Human Papillomavirus Infection, p16INK4a Expression and Genetic Alterations in Vietnamese Cervical Neuroendocrine Cancer

Ta, To Van; Nguyễn, Quang Ngọc; Truong, Van-Long; Tran, Toan Trung; Nguyen, Hung Phi; Vuong, Linh Dieu

doi:10.21315/mjms2019.26.5.15

Cited by 6 publications

(5 citation statements)

References 19 publications

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“… 27 , 28 Therefore, clinical trials exploring the therapeutic effects of PIK3CA/mTOR inhibitors in a subset of NECs are warranted. Similar to our findings, KRAS mutations were previously described in NEC 8 although another recent study 29 confirmed only NRAS but not KRAS mutations in a cohort of 30 NECs. The therapeutic utility of MEK inhibitors in KRAS-mutated NECs remains to be clinically explored.…”

Section: Discussionsupporting

confidence: 93%

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix

Cimic

Vranić

Arguello

et al. 2020

Applied Immunohistochemistry &Amp; Molecular Morphology

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Neuroendocrine carcinoma of the cervix (NEC) is a rare and highly aggressive cervical malignancy. Given that no targeted therapy has been approved specifically to NEC, we investigated the presence of novel, potentially targetable biomarkers in a large cohort of NEC. Sixty-two NEC were molecularly profiled for biomarkers of targeted therapies including antibody-drug conjugates [delta-like canonical notch ligand 3 (DLL3), a trophoblast cell surface antigen 2 (TROP-2), and folate receptor 1 (FOLR1)], NTRK1-3 gene fusions, and immune checkpoint inhibitors [programmed death-ligand 1 (PD-L1), tumor mutational burden, and microsatellite instability] using immunohistochemistry and DNA/RNA next-generation sequencing assays. A cohort of squamous cell carcinomas of the cervix (n = 599) was used for comparison for immune-oncology biomarkers. DLL3 expression was observed in 81% of the cases. DLL3 expression was inversely correlated with commonly observed pathogenic mutations in PIK3CA (17%) (P = 0.018) and PTEN (10%) (P = 0.006). Other more frequently seen pathogenic mutations (TP53 17%, KRAS 11%, and CTNNB1 5%) were not associated with DLL3 expression. TROP-2 expression was detected in only 1 case and no case expressed FOLR1. Although NTRK protein expression was observed in 21% of the cases, none of these had an NTRK gene fusion. PD-L1 expression (10%) and high tumor mutational burden (3%) were significantly less frequent in NEC compared with the squamous cell carcinoma cohort (79% and 11%, respectively). None of the NEC exhibited high microsatellite instability status. Despite frequent DLL3 expression in NEC, a potential therapeutic benefit of DLL3targeted drugs remains uncertain given the recent failure of the Rova-T therapeutic trial in small cell lung carcinomas. Small cohorts of NEC enriched in PIK3CA/PTEN/AKT and programmed cell death protein 1/PD-L1 alterations indicate therapeutic roles for their respective inhibitors.

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Section: Discussionsupporting

confidence: 93%

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix

Cimic

Vranić

Arguello

et al. 2020

Applied Immunohistochemistry &Amp; Molecular Morphology

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“…In our study, Both of Syn and CD56 were positive in 18 cases(85.7%,18/21),(85.7%,18/21), otherwise, CgA was positive in 9 cases(42.9%,9/21),and the positive staining was more often diffuse than focal. which was similar to previously reported positive rate (19).p16INK4a was diffuse or focally positive in 17 cases (81%,17/21), this was similar with To Van report (20).In their study,p16INK4a overexpression was not found to be correlated with p53 or NRAS mutation,suggested that p16INK4a overexpression was signi cantly correlated with the presence of high-risk HPV strains in neuroendocrine carcinoma of the cervix. Because it may occur in the cervix, p63 can be positive occasionally.…”

Section: Discussionsupporting

confidence: 89%

Neuroendocrine Carcinoma of the Cervix: Clinicopathologic Study and Review of the Literature

