What is the primary approach to managing a patient with HPV (Human Papillomavirus)-negative cervical adenocarcinoma?

Management of HPV-Negative Cervical Adenocarcinoma

HPV-negative cervical adenocarcinoma should be managed with stage-appropriate surgical resection or definitive chemoradiation, following the same FIGO staging-based treatment algorithms as HPV-positive disease, but with heightened vigilance for more aggressive behavior and worse prognosis. 1

Critical Recognition and Diagnostic Considerations

HPV-negative cervical adenocarcinomas represent a distinct biological entity comprising 5-11% of all cervical cancers, with fundamentally different molecular characteristics than HPV-associated tumors. 2, 3

Key histologic subtypes that are typically HPV-independent include:

• Clear-cell adenocarcinoma 1
• Mesonephric adenocarcinoma 1
• Gastric-type adenocarcinoma 3
• Endometrioid carcinoma 3

These tumors exhibit specific molecular alterations including TP53, PIK3CA, KRAS, STK11, and PTEN mutations rather than HPV E6/E7 oncogene expression. 3 They demonstrate lower proliferative activity, p53 immunostaining positivity, and decreased expression of p16, p14, and p27. 4

Staging and Pretreatment Evaluation

Complete staging workup must include:

• Contrast-enhanced CT or MRI for anatomic assessment of tumor size, stromal penetration, parametrial involvement, and vaginal extension 1
• PET-CT scan for lymph node assessment and distant metastases, with 53-73% sensitivity and 90-97% specificity for early-stage lymph node involvement 1
• Clinical examination under anesthesia for FIGO staging 1

Critical pitfall: HPV-negative tumors are frequently diagnosed at more advanced FIGO stages with higher rates of lymph node involvement and lymphovascular invasion compared to HPV-positive disease. 2, 4 This necessitates thorough staging before treatment decisions.

Stage-Specific Treatment Algorithm

Early-Stage Disease (FIGO IA1 without LVSI)

• Conization or simple trachelectomy for microinvasive disease without lymphovascular space invasion 1
• Fertility preservation is possible in highly selected cases 1

Early-Stage Disease (FIGO IA2-IB1)

• Radical hysterectomy with pelvic lymphadenectomy is the primary surgical approach 1
• Surgical margins >5mm are recommended when technically feasible 1
• Adjuvant therapy decisions based on pathologic risk factors:
  • High-risk features (positive margins, extranodal extension): platinum-based concurrent chemoradiation 5
  • Intermediate-risk features (perineural invasion, lymphovascular invasion, close margins <5mm, T3-T4a tumors): consider adjuvant radiation 5

Locally Advanced Disease (FIGO IB2-IVA)

• Platinum-based concurrent chemoradiation is the primary treatment modality 5
• Surgery is generally not recommended as initial therapy for advanced-stage HPV-negative disease given insufficient evidence and typically more aggressive biology 1

Recurrent, Persistent, or Metastatic Disease

• Combination chemotherapy with bevacizumab (anti-VEGF monoclonal antibody) improves survival 5
• Salvage surgery may be considered for isolated recurrences in previously irradiated fields 5

HPV-Negative Specific Considerations

HPV-negative cervical adenocarcinomas demonstrate:

• More aggressive clinical behavior with worse overall prognosis compared to HPV-positive tumors 2, 4
• Higher rates of distant metastasis even in early stages 4
• Reduced response to standard chemotherapy and immunotherapy due to immune-cold tumor microenvironment 3
• Earlier and more frequent lymph node involvement 4

Emerging targeted therapy options for selected patients include PI3K/mTOR inhibitors and KRAS inhibitors based on molecular profiling, though these remain investigational. 3

Post-Treatment Surveillance

Follow-up protocol:

• Pelvic examinations every 3-4 months for the first 2 years, then every 6 months for years 3-5 5
• Imaging (CT or PET-CT) as clinically indicated for suspected recurrence 1
• Continue surveillance for at least 25 years given the aggressive nature of HPV-negative disease 6

Common pitfall: Do not assume HPV-negative status represents a false-negative result without confirming histologic subtype, as truly HPV-independent adenocarcinomas require recognition of their distinct aggressive biology and potentially different therapeutic approaches. 2, 3

Fertility Preservation Considerations

Fertility-sparing approaches should be considered only in highly selected patients with stage IA1-IA2 disease, negative lymph nodes, and tumor size <2cm, with full counseling about increased recurrence risk given the more aggressive nature of HPV-negative disease. 1 Radical trachelectomy with pelvic lymphadenectomy may be considered in these exceptional cases, though data specific to HPV-negative tumors is limited.