To evaluate the prognostic factors and survival outcomes of patients with surgically treated high-grade neuroendocrine carcinoma of the cervix (NECC).

This multicenter, retrospective study involved 98 cervical cancer patients with stage IA2-IIA2 and IIIC1/2p high-grade NECC. We divided the patients into two groups based on histology: the pure and mixed groups. All clinicopathologic variables were retrospectively evaluated. Cox regression and Kaplan-Meier methods were used for analysis.

In our study, 60 patients were in the pure group and 38 patients were in the mixed group. Cox multivariate analysis showed that mixed histology was a protective factor impacting overall survival (OS) (P = 0.026) and progression free survival (PFS) (P = 0.018) in surgically treated high-grade NECC. Conversely, survival outcomes were negatively impacted by ovarian preservation (OS: HR, 20.84; 95% CI: 5.02-86.57, P < 0.001), age >45 years (OS: HR, 4.50; 95% CI: 1.0-18.83, P = 0.039), tumor size >4 cm (OS: HR, 6.23; 95% CI: 2.34-16.61, P < 0.001), parity >3 (OS: HR, 4.50; 95% CI: 1.02-19.91, P = 0.048), and perineural invasion (OS: HR, 5.21; 95% CI: 1.20-22.53, P = 0.027). Kaplan-Meier survival curves revealed notable differences in histologic type (OS: P = 0.045; PFS: P = 0.024), chemotherapy (OS: P = 0.0056; PFS: P = 0.0041), ovarian preservation (OS: P = 0.00031; PFS: P = 0.0023), uterine invasion (OS: P < 0.0001; PFS: P < 0.0001), and depth of stromal invasion (OS: P = 0.043; PFS: P = 0.022).

Patients with mixed histologic types who undergo surgery for high-grade NECC have a better prognosis. Meanwhile, ovarian preservation, tumor size >4 cm, parity >3, age >45 years and perineural invasion were poor prognostic predictors. Therefore, patients with high-risk factors should be considered in clinical practice.

Bladder neuroendocrine tumors are few and exhibit a high degree of aggressiveness. The bladder is characterized by four distinct forms of neuroendocrine tumors. Among them, large-cell neuroendocrine carcinoma is the least prevalent, but has the highest level of aggressiveness. The 5-year survival rate for large-cell neuroendocrine carcinoma of the bladder is exceedingly poor. To date, only a few dozen cases have been reported.

Here, we report the case of a 65-year-old man with large-cell neuroendocrine carcinoma of the bladder. The patient presented to the Department of Urology at our hospital due to the presence of painless hematuria without any identifiable etiology. During hospitalization, abdominal computed tomography revealed the presence of an irregular mass on the right anterior wall of the bladder. A cystoscopic non-radical resection of the bladder lesion was performed. The postoperative pathological examination revealed large-cell neuroendocrine bladder cancer. Previous reports on cases of large-cell neuroendocrine carcinoma cases were retrieved from PubMed, and the present paper discusses the currently recognized best diagnostic and treatment options for large-cell neuroendocrine carcinoma based on the latest research progress.

Large-cell neuroendocrine carcinoma of the bladder is an uncommon malignancy with a highly unfavorable prognosis. Despite ongoing efforts to prolong patient survival through multidisciplinary therapy, the prognosis remains unfavorable. Large-cell neuroendocrine carcinoma continues to be a subject of uncertainty.

Neuroendocrine tumors of the bladder are rare, accounting for less than 1% of all bladder tumors. Among these, large cell neuroendocrine carcinoma is an extremely uncommon subtype. We report on a histologically confirmed case of mixed both large and small cells neuroendocrine tumor of the bladder in a 64-year-old male with a history of bilharzial cystitis. The diagnosis was made after radical cystectomy with Immunohistochemical staining revealing positivity for synaptophysin, CD56, and AE1/3. While bilharzia is commonly linked to squamous cell carcinoma in the bladder, the potential relationship with neuroendocrine tumors is still relatively unexplored in this context. This case marks the first reported instance of the atypical coexistence of bilharzial cystitis and mixed large and small cell neuroendocrine carcinoma of the bladder. This unique case of coexisting highlights a rare phenomenon warranting further study. Similar associations have been documented in other organs, emphasizing the importance of exploring underlying mechanisms and clinical implications for improved patient care and outcomes.

