Neuroendocrine carcinoma of the skin, also known as Merkel cell carcinoma, is a rare and aggressive type of skin cancer that requires prompt diagnosis and specialized treatment approaches. Understanding the available treatment options—from surgery and radiation to cutting-edge immunotherapies being tested in clinical trials—is essential for patients and their families navigating this challenging diagnosis.

Understanding Treatment Goals and Options

When someone receives a diagnosis of neuroendocrine carcinoma of the skin, the treatment journey begins with understanding what can be achieved. The main goals of treatment include removing or controlling the cancer, preventing its spread to other parts of the body, reducing symptoms, and maintaining the best possible quality of life. Treatment decisions depend heavily on several factors: how early the cancer was caught, where it is located on the body, whether it has spread to nearby lymph nodes or distant organs, and the patient’s overall health and personal preferences.^[11]

This type of skin cancer tends to grow quickly and spread early, often first to nearby lymph nodes and then to other parts of the body such as the lungs, brain, or bones. Because of this aggressive nature, doctors typically recommend a combination of treatments rather than relying on just one approach. The treatment landscape includes well-established methods approved by medical societies around the world, as well as innovative therapies currently being studied in clinical trials. Research continues to advance our understanding of this disease, offering new hope through emerging treatment strategies.^[3][6]

Most patients will work with a team of specialists including surgeons, radiation oncologists, medical oncologists, and dermatologists. This multidisciplinary approach ensures that all aspects of the cancer are addressed and that treatment is tailored to each individual’s situation. The staging of the disease—whether it is confined to the skin, has spread to lymph nodes, or has reached distant organs—plays a crucial role in determining which treatments will be most beneficial.^[11]

Standard Treatment Approaches

The foundation of treatment for neuroendocrine carcinoma of the skin typically involves surgery. For localized disease that has not spread beyond the original site, doctors perform what is called a wide local excision. This means removing the visible tumor along with a margin of healthy-looking tissue around it to ensure that no cancer cells are left behind. The amount of tissue removed depends on the size and location of the tumor, but surgeons aim to achieve clean margins while preserving as much normal function and appearance as possible.^[11]

An important part of the surgical approach involves checking the lymph nodes. Even when cancer is not obviously visible in nearby lymph nodes, there is a significant risk that microscopic cancer cells may have spread there. For this reason, most patients undergo a procedure called sentinel lymph node biopsy. During this procedure, doctors identify and remove the first lymph node or nodes that drain from the area of the tumor. A specialist then examines these nodes under a microscope to look for cancer cells. If cancer is found in these sentinel nodes, additional lymph nodes may need to be removed in a procedure called lymph node dissection.^[10][11]

Radiation therapy is another cornerstone of standard treatment. It uses high-energy beams to kill cancer cells or prevent them from growing. Radiation may be used after surgery to destroy any remaining cancer cells in the area where the tumor was removed, reducing the risk of the cancer coming back in that location. This is called adjuvant radiation therapy. It is particularly important when the tumor was large, when the margins of removed tissue were close to the tumor, or when cancer was found in lymph nodes.^[11]

The radiation treatment typically involves daily sessions over several weeks. Each session lasts only a few minutes, though the overall appointment may take longer. The radiation beam is carefully targeted to the area where the cancer was located and sometimes to nearby lymph node regions. While radiation is generally well-tolerated, it can cause side effects in the treated area. These may include skin changes resembling sunburn, fatigue, and temporary hair loss in the radiated area. Most side effects gradually improve after treatment ends, though some skin changes may be permanent.^[11]

For patients whose cancer has spread to distant parts of the body, or when surgery and radiation are not sufficient, systemic therapy becomes necessary. Traditional chemotherapy has been used in these situations, with drugs that work throughout the entire body to kill rapidly dividing cancer cells. Chemotherapy regimens for neuroendocrine carcinoma of the skin have historically included combinations of drugs such as carboplatin and etoposide, similar to those used for small cell lung cancer, since these two cancers share some biological characteristics.^[6]

