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BACKGROUND: We investigate the correlation between programmed cell death-ligand 1 (PD-L1) and tumor-associated immune cell (TAIC) density in small-cell neuroendocrine carcinoma of the uterine cervix (SCNEC) and their correlation with clinicopathologic features. METHODS: PD-L1 and mismatch repair protein (MMR) expression in cancer cells and the density of TAIC were evaluated by immunohistochemistry in 89 SCNEC patients. The combined positive score (CPS), tumor proportion score (TPS), and immune cell score (ICS) of PD-L1 were measured, along with their correlation with clinicopathologic features in SCNEC patients using statistical analyses. RESULTS: CPS of PD-L1 ≥ 1 was seen in 68.5% of patients, positive TPS and ICS of PD-L1 were detected in 59.6% and 33.7% of patients, respectively. PD-L1CPS was higher in tumor-infiltrating immune cells (r = 0.387, p = 0.001) and positively correlated with programmed cell death-1 and forkhead box P3 + regulatory T cell (FOXP3 + Treg) infiltration (r = 0.443, p < 0.001; r = 0.532, p < 0.001). There was no statistical correlation between PD-L1 and MMR status. PD-L1CPS and PD-L1ICS positivity were independent prognostic factors, correlating with a favorable survival (HR (95%CI) = 0.363(0.139-0.950), p = 0.039 and HR (95% CI) = 0.199(0.050-0.802), p = 0.023, respectively). PD-L1ICS positivity was an independent indicator of recurrence in SCNEC patients and associated with better disease-free survival (HR (95% CI) = 0.124(0.036-0425), p = 0.001). TAIC and MMR levels had no statistical impact on survival results. CONCLUSIONS: PD-L1 positivity was seen in over half of SCNEC tumors. It may work synergistically with FOXP3 + Treg and other infiltrating immune cells to support an adaptive immune response. PD-L1 positivity may be a favorable prognostic factor in SCNEC.
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Objectives: To describe characteristics and outcomes of patients with small cell neuroendocrine carcinoma of the cervix (SCNCC) and determine the staging system most predictive of outcome-the two-tier (limited-stage [LS] vs. extensive-stage [ES]) or International Federation of Gynecology and Obstetrics (FIGO) staging system. Methods: Patients with SCNCC evaluated at our institution from 1/1/1990-6/30/2021 were included. Medical records were reviewed for variables of interest. Appropriate statistical tests were performed to determine associations. Survival curves were created using the Kaplan-Meier method. Concordance probability estimates (CPEs) were calculated to evaluate the prediction probability of the staging systems. Results: Of 63 patients, 41 had LS and 22 ES SCNCC. Patients with ES disease were significantly older than those with LS disease (median, 54 and 37 years, respectively; p < 0.001). Smoking status, race, and history of HPV were not associated with stage or outcomes. Forty-eight patients had metastatic disease (24 [50%] at initial diagnosis). The most common first sites of metastasis were lung (n = 20/48, 42%), lymph nodes (n = 19/48, 40%), and liver (n = 13/48, 27%). Nine patients had brain metastasis (8 symptomatic at recurrence; 1 asymptomatic at initial diagnosis). Both staging systems were associated with progression-free and overall survival. Adjusted CPE found the FIGO staging system was more predictive of outcomes than the two-tier staging system. Conclusions: Providers should have a low threshold to obtain brain imaging for patients with SCNCC, especially in the presence of visceral metastases. FIGO staging should be used to classify SCNCC. Further research is necessary to understand prognostic factors of this rare disease.
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OBJECTIVE: To screen for specific differentially expressed genes in small cell neuroendocrine carcinoma of the cervix (SCNEC) and to further explore their roles and mechanisms in tumor progression. METHODS: Differentially expressed genes in SCNEC compared with squamous cell carcinoma (SCC) and adenocarcinoma (AC) were screened by microarray and immunohistochemical analyses. The biological functions of the identified genes were examined in a SCNEC cell line using RNA interference and over-expression plasmid-transfection technologies. Co-expression network analysis and immunoprecipitation technology were used to explore the potential mechanisms. RESULTS: Compared with SCC and AC, UCHL1 (encoding ubiquitin C-terminal hydrolase L1) was identified as a specific differentially expressed gene in SCNEC, which was positively related to lymph node metastasis (LNM). Migration and invasion of SCNEC tumor cells were induced by UCHL1 over-expression and suppressed by UCHL1 down-regulation, as shown by scratch and transwell invasion assays. Co-expression network analysis suggested that Prospero homeobox protein 1 (PROX1) might interact with UCHL1, and in vivo immunoprecipitation and western blots verified that levels of ubiquitinated PROX1 were significantly decreased following UCHL1 overexpression. CONCLUSION: UCHL1 is a potential biomarker of LNM in SCNEC. UCHL1 might promote SCNEC cell migration and invasion by reducing PROX1 ubiquitination.
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Adenocarcinoma , Carcinoma Neuroendocrino , Carcinoma de Células Escamosas , Ubiquitina Tiolesterasa , Neoplasias del Cuello Uterino , Adenocarcinoma/genética , Adenocarcinoma/patología , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Cuello del Útero , Femenino , Proteínas de Homeodominio , Humanos , Metástasis Linfática , Proteínas Supresoras de Tumor , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
OBJECTIVE: This study sought to explore the outcomes and prognostic factors of patients with small cell neuroendocrine carcinoma of the cervix (SCNEC) and to determine the effects of adjuvant treatment on survival in patients with FIGO stage I-II SCNEC after radical surgery. METHODS: A single-institution retrospective analysis was performed in 92 patients who underwent radical surgery for SCNEC. All clinicopathological variables and treatment strategies were reviewed. Kaplan-Meier and Cox regression methods were used for survival analyses. RESULTS: During a median follow-up period of 38months (23.6-52.4), 43 (46.7%) patients experienced disease recurrence, and distant metastases were documented in 35 (81.4%) patients. The 3-year recurrence-free survival (RFS) for the entire group was 50.1%. The median RFS was 39months. The multivariate analysis confirmed that lymph node metastasis, positive parametrial extension and cycles of etoposide plus platinum (EP) were independent prognostic factors for disease recurrence. Adjuvant chemotherapy for at least 5cycles of EP (EP 5+, n=39) was associated with improved 5-year RFS compared with other treatments (n=46) (67.6% vs. 20.9%, p<0.001). Additional radiotherapy or concurrent chemoradiation failed to validate further improved RFS in patients with EP 5+, and this finding was consistent in the subset of patients with high-risk factors (positive lymph nodes or positive parametrium). CONCLUSIONS: Half of stage I-II SCNEC patients experienced disease failure within 3years, and distant metastasis was an outstanding issue. EP regimen for at least 5cycles improved long-term RFS after radical surgery. Additional radiation might be unnecessary, even in patients with high-risk factors.