To improve the understanding, diagnosis and treatment of bladder large cell neuroendocrine carcinoma (LCNEC).

A clinical case of bladder LCNEC admitted to our hospital was reported. The epidemiology, prognosis, diagnosis and treatment methods of large cell neuroendocrine carcinoma were reviewed. The diagnosis and treatment status and prognosis were discussed based on the literature.

The female patient was admitted to hospital for "more than 4 years after TURBT and intermittent hematuria for more than 2 years". She was diagnosed as recurrent bladder cancer and underwent "radical cystotomy + hysterectomy". The postoperative pathological findings were high-grade urothelial carcinoma of the bladder neck and large cell neuroendocrine carcinoma of the bladder. The patient recovered well after surgery, but refused radiotherapy and chemotherapy and is still under close follow-up.

Bladder LCNEC is clinically rare, has unique pathological features, is more aggressive than traditional urothelial carcinoma, and has a poor prognosis. Surgery, chemotherapy and radiotherapy should be combined with multi-mode treatment.

Large cell neuroendocrine carcinoma (LCNEC) is one of the rarest types of bladder cancer, with an aggressive course and a poor prognosis. We report a case of LCNEC of the bladder associated with a prostatic adenocarcinoma. A very rare association, to our knowledge, is described for the first time in the literature. The patient was a 76-year-old non-smoker male, who presented with intermittent hematuria and dysuria. Cystoscopy revealed a lesion on the right lateral bladder wall. Biopsy was in favor of a LCNEC with muscle invasion. The CT scan showed the presence of a second lesion in the prostate, confirmed by histological examination. The patient was treated by neoadjuvant chemotherapy of the cisplatin-etoposide type for large-cell bladder neuroendocrine carcinoma, and hormone therapy with luteinizing hormone-releasing hormone (LH-RH) analogs for prostatic adenocarcinoma, followed by radical surgery. Given the rarity of this tumor, LCNEC treatment lacks precision. Many cases are published with different therapeutic strategies. A literature review would be interesting to codify the therapeutic strategy for this rare tumor.

Large cell neuroendocrine carcinoma (LCNEC) of the bladder is a rare non-urothelial tumor of the bladder. The treatment of LCNEC of the bladder is different from that of urothelial carcinoma (UC); therefore, early and accurate diagnosis is particularly important. As LCNEC of the bladder is rare and its clinical symptoms and radiographic features are similar to those of urothelial tumors, the clinical diagnosis of the disease remains challenging.

We report a 72-year-old female patient who presented with gross hematuria for 3 mo. A solitary tumor located in the anterior wall of the bladder was found by cystoscopy. Pathological examination after biopsy suggested UC of the bladder in the absence of immunohistochemical assessment. The patient underwent partial cystectomy and was finally diagnosed with LCNEC (pT2bN0M0) based on the results of postoperative immunohistochemical examination. During the 10-mo follow-up, no signs of tumor recurrence or metastasis were found.

Immunohistochemical examination is essential for diagnosing LCNEC of the bladder. Accurate diagnosis and multidisciplinary treatment in the early stage of the disease are crucial for improving the prognosis.

