Neuroendocrine Tumours of the Cervix: A Comprehensive Overview

---

1. INTRODUCTION AND EPIDEMIOLOGY

• Peak incidence: 4th-5th decade (median age ~41 years for LCNEC; earlier for SCNEC)
• Strong association with HPV-18 (>90% of cases; HPV-16 less common)
• Cervix is the most common site of neuroendocrine neoplasms in the gynecologic tract
• Early distant metastasis to bone, brain, liver, and bone marrow is a defining feature
• Mixed tumours (NEC + adenocarcinoma or squamous) are common and carry similar prognosis

---

2. WHO 2020 CLASSIFICATION (5th Edition)

High-grade NECs (SCNEC and LCNEC) are by far the most common types in the cervix. Well-differentiated carcinoids are rare at this site.

---

3. PATHOGENESIS AND MOLECULAR BIOLOGY

• HPV-driven: HPV-18 identified in >80-90% of SCNEC cases; integration of HPV oncoproteins (E6, E7) causes p53 and Rb pathway disruption
• Genomic alterations: TP53 mutations, RB1 loss, CDKN2A deletions; KRAS/NRAS mutations uncommon - Schultheis et al., 2022 (PMID 33830625) identified targetable alterations including PIK3CA, MYC amplification
• Origin: Arise from neuroendocrine cells in the cervical transformation zone (reserve cells with multipotential differentiation)
• Immunohistochemical profile (see Section 5)

---

4. CLINICAL PRESENTATION

---

5. DIAGNOSIS

5.1 Pathological Diagnosis - Immunohistochemistry

Electron microscopy can demonstrate neurosecretory granules but is rarely needed today.

5.2 Diagnostic Workup Flowchart

PATIENT WITH CERVICAL LESION / ABNORMAL BLEEDING
                    │
                    ▼
    Pelvic exam + Colposcopy + Biopsy
                    │
                    ▼
    Histopathology + IHC panel
    (Synaptophysin, Chromogranin, CD56, Ki-67, p16)
                    │
          ┌─────────┴─────────┐
    NEC confirmed         NET confirmed
    (SCNEC / LCNEC)       (Carcinoid / Atypical)
          │
          ▼
    STAGING WORKUP (mandatory)
    ┌─────────────────────────────────┐
    │  • Pelvic MRI (mandatory)       │
    │  • CT chest/abdomen/pelvis      │
    │  • PET-CT (preferred)           │
    │  • Bone scan                    │
    │  • Bone marrow biopsy*          │
    │  • LFTs, CBC, LDH               │
    │  • Brain MRI (if symptoms)      │
    │  * if bone involvement suspected│
    └─────────────────────────────────┘
                    │
                    ▼
          MDT Discussion & Treatment Planning

5.3 Imaging Features (per [Gayathri et al., 2026, PMID 41823182])

---

6. FIGO STAGING (2018) - Applied to NECC

Note: Overall 5-year OS for early-stage NECC ~61%; advanced-stage ~12-27% (Neuroendocrine Cervical Tumor Registry data).

---

7. MANAGEMENT

7.1 Overview - Treatment Principles

• Multimodal therapy is standard for all stages due to high propensity for systemic spread
• Even apparently localized disease (Stage I) requires adjuvant systemic chemotherapy
• Regimens borrowed from small-cell lung cancer (SCLC) management, principally etoposide + platinum - Berek & Novak's Gynecology
• No randomized controlled trials exist specifically for NECC - all recommendations based on retrospective series and expert consensus

7.2 Stage-Based Management Flowchart

NECC CONFIRMED + STAGED
        │
        ├─── EARLY STAGE (FIGO IA1 - IB2, <4cm)
        │           │
        │           ▼
        │    Radical Hysterectomy + Pelvic LND (preferred surgical approach)
        │    [PLND + consider PALND]
        │           │
        │           ▼
        │    Adjuvant Chemotherapy (EP × 4-6 cycles)
        │    ± Adjuvant CCRT (if high-risk pathological features)
        │
        ├─── LOCALLY ADVANCED (FIGO IB3 - IVA)
        │           │
        │           ▼
        │    Concurrent Chemoradiation (CCRT)
        │    [Cisplatin-based + EBRT + Brachytherapy]
        │           │
        │           ▼
        │    Consolidation Chemotherapy (EP × 4 cycles)
        │    OR
        │    Neoadjuvant EP → Surgery → Adjuvant CCRT
        │
        └─── METASTATIC / ADVANCED (FIGO IVB)
                    │
                    ▼
             Systemic Chemotherapy
             First-line: Cisplatin/Carboplatin + Etoposide (EP)
             ± Atezolizumab or Durvalumab (NCCN 2026 - other recommended)

