Dermatology MCQ - Viral Infections - Human papillomavirus in acquired immunodeficiency

A 45-year-old man who is 8 years post-renal transplant on stable immunosuppression (tacrolimus, mycophenolate mofetil, prednisone) presents with a rapidly growing, verrucous plaque on the dorsum of his hand. The lesion is hyperkeratotic and has recently ulcerated. A shave biopsy confirms a well-differentiated invasive squamous cell carcinoma (SCC). Molecular testing reveals the presence of multiple beta-genus human papillomavirus (HPV) types. Which of the following best describes the role of HPV in the pathogenesis of this malignancy in the context of iatrogenic immunosuppression?

A) HPV is a harmless bystander with no causal role in cutaneous SCC
B) HPV acts as a primary oncogenic driver through viral integration and E6/E7 overexpression
C) HPV acts as a co-carcinogen with ultraviolet radiation, promoting cellular transformation
D) HPV causes direct cytotoxic effects leading to malignant degeneration
E) HPV induces immunosuppression, allowing for uncontrolled tumor growth

Correct Answer: C) HPV acts as a co-carcinogen with ultraviolet radiation, promoting cellular transformation

Explanation

This question addresses the complex role of HPV, particularly beta-HPV types, in the development of cutaneous squamous cell carcinoma (cSCC) in immunocompromised patients, such as organ transplant recipients (OTRs).

Key Concepts in HPV-Associated Carcinogenesis in Immunosuppression:

• Epidemiology: OTRs have a 65- to 250-fold increased risk of cSCC compared to the general population. These tumors are often more aggressive and occur at a younger age.

• Beta-HPV Types: Beta-genus HPV types (e.g., HPV5, HPV8, HPV38) are frequently detected in cSCCs from OTRs and are implicated as co-carcinogens.

• Co-carcinogenesis with UV Radiation:

  • UV radiation is the primary carcinogen, causing DNA mutations (e.g., in TP53).

  • Beta-HPV is thought to act as a "hit-and-run" carcinogen. Its viral proteins (e.g., E6, E7) may disrupt DNA repair mechanisms, apoptosis, and cellular differentiation, amplifying the carcinogenic effects of UV exposure.

  • Unlike in cervical cancer (where high-risk alpha-HPV types integrate and drive malignancy via E6/E7), beta-HPV does not typically integrate or show consistent overexpression of oncoproteins in cSCC.

• Immunosuppression: Impairs immune surveillance against both HPV and malignant cells, allowing for persistence and progression of lesions.

Why Not the Other Options?

• (A) Harmless bystander: The high prevalence of beta-HPV in cSCCs of OTRs and functional studies suggest a contributory role, not mere bystander status.

• (B) Primary oncogenic driver: This is true for alpha-HPV in anogenital cancers (e.g., cervical SCC) but not for beta-HPV in cutaneous SCC. Beta-HPV does not typically integrate or directly drive transformation.

• (D) Direct cytotoxic effects: HPV can cause cytopathic effects (e.g., warts), but this is not directly oncogenic. Malignancy arises from mutagenesis and disrupted repair.

• (E) Induces immunosuppression: HPV does not cause systemic immunosuppression. The immunosuppression here is iatrogenic (post-transplant).

Clinical Implications:

• Aggressive skin cancer surveillance is crucial in OTRs.

• The role of HPV vaccination in preventing cSCC in OTRs is under investigation but not yet established.

Prognosis:
OTRs with cSCC require close follow-up due to high risk of recurrence and metastasis. Reduction of immunosuppression (if possible) may decrease risk.

Note: The role of beta-HPV in cSCC is an area of active research. While it is not yet actionable for treatment, understanding this association underscores the importance of sun protection and skin surveillance in immunocompromised patients.