However, chemotherapy comes with significant side effects. Because these drugs affect all rapidly dividing cells in the body, not just cancer cells, patients may experience nausea, vomiting, hair loss, fatigue, increased risk of infections due to low blood counts, and numbness or tingling in the hands and feet. The intensity and duration of these side effects vary from person to person, and doctors can prescribe supportive medications to help manage them. Chemotherapy is typically given in cycles, with periods of treatment followed by rest periods to allow the body to recover.^[6]

Promising Treatments in Clinical Trials

The treatment landscape for neuroendocrine carcinoma of the skin has been transformed in recent years by the development of immunotherapy, a type of treatment that harnesses the body’s own immune system to fight cancer. Several immune checkpoint inhibitors have shown remarkable promise in clinical trials and are now being used in various stages of the disease. These drugs work by blocking proteins that prevent immune cells from attacking cancer cells, essentially releasing the brakes on the immune system.^[10]

One major breakthrough involves drugs called PD-1 inhibitors and PD-L1 inhibitors. PD-1 (programmed death-1) is a protein on immune cells that, when bound by PD-L1 (programmed death-ligand 1) on cancer cells, prevents the immune cells from attacking. By blocking this interaction, these drugs allow immune cells to recognize and destroy cancer cells more effectively. Several of these checkpoint inhibitors have been studied in clinical trials for neuroendocrine carcinoma of the skin, with some showing impressive results.^[10]

Clinical trials have been conducted in different phases to test these treatments. Phase I trials focus primarily on safety, determining the appropriate dose and identifying potential side effects. Phase II trials examine whether the treatment works against the cancer, looking at how many tumors shrink and how long patients remain free of cancer progression. Phase III trials compare the new treatment to standard treatment to see if it offers better outcomes.^[10]

Importantly, research has explored using immunotherapy at different points in the treatment journey. Some recent studies have investigated neoadjuvant immunotherapy, which means giving these drugs before surgery. The idea is to shrink the tumor and activate the immune system against cancer cells before they are surgically removed. Early results have been encouraging, with some patients showing dramatic tumor shrinkage and even complete responses. This approach may also help the immune system create a memory of the cancer, potentially preventing recurrence after surgery.^[10]

The side effects of immunotherapy differ significantly from those of chemotherapy. Because these treatments work by activating the immune system, they can sometimes cause the immune system to attack normal tissues in the body. This can lead to what doctors call immune-related adverse events. These may include inflammation of the intestines causing diarrhea, inflammation of the liver, thyroid problems, skin rashes, or inflammation of the lungs. Most of these side effects can be managed with medications that calm down the immune system, such as corticosteroids. While these side effects require careful monitoring, many patients tolerate immunotherapy better than traditional chemotherapy.^[10]

Another area of active research involves understanding the role of Merkel cell polyomavirus in this cancer. Scientists discovered that about 80% of neuroendocrine carcinomas of the skin contain DNA from this virus integrated into the cancer cells. This discovery has opened new avenues for treatment development. Researchers are investigating whether targeting the viral proteins produced by cancer cells could be an effective treatment strategy. This approach represents a form of precision medicine, where treatments are tailored to specific characteristics of each patient’s tumor.^[4][10]

Clinical trials are being conducted at medical centers around the world, including in the United States, Europe, and other regions. Eligibility for these trials depends on various factors including the stage of disease, previous treatments received, and overall health status. Some trials accept patients who have not yet received any treatment, while others are designed for patients whose cancer has returned after initial treatment or has not responded to standard therapies. Each trial has specific inclusion and exclusion criteria to ensure patient safety and the validity of the research.^[10]

An emerging tool in the management of neuroendocrine carcinoma of the skin is circulating tumor DNA (ctDNA) testing. This blood-based test looks for small fragments of DNA shed by cancer cells into the bloodstream. Research suggests that ctDNA testing may help doctors detect cancer recurrence earlier than traditional imaging scans, potentially allowing for earlier intervention. This technology is particularly valuable for surveillance after initial treatment, helping to identify which patients might benefit from additional therapy before the cancer becomes widely spread.^[10]