7.3 Chemotherapy Regimens (NCCN 2026 Cervical Cancer Guidelines)

2026 NCCN Update: Ipilimumab + nivolumab has been added as an "other recommended" second-line/subsequent therapy option for SCNEC (ASCO Post, 2026).

7.4 Radiation Therapy

7.5 Surgery

• Radical hysterectomy + PLND for early-stage NECC is supported by retrospective data
• The Lancet Oncology multicenter SEER + Chinese registry study (Chu et al., 2023, PMID 37269846) of 1,288 patients showed surgery was independently associated with better OS even in locally advanced disease (HR 0.53, p=0.0005)
• The LCNEC systematic review/meta-analysis (Prodromidou et al., 2022, PMID 35093830) confirmed surgery and lymphadenectomy were the only factors independently associated with improved survival (Surgery HR 0.14, p=0.018)
• Minimally invasive surgery should be used with caution given concerns from the LACC trial (applicable to all cervical cancers)

7.6 Surveillance After Treatment

---

8. PROGNOSIS

• Stage I: ~55-70%
• Stage II: ~30-40%
• Stage III: ~15-25%
• Stage IV: ~10-12%

---

9. FERTILITY PRESERVATION IN NECC

9.1 Current Guideline Position

"Fertility-sparing treatment should NOT be recommended for uncommon and rare histological types/subtypes of cervical cancer with aggressive behavior including neuroendocrine carcinomas, HPV-independent adenocarcinomas and carcinosarcomas." [Evidence level V, Grade D]

1. Extremely high rate of lymphovascular invasion (>80%)
2. Early occult distant metastasis at presentation even in Stage IA-IB
3. No adequate free surgical margin possible without compromising oncologic control
4. Aggressive biology with rapid progression makes delay dangerous

9.2 What CAN Be Offered - Oncofertility Options

9.3 Oncofertility Flowchart for NECC

YOUNG PATIENT WITH NECC WHO DESIRES FERTILITY
                    │
                    ▼
    ESGO 2023: Fertility-sparing SURGERY is CONTRAINDICATED
                    │
                    ▼
    Refer to Onco-fertility Centre BEFORE treatment initiation
                    │
                    ▼
          ┌─────────────────────────┐
          │  Stage IA-IB (early)    │
          │  Need surgery + chemo   │
          └──────────┬──────────────┘
                     │
                     ▼
     Options to discuss with patient:
     1. Oocyte/Embryo cryopreservation BEFORE treatment
     2. Ovarian transposition (if pelvic RT planned + N0 status)
     3. Surrogacy or adoption post-treatment
     4. Proceed with radical hysterectomy + adjuvant chemo
                    │
                    ▼
     Document informed consent + MDT discussion
     ± Clinical trial enrollment if available

In more advanced cases, ovarian transposition, oocyte/embryo/ovarian tissue preservation, and egg donation should be discussed with the patient. The aim is to offer the most efficient approach in accordance with legal country-specific regulations while not increasing oncological risk (ESGO 2023).

---

10. NEUROENDOCRINE CERVICAL CARCINOMA IN PREGNANCY

10.1 Background

• Aggressive biology demanding prompt treatment
• Fetal wellbeing and gestational age considerations
• Limited safety data for chemotherapy/RT in pregnancy
• High psychological burden on the patient and family

10.2 Diagnostic Approach in Pregnancy

10.3 Management Decision Framework

NECC DIAGNOSED IN PREGNANCY
            │
    ┌────────┴────────┐
    │                 │
 FIRST TRIMESTER   SECOND/THIRD TRIMESTER
    │                 │
    ▼                 ▼
High urgency to   Gestational age assessment
treat given       vs. Fetal viability
aggressive biology│
    │            ├─ <24-26 weeks (pre-viable)
    ▼            │        │
 Counsel re:     │        ▼
 Pregnancy       │   Terminate pregnancy
 termination     │   → Immediate aggressive
 + immediate     │     treatment
 aggressive      │
 treatment       ├─ 24-32 weeks (viable, preterm)
                 │        │
                 │        ▼
                 │   Platinum-based ChemoRx
                 │   from 14-16 weeks safely
                 │   Target delivery ~34-36 wks
                 │   → Post-delivery: complete
                 │     CCRT/surgery
                 │
                 └─ ≥34 weeks (near-term)
                          │
                          ▼
                   Consider expedited delivery
                   (CS preferred - avoid tumor
                   in birth canal)
                   → Immediate post-partum
                     aggressive treatment

