skin cancers like squamous cell or basal cell carcinoma. When a person has a rounded, raised, reddish, or purplish bump on the head, neck, or other sun-exposed skin, he or she may be asked about lifetime sun exposure, history of skin or other types of cancer, and whether he or she has any immune-suppressing health conditions.

To diagnose Merkel cell carcinoma, the doctor will closely examine any lesions and bumps on the skin, checking for features that may indicate Merkel cell carcinoma. The features correspond to the acronym AEIOU:

• Asymptomatic (in about 88% of cases, Merkel cell carcinoma skin lesions do not cause symptoms)
• Expanding rapidly (in about 63% of cases, the skin lesions have substantial growth within the past three months)
• Immune suppression (in about 8% of cases, people have HIV infection, chronic lymphocytic leukemia, received a solid organ transplant, or have a suppressed immune system due to other causes)
• Older than 50 years of age (90% of cases occur in people over 50)
• Ultraviolet-exposed area of skin on people with fair skin (accounting for around 81% of cases)

Doctors typically suspect Merkel cell carcinoma in people with three or more of these features. In these cases, doctors will biopsy the site to check for the presence of Merkel cell carcinoma cells. A blood test may also be used to check for the presence of Merkel cell polyomavirus antibodies or for circulating tumor DNA in order to assist with surveillance and management of Merkel cell carcinoma.

Sometimes, doctors order the following imaging tests to determine if the cancer has spread to other parts of the body:

• Computed tomography (CT) scan
• Positron emission tomography (PET) scan

If Merkel cell carcinoma is diagnosed, doctors will determine the stage of the disease based on tumor size and whether the cancer has spread to the lymph nodes or other parts of the body. This may involve additional imaging tests and typically will also include a sentinel lymph node biopsy. Staging the cancer allows doctors to tailor treatment and establish a prognosis for each patient.

Merkel cell carcinoma may be treated in the following ways:

• Surgery. The primary treatment for Merkel cell carcinoma is surgery to remove the tumor, plus a wide margin of healthy surrounding skin. (Mohs surgery, a procedure in which the visible tumor and surrounding layer of tissue are removed and checked for the presence of cancer cells, is rarely used.) Doctors also perform a sentinel node biopsy of the lymph nodes near the site of the cancer to determine if the cancer has spread.
• Radiation therapy. Merkel cell carcinoma is very sensitive to radiation. Radiation is used after surgery in the majority of cases to decrease the chance of recurrence. It is also used to treat the lymph node basin if the Merkel cell has spread to draining lymph nodes. Radiation can also be used if surgery is not possible due to other medical conditions or if a metastatic tumor is causing symptoms.
• Immunotherapy. If a patient has recurrent Merkel cell carcinoma or metastatic disease, immunotherapy is used to help boost the body’s immune system to fight the cancer cells. Immunotherapy has become the standard of care in advanced disease, as it is highly effective.
• Chemotherapy, which kills cancer cells, along with some healthy cells, may also be used when immunotherapy is unsuccessful or in patients who cannot receive immunotherapy due to other medical conditions.

When Merkel cell carcinoma is discovered and treated early and hasn’t spread to other parts of the body, about 75% of people live for at least five years after diagnosis. The outcomes tend to be worse if the cancer spreads; thus, early detection and treatment are important.

Because Merkel cell carcinoma can recur, patients may undergo screening every three to six months for the first two years after treatment, then every six to 12 months onward.

“At Yale, we are applying the latest findings in the field and working to develop the next generation of therapies to improve the care of patients with Merkel cell carcinoma,” says Yale Medicine medical oncologist Jeffrey Ishizuka, MD.

The Yale Cancer Center has created a unique multidisciplinary treatment team that includes a translational program to develop the next generation of advances for Merkel cell carcinoma, notes Kelly Olino, MD, a Yale Medicine surgical oncologist with additional training in cancer immunotherapy. “We are using state-of-the-art technology to better follow our patients and participate in clinical trials to give our patients the greatest of care,” she says.