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Small cell neuroendocrine cervical carcinoma (SCNECC) is an aggressive gynecological malignancy with poor prognosis. The precision therapeutic strategies for SCNECC are severely limited by the complex tumor microenvironment. Here, we mapped the single-cell landscape of a total of six samples from matched SCNECC cancerous foci and normal adjacent cervical tissues. Through analysis of 68,455 high-quality cells, malignant epithelial cells were identified with increased neuroendocrine differentiation and reduced keratinization. Within four epithelial cell clusters, the key transcription factors ASCL1, NEUROD1, POU2F3, and YAP1 defined molecular subtypes. Transitional trajectory among subtypes characterized two distinct carcinogenesis pathways in SCNECC. The P-type SCNECC showed potentially enhanced immune infiltration over other subtypes. Intercellular communication analysis identified several immune checkpoints and differentially expressed signaling pathways among subtypes. Through western blotting, the TC-YIK cell line was identified as an N-type SCNECC cell with high expression of SLFN11 and mTOR. Based on immunohistochemical staining of malignant subtyping markers, a cohort of 66 SCNECC patients from our hospital were divided into five subtypes. We further combined YAP1 expression with other clinicopathological factors (Cox p < 0.05) to establish a prognostic nomogram. Overall, these findings provide clues for tumorigenesis, precision treatments and prognostic prediction in SCNECC., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Currently, optimal treatment strategy for resectable primary small cell carcinoma of the esophagus (PSmCCE) remains controversial. To address this, we conducted a multicenter study to evaluate treatment patterns and long-term survival of PSmCCE patients who underwent radical resection., Methods: This retrospective multicenter study included resected PSmCCE patients who received radical resection at seven high-volume cancer centers. Overall survival (OS) and median survival time (MST) were calculated by using a Kaplan-Meier method and the log-rank test was utilized to assess differences. Multivariable Cox analysis was performed to identify independent prognostic factors., Results: A total of 352 patients with resected PSmCCE were included. For PSmCCE with stage cT1-2N0M0, patients who received surgery plus adjuvant therapy showed better survival than those who received surgery alone (5-year OS rate: 32.8% vs. 19.2%, MST: 44.0 vs. 33.0 months, P = 0.035). Multivariable Cox survival analysis revealed an independent correlation between receiving surgery plus adjuvant therapy and improved OS (hazard ratio [HR] 0.529; 95% confidence interval [CI] 0.280-0.997; P = 0.049). For stage cT3N0M0/T1-3N1M0 PSmCCE, patients who received neoadjuvant therapy followed by surgery had superior long-term survival compared with those who received surgery combined with adjuvant therapy and those who received surgery alone (5-year OS rate: 27.2% vs. 9.5% vs. 0%, MST: 36.0 vs. 24.0 vs. 20.0 months, P = 0.014). Multivariable Cox survival analysis showed that neoadjuvant therapy was independently associated with improved OS (HR 0.384, 95% CI 0.203-0.728; HR 0.550, 95% CI 0.312-0.968; P = 0.013)., Conclusions: Adjuvant therapy was associated with improved survival in stage cT1-2N0M0 PSmCCE, but this should be confirmed in prospective studies. For stage cT3N0M0/T1-3N1M0 cases, neoadjuvant therapy followed by surgery should be considered., Competing Interests: Disclosure: All authors have no conflicts of interest to declare., (© 2024. Society of Surgical Oncology.)

Small cell neuroendocrine cervical carcinoma is a highly aggressive tumor characterized by early metastasis, a high recurrence rate, and poor prognosis. This study represents the first instance of single-cell sequencing conducted on small cell neuroendocrine carcinoma of the cervix worldwide. Analysis of gene expression regulatory networks revealed that the transcription factor TFF3 drived up-regulation of ELF3. Furthermore, our findings indicated that the neuroendocrine marker genes and gene regulatory networks associated with small cell neuroendocrine cervical carcinoma differed from those observed in lung, small intestine, and liver neuroendocrine carcinoma within the GEO database, suggesting tissue-specific origins for these malignancies. Overall, this study addresses a significant research in understanding small cell neuroendocrine cervical carcinoma in vivo and provides valuable insights for guiding radiotherapy, chemotherapy, and targeted therapy., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Obstetrics and Gynecology Hospital of Fudan University(2024-113). Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patient to publish this paper. Consent for publication: Not applicable. Competing interests: The authors declare no conflicts of interest., (© 2024. The Author(s).)

Small-cell neuroendocrine cancer (SCNEC) of the uterine cervix is an exceedingly rare, highly aggressive tumor with an extremely poor prognosis. The cellular heterogeneity, origin, and tumorigenesis trajectories of SCNEC of the cervix remain largely unclear. We performed single-cell RNA sequencing and whole-exome sequencing on tumor tissues and adjacent normal cervical tissues from two patients diagnosed with SCNEC of the cervix. Here, we provide the first comprehensive insights into the cellular composition, HPV infection-related features, and gene expression profiles of SCNEC of the cervix at single-cell resolution. Correlation analyses suggested that SCNEC of the cervix may originate from squamous epithelial cells, and this observation was validated with bulk RNA-seq data from external cervical neuroendocrine cancer. Furthermore, sex-determining region Y-box 2 (SOX2), a key transcription factor that functions in direct neural differentiation, was located in the copy number gain region and highly expressed in neuroendocrine tumor cells from both patients. Notable, the distributions of the HPV-infected epithelium and SOX2 highly expressed epithelium were consistent with each other. Therefore, we supposed that high-risk HPV infection and amplification of SOX2 in the squamous epithelium may contribute to the progression of small-cell neuroendocrine tumorigenesis in the cervix., (© 2025 Wiley Periodicals LLC.)

