Surgical and Biomarker Management of Cervical Cancer

Pelvic and Para-aortic Assessment

If the sentinel nodes are positive, or if the tumor meets certain criteria, a formal pelvic lymphadenectomy is required. Furthermore, clinicians must assess the para-aortic lymph nodes, as involvement there is linked to pelvic node metastasis and larger tumor size ($>2$ cm). Para-aortic lymphadenectomy is generally recommended for patients with $\ge$ stage IB1 disease.

Pathologic Risk Stratification

Once a specimen is resected, pathologists use specific classification systems to guide adjuvant treatment decisions.

The Silva Classification System

For HPV-associated endocervical adenocarcinoma (EAC), the Silva classification system is used to stratify risk based on the pattern of stromal invasion and the presence of lymphovascular invasion (LVSI).

• Category A: No LVSI; associated with an excellent prognosis.
• Category B: Some LVSI; represents an intermediate risk.
• Category C: Widespread LVSI; indicates a high risk of metastasis and recurrence.

Sedlis Criteria

The Sedlis Criteria are utilized to identify intermediate-risk factors that may necessitate adjuvant radiation therapy following radical hysterectomy in node-negative, margin-negative cases. These factors include:

• Stromal invasion $>1/3$ of the cervical stroma.
• Presence of capillary lymphatic involvement.
• Tumor diameter $>4$ cm.

Biomarkers in Advanced and Recurrent Disease

The management of advanced, recurrent, or metastatic cervical cancer has been revolutionized by Multigene Panel Testing (MGPT). Identifying specific molecular drivers allows for the use of targeted therapies.

Immunotherapy Biomarkers

• PD-L1: Testing via immunohistochemistry (IHC) is recommended for patients with metastatic or recurrent disease. For patients who are PD-L1 positive (defined by a Combined Positive Score $\text{CPS} \ge 1$), pembrolizumab is a preferred regimen.
• dMMR/MSI-H: Patients demonstrating deficient Mismatch Repair (dMMR) or High Microsatellite Instability (MSI-H) may benefit from immunotherapy, such as dostarlimab.
• Tumor Mutational Burden (TMB): A high TMB ($\ge 10$ mut/Mb) serves as a predictor for response to pembrolizumab.

Targeted Molecular Drivers

Beyond immunotherapy, several rare but actionable genetic alterations can be targeted:

• NTRK Gene Fusions: Patients with $NTRK1/2/3$ fusions can be treated with agents like larotrectinib, entrectinib, or repotrectinib.
• HER2 Expression: Testing via IHC (with reflex to FISH for equivocal results) is recommended. For HER2-positive tumors, trastuzumab deruxtecan is a useful therapeutic option.
• RET Gene Fusions: In metastatic cases, selpercatinib may be considered.

Exam Tip: When evaluating adenocarcinoma, always check for p16 IHC status or HPV status (via ISH or molecular testing) to confirm the HPV-associated nature of the tumor, as this informs the use of the Silva classification.

In summary, the modern management of cervical cancer requires a dual focus: precise surgical staging to ensure local control and comprehensive molecular profiling to guide systemic therapy in advanced stages.