Squamous Cell Carcinoma and HPV
Squamous cell carcinoma (SCC) is the second most common non-melanoma skin cancer (NMSC). It arises from abnormal, uncontrolled growth of keratinocytes in the spinous layer of the epidermis. For decades, ultraviolet (UV) radiation was regarded as the classic risk factor, but modern molecular research has shown a close link between human papillomavirus (HPV) and the development of SCC, both on the skin (cutaneous SCC) and on the mucosal and semi-mucosal surfaces of the anogenital area and around the nails (mucosal and periungual SCC).
HPV drives malignant change by integrating its DNA into the host cell's genome, leading to overproduction of two key oncoproteins, E6 and E7. These directly disable the cell-cycle checkpoints (p53 and pRb). Combined with the mutagenic effect of UV light or a weakened immune system, this speeds the transformation of precancerous lesions (actinic keratosis, Bowen disease) into invasive SCC.
At Haute-Derma, our management of HPV-related SCC follows current dermato-oncology standards: early screening with high-magnification digital dermoscopy, p16INK4a biomarker testing and real-time HPV PCR, accurate histopathology, excision with safe margins or Mohs micrographic surgery, photodynamic therapy (PDT), and comprehensive skin restoration.
Pathogenesis, Genome Integration and How HPV Drives Cancer
HPV Types and Sites of Malignant Change
- High-risk mucosal types (genital and nail area):
- HPV 16, 18, 31, 33, 35, 45, 52, 58: The leading causes of Bowen disease (SCC in situ), erythroplasia of Queyrat, SCC of the fingers and nail unit (subungual SCC) and anogenital SCC.
- Cutaneous EV-HPV types:
- HPV 5, 8, 14, 17, 20: Cause skin cancer in people with epidermodysplasia verruciformis (EV) and in organ transplant recipients on long-term anti-rejection drugs.
How the E6 and E7 Oncoproteins Damage the Cell
- E6 and the p53 pathway: E6 binds the ubiquitin ligase E6AP, forming a complex that targets p53 for destruction by the proteasome. Without p53, the cell can no longer pause at the G1/S checkpoint to repair DNA, and it becomes resistant to programmed cell death (apoptosis).
- E7 and the pRb pathway: E7 binds and inactivates the retinoblastoma protein (pRb), freeing the transcription factor E2F. Free E2F pushes the cell straight into S phase and continuous DNA replication.
- p16INK4a overexpression: Because pRb is inactivated, the negative feedback loop is lost and p16INK4a builds up inside the cell. On immunohistochemistry, this is considered the most important biomarker for diagnosing SCC driven by high-risk HPV.
Clinical Forms of HPV-Related SCC
Bowen Disease and Erythroplasia of Queyrat (SCC In Situ):
- Appearance: A well-defined red patch covered with thick, dry gray scale, or a moist, velvety red patch on the glans (erythroplasia of Queyrat).
- Cause: Mainly persistent, integrated HPV 16. These lesions progress slowly, but up to 10% can invade through the basement membrane.
Periungual and Subungual SCC:
- Clinical picture: Early on, it closely resembles an ordinary periungual wart or treatment-resistant nail fungus. Over time, it becomes a thickened, fissured growth that deforms the nail plate, destroys the nail and can invade the bone of the finger or toe.
- Cause: HPV 16 is detected in more than 80% of cases. Diagnosis is often delayed because it is mistaken for a benign nail condition.
Invasive Cutaneous SCC (Exophytic / Ulcerated):
- Clinical picture: A firm, raised tumor with central necrosis covered by adherent necrotic keratin, which bleeds easily and has a wide, firm, infiltrated border.
- Contributing factors: EV-HPV (HPV 5/8) combined with UV exposure on sun-exposed skin (face, forehead, backs of the hands).
Differential Diagnosis of Keratinizing Lesions and Epithelial Skin Tumors
| Squamous cell carcinoma (SCC) | Actinic keratosis | Common wart (verruca vulgaris) |
|---|---|---|
| Malignant, invades the dermis | Precancerous, confined to the epidermis | Benign (hyperplasia) |
| High-risk HPV + UV | UV alone | Low-risk HPV (1, 2, 4) |
| Coiled vessels, keratin pearls, white halos | Red pseudo-network (strawberry pattern) | Black dots from thrombosed papillary capillaries |
| Invasive atypical keratinocytes, keratin pearls | Atypia limited to the lower third of the epidermis | Papillomatosis, koilocytes |
Diagnostic Process at Haute-Derma
High-magnification digital dermoscopy: To identify features of malignancy: keratin pearls, yellow-white structureless areas, coiled or linear vessels (polymorphous/targetoid vessels) at the edge of the tumor, and target-like follicular openings.
Biopsy and Immunohistochemistry (Gold Standard):
- Punch biopsy or deep incisional biopsy: Looks for loss of polarity in the spinous layer, atypical hyperchromatic keratinocytes, abnormal mitoses, keratin pearls and, above all, cancer cells breaking through the basement membrane into the dermis.
- p16INK4a staining: Confirms the role of high-risk HPV in the malignant transformation.
Molecular testing (real-time PCR HPV genotyping): DNA is extracted from the biopsy to identify the exact high-risk HPV types (HPV 16, 18, 31, 33, etc.), helping us assess the risk of lymph node spread and plan whole-body follow-up.
Management, Surgery and Treatment at Haute-Derma
Complete Excision and Mohs Surgery
- Mohs micrographic surgery: The first choice for HPV-related SCC on the face, around the nails, on the fingers and in the genital area. The surgeon removes tissue layer by layer and checks the margins immediately on frozen sections, achieving the highest rate of margin control while preserving as much healthy tissue as possible.
- Wide local excision: Used for tumors on the trunk and limbs, with a safety margin of 4–6 mm from the visible edge.
Tissue-Sparing and Advanced Treatments (for SCC In Situ / Bowen Disease)
- Photodynamic therapy (PDT):
- The photosensitizer 5-ALA (5-aminolevulinic acid) is applied for 3–4 hours, followed by red light at 630 nm. This generates reactive oxygen species (ROS) that selectively destroy malignant keratinocytes without leaving unsightly scars.
- Superpulsed CO2 laser ablation: For large, superficial patches of Bowen disease in older patients who are not candidates for surgery.
Adjuvant Treatment and Vaccination
- Topical treatments (5-fluorouracil 5%, imiquimod 5%): Used to treat widespread precancerous changes surrounding the tumor.
- Gardasil 9 vaccination: HPV vaccination builds immunity against reinfection or new infection with dangerous high-risk HPV types.