Introduction: Small cell neuroendocrine carcinoma of the urinary tract (SCNEC-URO) has an inferior prognosis compared to conventional urothelial carcinoma (UC). Here, we evaluate the predictors and patterns of relapse after surgery., Materials and Methods: We identified a definitive-surgery cohort (n = 224) from an institutional database of patients with cT1-T4NxM0 SCNEC-URO treated in 1985-2021. Histopathologic review was conducted by independent pathologists. Relapse event was the time-to-event outcome, and relapse probabilities were estimated using a competing risk method with cumulative incidence functions (CIFs). Fine-Gray distribution models assessed covariate associations., Results: Most patients (161, 71.9%) received neoadjuvant chemotherapy (neoCTX). Ninety two (41%) patients had relapse with 77 (83.7%) having distant organs as first metastatic sites, including 10 (10.9%) with exclusive central nervous system (CNS) metastases, mostly (9/10) within 1 year of surgery. Patients with pathologic complete response (pCR) after neoCTx had the lowest 5-year CIF (16.5% [95% CI 9.3%-25.6%]). Patients with remaining exclusively small cell (SC) histology had the highest CIF (85.7% [95% CI 46.6-96.9]). Patients with eradicated SCNEC but remaining UC components had an intermediate-risk CIF (32.5% [95% CI 18.6-47.2]). Multivariable analysis adjusting for neoCTx, clinical stage at diagnosis (T3/4, N0/N+ vs. T1/T2, N0), and pathologic stage (pN+ vs. pN0) demonstrated that any SCNEC histology at resection (vs. pCR) was associated with relapse risk (hazard ratio = 3.69 [95% CI 1.91-7.13], p = 0.0001)., Conclusions: SCNEC-URO is a systemic disease with high risk of distant relapse including CNS. Our findings highlight unmet needs for neoadjuvant/adjuvant approaches targeting the rare SCNEC subtype and suggest adding CNS surveillance within the first year after definitive surgery to high-risk patients. PRÉCIS (CONDENSED ABSTRACT): Alongside neoadjuvant chemotherapy and cancer stage, histology at resection strongly impacts relapse risk in small cell neuroendocrine carcinomas of the urinary tract. The incidence of brain metastasis is notably higher than in "traditional" urothelial cancer within the first year after surgery, especially if small cell cancer persists, thus necessitating close neurological monitoring during this period., (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To investigate the clinicopathological, molecular pathological features, and family genetic pedigree of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Methods: A total of 16 cases of SCCOHT diagnosed in Obstetrics and Gynecology Hospital of Fudan University from January 2013 to January 2023 were collected. The clinicopathologic features, SMARCA4/2/B1 protein expression, outcomes and SMARCA4 gene detection were reported. A follow-up study was also carried out. Results: The average age at diagnosis was 28.7 years (range 17-38 years). The preoperative calcium level was evaluated in 3 of 6 patients. The tumor was unilateral in all 16 cases, ranged from 8 to 26 cm (average 15.8 cm) in the greatest dimension. Extraovarian spread was present in 7 cases. In 10 cases, the tumors were initially misinterpreted as other ovarian neoplasms. BRG1 and BRM expression by immunohistochemistry were all lost in detected cases, while INI1 exhibited retained nuclear expression. All BRM-negative SCCOHTs also lacked BRG1 protein,but retained INI1 expression. SCCOHTs were only focally positive for EMA, CKpan, Calretinin, SALL4, and diffusely positive for WT1. Two of nine cases exhibited mutation-type p53 immunoreactivity. Ki-67 index was 58% on an average. ER, PR, FOXL2, α-inhibin, chromogranin A and LCA were negative in all the cases. SMARCA4 sequencing was available in 8 cases of SCCOHT, which revealed a germline SMARCA4 mutation in one patient, and others carried somatic mutation. Furthermore, two daughters, mother and an aunt of a patient with germline mutation were reported to be SMARCA4 mutation carriers. Follow-up was available for 15 patients, and the 6-month, 1-year and 2-year survival rate was 65.8%, 45.1%, and 22.6%, respectively. For patients in FIGO stages Ⅱ+Ⅲ, 6-month, 1-year survival rate was 53.6% and 35.7% respectively, compared to 80% (6-month) and 60% (1-year) in patients of staged I ( P= 0.358). Conclusions: With dismal prognosis of SCCOHT, accurate diagnosis is necessary. The typical age distribution, a panel of various staining results, especially concomitant loss of BRG1 and BRM may be of diagnostic aid and can be used to distinguish SCCOHT from its histological mimics. After the diagnosis of SCCOHT, genetic testing and genetic counseling are recommended.

