[Clinicopathological Features of Primary Small Cell Neuroendocrine Carcinoma of the Bladder].

Objective To investigate the clinicopathological features,immunohistochemical features,diagnosis,and relationship with sporadic prostate cancer in primary small cell neuroendocrine carcinoma of the bladder. Methods We retrospectively analyzed the clinical characteristics of 12 patients with primary small cell neuroendocrine carcinoma of the bladder diagnosed at Beijing Chao-Yang Hospital affiliated to Capital Medical University from January 2013 to September 2022.The histological features of primary small cell neuroendocrine carcinoma of the bladder were re-evaluated by two pathologists according to the 2022 revision of the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs.Electronic medical records were retrieved,and telephone follow-up was conducted from the time of histopathological diagnosis to the death or the end of the last follow-up until January 31,2023. Results The 12 patients include 7 patients in pT3 stage and 1 patient in pT4 stage.Eight patients were complicated with other types of tumors,such as high-grade urothelial carcinoma of the bladder and squamous cell carcinoma.Five patients had sporadic prostate cancer.Immunohistochemical staining showed that 12 (100.0%),10 (83.3%),and 8 (66.7%) patients were tested positive for CD56,Syn,and CgA,respectively.The Ki67 proliferation index ranged from 80% to 90%.Five patients with urothelial carcinoma were tested positive for CK20,GATA3,and CK7.P504S was positive in all the 5 patients with prostate cancer,while P63 and 34ßE12 were negative.The follow-up of the 12 patients lasted for 3-60 months.Eight of these patients died during follow-up,with the median survival of 15.5 months.Four patients survived. Conclusions Primary small cell neuroendocrine carcinoma of the bladder is a rare urological tumor with high aggressiveness and poor prognosis.In male patients with bladder prostatectomy,all prostate tissue should be sampled.If prostate cancer is detected,the prostate-specific antigen level should be monitored.

The prognostic impact of the immune microenvironment in small-cell neuroendocrine carcinoma of the uterine cervix: PD-L1 and immune cell subtypes.

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.

The next generation sequencing of cancer-related genes in small cell neuroendocrine carcinoma of the cervix.

OBJECTIVE: Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a lethal malignancy and little treatment progress has been made for decades. We sought to map its genetic profiles, and identify whether SCNEC harbor mutations and potential targets for therapeutic interventions. METHODS: Primary tumor tissue and blood samples were obtained from 51 patients with SCNEC. The next-generation sequencing was carried out to detect mutations of 520 cancer-related genes, including the entire exon regions of 312 genes and the hotspot mutation regions of 208 genes. Quantitative multiplex PCR was performed for the detection of seven high-risk HPV types. RESULTS: Of the 51 detected patients, 92.16% were positive for HPV 18. Ninety-eight percent of cases harbored genetic alterations. Two cases were observed with hypermutated phenotype and determined as MSI-H/dMMR. Genetic mutations were clustering in RTK/RAS(42.86%), PI3K-AKT(38.78%), p53 pathway(22.45%) and MYC family(20.41%). Mutations in genes involved in the p53 pathway indicate a poorer prognosis (3-year OS, 33.5% vs 59.9%, p = 0.031). A total of seven patients harboring mutations in homogeneous recombination repair (HRR) genes were reported. In addition, IRS2 and SOX2 were amplified in 14.9% and 6.12% of SCNEC patients, respectively. CONCLUSIONS: SCNEC is specifically associated with HPV 18 infection. Its genetic alterations are characterized by a combined feature of high-risk HPV driven events and mutations observed in common neuroendocrine carcinoma. We identified several targetable mutated genes, including KRAS, PIK3CA, IRS2, SOX2, and HRR genes, indicating the potential efficacy of target therapies in these patients. MSI-H/dMMR individuals may benefit from checkpoint blockade therapies.

Cytomorphological features of cervical small cell neuroendocrine carcinoma in SurePath™ liquid-based cervical samples.

