Merkel Cell Carcinoma: Symptoms, Types, Causes and Treatment

Merkel cell carcinoma (MCC) is a rare but highly aggressive skin cancer. While its name might not be familiar to most people, MCC's rapid growth and tendency to spread make it a major concern for dermatologists and oncologists. Over the past decade, researchers have uncovered much about its symptoms, underlying causes, various types, and treatment strategies. This comprehensive guide aims to demystify MCC, empower patients and caregivers, and highlight the latest science on this challenging cancer.

Symptoms of Merkel Cell Carcinoma

Merkel cell carcinoma often appears deceptively benign at first. Recognizing its early signs is critical, as early detection can dramatically improve outcomes. MCC most commonly presents on sun-exposed areas of older adults and those with fair skin, and it may not cause pain or discomfort, making it easy to overlook.

Symptom	Description	Frequency/Notes	Source(s)
Asymptomatic	Lacks tenderness/pain	88% of cases	1
Rapid Growth	Expands quickly	63% of lesions grew rapidly in prior 3 months	1
Red/Pink Nodule	Red or pink skin lesion	56% of cases	1 7
Sun-exposed Site	Appears on UV-exposed skin	81% of cases	1 7
Elderly	Age over 50	90% of cases	1
Immune Suppressed	Weakened immune system	7.8% of patients	1 5 7
Firm, Mobile Mass	Especially vulvar MCC	Firm, mobile, sometimes with pain or ulceration	2

Table 1: Key Symptoms of Merkel Cell Carcinoma

Classic AEIOU Features

Researchers have summarized the most significant features into the acronym AEIOU:

• Asymptomatic/lack of tenderness
• Expanding rapidly
• Immune suppression
• Older than 50 years
• Ultraviolet-exposed site (especially in fair-skinned individuals)

Nearly 9 out of 10 MCCs present with three or more of these features, making the AEIOU criteria a valuable tool for early detection 1.

Appearance and Course

MCC typically starts as a single, painless, firm nodule, often red or pink. It most commonly appears in sun-exposed areas, such as the head, neck, arms, and legs. Lesions can be mistaken for benign cysts or acneiform nodules, leading to delays in diagnosis. In rare cases, such as vulvar MCC, symptoms can include pain, itching, swelling, and ulceration 2.

Risk Groups and Presentation

• Elderly and immunosuppressed individuals are at higher risk 1 5 7.
• Chronic lymphocytic leukemia and other immune-compromising conditions dramatically increase risk 1.
• MCC may masquerade as harmless skin bumps, so persistent, fast-growing, painless nodules in at-risk populations should prompt a biopsy.

Types of Merkel Cell Carcinoma

Although MCC is rare, it is not a single disease. Recent research shows that MCC can be classified into two main types, each with distinct origins and molecular characteristics. Understanding these differences can influence prognosis and treatment.

Type	Cause/Origin	Key Features	Source(s)
Virus-positive	Merkel cell polyomavirus	Lower mutational burden, better prognosis	3 4 5 6
Virus-negative	UV-induced DNA mutations	High mutational load, worse prognosis	3 4 5 6
Site-specific	e.g., vulvar, head/neck	Rare, site-driven clinical features	2 12

Table 2: Types of Merkel Cell Carcinoma

Virus-positive MCC

About 70–80% of MCC cases are linked to the Merkel cell polyomavirus (MCPyV). The virus integrates into the host DNA and produces oncoproteins that drive tumor growth. These cancers generally have a lower number of DNA mutations and, interestingly, may be more responsive to immune-based therapies. They also tend to have a somewhat better prognosis 3 4 5 6 11.

Virus-negative (UV-induced) MCC

The remaining 20–30% of MCC cases are virus-negative. These tumors arise through ultraviolet (UV) light–induced mutations, leading to a high mutational burden. This type is more common in areas with intense sun exposure and is associated with a worse prognosis. They may also be more likely in immunosuppressed individuals 3 4 5 6 7.

Site-specific Variants

While most MCCs arise on sun-exposed skin, rare cases can appear in unusual locations like the vulva. These variants may display unique features (e.g., pain, ulceration) but generally follow the aggressive course typical of MCC 2.

Distinct Cells of Origin

Emerging evidence suggests that virus-positive and virus-negative MCCs may arise from different cells: virus-negative tumors from epidermal keratinocytes, and virus-positive from dermal fibroblasts. This distinction is under active investigation and may impact future prevention and therapeutic strategies 6.

Causes of Merkel Cell Carcinoma

The causes of MCC are multifactorial, combining environmental, viral, and host-related risk factors. An understanding of these mechanisms is crucial for both prevention and early recognition.

Cause	Mechanism/Explanation	Notes	Source(s)
MCPyV Infection	Viral integration and oncoprotein action	Most common cause	3 4 5 6 9 10 11
UV Exposure	DNA damage and somatic mutations	Especially for virus-negative MCC	3 4 5 7 11
Immunosuppression	Weakened immune surveillance	Increases both viral and UV-MCC risk	1 4 5 7 11
Advanced Age	Accumulated risk factors	Most patients >50 years old	1 5 7 11
Fair Skin	Increased vulnerability to UV damage	Predominantly affects white populations	1 7 11
Chronic Conditions	e.g., leukemia, HIV/AIDS, organ transplants	Higher rates of MCC development	1 7 11

Table 3: Causes and Risk Factors of Merkel Cell Carcinoma

Merkel Cell Polyomavirus (MCPyV)

The most common cause of MCC is infection with MCPyV. The virus becomes embedded in the DNA of skin cells and produces proteins that disrupt normal cell cycle regulation, leading to cancer. MCPyV is widespread in the general population but only rarely leads to cancer, typically when immune surveillance is compromised 3 4 5 9 10 11.