Background: This retrospective study aims to provide a comprehensive analysis of the demographics, survival rates, and therapeutic approaches of small-cell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC) while highlighting key differences compared to common urinary bladder cancers., Methods: Our analysis utilized the Surveillance, Epidemiology, and End Results database (SEER), and data was collected from 2000-2020., Results: A total of 1040 cases of urinary bladder SCNEC and LCNEC were identified. Most patients were over the age of 80 years (33.2%), male (78.9%), and Caucasian (83.6%). Most tumors were over 4.1cm (47.4%) and in the lateral wall of the bladder (37.8%). The overall 5-year survival was 22.1% (95% confidence interval (95% CI):20.7-23.5). The 5-year survival by sex was greatest for the female population (28.0%; (95% CI: 24.5-35.0). For treatment modality, the 5-year survival for each was as follows: surgery, 12.5% (95% CI: 10.5-14.5) multimodality therapy (surgery and chemotherapy), 31.1% (95% CI: 28.5-33.7) and combination (surgery, chemotherapy, and radiation) 32.8% (95% CI: 29.1-36.5). On multivariable analysis, positive nodal status hazar ratio (HR)(HR3.65 [95% CI: 2.34-5.71], P < .001) was identified as a negative predictor for survival, and increasing age was nearly significant for a worse prognosis (P = .052). The prognostic nomogram that was created to predict patient survivability mirrored the findings from the statistical analysis, with a statistically significant difference found in race, treatment modality, and tumor stage., Conclusions: SCNEC and LCNEC are rare yet highly intrusive subtypes of bladder cancer that usually affect Caucasian males over the age of 80 years old. The study identifies older age and positive nodal status as adverse prognostic indicators. Our findings offer crucial insights that can inform future clinical guidelines and serve as a basis for more tailored treatment strategies for these aggressive subtypes of bladder cancer., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Small cell bladder cancer (SCBC) is a rare histologic subtype with relative paucity of data regarding treatment response and outcomes. We reviewed 2 databases to compare outcomes in patients with localized SCBC treated with cystectomy versus concurrent chemoradiotherapy (CCRT). We hypothesized that survival would be similar with these therapy approaches., Methods: We retrospectively reviewed our institutional and SEER-Medicare databases to identify patients with SCBC. Overall survival (OS) was determined from the date of diagnosis to last follow-up/death. For those with nonmetastatic disease, a multivariate Cox analysis was used to compare locoregional therapy with neoadjuvant chemotherapy (NAC) + cystectomy versus CCRT., Results: We identified 53 patients in our institutional database and 1166 patients in SEER-Medicare with localized SCBC. Median OS (mOS) with NAC + cystectomy was 46 months (95% CI, 21-72) and 45 months (95% CI, 0-104) in the institutional and SEER-Medicare databases, respectively, whereas mOS with CCRT was 26 months (95% CI, 5-47) and 23 months (95% CI, 18-28) in the 2 series, respectively. In multivariate analysis, NAC followed by cystectomy was associated with an approximately 30% reduction in mortality compared to CCRT in both institutional and national databases but did not reach statistical significance (Institution HR 0.71, 95% CI, 0.22-2.4, P = .58; SEER HR 0.73, 95% CI, 0.49-1.08; P = .11)., Conclusions: SCBC is very aggressive with limited survival observed in our institutional and SEER-Medicare datasets regardless of locoregional therapy used. There is an unmet need to define the optimal locoregional therapy for nonmetastatic stage and identify novel therapeutic targets., Competing Interests: Disclosure Dimitra Rafailia Bakaloudi: no conflicts to disclose. Elizabeth L. Koehne: no conflicts to disclose. Leonidas N. Diamantopoulos: no conflicts to disclose. Sarah K. Holt: no conflicts to disclose. Rishi R. Sekar: no conflicts to disclose. Fady Ghali: Consulting: Immunitybio Funda Vakar-Lopez: no conflicts to disclose. Yaw A. Nyame: no conflicts to disclose. Sarah P. Psutka: Research Funding: National Institute on Aging; Bladder Cancer Advocacy Network; PRIME Education, Inc; Guidelines Committee: American Urological Association: Upper Tract Urothelial Carcinoma Guidelines 2023 Advisory/Consultancy: Janssen (SunRise-4 Global Co-PI), Immunity Bio, Merck, CG Oncology John L. Gore: Research Grant funding from Ferring Pharmaceuticals. Claire de la Calle: no conflicts to disclose. Daniel W. Lin: DSMB for the POTOMAC study with AstraZeneca; Consulting or Advisory Role—Astellas Pharma, Clovis Oncology, Janssen Oncology, and Lantheus, Research Funding –Veracyte; MDxHealth. George R. Schade: Advisor ImmunityBio, Consultant EDAP. Intellectual property licensed to Petal Surgical. Jay Liao: no conflicts to disclose. Andrew C. Hsieh: Honoraria—Hotspot Therapeutics; Research Funding—eFFECTOR Inc; Patents, Royalties, Other Intellectual Property—MTOR modulators and uses thereof Patent number: 9629843; Use Of Translational Profiling To Identify Target Molecules For Therapeutic Treatment, Publication number: 20140288097. Todd Yezefski: Institutional research funding from AstraZeneca, Astellas, participation in educational programs for Dendreon Jessica E. Hawley: consulting for Seagen, Daiichi-Sankyo, Immunity Bio; institutional research support from AstraZeneca, Bristol-Meyers Squibb, Crescendo Biologics, Macrogenics, Johnson & Johnson Innovative Medicine, PromiCell, Amgen, and Vaccitech. Evan Y. Yu: consulting for Aadi Bioscience, Advanced Accelerator Applications, Bayer, Bristol-Myers Squibb, Janssen, Lantheus, Loxo, Merck, Oncternal; institutional research support from Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Lantheus, Merck, Oncternal, Seagen, Surface, Taiho, Tyra. Robert B. Montgomery: Research Funding—AstraZeneca, Bayer, Clovis, Janssen Oncology. Petros Grivas (unrelated to this manuscript in the last 2 years): consulting for MSD, Bristol Myers Squibb, AstraZeneca, EMD Serono, Seagen, Pfizer, Janssen, Roche, Astellas Pharma, Gilead Sciences, Silverback Therapeutics, BostonGene, Fresenius Kabi, Lucence Health, PureTech, G1 Therapeutics, Aadi Biosciences, CG Oncology, Strata Oncology, ImmunityBio, Asieris Pharmaceuticals, AbbVie; Institutional research funding: Pfizer, Bristol Myers Squibb, MSD, QED Therapeutics, GlaxoSmithKline, Mirati Therapeutics, EMD Serono, G1 Therapeutics, Gilead Sciences, Acrivon Therapeutics, ALX Oncology, Genentech. Jonathan L. Wright: Royalties—UpToDate; Clinical Trials/Research—Merck, Nucleix, Altor Biosciences, Pacific Edge, Seagen, Janssen, Veracyte; Consulting—ImmunityBio; Pacific Edge., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuroendocrine tumors of the lung display characteristic cytomorphologic features allowing direct diagnosis. The specificity of these features in distinguishing subtypes of neuroendocrine tumors, and their differences among types of cytologic specimen poses as interpretative potential pitfalls. This study reviewed and compared bronchial, effusion fluid and fine-needle aspiration cytology specimens of neuroendocrine tumors of the lung to address these issues. Histology-proven cytology specimens of neuroendocrine tumors were reviewed for cytomorphological parameters focusing on reported specific neuroendocrine nuclear and background features. Totally, 46 cases (26 bronchial, 11 effusion and 9 aspirate specimens), corresponding to 37 small cell carcinomas, 7 neuroendocrine carcinomas and 2 carcinoids were reviewed. Nuclear moulding (n = 35/37, 95 %), naked nuclei (n = 33/37, 89 %) and marked nuclear irregularity (n = 32/37, 86 %) were the three most common features of small cell carcinoma. The only specific feature for small cell carcinoma was the lack of prominent nucleoli (p = 0.004). For pulmonary carcinoids, in addition to the above features, other features associated with neuroendocrine carcinoma reviewed including crush artifact and necrotic material were absent. Compared to bronchial and aspiration cytology, crush artifact (p < 0.001) and necrotic material (p = 0.014) were absent on effusion fluid specimens and naked nuclei were less frequently seen (p = 0.022), while prominent nucleoli were more often observed (p = 0.005). Nuclear moulding, irregularity and naked nuclei are common but not unique features to small cell carcinomas. Effusion fluid specimens have "cleaner" backgrounds while displaying greater nuclear atypia. The type of cytologic preparation/specimen is an important factor which must be considered during diagnostic interpretation., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Small cell neuroendocrine cancers share biologic similarities across tissue types, including transient response to platinum-based chemotherapy with rapid progression of disease. We report a phase 1b study of pembrolizumab in combination with platinum-based chemotherapy in 15 patients with stage III-IV small cell bladder (cohort 1) or small cell/neuroendocrine prostate cancers (cohort 2). Overall response rate (ORR) is 43% with two-year overall survival (OS) rate of 86% (95% confidence interval [CI]: 0.63, 1.00) for cohort 1 and 57% (95% CI: 0.30, 1.00) for cohort 2. Treatment is tolerated well with grade 3 or higher adverse events occurring in 40% of patients with no deaths or treatment cessation secondary to toxicity. Single-cell and T cell receptor sequencing of serial peripheral blood samples reveals clonal expansion of diverse T cell repertoire correlating with progression-free survival. Our results demonstrate promising efficacy and safety of this treatment combination and support future investigation of this biomarker. This study was registered at ClinicalTrials.gov (NCT03582475)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Small-cell undifferentiated carcinoma (SmCC), as an aggressive malignancy, are most commonly arising in lung. Extrapulmonary SmCC is rare. It was reported that SmCC accounts for only 0.1% to 0.2% of colorectal cancers. Currently, no standard treatment regimen is recommended. Here, we presented a case of SmCC from rectum. The patient achieved pathological complete response (pCR) after surgery, which makes us feel gratified, and we are also eager to share this successful case with more peers to provide more references for clinical decision-making., Patient Concerns: A 32-year-old male patient presented himself to our outpatient clinic with defecation difficulty for more than 1 month in November 2021., Diagnoses: Colonoscopy revealed a rectal mass 4 cm from the anal margin. Pelvic magnetic resonance imaging revealed a mass in the rectal wall, consistent with the appearance of rectal carcinoma. Cancer cell was found after several biopsies and the immunohistochemistry indicated rectal SmCC., Interventions: Considering that the patient is very young and the malignancy of SmCC is very high, our treatment plan is also very cautious. Many literatures were also searched, but the literature on rectal SmCC is few and the prognosis is poor. Subsequently, we combined the treatment principles of rectal cancer and small cell lung cancer to develop an individualized treatment plan for patients. The patient received neoadjuvant chemoradiotherapy (nCRT) (short-course radiotherapy: 25 Gy/5 fractions, chemotherapy: etoposide + nedaplatin) combined with immune checkpoint inhibitors (ICIs) (tislelizumab). Then, the patient received laparoscopic radical transabdominal resection of rectal carcinoma with a temporary stoma on June 27, 2022., Outcomes: Postoperative pathology showed that there was chronic inflammation in the rectal mucosa without residual cancer, which meant that the patient achieved pCR after nCRT combined with ICIs. On August 15, 2024, the patient returned to our hospital for review, and no signs of recurrence and metastasis were found. By the time this article is submitted, the patient has survived for more than 35 months., Lessons: This is the first to be reported in a rectal SmCC patient who achieved pCR after nCRT combined with ICIs, which may provide supporting data for using this treatment option for rectal SmCC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Based on lineage-specific transcription factors, small-cell neuroendocrine carcinoma (SmCC) of the urinary bladder has recently been subtyped into three molecular subtypes: ASCL1, NEUROD1 and POU2F3. The latter is a master transcriptional regulator of tuft cells (TCs) which are rare solitary cells found in various mucosal epithelia such as the gastrointestinal tract, but which have not been reported in the bladder. The POU2F3 subtype shows low or absent neuroendocrine marker expression. A case of mixed SmCC and conventional-type urothelial carcinoma (CUC) of the urinary bladder with POU2F3-expressing intraepithelial small-cell carcinoma in keeping with a tuft cell phenotype, arising in association with intestinal metaplasia (IM) is described. The presence of POU2F3-expressing cells in normal urothelium, cystitis cystica glandularis and IM of the urinary bladder is demonstrated in separate cases of cystitis cystica glandularis with IM. Also, POU2F3 expression is identified in a subset of bladder SmCC., Competing Interests: Declarations Ethics statement The study was approved by the Royal Melbourne Hospital, Victoria, Australia (QA2019134). Consent to participate Retrospective study not interfering with diagnosis and patient management. Conflict of interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The purpose of this study was to analyze survival outcomes and pathologic response of patients with cT1N0 small-cell neuroendocrine carcinoma (SCNEC) of the bladder treated with neoadjuvant chemotherapy (neoCTX)., Materials and Methods: All cases of bladder SCNEC treated at our institution from January 1996 to July 2023 were identified. cT1N0 was defined as transurethral resection pathology showing lamina propria invasion with present and uninvolved muscularis propria. Pathologic downstaging and recurrences were evaluated. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox regression and Kaplan-Meier method., Results: A total of 30 patients with cT1N0 bladder SCNEC were included. Median follow-up was 88 months [95% confidence interval (CI) 44-131 months]. NeoCTX was given to 21 (70%) patients with a median of 4 cycles (range 1-6 cycles). A total of 27 (90%) patients received definitive local therapy. In cT1 bladder SCNEC, neoCTX was associated with decreased odds of pathologic upstaging [odds ratio = 0.07 (95% CI 0.01-0.45), P = 0.004], decreased odds of relapse [odds ratio = 0.12 (95% CI 0.02-0.65), P = 0.01], improved DFS [hazard ratio (HR) 0.30, 95% CI 0.09-0.96, P = 0.04], and improved OS (HR 0.32, 95% CI 0.10-1.02, P = 0.05). Compared with cT2N0 treated with neoCTX, cT1N0 treated with neoCTX had improved median DFS (HR 0.44, 95% CI 0.19-1.03, P = 0.05) and improved median OS (HR 0.52, 95% CI 0.22-1.24, P = 0.14)., Conclusions: NeoCTX had suggestive benefit in patients with cT1 bladder SCNEC with decreased odds of pathologic upstaging, metastatic relapse, and improved survival., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Head and neck small-cell carcinoma (HNSmCC) is a rare and aggressive cancer with a high tendency for distant metastasis. It is treated with multimodal treatment involving chemotherapy. Occasionally, surgery is performed for the management of locoregional HNSmCC. However, the benefits of surgery in this context have not yet been elucidated. Therefore, in this study, we aimed to investigate whether surgery could improve the survival of patients with HNSmCC., Patients and Methods: We obtained data from patients with locoregional HNSmCC treated with chemoradiation therapy (CRT) from the Surveillance, Epidemiology, and End Results database. Patients who did and did not undergo surgery were matched using propensity scores. The overall survival (OS) and disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios (HRs) were calculated using the Cox proportional hazard model., Results: The 5-year OS rates of the patients who did and did not undergo surgery were 57.2% and 50.6%, respectively (P = 0.689); the corresponding 5-year DSS rates were 61.0% and 57.5% (P = 0.769). The adjusted HRs for surgery were 0.85 (95% confidence interval [CI]: 0.54-1.33) for OS and 0.87 (95% CI: 0.51-1.49) for DSS., Conclusion: The addition of surgery to CRT did not improve the survival of patients with locoregional HNSmCC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hosokawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Small cell carcinoma of the bladder (SCCB) is a rare, highly malignant neuroendocrine tumor. This study attempted to analyze tumor characteristics, treatments and clinical outcomes in China. We conducted a retrospective analysis of patients diagnosed with non-metastatic SCCB at multi-institutions between January 2007 and January 2022. The Kaplan-Meier method was used to calculate survival. A total of 20 patients were included. 10 had localized disease (T1-2N0), and 10 had locally advanced disease (≥ T3 or N+). 13 received local treatment (partial cystectomy or transurethral resection of the bladder tumor) and 7 received radical treatment (radical cystectomy or radiotherapy). A total of 18 patients (90%) received chemotherapy (CT), either neoadjuvant CT (n = 5) or adjuvant CT (n = 13). The median OS for the receiving local treatment was 65.3 months (95% CI 0 to 138 months) and the corresponding 1-year, 2-year, and 3-year OS was 77%, 54%, and 54%, respectively. The median OS for the receiving radical treatment was not reached and the corresponding 1-year, 2-year, and 3-year OS was 100%, 100%, and 75%, respectively. The median PFS for receiving local treatment was 13.8 months (95% CI 9.3 to 18.3 months) and the corresponding 1-year, 2-year, and 3-year PFS was 46%, 31%, and 31%, respectively. The median PFS for the receiving radical treatment was not reached and the corresponding 1-year, 2-year, and 3-year PFS was 83%, 56%, and 56%, respectively. This study reported the largest cohort of non-metastatic SCCB among Chinese population. Given its metastatic potential, CT remained an essential part of the treatment. The survival outcomes of radical cystectomy and RT in non-metastatic SCCB were encouraging., (© 2024. The Author(s).)

Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and prometastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell NEC (LCNEC) assembled in tissue microarrays. Coexpression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence-free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified 5 distinct molecular subtypes in bladder SMC based on the expression of ASCL1, NEUROD1, and POU2F3: ASCL1+/NEUROD1- (n = 33; 34%), ASCL1- /NEUROD1+ (n = 21; 21%), ASCL1+/NEUROD1+ (n = 17; 17%), POU2F3+ (n = 22, 22%), and ASCL1- /NEUROD1- /POU2F3- (n = 5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (P < .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (P < .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1, and POU2F3. POU2F3-expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like) small cell pattern, frequently indistinguishable from small cell neuroendocrine carcinoma (SCNEC). However, the histogenesis of RMS and SCNEC and their inter-relationship have not been well studied and remained controversial. We herein analyzed 23 SCNEC and 3 small round cell RMS of the bladder for neuroendocrine (synaptophysin + chromogranin A) and myogenic (desmin + myogenin) marker expression and for TERT promoter mutations. In addition, the RMS cohort and one SCNEC that was revised to RMS were tested for gene fusions using targeted RNA sequencing (TruSight Illumina Panel which includes FOXO1 and most of RMS-related other genes). Overall, significant expression of myogenin and desmin was observed in one of 23 original SCNEC justifying a revised diagnosis to RMS. On the other hand, diffuse expression of synaptophysin was noted in 2 of the 4 RMS, but chromogranin A was not expressed in 3 RMS tested. TERT promoter mutations were detected in 15 of 22 (68%) SCNEC and in two of three (67%) assessable RMS cases, respectively. None of the four RMS cases had gene fusions. Our data highlights phenotypic and genetic overlap between SCNEC and RMS of the urinary bladder. High frequency of TERT promoter mutations in SCNEC is in line with their presumable urothelial origin. In addition, the presence of TERT promoter mutation in 2 of 3 RMS and lack of FOXO1 and other gene fusions in all 4 RMSs suggest a mucosal (urothelial) origin, probably representing extensive monomorphic rhabdomyoblastic transdifferentiation in SCNEC., (© 2024. The Author(s).)

