Preferred method of therapy for patients with early-stage high-grade neuroendocrine carcinoma of the cervix
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8493402 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In order to improve treatment selection for high grade neuroendocrine carcinomas of the cervix (NECC), we performed a comparative genomic analysis between this rare tumor type and other cervical cancer types, as well as extra-cervical neuroendocrine small cell carcinomas of the lung and bladder. We performed whole exome sequencing on fresh-frozen tissue from 15 NECCs and matched normal tissue. We then identified mutations and copy number variants using standard analysis pipelines. Published mutation tables from cervical cancers and extra-cervical small cell carcinomas were used for comparative analysis. Descriptive statistical methods were used and a two-sided threshold of P < .05 was used for significance. In the NECC cohort, we detected a median of 1.7 somatic mutations per megabase (range 1.0-20.9). PIK3CA p.E545K mutations were the most frequency observed oncogenic mutation (4/15 tumors, 27%). Activating MAPK pathway mutations in KRAS (p.G12D) and GNAS (p.R201C) co-occurred in two tumors (13%). In total we identified PI3-kinase or MAPK pathway activating mutations in 67% of NECC. When compared to NECC, lung and bladder small cell carcinomas exhibited a statistically significant higher rate of coding mutations (P < .001 for lung; P = .001 for bladder). Mutation of TP53 was uncommon in NECC (13%) and was more frequent in both lung (103 of 110 tumors [94%], P < .001) and bladder (18 of 19 tumors [95%], P < .001) small cell carcinoma. These comparative genomics data suggest that NECC may be genetically more similar to common cervical cancer subtypes than to extra-cervical small cell neuroendocrine carcinomas of the lung and bladder. These results may have implications for the selection of cytotoxic and targeted therapy regimens for this rare disease.
| S-EPMC7297329 | biostudies-literature
Project description:PurposeOvarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors.Experimental designWe performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I-IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study.ResultsAge of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic.ConclusionsEarly-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730.
| S-EPMC7612959 | biostudies-literature
Project description:Background:The objective of this study is to investigate small cell neuroendocrine carcinoma of the cervix (SCCC), using a retrospective clinicopathological characteristic and treatment approach. Method:We retrospectively analyzed cases of early-stage SCCC, identified between 2006 and 2016, in women who received radical surgery and adjuvant chemotherapy with or without radiotherapy. Kaplan-Meier and one-way ANOVA analyses were performed. Result:A total of 37 cases of SCCC are presented in this study, of which 21 had stage IB1 SCCC, 12 had stage IB2, 3 had stage IIA1, and 1 had stage IIA2. All patients were treated with radical surgery and adjuvant chemotherapy, specifically, 26 with radical surgery followed by adjuvant chemotherapy plus radiation and 11 with neoadjuvant chemotherapy (NACT) followed by radical surgery. After a median follow-up time of 27 months (range, 8-115 months), the 2-year and 5-year disease-free survival rate for all patients was 51.9% and 34.1%, respectively, and the overall survival rate was 60.3% and 38.6%, respectively. Univariate analysis showed that International Federation of Gynecology and Obstetrics (FIGO) stage and tumor size may be a predictor of a poor prognosis. NACT and adjuvant radiation did not improve survival over adjuvant chemotherapy alone but should not be a significant independent prognostic factor for survival. Conclusion:Even in patients with early-stage SCCC, the prognosis is poor, although FIGO stage and tumor size may act as surrogate factors prognostic of survival.
| S-EPMC6501769 | biostudies-literature
Project description:Human papillomavirus (HPV)-negative cervical carcinomas are uncommon and typically encompass unusual histologic subtypes. Mesonephric adenocarcinoma is one such subtype. Mesonephric tumors in the female genital tract are thought to arise from Wolffian remnants, and are extremely rare tumors with widely variable morphology. Sarcomatoid dedifferentiation has been previously described in a few cases, but other forms of dedifferentiation have not been reported. Neuroendocrine carcinoma of the cervix (e.g. small cell carcinoma) is associated with HPV infection, typically HPV 18. These tumors often arise in association with a conventional epithelial component such as squamous cell carcinoma or usual-type endocervical adenocarcinoma. We describe a case of mesonephric adenocarcinoma of the uterine cervix associated with an HPV-negative high-grade neuroendocrine carcinoma at the morphologic and immunophenotypic level, for which we performed targeted massively parallel sequencing analysis of the 2 elements. Both components shared identical mutations in U2AF1 p.R156H (c.467G>A) and GATA3 p.M422fs (c.1263dupG), as well as MYCN amplification. In addition, the neuroendocrine carcinoma harbored TP53 and MST1R mutations not present in the mesonephric carcinoma. Our data suggest a clonal origin of the 2 components of this rare entity, rather than a collision tumor.