Small cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare, highly aggressive tumour with poor prognosis and high propensity for distant metastases. The cytological features of SCNEC have rarely been described in cervical samples, and to the best of our knowledge, there are no previous reports using SurePath™ liquid-based cytology. In the present report we present the cytomorphological features of histopathologically confirmed cases of cervical SCNEC in SurePath preparations. On cytological examination, all three cases demonstrated variable numbers of tumour cells, ranging from a few dispersed cells and tiny micro-biopsies to large aggregates of small tumour cells with a high nucleus-to-cytoplasmic ratio, stippled chromatin, inconspicuous nucleoli, and scant cytoplasm. Immunocytochemistry for CD56 on the cervical preparation confirmed the diagnosis in one case. The presence of small tumour cells with characteristic stippled/salt-and-pepper type nuclear chromatin were the most consistent cytological features in these cases. Knowledge of these characteristic cytological features can help in suggesting a diagnosis of SCNEC in cervical samples which can then be confirmed by immunocytochemistry.

Evaluation of Therapeutic Targets in Histological Subtypes of Bladder Cancer.

Histologically, bladder cancer is a heterogeneous group comprising urothelial carcinoma (UC), squamous cell carcinoma, adenocarcinomas (ACs), urachal carcinomas (UrCs), and small cell neuroendocrine carcinomas (SCCs). However, all bladder cancers have been treated so far uniformly, and targeted therapy options are still limited. Thus, we aimed to determine the protein expression/molecular status of commonly used cancer targets (programmed cell death 1 ligand 1 (PD-L1), mismatch repair (MMR), androgen and estrogen receptors (AR/ER), Nectin-4, tumor-associated calcium signal transducer 2 (Tacstd2, Trop-2), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and fibroblast growth factor receptor 3 (FGFR3)) to give first insights into whether patients with SCC, AC/UrCs, and squamous-differentiated carcinomas (Sq-BLCA) of the bladder could be eligible for targeted therapies. In addition, for MMR-deficient tumors, microsatellite instability was analyzed. We completed our own data with molecular data from The Cancer Genome Atlas (TCGA). We present ratios for each drug and cumulative ratios for multiple therapeutic options for each nonurothelial subtype. For example, 58.9% of SCC patients, 33.5% of AC/UrCs patients, and 79.3% of Sq-BLCA patients would be eligible for at least one of the analyzed targets. In conclusion, our findings hold promise for targeted therapeutic approaches in selected patients in the future, as various drugs could be applied according to the biomarker status.

[Diagnosis and treatment of small cell neuroendocrine carcinoma of the prostate].

OBJECTIVE: To explore the clinical manifestations, pathological features and treatment of small cell neuroendocrine carcinoma of the prostate (SCPCa). METHODS: We reported 1 case of SCPCa treated in Jinan People's Hospital and analyzed the clinical data on another 57 cases reported in China. RESULTS: Of the total number of cases, 52 (91.2%) had urinary tract symptoms, including 40 cases of urinary tract obstruction symptoms and 53 (91.2%) had abnormal prostatic nodules on digital rectal examination, 17 (29.8%) with PSA > 4 µg/L. The clinical data on 43 (75.4%) of the cases were valuable for the assessment of clinical stages, including 30 cases with confirmed metastases and another 20 with lymph node and distant metastases. Thirty-seven of the cases (64.9%) were reported with immunohistochemical results, 30 (52.6%) with follow-up data (followed up for 1－24 months, with median survival time of 8 months, and a 1-year survival rate of 16.7%), and another 26 with therapeutic information, 14 treated by chemotherapy, with a median survival time of 11 months and a 1-year survival rate of 28.6%, significantly higher than in the non-chemotherapy groups (P<0.01). CONCLUSIONS: Small cell carcinoma of the prostate is highly malignant with poor prognosis. Its clinical symptoms mainly include urinary tract obstruction, its definite diagnosis chiefly depends on histopathology and immunohistochemistry, and its treatment recommended is chemotherapy-based comprehensive protocol.

A clinical analysis of small-cell neuroendocrine carcinoma of the gynecologic tract: report of 20 cases.