Introduction: Lurbinectedin is FDA approved for treatment of metastatic small cell lung cancer (SCLC) following progression on or after platinum-based chemotherapy. Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) behaves like SCLC; however, no safety or efficacy data for lurbinectedin in SC/NEPC exists., Patients and Methods: All SC/NEPC patients treated with lurbinectedin across 4 academic oncology centers were identified. Baseline patient data and lurbinectedin outcomes including radiographic responses (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), progression free survival (PFS), overall survival (OS), and treatment-related adverse events (trAEs) were described. Clinical benefit rate (CBR) included CR, PR, or SD on imaging. Descriptive statistics were performed., Results: At first lurbinectedin dose, all 18 patients had metastatic disease. Median age was 63.5 (Range: 53-84), number of prior systemic therapies was 4 (Range: 2-7), and lurbinectedin cycles completed was 5 (Range: 1-10). ADT was administered during lurbinectedin treatment in 9/18 patients. CBR was 9/16 (56%). The most common trAEs were fatigue and anemia. Median OS and PFS were 6.01 (0.23-16.69) and 3.35 (0.16-7.79) months., Conclusions: Lurbinectedin showed modest but significant clinical benefit in some patients with SC/NEPC and demonstrated an acceptable toxicity profile with no hospitalizations from trAEs. SC/NEPC is an aggressive disease with a poor prognosis for which more treatment options are needed. Evidence for subsequent treatments after platinum-based chemotherapy is lacking. Lurbinectedin is an active treatment option for SC/NEPC; however, larger confirmatory studies are needed., Competing Interests: Disclosures Haley M Meyer. No Relationships to Disclose, Rajitha Sunkara, No Relationships to Disclose, Himisha Beltran, Consulting or Advisory Role - Amgen; AstraZeneca; Bayer; Blue Earth Diagnostics; Curie Therapeutics; Daicchi Sankyo; Foundation Medicine; Janssen Oncology; Loxo/Lilly; Merck; Novartis; Pfizer; Sanofi, Research Funding - Abbvie/Stemcentrx (Inst); Bristol Myers Squibb Foundation (Inst); Daiichi Sankyo (Inst); Janssen (Inst). Travel, Accommodations, Expenses - Janssen Oncology, Emily Rothmann, No Relationships to Disclose, Kevin Dale Courtney. Consulting or Advisory Role - Novartis, Research Funding - Amgen (Inst); Astellas Pharma (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Celgene/Bristol-Myers Squibb (Inst); Clovis Oncology (Inst); Exelixis (Inst); Harpoon therapeutics (Inst); Lilly (Inst); Myovant Sciences (Inst); Novartis (Inst); Pfizer (Inst); Stemline Therapeutics (Inst); Surface Oncology (Inst), Patents, Royalties, Other Intellectual Property - My spouse receives patent royalties from Athena Diagnostics, Inc. (I) Andrew J. Armstrong. Consulting or Advisory Role - Astellas Scientific and Medical Affairs Inc; AstraZeneca; Bayer; Bristol-Myers Squibb; Epic Sciences; Exelixis; GoodRx; Janssen; Merck; Myovant Sciences; Novartis; Pfizer; ZAlpha, Research Funding - Amgen (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Bayer (Inst); BeiGene (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Constellation Pharmaceuticals (Inst); FORMA Therapeutics (Inst); Gilead Sciences (Inst); Janssen Oncology (Inst); Merck (Inst); Novartis (Inst); Pfizer (Inst); Roche/Genentech (Inst), Patents, Royalties, Other Intellectual Property - Circulating tumor cell novel capture technology (Inst), Travel, Accommodations, Expenses - Astellas Scientific and Medical Affairs Inc, Alan Haruo Bryce, Honoraria - Advanced Accelerator Applications/Novartis; Astellas Pharma; Astellas Pharma; AstraZeneca; Bayer; Bayer; Bayer; Castle Biosciences; Horizon CME; Janssen; Janssen Oncology; Lilly; Myovant Sciences; Myovant Sciences; Novartis; Novartis; Pfizer; Pfizer; Pfizer; Research to Practice; Research to Practice; Verity Pharmaceuticals; Verity Pharmaceuticals, Consulting or Advisory Role - Astellas Pharma, Research Funding - Janssen Oncology (Inst). Travel, Accommodations, Expenses - Bayer; Clovis Oncology (Inst); Pfizer; Pfizer (Inst); Phosplatin Therapeutics (Inst), Andrea Lippucci, Andrea Lippucci is currently a Genitourinary Oncology medical science liaison for Johnson and Johnson. The content production and involvement with this research project and manuscript were completed prior to her employment with Johnson and Johnson. This publication in no way reflects the viewpoint of Johnson and Johnson nor is it an endorsement of a particular treatment approach. Melissa L. Stanton, Consulting or Advisory Role - PAREXEL, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Small cell carcinoma of the bladder (SCCB) is a rare malignant tumor of the bladder. This study aims to explore its clinicopathological features and prognostic factors and to explore the role of perioperative treatment methods., Methods: The clinical data of SCCB patients admitted to West China Hospital, Sichuan University over 8 years from January 2016 to January 2024 were collected. The clinicopathological features of SCCB were summarized. The survival outcomes and prognostic factors were analyzed. The effect of perioperative treatment on the improvement in prognosis was explored., Results: A total of 31 confirmed cases of SCCB were enrolled. We observed a number of clinicopathologic features. All cases had advanced clinical staging, with the T staging status being above T2 in all cases, and distant metastasis was found in 23% of the newly diagnosed cases. A high proportion of the SCCB cases were combined with other histologic types, with 96% showing combination with urothelial carcinoma (UC). The SCCB patients had a poor prognosis, presenting a median survival of 12 months, 1-year overall survival (OS) of 57.9%, and 3-year OS of 27.6%. Patients with extensive-stage SCCB had a significantly worse prognosis than those with limited-stage SCCB did (median OS time of 17.0 months vs. 4.4 months, P <0.05). In limited-stage SCCB, the median OS of patients who underwent radical cystectomy (RC) was 19.9 months, while that of the patients who did not undergo RC was 15.2 months ( P <0.05). The OS of patients who received perioperative therapy in combination with RC had longer OS than those who received only RC did ( P <0.05). Among these, patients recevied neoadjuvant therapy (NAT) had a significantly longer OS than patients who didn't receive NAT ( P <0.05). Subgroup analysis revealed that patients who were responsive to neoadjuvant therapy had longer disease-free survival and longer OS than those who were not responsive did ( P <0.05). Lymph node metastasis was an independent factor of poor prognosis (hazard ratio [HR]=15.21, 95% confidence interval [CI]: 1.732-133.912, P =0.014). NAT prior to RS was an independent protective factor, significantly reducing the risk of death compared with RC alone (HR=0.03, 95% CI: 0.001-0.724, P =0.031)., Conclusion: RC is an effective treatment that prolongs the survival of patients with limited-stage SCCB. RS combined with NAT can further improve their survival., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