| S-EPMC5500437 | biostudies-literature
Project description:IntroductionPrimary carcinomas of the trachea are rare, with a reported annual incidence of one in a million. We present a case of a previously undescribed polypoid high-grade neuroendocrine carcinoma of the trachea. Resection of the carcinoma revealed only superficial invasion of the mucosa and without evidence of local or distant metastatic disease. Histologically, the tumor had high-grade features with necrosis and a high mitotic index.MethodsCharacterization of this rare neuroendocrine carcinoma of the trachea was performed by immunohistochemistry and whole-genome sequencing.ResultsImmunohistochemistry result was positive for neuroendocrine markers, p16 and an elevated Ki-67. Whole-genome sequencing of the lesion was performed and revealed a very unusual and very distinct mutational signature without relationship to other relevant neuroendocrine carcinomas. Neither known driver nor targetable mutations were found by whole-genome sequencing. Analysis of the sequence of numerous viral elements of human papillomavirus-18 suggests that the pathogenesis of the lesion is related to viral integration. The patient developed distal recurrence, which progressed to widespread pulmonary dissemination, presumably through aerogenous spread of disease.ConclusionsThis is the first characterization of this type of tracheal tumor, including genomic findings, pathogenesis, and natural history.
| S-EPMC8474438 | biostudies-literature
Project description:Low-grade early-stage endometroid cancer (EC) is the most frequently diagnosed tumor type of the uterine corpus. Our study aimed to assess dysregulated pathways in this specific subset of tumors through proteomic analysis. There is still a knowledge gap in the molecular pathways that determine the biological behaviour of these tumors. The purpose of this study was to describe dysregulated molecular pathways from EC patients. Paired healthy controls were collected and both subjected to MS/MS proteomic analysis.
2021-03-08 | PXD022733 | Pride
Project description:Neuroendocrine carcinomas of the cervix (NECC) are rare and thought to be aggressive. We performed a population-based analysis to examine the natural history, treatment patterns and outcomes of women with NECC compared to squamous cell carcinoma (SCCC) and adenocarcinoma (AC) of the cervix.The National Cancer Database (NCDB) was utilized to identify women with NECC, SCCC, and AC treated from 1998 to 2011. Clinical, demographic, and treatment characteristics were compared between the groups. The association between tumor histology and survival was examined using Kaplan-Meier analyses and multivariable Cox proportional hazards regression models.We identified 127,332 patients, including 1,896 (1.5%) with NECC and 101,240 (79.5%) with SCCC and 24,196 (19.0%) with AC. Patients with NECC were younger, more often white, commercially insured, and diagnosed with metastatic disease at presentation compared to women with SCCC. Patients with early-stage NECC were more likely to receive adjuvant chemotherapy and radiation after surgery (P<0.05 for both). In multivariable models stratified by stage and adjusted for clinical and demographic characteristics, the risk of death was higher for patients with NECC compared to SCCC for all stages of disease: stages IB-IIA (HR=2.96; 95% CI, 2.48-3.52), stages IIB-IVA (HR=1.70; 95% CI, 1.45-1.99) and stage IVB (HR=1.14; 95% CI, 0.91-1.43).NECC are aggressive tumors associated with an increased risk of death. Survival is inferior for NECC compared to squamous cell tumors for women with both early and advanced stage disease.
| S-EPMC4844781 | biostudies-literature
Project description:High-grade neuroendocrine carcinomas (NECs) of the cervix are rare, aggressive cancers accounting for about 1-1.5% of all cervical cancer. The 5-year survival is up to 36% for early-stage disease; however, the advanced-stage disease has <10% survival, with relapse rates exceeding 90%. These cancers are likely to have a vascular invasion and nodal or visceral metastasis. Unfortunately, NEC of the cervix affects young women with a median age of 37. High-grade NECs of other gynecologic origins are even rarer, share similar aggressive behavior and poor outcomes. We performed stranded paired-end RNA-seq of 13 samples, including 12 samples with matched whole exome sequencing (WES) data. Sites of origin for tumors in our cohort were the cervix (69%), ovary (19%), and endometrium (12%). The median number of prior lines of therapy was 1. Median PFS and OS were 1 and 12 months, respectively, indicating their highly lethal nature. Comparing transcriptomic profiles with TCGA cervical and ovarian cancers, chromatin assembly and nucleosome organization were the top GO functions for significantly over-expressed genes in our cohort. Remarkably, under-expressed genes in our cohort were enriched for protein modification and catabolic processes, and neutrophil-mediated immunity. Compared to small cell lung cancer (SCLC), our cohort showed highly distinct transcriptomic patterns, and represented the YAP1 high molecular subtype.