Zhang

Shen

et al. 2021

Preprint

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BackgroundNeuroendocrine carcinoma of the cervix (CNECC) is a rare variant of cervical cancer. The prognosis of women with CNECC is poor and there is no standardized therapy for this type of malignancy. To discuss the clinical and pathological features and prognosis of CNECC.MethodsTwenty one patients diagnosed as CNECC of cervix from May 2008 to September 2021 were retrospectively analyzed at Peking University people's hospital, were analyzed retrospectively including hematoxylin-eosinstaining （HE）slides review, immunohistochemistry results,Thinprep cytology test(TCT) and human papillomavirus (HPV) Hybrid Capture 2(HC2) assay. and their data were analyzed retrospectively. Telephone and medical records were followed up for 3-160 months with an average follow-up time of 49.8 month.ResultsThe patient's average age was 48.6 years old (range: 33–69 years). The first symptoms of 11 cases had vaginal bleeding, 2 cases had vaginal discharge, and the others were asymptomatic. Among the 21 patients, 17 cases were diagnosed as neuroendocrine carcinoma by biopsy. There were 9 cases with TCT examination and HC2 tests before biopsy, TCT results of 4 cases were positive. High-risk HPV of 7 cases were positive. The morphology of cancer cells were relatively consistent, the cytoplasm was sparse, the nuclei were obviously blue stained, and accompanied by extensive neoplastic necrosis. 13 cases were pure CNECC(61.9%), 8 cases were mix types of CNECC(38.1%).There were 3 cases accompanied by squamous cell carcinoma,5 cases accompanied by adenocarcinoma.The positive detection rate of Syn, CgA, CD56,p16 and TTF1 were 85.7%(18/21), 42.9%(9/21), 85.7% (18/21), 81%(17/21) 52.4%(11/21),respectively.The overall survival rate of 21 NECC cases was 71.4%(15/21).ConclusionsCNECC was a extremely rare primary tumor.The tumor was associated with HPV infection. Combined examination of TCT and HPV could significantly improve the detection rate of neuroendocrine carcinoma before biopsy.Pthology diagnosis was based on histological and immunohistochemical examination. It was considered to be highly aggressive malignancy with very poor prognosis.

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“…High-risk HPV has been reported to be associated with most cervical cancers, including SCC and ACC. Recent studies have found that NECC is associated with high-risk HPV, mainly HPV16 and HPV18 types ( 50 ). Although HPV18 infection was found to be statistically more common in patients with NECC than in patients with other histological subtypes, no significant differences were found in the mutational profiles of NECC with and without HPV18 ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing identifies common mutational landscape of cervix and endometrium small cell neuroendocrine carcinoma

Wang,

Zhang,

et al. 2023

Front. Oncol.

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BackgroundPrimary small cell neuroendocrine carcinomas of the cervix and endometrium are rare gynecological malignancies with limited treatment options. This study aimed to improve the understanding of the carcinogenesis process and identify potential therapeutic targets for these two tumor types by constructing the mutational landscape at the whole exome level.MethodsPrimary tumor tissues and their matched blood samples were obtained from 10 patients with small cell cervical neuroendocrine carcinoma (NECC) and five patients with small cell endometrial neuroendocrine carcinoma (NECE). Whole exome sequencing was performed to construct the somatic mutation profiles. Mutational signature and recurrent mutated gene analysis were used to identify tumor subtypes and common carcinogenesis processes.ResultsBased on the burden of different mutational signatures, the NECCs in this work can be divided into two subtypes, including the mismatch repair deficiency like (dMMR-like) type (4/10) and the high spontaneous deamination type (6/10). Components of the PI3K/AKT signaling and RAS signaling were exclusively mutated in these two subtypes, respectively. The integration of human papillomavirus made a limited contribution to tumorigenesis in NECC (20%). The dysfunction of the mismatch repair system and microsatellite instability are the major features of NECE. PI3K/AKT, JAK/STAT signaling, and chromatin remodeling activity were the common mutated pathways in NECE. PIK3CA, WNK2, and KMT2B underwent mutations in both the dMMR-like subtype of NECC (50% – 75%) and in NECE (60% – 80%) specimens, while exhibiting infrequent mutational occurrences in publicly available data pertaining to neuroendocrine carcinomas of the lung or bladder (< 10%).ConclusionWe identified the two subtypes of NECC with distinct mutated pathways and potential therapy targets. The dMMR-like type NECC and NECE may share a similar carcinogenesis process that include dysfunction of PI3K/AKT signaling, cell cycle, antiapoptotic processes, and chromatin remodeling activity.

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Human Papillomavirus Infection, p16INK4a Expression and Genetic Alterations in Vietnamese Cervical Neuroendocrine Cancer

Cited by 6 publications

References 19 publications

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix

Neuroendocrine Carcinoma of the Cervix: Clinicopathologic Study and Review of the Literature

Whole exome sequencing identifies common mutational landscape of cervix and endometrium small cell neuroendocrine carcinoma

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