A relatively healthy male patient in his 60s presented with chest pain and shortness of breath in addition to a history of significant weight loss over the preceding months. He was admitted to the hospital and investigated with a CT pulmonary angiogram, which did not demonstrate a pulmonary embolus, but he subsequently went on to have an ultrasound and CT scan because of abnormal findings. His CT demonstrated some thickening of the mid-transverse colon, and, in addition, large volume liver metastases described as innumerable and probably replacing most of the liver.Initially, his liver function tests were only mildly deranged at the presentation. Flexible sigmoidoscopy was performed, and a transverse colonic malignancy was identified and biopsied, which demonstrated an extrapulmonary small cell carcinoma (EPSCC). He was admitted for urgent chemotherapy for newly diagnosed metastatic small-cell colonic cancer; he developed tumour lysis syndrome following his first dose of chemotherapy. He continued to decline following this and died soon after his admission. Metastatic small-cell colonic cancer is a rare diagnosis which is challenging to manage due to the lack of trial evidence to drive treatment strategies. The management largely follows the pulmonary small cell cancer pathway. We, therefore, present a colonic EPSCC case outlining the diagnostic and treatment strategies for this disease., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Small cell neuroendocrine carcinoma (NEC) of the cervix is a rare gynecological malignancy, constituting 2%-5% of all such cases. As high-risk Human Papilloma Virus (HR-HPV) infections contribute to 85% of these tumors, small cell NEC poses a significant risk for solid organ transplant recipients, increasing their risk of progressive disease. We present a case of an uterine cervix small cell NEC with metastasis to the bladder and pleural cavities in a 53-year-old woman with a past medical history of kidney transplantation, who presented with abnormal uterine bleeding. The initial liquid preparation (ThinPrep) cytology stained with Papanicolaou (Pap) showed an adenocarcinoma not otherwise specified. At the time of diagnosis, the patient had diffusely metastatic disease. A subsequent uterine cervix biopsy was consistent with a small cell NEC. Despite treatment with chemotherapy, the patient's condition deteriorated, evidenced by a worsening right-sided pleural effusion one-month postdiagnosis. A pleural effusion showed a tumor with glandular features, with immunohistochemistry suggestive of metastatic adenocarcinoma. HR HPV E6/E7 RNA in situ hybridization (ISH) was positive. Bladder washing showed cytopathologic findings consistent with bladder involvement by small cell carcinoma. The patient's lesions in both urine and pleural fluids showed distinct cytomorphology. Within a year of diagnosis, the patient was declared deceased. This case highlights the existence of carcinoma admixed with NEC tumor, such as an HPV associated adenocarcinoma admixed with a NEC and underscores the elevated risk of HPV-related genital lesions in renal transplant patients. In patients with a history of solid organ transplant or other immunosuppressive conditions, there is an increased necessity for enhanced surveillance and appropriate cancer screening., (© 2024 Wiley Periodicals LLC.)

Objective: This study aimed to evaluate the efficacy of CT and MRI findings to differentiate small cell neuroendocrine carcinoma (SCNEC) from urothelial carcinoma (UC) of the urinary bladder., Materials and Methods: This study included 90 patients with histopathologically confirmed bladder cancer (10 SCNECs and 80 UCs). Eight patients with bladder SCNEC and 80 with UC underwent CT and MRI, whereas the remaining two patients with SCNEC underwent CT alone before treatment. CT and MRI findings were retrospectively evaluated and compared between the two pathologies., Results: The maximum diameter (36.5 mm vs. 19.0 mm, p < 0.01) and height (22.0 mm vs. 14.0 mm, p < 0.01) of the tumor in bladder SCNEC were higher than in UC. The pedunculated configuration (20% vs. 61%, p < 0.05) and irregular tumor margins (20% vs. 76%, p < 0.01) in bladder SCNEC were less common than in UC. The CT attenuation of the solid component in unenhanced CT images was higher in bladder SCNEC than in UC (37 Hounsfield unit [HU] vs. 34 HU, p < 0.01). The apparent diffusion coefficient (ADC) of the solid component in bladder SCNEC was lower than in UC (0.49 × 10 -3 mm 2 /s vs. 1.02 × 10 -3 mm 2 /s, p < 0.01)., Conclusion: In comparison with UC, bladder SCNEC was larger, had higher unenhanced CT attenuation, and had a lower ADC value. The pedunculated configuration and irregular tumor margins were typical of bladder UC., (© 2024. The Author(s).)

Background: There is currently scarcity of information on small cell neuroendocrine carcinoma of the nasopharynx (SCNEC-nasopharynx). It is believed that this type of cancer is not associated with Epstein-Barr virus (EBV) infection and is indistinguishable from classic SCNEC occurring in other organs., Materials and Methods: Herein we provided 3 cases of nasopharyngeal mass in our hospital, two males and one female. On admission, these patients were considered nasopharyngeal carcinoma with lymph node metastasis, and one of them had liver metastasis. The nasopharyngeal mucosal tissues were biopsied for pathological examination including immunohistochemistry and in situ hybridization. PubMed database was searched for articles about SCNEC-nasopharynx published up to April 2024 in any language., Result: The 3 cases had similar histological features of SCNEC in other organs but differed in rich- tumor-infiltrating lymphocytes (TILs). All of them stained for pancytokeratin (panCK) and epidermal growth factor receptor (EGFR). Case 1 and Case 2 diffusely expressed insulinoma-associated protein 1(INSM-1) and synaptophysin (Syn), Case 3 strongly stained for CD56 and Syn. Immunostaining of all 3 cases for p40, p63, TTF-1, CK20, S-100 and NUT showed negative. BRG-1, INI-1 and Rb were retained. And p53 all showed wild-type expression. The Ki-67 labeling indiced of case 1, 2, and 3 were 80%, 90%, and 80%, respectively. In situ hybridization showed strong and uniform nuclear positivity of EBV-encoded small RNAs (EBER) in the neoplastic cells of 3 cases., Conclusion: EBV-positive SCNEC-nasopharynx was exactly rare. The origin of this tumor is still controversial. It may originate from EBV-infected mucosal epithelium like nasopharyngeal carcinoma. Based on our cases and relevant literature, we found EBV-positive SCNEC-nasopharynx as a probably site-specific subtype of SCNEC with differing pathogenetic mechanism. The subtype not only virus positivity but also that it was associated with TILs and did not show p53 or Rb alterations by immunohistochemistry. It may be more responsive to treatment and have a better prognosis than classic SCNEC. We will continue to follow-up these patients and collect additional cases to further understand the unique biology of this rare solid tumor., (© 2024. The Author(s).)