10.4 Treatment Options During Pregnancy

10.5 Key Clinical Scenarios

• Counsel regarding termination of pregnancy
• If accepted: gravid radical hysterectomy + PLND, then adjuvant EP chemotherapy
• If declined: discuss risks of delay; neoadjuvant EP from 14 weeks; plan delivery ~34-36 weeks; post-delivery surgery and/or CCRT

• Fetal lung maturity therapy
• Cesarean section delivery
• Initiate EP chemotherapy postpartum + CCRT
• Note: reported case of stage IVB LCNEC at 30 weeks - CS + post-delivery chemotherapy; patient died at 6 months; infant discharged healthy

• EP chemotherapy initiated at 19 weeks gestation
• Delivery at 34 weeks
• RT initiated post-delivery
• Patient developed metastatic disease at 6 months post-delivery

10.6 ESGO 2023 Guidelines - Cervical Cancer in Pregnancy

• MDT is mandatory (perinatologist + neonatologist + radiation oncologist + gynecologic oncologist)
• Intentional treatment delays of 6-32 weeks reported for stage I-II disease without significant compromise in outcome (Creasy & Resnik Maternal-Fetal Medicine)
• For locally advanced disease: termination + immediate CCRT recommended in first trimester
• For second half of pregnancy: short delay to fetal maturity may be considered for limited-stage disease
• Cesarean delivery is preferred (avoid passage through tumor-involved cervix)
• Neoadjuvant chemotherapy (platinum-based) may be used from 14-16 weeks if delay is necessary
• Vaginal transmission risk: rare but reported (PMID 33406329, NEJM 2021) - supports CS delivery

NECC is even more aggressive than standard cervical cancers, so thresholds for immediate treatment should be lower and MDT decisions must weigh the extremely poor prognosis against fetal considerations.

---

11. EMERGING THERAPIES AND FUTURE DIRECTIONS

---

12. MULTIDISCIPLINARY TEAM (MDT) REQUIREMENTS

• Gynecological oncologist (surgery)
• Medical oncologist (systemic therapy)
• Radiation oncologist (EBRT + brachytherapy)
• Pathologist (expert IHC interpretation)
• Radiologist (MRI/PET expertise)
• Onco-fertility specialist (for reproductive-age patients)
• Palliative care team
• Perinatologist/neonatologist (if pregnant)
• Psycho-oncologist

---

13. SUMMARY TABLE: NECC vs STANDARD CERVICAL CANCER

---

14. KEY GUIDELINE REFERENCES

---

Key Takeaways

1. NECC is rare (<2%) but disproportionately aggressive - early distant metastasis is the rule, not the exception.
2. WHO 2020 unifies NEN terminology: well-differentiated NETs (typical/atypical carcinoid) vs poorly differentiated NECs (SCNEC/LCNEC). High-grade NEC dominates in the cervix.
3. Diagnosis requires IHC (synaptophysin, chromogranin, CD56, Ki-67) plus extended systemic staging with PET-CT/MRI.
4. Multimodal treatment is mandatory even for early-stage disease. First-line is etoposide + platinum (EP) ± surgery ± CCRT.
5. NCCN 2026 now includes immunotherapy combinations (atezolizumab, durvalumab, and newly added ipilimumab + nivolumab) as options for recurrent/metastatic NECC.
6. Fertility-sparing surgery is absolutely contraindicated per ESGO 2023. Oncofertility counselling (oocyte/embryo preservation, ovarian transposition) should be offered BEFORE treatment.
7. NECC in pregnancy is extremely rare and requires urgent MDT. Platinum-based chemotherapy is safe from 14 weeks; RT must be deferred post-delivery; CS delivery is preferred to avoid neonatal tumor transmission.