OBJECTIVE: The aim of this retrospective observational study was to analyze the clinical and pathological characteristics of small-cell neuroendocrine carcinoma of the gynecologic tract (SCNCGT). METHODS: Twenty patients with SCNCGT were enrolled and their clinic-pathological features were analyzed. All patients were treated at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, China, and were followed up until December 31, 2017. RESULTS: (1) Patient characteristics: The incidence of SCNCGT was 0.3% (20/6578) of gynecologic cancer in our hospital from January 1, 2007, to December 31, 2017. The average age of the patients was 42.0 ± 11.8 (23-63 years). Out of 20 patients enrolled, seven (35.0%) had lymph node metastasis. Out of 17 patients treated with complete surgery, 14 (82.4%) had lymph-vascular space invasion. (2) Treatment: Eleven out of the 14 patients with small-cell neuroendocrine carcinoma of the cervix (SCNCC) were treated with radical surgery; all the 11 patients received chemotherapy and radiotherapy postoperatively. The remaining three patients received comprehensive chemotherapy and/or radiotherapy instead of radical surgery. The six patients who had one or the other type of SCNCGT (involving the ovary, endometrium, or vagina) were all treated with comprehensive surgery. (3) Prognosis: The follow-up time for the study ranged from 8 to 87 months. Three (15.0%) of the 20 patients were diagnosed with distant metastasis at the beginning of the study. Eight (40.0%) patients died as of December 31, 2017, while the other 12 patients were in follow-up. The average survival time was 43.6 months (16-77 months). CONCLUSION: SCNCGT is a highly malignant tumor characterized by rare morbidity, a propensity for metastasis, and poor prognosis. Comprehensive treatment may be a good approach to prolong survival in some patients.

Clinicopathological Aspects of Small Cell Neuroendocrine Carcinoma of the Uterine Cervix: a Multicenter Retrospective Study and Meta-Analysis.

BACKGROUND/AIMS: To evaluate the clinicopathologic aspects of small cell neuroendocrine carcinoma of the uterine cervix (SCNEC). METHODS: A retrospective review of 40 patients with SCNEC in 3 hospitals from 2009 to 2015 was conducted to assess the survival rates and examine the associations between clinicopathological variables and overall survival (OS). A meta-analysis of 22 studies containing 1901 patients was also conducted to further confirm the results. RESULTS: In the clinical group of 40 patients, the 5-year OS rate was 20%. Advanced International Federation of Gynecology and Obstetrics (FIGO) stage and radiation therapy (RT) were associated with poor survival. However, radical surgery was associated with prolonged survival. In the meta-analysis of 1901 patients, the 2-year disease-free survival (DFS) rate, 5-year DFS rate, 2-year OS rate, 3-year OS rate and 5-year OS rate of SCNEC were 48%, 35%, 62%, 35%, and 35% respectively. Advanced FIGO stage, larger tumor size, lymph node metastasis (LNM) (+), lymphovascular space involvement (LVSI) (+), parametrial involvement (PI) (+), depth of stromal invasion (DSI) > 2/3, and RT were associated with poor survival. However, a chemotherapy regimen similar to that for small cell lung cancer was associated with prolonged survival. CONCLUSION: Advanced FIGO stage, larger tumor size, LNM (+), LVSI (+), DSI > 2/3, PI (+), and RT were independent predictors of poor prognosis of SCNEC. Radical surgery combined with a chemotherapy regimen similar to that of small cell lung cancer may be a potential therapeutic approach for SCNEC.

Establishment and Characterization of a Novel Cell Line Derived from a Small Cell Neuroendocrine Carcinoma of the Anal Canal.

BACKGROUND: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are biologically aggressive tumors, associated with a very poor survival. Due to their rarity, our knowledge on GEP-NEC biology is very limited. The aim of this study was to establish a GEP-NEC cell line model that might contribute to a better understanding of this rare malignant disease to further develop novel therapeutic approaches in preclinical studies. METHODS: Small cell neuroendocrine cancer cell line NEC-DUE3 was derived from a lymph node metastasis of a neuroendocrine carcinoma (NEC) located at the anal canal. Morphological characteristics and the expression of neuroendocrine markers were comprehensively investigated. For genetic profiling, NEC-DUE3 cells were analyzed by DNA fingerprinting. Chromosomal aberrations were mapped by array comparative genomic hybridization. NEC-DUE3 cell tumorigenicity was evaluated in vivo and the sensitivity to chemotherapeutic agents was assessed in vitro. RESULTS: NEC-DUE3 cells were characterized by the expression of molecular markers that are commonly observed in GEP-NECs, were sensitive to treatment with cisplatin, and able to form tumors in immunodeficient mice. CONCLUSION: We established and characterized the first small cell GEP-NEC cell line that may serve as a valuable tool to create a better understanding of the biology of these rare tumors and to develop novel treatment strategies.