[Pregnancy-preserving and maternal-fetal management in a patient with rare large cell neuroendocrine carcinoma of the uterine cervix]

Abstract

Objective: To explore the strategy of pregnancy-preserving and maternal- fetal management in patients with primary gynecologic neuroendocrine tumors (gNETs) during pregnancy.

Methods: We performed whole genome sequencing (WGS) for analyzing maternal and fetal somatic and germline single nucleotide variations (SNVs) and small insertions and deletions (InDels) for a 29-year-old pregnant woman diagnosed with stage IB2 large cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma in the cervix. A systematic literature review was performed to explore the strategies for treatment of such rare histological type while maintaining pregnancy.

Results: Global case analysis of cervical NETs during pregnancy suggested that negative lymph node metastasis and an early FIGO stage were potentially associated with a good prognosis of the patients. In the case presented herein, a pregnancy-preserving strategy was adopted and favorable maternal-fetal outcomes were achieved after neoadjuvant chemotherapy, radical surgery and postoperative systemic chemotherapy. At 35⁺⁵ weeks, the fetus was delivered by caesarian section, and the patient has by now had a disease-free survival of 19 months postoperatively. WGS analysis revealed 6 missense somatic pathogenic mutations in two cancer tissues of the patient, and among them KARS and VEGFA were related with targeted therapy. Five pathogenic germline variants were detected in the patient and her son, suggesting the necessity of a long-term follow-up schedule including precise genetic counselling for both the mother and the child.

Conclusion: Although gNETs in pregnancy are rare and highly risky, pregnancy-preserving managements of gNETs can still be considered and favorable maternalfetal outcomes are possible with proper assessment of the clinical indications and implementation of multimodal treatments. Precise treatment and follow-up strategies based on the results of WGS for risk-reducing intervention of cancer recurrence or occurrence can potentially benefit the patient and the neonate.

Keywords: cancer predisposing genes; large cell neuroendocrine carcinoma; maternal-fetal management; pregnancy- preserving management; primary gynecologic neuroendocrine tumors.

1

Histology of large cell neuroendocrine carcinoma and adenocarcinoma of the cervix. A: HE staining shows a trabecular solid growth pattern of the tumor cells (Original magnification: ×40). B: HE staining shows pleomorphic tumor cells with prominent nucleoli, frequent mitoses and apoptosis (× 80). C: Ki-67 staining shows positivity in over 90% of the tumor cells (× 80). D: Immunohistochemistry shows positivity for neuroendocrine marker synaptophysin in the tumor cells (×80).

2

Imaging diagnosis with DWI/MRI and cesarean section. A: DWI/MRI demonstrates abnormal high signal in the posterior lip of the uterine cervix with a size of 28 mm×15 mm×24 mm (red arrow). The vaginal fornix and parametrium remain intact, and no pelvic lymph node swelling is observed. B: The patient underwent cesarean section on the lower middle part of the corpus uteri.

3

Screening for germline pathogenic and uncertainly significant mutations from the patient and her child. A: Germline pathogenic mutations. B: Germline uncertainly significant mutations. AR: Androgen receptor; GNAS: Guanine nucleotide-binding protein G(s) subunit alpha; POLD1: Subunit of the DNA polymerase δ complex; RECQL: ATP-dependent DNA helicase Q1-like; CNTNAP2: Contactin associated protein-like 2; PMS2: Postmeiotic segregation increased 2.