Objective: This study aimed to comprehensively analyze the clinical characteristics and treatment status of Chinese small cell carcinoma of the ovary hypercalcemic type (SCCOHT) patients, providing insights into this unique population and comparing findings with international literature., Methods: Through a meta-analysis, we collected data from published case reports and records from the Obstetrics & Gynecology Hospital of Fudan University. Demographic information, clinical presentations, tumor attributes, treatment modalities, and survival outcomes were extracted and examined alongside relevant global studies., Results: The analysis encompassed 80 Chinese SCCOHT patients, of which 62 from 33 previously reported literatures, and the other 18 were from Obstetrics & Gynecology Hospital of Fudan University. In 62 cases with stage information, A total of 25 tumors were International Federation of Gynecology and Obstetrics stage I, 3 were stage II, 19 were stage III, and 15 were stage IV. Most patients received surgery and chemotherapy, but regimens were varied. Median follow-up was 10 months (range=4-120). Elevated carbohydrate antigen 125 and serum calcium levels were consistent findings. Recurrence rates were notable, especially among stage I patients. Platinum-based chemotherapy, paclitaxel and carboplatin (n=11, 13.4%), constituted common treatment regimens., Conclusion: This study observed demographic and clinical similarities with international datasets. And the findings emphasize the urgency for innovative therapeutic approaches to improve outcomes in SCCOHT patients. Continued research efforts are essential to enhance the knowledge surrounding this rare malignancy and to optimize its clinical management., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Small cell cervical carcinoma (SCCC) is the most common neuroendocrine tumor in the female genital tract, with an unfavorable prognosis and lacking an evidence-based therapeutic approach. Until now, the distinct subtypes and immune characteristics of SCCC combined with genome and transcriptome have not been described. We performed genomic (n = 18), HPV integration (n = 18), and transcriptomic sequencing (n = 19) of SCCC samples. We assessed differences in immune characteristics between SCCC and conventional cervical cancer, and other small cell neuroendocrine carcinomas, through bioinformatics analysis and immunohistochemical assays. We stratified SCCC patients through non-negative matrix factorization and described the characteristics of these distinct types. We further validated it using multiplex immunofluorescence (n = 77) and investigated its clinical prognostic effect. We confirmed a high frequency of PIK3CA and TP53 alterations and HPV18 integrations in SCCC. SCCC and other small cell carcinoma had similar expression signatures and immune cell infiltration patterns. Comparing patients with SCCC to those with conventional cervical cancer, the former presented immune excluded or 'desert' infiltration. The number of CD8+ cells in the invasion margin of SCCC patients predicted favorable clinical outcomes. We identified three transcriptome subtypes: an inflamed phenotype with high-level expression of genes related to the MHC-II complex (CD74) and IFN-α/β (SCCC-I), and two neuroendocrine subtypes with high-level expression of ASCL1 or NEUROD1, respectively. Combined with multiple technologies, we found that the neuroendocrine groups had more TP53 mutations and SCCC-I had more PIK3CA mutations. Multiplex immunofluorescence validated these subtypes and SCCC-I was an independent prognostic factor of overall survival. These results provide insights into SCCC tumor heterogeneity and potential therapies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8 + T cell in SCCE for the first time., Materials and Methods: Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density., Results: No patients had PD-L1 expressed in their tumor cells. PD-L1 + expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68 + monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression ( Ptrend <0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS., Conclusion: Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Neuroendocrine carcinoma arising from the urachus is extremely rare. We describe a case of a 33-year-old gentleman who presented with hematuria and diagnosed to have a composite adenocarcinoma and small cell neuroendocrine carcinoma arising from the urachus. The patient also had widespread metastasis at the time of presentation, therefore, he was referred for chemotherapy. However, the disease showed progression despite treatment. Recognition of neuroendocrine carcinoma component in urachal tumors, although rare, is very essential as this histologic type carries poor prognosis with aggressive clinical outcome., (© 2024. The Author(s).)

Small-cell neuroendocrine carcinomas (SCNECs) of the female genital tract are rare and aggressive tumors that are characterized by a high rate of recurrence and poor prognosis. They can arise from various sites within the female genital tract, including the cervix, endometrium, ovary, fallopian tube, vagina, and vulva. They are composed of cells with neuroendocrine features, such as the ability to produce and secrete hormones and peptides, and a high mitotic rate. Immunohistochemical staining for neuroendocrine markers, such as chromogranin A, synaptophysin, and CD56, can aid in the diagnosis of these tumors. This article provides an overview of the epidemiology, etiology, and risk factors associated with these tumors, as well as their clinical presentation, cellular characteristics, diagnosis, and finally the current treatment options for SCNECs, including surgery, chemotherapy, and radiation therapy, alone or in combination., (© 2024 British Society for Neuroendocrinology.)

Small cell/neuroendocrine bladder cancers (SCBCs) are rare and highly aggressive tumors that are associated with poor clinical outcomes. We discovered that lineage-specific transcription factors (ASCL1, NEUROD1, and POU2F3) defined three SCBC molecular subtypes that resemble well-characterized subtypes in small cell lung cancer. The subtypes expressed various levels of neuroendocrine (NE) markers and distinct downstream transcriptional targets. Specifically, the ASCL1 and NEUROD1 subtypes had high NE marker expression and were enriched with different downstream regulators of the NE phenotype (FOXA2 and HES6, respectively). ASCL1 was also associated with the expression of delta-like ligands that control oncogenic Notch signaling. POU2F3, a master regulator of the NE low subtype, targeted TRPM5, SOX9, and CHAT. We also observed an inverse association between NE marker expression and immune signatures associated with sensitivity to immune checkpoint blockade, and the ASCL1 subtype had distinct targets for clinically available antibody-drug conjugates. These findings provide new insight into molecular heterogeneity in SCBCs with implications for the development of new treatment regimens. PATIENT SUMMARY: We investigated the levels of different proteins in a specific type of bladder cancer (small cell/neuroendocrine; SCBC). We could identify three distinct subtypes of SCBC with similarity to small cell/neuroendocrine cancers in other tissues. The results may help in identifying new treatment approaches for this type of bladder cancer., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: None declared.

