Dermatology MCQ - Viral Infections - Human polyomaviruses and keratinocyte skin cancers

A 75-year-old fair-skinned man with a history of prolonged azathioprine use for rheumatoid arthritis presents with a rapidly growing, ulcerated nodule on his right forearm. Biopsy reveals an invasive squamous cell carcinoma (SCC). Molecular analysis of the tumor tissue detects DNA from multiple human polyomaviruses, including HPyV6 and HPyV7. Which of the following best describes the current evidence regarding the role of these polyomaviruses in keratinocyte skin cancer pathogenesis?

A) They are primary oncogenic drivers through viral T-antigen expression and p53 inactivation
B) They are harmless bystanders with no role in carcinogenesis
C) They may act as cofactors in carcinogenesis in the context of immunosuppression and UV exposure
D) They directly integrate into the host genome, similar to Merkel cell polyomavirus
E) They cause viral cytopathic effect leading to malignant transformation

Correct Answer: C) They may act as cofactors in carcinogenesis in the context of immunosuppression and UV exposure

Explanation

This question addresses the emerging but not yet fully defined role of certain human polyomaviruses (HPyVs) in keratinocyte skin cancers, particularly in immunocompromised patients.

Key Evidence and Concepts:

• Association, Not Causation: HPyV6, HPyV7, and other polyomaviruses (e.g., HPyV9) have been detected in squamous cell carcinomas (SCC) and premalignant actinic keratoses at higher rates compared to normal skin, especially in immunocompromised individuals (e.g., organ transplant recipients, patients on long-term immunosuppressants like azathioprine).

• Cofactor Theory: The current hypothesis is that these viruses may act as co-carcinogens alongside:

  • UV radiation: The primary driver of SCC, causing DNA mutations (e.g., in p53).

  • Immunosuppression: Impairs immune surveillance against both viral infections and nascent tumor cells.

• Contrast with MCPyV: Unlike Merkel cell polyomavirus (MCPyV), which is a proven primary oncogenic driver in Merkel cell carcinoma (through T-antigen expression and RB1/p53 inactivation), HPyV6/7 do not consistently demonstrate viral integration, T-antigen expression, or direct oncogenic mechanisms in SCC.

• Bystander Potential: Some studies suggest these viruses could be mere bystanders, but their increased prevalence in SCCs, particularly in immunosuppressed hosts, suggests a potential contributing role.

Why Not the Other Options?

• (A) Primary oncogenic drivers: This is definitively true only for MCPyV in Merkel cell carcinoma, not for HPyVs in SCC.

• (B) Harmless bystanders: While possible, the increased detection in SCCs suggests a potential role beyond simple colonization.

• (D) Direct genome integration: This is a hallmark of MCPyV in MCC. HPyV6/7 have not been shown to integrate into the host genome in SCC.

• (E) Viral cytopathic effect causing transformation: Polyomaviruses can cause cytopathic effect (e.g., in trichodysplasia spinulosa), but this leads to benign follicular hyperplasia, not direct malignant transformation.

Clinical Implications:

• This association reinforces the importance of aggressive skin cancer surveillance in immunocompromised patients.

• The role of antiviral therapies or vaccines targeting these viruses is purely theoretical and not currently indicated.

Takeaway:
The detection of HPyV6/7 in SCC likely represents a complex interaction between viral infection, UV damage, and immune dysfunction, rather than a direct causal relationship. More research is needed to define their precise role.