Ultraviolet (UV) Light Exposure

UV radiation is a key driver of MCC, particularly in virus-negative cases. Chronic sun exposure causes direct DNA damage, resulting in a high number of mutations that can trigger cancer development. UV exposure likely also plays a role in immunosuppression, further increasing risk 3 4 5 7 11.

Immune Suppression

Individuals with weakened immune systems—whether due to age, medical illness (such as HIV/AIDS or leukemia), or immunosuppressive drugs (e.g., organ transplant recipients)—are at significantly higher risk for developing MCC. Immunosuppression can increase susceptibility to both viral infection and UV-induced mutations 1 4 5 7 11.

Demographic and Genetic Factors

• MCC is most common in elderly, fair-skinned individuals.
• It is rare in individuals with darker skin, reflecting the protective effect of melanin against UV damage 1 7 11.
• Certain underlying conditions, such as chronic lymphocytic leukemia, are significantly overrepresented among MCC patients 1.

Treatment of Merkel Cell Carcinoma

Treating MCC is challenging due to its aggressive nature and tendency to recur or spread. However, advances in surgery, radiotherapy, and immunotherapy have significantly improved outcomes for many patients.

Treatment	Approach	Key Points/Use Case	Source(s)
Surgical Excision	Wide local excision ± margins	First-line for localized MCC	7 12 13 14
Sentinel Node Biopsy	Staging tool	Detects microscopic spread	7 13 14
Radiation Therapy	Adjuvant or primary treatment	Reduces recurrence; used if surgery unfeasible	3 7 12 13 14
Immunotherapy	PD-1/PD-L1 checkpoint inhibitors	First-line systemic in advanced MCC	3 5 7 11 14
Chemotherapy	Systemic cytotoxic agents	For refractory or intolerant patients	7 12 13 14
Clinical Trials	Investigational therapies	Recommended for advanced/metastatic MCC	13 14

Table 4: Main Treatment Approaches for Merkel Cell Carcinoma

Surgery

• Wide local excision is the standard initial treatment for localized MCC. Margins of 1–2 cm are typically recommended, and complete excision is vital 7 12 13.
• Sentinel lymph node biopsy is recommended even when nodes are not clinically involved, as MCC frequently spreads microscopically at an early stage 7 13 14.
• Radical lymphadenectomy may be necessary if lymph node metastases are detected 7 13.

Radiation Therapy

Radiation is frequently used as an adjuvant (post-surgical) therapy to reduce the risk of local recurrence. In patients who cannot undergo surgery, radiotherapy may serve as the primary treatment 3 7 12 13 14.

Immunotherapy

Recent years have seen a revolution in MCC treatment with the use of immune checkpoint inhibitors targeting PD-1 or PD-L1. These drugs can provide durable responses, especially in advanced or metastatic MCC, though not all patients benefit 3 5 7 11 14.

• Immunotherapy is now the preferred first-line systemic treatment for advanced MCC 7 14.
• Ongoing research seeks to determine if viral status affects immunotherapy response 14.

Chemotherapy

Traditional chemotherapy regimens (such as platinum-based combinations) can induce remission but responses are often short-lived, and recurrence is common 7 12 13 14. Chemotherapy is reserved for patients who do not respond to or cannot tolerate immunotherapy.

Clinical Trials and Future Therapies

Given MCC’s rarity and aggressiveness, participation in clinical trials is strongly encouraged for patients with advanced or metastatic disease 13 14. Ongoing research is exploring targeted therapies, novel immunomodulators, and personalized medicine approaches.

Prognosis and Factors Affecting Outcome

• Early-stage disease and female sex are associated with better survival 12.
• Five-year survival rates range from 48% to 68%, dropping with advanced disease 7 12.
• Recurrence rates are high, particularly within the first year after treatment 8 12.

Conclusion

Merkel cell carcinoma, though rare, is an aggressive cancer that demands early recognition and specialized treatment. Recent advances in understanding its symptoms, molecular types, causes, and therapies are reshaping patient care and hope for the future.

Key takeaways:

• MCC often presents as a rapidly growing, painless, red or pink nodule on sun-exposed skin, especially in older, fair-skinned, or immunosuppressed individuals.
• There are two main types: virus-positive (usually linked to MCPyV) and virus-negative (UV-induced), with distinct origins and implications for therapy.
• Major risk factors include MCPyV infection, chronic UV exposure, immune suppression, and advanced age.
• Treatment is multidisciplinary: surgery and radiation for localized disease, and immune checkpoint inhibitors for advanced cases. Chemotherapy is now secondary to immunotherapy.
• Early diagnosis and participation in clinical trials are critical for improving outcomes in this challenging disease.

With increased awareness and ongoing research, the outlook for MCC patients continues to improve, reinforcing the importance of vigilance and early action.