POU class 2 homeobox 3 (POU2F3)-positive small cell bladder carcinoma (SCBC) is an extremely rare entity, and its clinicopathologic features have not been fully described. Here, we investigated the clinicopathologic features of 4 cases of POU2F3-positive small cell bladder carcinoma (SCBC) and reviewed the literature. We collected 12 cases of SCBC from our departmental archives and detected the expression of POU2F3 by immunohistochemical (IHC) staining. Selected cases with or without POU2F3 expression were subjected to gene expression analysis between two different groups using DESeq2 software. We identified 4 POU2F3-positive SCBC patients, 2 males and 2 females, with a mean age of 77 years. Three patients had hematuria, and 1 patient had dysuria. Radiologic findings showed a bladder mass. Pathologic diagnosis showed that 3 cases were pure SCBC and 1 was mixed urothelial cancer (UC). Histopathologically, four POU2F3-positive SCBC tumors were composed of small round cells with sparse cytoplasm, the nuclei were salt-and-pepper-like or finely granular. Tumor cells showed characteristic cytoplasmic staining with punctate positive signals for cytokeratin. Syn and CD56 were diffusely positive in all the 4 patients. CgA was positive in only one patient. POU2F3-positive SCBC showed higher expression levels of POU2F3, HMGA2 and PLCG2 genes by RNA-Seq. Our data showed the specific clinicopathologic features of 4 rare POU2F3-positive SCBC cases, and the distinct molecular feature was observed between POU2F3-positive and negative SCBC in the limited number of cases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Pulmonary large-cell neuroendocrine carcinoma (LCNEC), a disease with poor prognosis, is classified as pulmonary high-grade neuroendocrine carcinoma, along with small-cell lung cancer. However, given its infrequent occurrence, only a limited number of preclinical models have been established. Here, we established three LCNEC tumoroids for long-term culture. Whole-exome sequencing revealed that these tumoroids inherited genetic mutations from their parental tumors; two were classified as small-cell carcinoma (S-LCNEC) and one as non-small cell carcinoma (N-LCNEC). Xenografts from these tumoroids in immunodeficient mice mimicked the pathology of the parent LCNEC, and one reproduced the mixed-tissue types of combined LCNEC with a component of adenocarcinoma. Drug sensitivity tests using these LCNEC tumoroids enabled the evaluation of therapeutic agent efficacy. Based on translational research, we found that a CDK4/6 inhibitor might be effective for N-LCNEC and that Aurora A kinase inhibitors might be suitable for S-LCNEC or LCNEC with MYC amplification. These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. T. Yamatsuji reports grants from MSD, Chugai Pharmaceutical, Japan; Takeda Pharmaceutical, Japan; Daiichi-Sankyo, Japan; Kaken Pharmaceutical, Japan; Astellas Pharma, Japan; Eli Lilly Japan, Japan; Shionogi, Japan; Taiho Pharmaceutical, Japan; Bayer Yakuhin, Japan; and Otsuka Pharmaceutical Co., Ltd. Japan and personal fees from Yakult Honsha, Japan outside the submitted work. N. Takigawa reports grants and personal fees from Eli Lilly Japan, Japan; AstraZeneca, United Kingdom; Daiichi-Sankyo, Japan; Chugai Pharmaceutical, Japan; Taiho Pharmaceutical, Japan; Pfizer Inc., United States; Boehringer-Ingelheim Japan, Japan and Ono Pharmaceutical, Japan; grants from Kyowa Hakko Kirin, Japan; Nippon Kayaku, Japan and Takeda Pharmaceutical, Japan and personal fees from MSD and Bristol-Myers Squibb Company, United States outside the submitted work. No disclosures have been reported by the other authors., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Small cell carcinoma (SCC) in the nasal cavity and sinuses is extremely rare. The clinical data of 15 patients with primary SCC in nasal cavity and sinuses were analyzed retrospectively. All patients were treated with surgery, radiotherapy, and chemotherapy. Of the 15 patients, 2 patients are alive for more than 6 years, and 5 patients died after the median follow-up period (11 months). Most of our patients represent the later stage (73% presented at stage III or IV) and had surgery combined with radiotherapy and chemotherapy; however, nearly half of patients have tumor recurrence and/or distant metastasis. SCC of nasal cavity and sinuses often invades surrounding tissues, and the long-term curative rate is generally low. Early diagnosis and comprehensive treatment are key to improve survival. Although the overall survival time of SCC is not optimistic, it is still recommended that patients take comprehensive treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Small cell carcinoma of the genitourinary tract (GU SCC) is a rare disease with a poor prognosis. There are only limited treatment options due to insufficient understanding of the disease. In this study, we analyzed the clinical outcomes of patients with GU SCC and their association with the tumor immune phenotype., Materials and Methods: Patients diagnosed with GU SCC were included. Survival outcomes according to the primary location (prostate and non-prostate) and stages (limited disease [LD] and extensive disease [ED]) were analyzed. We performed multiplex immunohistochemistry (IHC) in non-prostate SCC patients and analyzed the immune cell population., Results: A total of 77 patients were included in this study. Their median age was 71 years, 67 patients (87.0%) were male, and 48 patients (62.3%) had non-prostate SCC. All patients with ED (n=31, 40.3%) received etoposide plus platinum (EP) as initial treatment and median overall survival (OS) was 9.7 months (95% confidence interval [CI], 7.1 to 18.6). Patients with LD (n=46, 59.7%) received EP followed by radiotherapy or surgery, and 24-months OS rate was 63.6% (95% CI, 49.9 to 81.0). The multiplex IHC analysis of 21 patients with non-prostate SCC showed that patients with a higher density of programmed death-ligand 1-expressing CD68+CD206+ M2-like macrophages had significantly worse OS outcomes with an adjusted hazards ratio of 4.17 (95% CI, 1.25 to 14.29; adjusted p=0.02)., Conclusion: Patients with GU SCC had a poor prognosis, even those with localized disease. The tumor immune phenotypes were significantly associated with survival. This finding provides new insights for treating GU SCC.

Background: Esophageal cancer is quite prevalent worldwide and usually carries a poor prognosis. Histologically, although squamous cell carcinoma and adenocarcinoma predominate, small cell carcinoma (SmCC) cases have been reported. Overall, there is a paucity of literature regarding this variant. In this article, we aim to highlight this uncommon entity of carcinoma esophagus and share our experience of SmCC patients seen over a decade at our institute., Method: Records of patients with SmCC histology from 2010 to 2020 were assessed. Patients' demographic characteristics, clinical characteristics, treatment received, and outcomes were taken into consideration. Results were analyzed statistically using SPSS version 22., Results: Fourteen patients (nine males and five females) with a median age of 57 years (range: 35 - 72 years) were analyzed. The majority of the patients 10/14 (71.4%) received palliative radiotherapy of either 30Gy/10 fractions or 35Gy/15 fractions. Only 1/14 (7.14%) patients received neoadjuvant chemotherapy and concurrent chemoradiation (CCRT). Overall, partial response was noted in all 11 patients (78.6%) who received treatment. The average median survival was 5 months (range: 1-11 months)., Conclusion: Although the small sample size of the study prevents us from drawing a firm conclusion, we propose national and international collaborative prospective studies for framing definitive oncologic management strategies for this rare histological variant of esophageal cancer., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

We report a case of small cell carcinoma of the urethra with inguinal lymph node metastases. A 50- year-old female patient presented with gross hematuria. Cystoscopy and computed tomography (CT) revealed a tumor surrounding the urethra and an inguinal lymphadenopathy. Biopsy of the urethral tumor demonstrated small cell carcinoma. Four courses of chemotherapy with etoposide and cisplatin, followed by 66 Gy of irradiation achieved complete remission. Unfortunately, 14 months later, positroemission-CT scan revealed recurrence of inguinal lymph node metastases. Although seven courses of chemotherapy with nogitecan were carried out, a new metastatic bone tumor developed. Amrubicin was administered as a third-line treatment, but was canceled after one course because of side effects. The patient died at 39 months after diagnosis. Small cell carcinoma of urethra with metastases has extremely poor prognosis, as is demonstrated by this case.

Context.—: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal tumor, characterized by hypercalcemia and early onset and associated with germline and somatic SMARCA4 variants., Objective.—: To identify all known cases of SCCOHT in the Slovenian population from 1991 to 2021 and present genetic testing results, histopathologic findings, and clinical data for these patients. We also estimate the incidence of SCCOHT., Design.—: We conducted a retrospective analysis of hospital medical records and data from the Slovenian Cancer Registry in order to identify cases of SCCOHT and obtain relevant clinical data. Histopathologic review of tumor samples with assessment of immunohistochemical staining for SMARCA4/BRG1 was undertaken to confirm the diagnosis of SCCOHT. Germline and somatic genetic analyses were performed using targeted next-generation sequencing., Results.—: Between 1991 and 2021, we identified 7 cases of SCCOHT in a population of 2 million. Genetic causes were determined in all cases. Two novel germline loss-of-function variants in SMARCA4 LRG&#95;878t1:c.1423&#95;1429delTACCTCA p.(Tyr475Ilefs*24) and LRG&#95;878t1:c.3216-1G>T were identified. At diagnosis, patients were ages 21 to 41 and had International Federation of Gynecology and Obstetrics, or FIGO, stage IA-III disease. Outcomes were poor, with 6 of 7 patients dying of disease-related complications within 27 months from diagnosis. One patient had stable disease for 12 months while receiving immunotherapy., Conclusions.—: We present genetic, histopathologic, and clinical characteristics for all cases of SCCOHT identified in the Slovenian population during a 30-year period. We report 2 novel germline SMARCA4 variants, possibly associated with high penetrance. We estimate the minimal incidence of SCCOHT to be 0.12 per 1 million per year., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Background: Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1-0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small cell lung cancer (SCLC), justified by analogous histological and clinical features., Aims: We conducted a retrospective cohort study comparing the outcomes of extensive-stage (ES) SCLC and EPSCC., Methods: Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and overall response rates (ORRs)., Results: Three hundred and eighty-four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5-1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58-1.46, P = 0.74) and ORR were 73% versus 68%., Conclusions: EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitro and in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state., Competing Interests: Disclosure Statement J.K., K.O., and M.I. are members of the Department of Clinical Bio-resource Research and Development at Kyoto University, which is sponsored by KBBM, Inc. H.U. is an employee of KBBM, Inc., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)