Primary bladder large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive neoplasm with high recurrence rates and poor prognosis. Traditional management has heavily relied on radical cystectomy, which, despite its aggressiveness, often results in unsatisfactory outcomes. Emerging evidence suggests the potential for less invasive, bladder-sparing approaches, yet detailed reports and long-term outcomes remain scarce. We report a groundbreaking case of a 59-year-old male diagnosed with primary bladder LCNEC, managed through a pioneering bladder-sparing multimodal treatment. This novel strategy included transurethral resection followed by a tailored chemoradiation protocol, resulting in exceptional disease control and preservation of bladder function over a 20-month follow-up period, without evidence of recurrence. This case underscores the viability of bladder conservation strategies as a legitimate alternative to radical cystectomy for managing LCNEC, presenting a beacon of hope for patients wishing to preserve bladder functionality. It prompts a reevaluation of traditional treatment paradigms and advocates for further research into multimodal, organ-sparing approaches for this challenging malignancy.

Cases of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the urinary system are rare, and reports of primary MiNENs in the ureter are lacking. Herein, we present the case of a 71-year-old man who presented with painless gross hematuria and weight loss. Contrast-enhanced abdominal computed tomography (CT) revealed a tumor, comprising small cell neuroendocrine carcinoma (SCNEC) and adenocarcinomatous components, attached to the ureter. The SCNEC components were strongly positive for synaptophysin, CD56 and INSM1 and adenocarcinomatous components were strongly positive for CDX2 and cytokeratin 20, respectively. Four weeks post-surgery, the patient received four cycles of cisplatin-based chemotherapy; the 7-month follow-up CT confirmed that he was healthy without disease recurrence. The occurrence of MiNEN in the ureter with SCNEC and adenocarcinomatous components is extremely rare, wherein histopathological and immunohistochemical features aid in the diagnosis MiNEN. With its aggressive nature, MiNEN can only be effectively treated by early diagnosis and radical surgery.

The most common neuroendocrine tumor in the urinary bladder is small cell carcinoma, which can be pure or mixed with components of urothelial or other histologic subtypes. Large cell neuroendocrine carcinoma of the bladder is rare and remains ill-defined but is increasingly recognized. Well-differentiated neuroendocrine tumor and paraganglioma can arise in the bladder but are very rare in this location. Recent advances in molecular characterization allowed for better classification and may offer improved stratification of these tumors.

The large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder is a rare malignancy. With its high aggressiveness and poor prognosis, the disease is often accompanied by metastasis or recurrence. The lack of specific clinical manifestations and imaging features causes considerable challenges for clinical diagnosis and treatment.

We report a case of LCNEC of the urinary bladder. The patient was a 79-year-old male admitted to our hospital with recurrent episodes of asymptomatic gross hematuria. Based on the computed tomography (CT) scan findings, our patient presented with a bladder mass displaying invasion into the serosal layer, suggestive of muscle involvement and indicative of malignancy. The patient received a radical cystectomy, and the postoperative pathology confirmed primary, pure LCNEC of the urinary bladder. We gave him 16 cycles of toripalimab immunotherapy. As of follow-up, the patient was alive, and periodic CT reexamination showed no evidence of recurrence.

We reviewed domestic and foreign literature and found no explicit treatment protocols exist for the disease. Surgical resection combined with chemotherapy were the most common treatments. Herein, we reported the first case of primary, pure LCNEC of the urinary bladder treated by radical cystectomy combined with pure immunotherapy, achieving sustained remission, which provides a new idea for the immunotherapy and integrative treatment of the disease.

Primary urinary neuroendocrine neoplasms (U-NENs) are extremely rare thus optimal treatment is unknown. Grading and treatment are typically extrapolated from other primary sites. Since 2010, the clinical landscape for NENs has changed substantially. We performed a retrospective review of U-NENs to assess treatment patterns and oncologic outcomes of patients treated in the recent era of NEN therapy.

A multicenter retrospective review of patients diagnosed after 2005 and alive after 2010. Time to treatment failure (TTF) was used to evaluate progression and toxicity for systemic therapy. Tumors were categorized as having either well-differentiated neuroendocrine tumor (WDNET) or poorly differentiated neuroendocrine carcinoma (PDNEC) histology.