2021-09-01 | GSE157601 | GEO
Project description:BackgroundNeuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for this type of malignancy based on controlled trials.MethodsWe performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials describing the management and outcome of women with NECC.ResultsThree thousand five hundred thirty-eight cases of NECC in 112 studies were identified. The pooled proportion of NECC among women with cervical cancer was 2303/163470 (1.41%). Small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early and late stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively. Tumors expressed synaptophysin (424/538 cases; 79%), neuron-specific enolase (196/285 cases; 69%), chromogranin (323/486 cases; 66%), and CD56 (162/267; 61%). The most common primary treatment was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy, described in 42/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies). Overall, the prognosis of women with NECC was poor with a mean recurrence-free survival of 16 months and a mean overall survival of 40 months. Immune checkpoint inhibitors and targeted agents were reported as being active in three case reports.ConclusionNECC is a rare variant of cervical cancer with a poor prognosis. Multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early stage disease while chemotherapy with cisplatin and etoposide or topotecan, paclitaxel, and bevacizumab is appropriate for women with locally advanced or recurrent NECC. Immune checkpoint inhibitors may be beneficial, but controlled evidence for their efficacy is lacking.
| S-EPMC5935948 | biostudies-literature
Project description:BackgroundHigh-grade neuroendocrine carcinomas are rare in the gastrointestinal tract. However, treatment patterns and outcomes have not been well described.Subjects, materials, and methodsThe National Cancer Database was analyzed. The primary objective was to describe the clinical outcomes and identify prognostic factors. Univariate and multivariate analyses were done to identify factors associated with patient outcome.ResultsA total of 1,861 patients were identified between 2004 and 2013. The mean age was 63 years (standard deviation ±13). The majority of the patients (78.1%) were non-Hispanic whites. The most common primary sites were pancreas (pancreatic neuroendocrine tumor [PNET] = 19.4%), large intestine (18.1%), esophagus (17.8%), and rectum (15.5%). Stage at presentation was I (6.6%), II (10.5%), III (18%) and IV (64.6%). Only 1.6% of the patients had brain metastases. Surgical resection was the primary therapy in 27.9%, and their median overall survival (OS) was 13.3 months. Patients treated with palliative chemotherapy had a median OS of 11.2 months, compared with 1.7 months for untreated patients. The median OS for high-grade PNET was 6 months, compared with 9.9 months for other high-grade gastrointestinal neuroendocrine carcinomas (HG GI NEC). On univariable analysis, age < 65 years (hazard ratio [HR] 0.72; 0.66-0.8; p < .001) and treatment at an academic center (HR 0.88; 0.79-0.99; p < .034) were associated with improved survival. Multivariable analysis confirmed prognostic advantage of treatment at an academic center.ConclusionThis is the largest series of HG GI NEC. Most patients present with metastatic disease, and overall survival remains poor. Treatment at an academic center, younger age, and use of chemotherapy were associated with improved survival. Multiagent chemotherapy was found to be associated with superior survival compared with single-agent chemotherapy, which was superior to no chemotherapy. Temporal sequences of chemotherapy, surgery, and radiation administration were not found to be associated with survival differences on multivariable analysis.Implications for practiceManagement of patients with high-grade gastrointestinal neuroendocrine carcinomas (HG GI NEC) is based on experience with small-cell lung cancer. In this retrospective review, most patients had advanced disease and pancreatic primary had worse outcomes. Treatment at an academic center, younger age, and use of chemotherapy are associated with improved survival. Patients with early-stage disease treated with resection alone had inferior outcomes compared with patients who received neoadjuvant or adjuvant therapy, suggesting that micrometastases contribute to poor surgical outcomes. The relatively high proportion of positive surgical margin favors downstaging with neoadjuvant therapy to improve resection and lower the risk of systemic recurrence.
| S-EPMC6656466 | biostudies-literature