Most common treatment methods

• Surgery
  • Wide local excision removes the tumor along with surrounding healthy tissue to ensure clear margins
  • Sentinel lymph node biopsy identifies and examines the first lymph nodes draining from the tumor site
  • Lymph node dissection removes additional lymph nodes when cancer is found in sentinel nodes
• Radiation Therapy
  • Adjuvant radiation after surgery helps destroy remaining cancer cells and reduce recurrence risk
  • Treatment typically involves daily sessions over several weeks targeting the tumor site and nearby lymph node regions
  • May cause temporary side effects including skin changes, fatigue, and hair loss in treated areas
• Immunotherapy
  • PD-1 and PD-L1 checkpoint inhibitors release the immune system’s brakes, allowing it to attack cancer cells
  • Can be used before surgery (neoadjuvant), after surgery, or for advanced disease
  • May cause immune-related side effects requiring monitoring and management with medications
• Chemotherapy
  • Systemic drugs that work throughout the body to kill rapidly dividing cancer cells
  • Often uses combinations similar to those for small cell lung cancer, such as carboplatin and etoposide
  • Given in cycles with rest periods, may cause nausea, hair loss, fatigue, and increased infection risk
• Surveillance and Monitoring
  • Regular follow-up examinations and imaging to detect recurrence early
  • Emerging circulating tumor DNA testing may identify cancer return before it’s visible on scans
  • Critical for long-term management given the cancer’s tendency to recur

Treatment for Different Disease Stages

Treatment strategies vary significantly depending on whether the cancer is localized to the skin, has spread to nearby lymph nodes, or has metastasized to distant organs. For Stage I and Stage II disease, where the cancer is confined to the skin without evidence of lymph node involvement, the standard approach combines wide local excision with sentinel lymph node biopsy, often followed by radiation therapy. This combination has been shown to reduce the risk of the cancer returning in the same area.^[11]

Stage III disease involves cancer that has spread to nearby lymph nodes. Treatment typically includes surgery to remove the primary tumor and affected lymph nodes, followed by radiation therapy to the surgical site and regional lymph node areas. For some patients, particularly those with multiple involved lymph nodes or other high-risk features, doctors may recommend additional treatment with immunotherapy or chemotherapy to reduce the risk of distant spread.^[11]

When cancer has spread to distant parts of the body (Stage IV disease), treatment focuses on controlling the cancer throughout the body while managing symptoms and maintaining quality of life. Immunotherapy has become a preferred first-line treatment for many patients with metastatic disease, based on encouraging results from clinical trials. For patients whose cancer does not respond to immunotherapy or who cannot tolerate it, chemotherapy remains an option. Some patients may also benefit from radiation therapy to specific sites of disease to relieve symptoms or prevent complications.^[11]

Unfortunately, neuroendocrine carcinoma of the skin can return after initial treatment. Recurrent disease may appear near the original site, in distant lymph nodes, or in organs such as the lungs, liver, or brain. Treatment for recurrence depends on where the cancer has returned, what treatments were used previously, and how long it has been since the initial treatment. Options may include additional surgery if feasible, radiation therapy, immunotherapy, or chemotherapy. Clinical trials of new treatments may be particularly appropriate for patients with recurrent disease.^[11]

Factors Affecting Treatment Outcomes

Several factors influence how well treatments work and the overall outlook for patients with neuroendocrine carcinoma of the skin. The stage at diagnosis is one of the most important factors—cancers caught early, before they have spread, generally have better outcomes than those diagnosed at more advanced stages. The size of the original tumor also matters, with smaller tumors associated with better prognoses.^[6]

Patient age and overall health play significant roles in treatment decisions and outcomes. While this cancer most commonly affects people over 50, particularly those over 70, younger patients with good overall health may be better able to tolerate intensive treatments. The immune system’s status is also crucial—patients with weakened immune systems due to conditions such as HIV infection, organ transplantation, or certain blood cancers tend to have more aggressive disease and may respond differently to treatments.^[3][10]

Sex appears to influence outcomes as well. Studies have shown that survival rates differ between males and females, with women generally having better outcomes. However, the reasons for this difference are not entirely clear and continue to be investigated.^[6]

Sun exposure history is a known risk factor for developing this cancer, and patients with significant sun damage to their skin may have different tumor characteristics. Similarly, whether the tumor is associated with Merkel cell polyomavirus may affect how it responds to treatments, particularly immunotherapy. Researchers are actively studying whether virus-positive and virus-negative tumors should be treated differently.^[4][10]