What causes inverted papilloma?

Causes of Inverted Papilloma

Human papillomavirus (HPV) infection is the primary cause of inverted papilloma, with HPV being detected in up to 63% of cases and strongly associated with recurrence and malignant transformation. 1, 2

Primary Etiologic Factors

Viral Infection

• Human Papillomavirus (HPV):
  • HPV has been detected in a significant percentage of inverted papillomas (up to 40-63% of cases) 1, 3
  • HPV-positive inverted papillomas show substantially increased rates of both recurrence and malignant transformation 1
  • A significant association exists between HPV DNA in inverted papilloma and recurrence after surgical excision (p<0.00002) 2
  • HPV types 6 and 11 (low-risk) are commonly detected, but high-risk types 16 and 18 may also be present 4

Cellular and Molecular Factors

• Cell cycle regulatory proteins and angiogenic factors:
  • Dysregulation of proliferation and apoptosis pathways 5
  • Altered expression of cell cycle proteins facilitates migration and tumor invasion 5
  • These molecular changes contribute to the endophytic growth pattern characteristic of inverted papillomas 4

Secondary Contributing Factors

Environmental and Occupational Exposures

• Occupational factors:
  • Exposure to welding fumes and organic solvents 5
  • Cigarette smoking (more strongly associated with recurrence and dysplasia than initial occurrence) 5
  • Environmental pollutants may act as co-factors with HPV infection 5

Chronic Inflammation

• Persistent inflammatory processes in the sinonasal tract may contribute to papilloma development 5
• The exact mechanism linking inflammation to inverted papilloma formation remains unclear 5

Host Factors

• Immune status:
  • Immunosuppression may increase susceptibility to HPV infection and persistence 4
  • HIV-positive individuals have higher risk for HPV-related lesions 4

Pathophysiology and Classification

Inverted papilloma is characterized by an endophytic growth pattern of epithelial tissue into the underlying stroma, rather than an exophytic growth pattern seen in other papillomas 4. According to the WHO/ISUP classification system, inverted papillomas can be categorized as:

1. Inverted papilloma: Shows endophytic growth of non-hyperplastic, non-atypical epithelium with peripheral palisading 4, 6
2. Inverted PUNLMP (Papillary Urothelial Neoplasm of Low Malignant Potential): Hyperplastic epithelium growing in an endophytic pattern 4, 6
3. Inverted papillary carcinoma: Shows greater cellularity, loss of polarity, and cytologic atypia 4, 6

Clinical Implications

• Recurrence risk: HPV-positive inverted papillomas have a significantly higher recurrence rate (13 of 15 HPV-positive cases recurred vs. 0 of 10 HPV-negative cases) 2
• Malignant transformation: The risk of malignant transformation is higher in HPV-positive cases, particularly those with high-risk HPV types 1
• Surgical planning: Complete surgical removal is essential, with the approach determined by disease extent and location 6
• Follow-up requirements: Long-term surveillance is necessary due to the risk of late recurrence and malignant transformation 6, 3

Diagnostic Considerations

• PCR is the preferred method for HPV detection in inverted papilloma specimens 1
• Fresh or frozen tissue samples provide the most reliable results for HPV testing 1
• Histopathological evaluation is essential to confirm diagnosis and exclude invasive components 6

While the association between HPV and inverted papilloma is well-established, further research is needed to fully elucidate the underlying molecular pathways and to develop targeted therapies based on these etiologic factors.