A total of 134 patients from 6 centers were included in our analysis, including 94 (70%) bladder, 32 (24%) kidney, 2 (1.5%) urethra and 4 other urinary primaries (3.0%). Poorly-differentiated neuroendocrine carcinoma was more common in bladder (92%) than non-bladder tumors (8%). Median Ki-67 available in bladder primary was 90% (n = 24), kidney 10% (n = 23), ureter 95% (n = 1), urethra 54% (n = 2), and others 90% (n = 3). Patients received a median of 2 therapies (range 0-10). Median time to death was not reached in locoregional WDNETs versus 8.2 years (95% CI, 3.5-noncalculable) in metastatic WDNETs (predominantly renal primary). Median time to death was 3.6 years (95% CI, 2.2-9.2) in locoregional PDNECs versus 1 year (95% CI, 0.8-1.3) in metastatic PDNECs (predominantly bladder primary).

This is the most extensive series examining treatment patterns in patients with U-NENs in the recent era of NEN therapy. The apparent inferior survival for bladder NENs is likely due to the preponderance of PDNECs in this group. As predicted, treatments for U-NENs mirrored that of other more common NENs. In our retrospective cohort, we observed that patients with WD-UNETs treated with peptide receptor radionuclide therapy (PRRT) and everolimus suggested potential activity for disease control in WD-UNETs. Prospective studies are needed to assess the activity of new oncology drugs in UNENs.

Extrapulmonary neuroendocrine carcinomas (EP-NECs) are associated with a poor clinical outcome, and limited information is available on the biology and treatment of EP-NECs. We studied EP-NECs by applying the recent novel findings from studies of pulmonary neuroendocrine carcinomas, including POU2F3, the master regulator of tuft cell variant of small cell lung carcinomas. A cohort of 190 patients with surgically resected EP-NECs or poorly differentiated carcinomas (PDCs) were established. Immunohistochemistry (IHC) for POU2F3 along with ASCL1, NEUROD1, YAP1, and conventional neuroendocrine markers was performed on tissue microarrays. Selected cases with or without POU2F3 expression were subjected to targeted gene expression profiling using nCounter PanCancer Pathway panel. POU2F3-positive tuft cell carcinomas were present in 12.6% of EP-NEC/PDCs, with variable proportions according to organ systems. POU2F3 expression was negatively correlated with the expression levels of ASCL1, NEUROD1, and conventional neuroendocrine markers ( P <0.001), enabling IHC-based molecular classification into ASCL1-dominant, NEUROD1-dominant, POU2F3-dominant, YAP1-dominant, and not otherwise specified subtypes. Compared wih POU2F3-negative cases, POU2F3-positive tuft cell carcinomas showed markedly higher expression levels of PLCG2 and BCL2 , which was also validated in the entire cohort by IHC. In addition to POU2F3, YAP1-positive tumors were a distinct subtype among EP-NEC/PDCs, characterized by unique T-cell inflamed microenvironment. We found rare extrapulmonary POU2F3-positive tumors arising from previously unappreciated cells of origin. Our data show novel molecular pathologic features of EP-NEC/PDCs including potential therapeutic vulnerabilities, thereby emphasizing the need for focusing on unique features of EP-NEC/PDCs.

Immunohistochemistry is widely used in diagnostic and scientific analysis of urothelial carcinoma. Objective interpretation of staining results is mandatory for accuracy and comparability in diagnostic and therapeutic patient care as well as research.Herein we summarize and explain standardized microscopic evaluation and scoring approaches for immunohistochemical stainings. We focus on commonly used and generally feasible approaches for different cellular compartments and comment on their utility in diagnostics and research practice.

High-grade neuroendocrine carcinoma (HGNEC) is subclassified into small cell carcinoma (SmCC) and large cell neuroendocrine carcinoma (LCNEC). Although both are clinically aggressive, the SmCC and LCNEC need to have different treatment strategies, and accurate pathologic diagnosis is challenging. We studied a large retrospective cohort (186 cases) of HGNEC of bladder and lung to investigate the abundance of cytokeratin (CK) 7 expression and staining pattern in SmCC and LCNEC. Overall, the pulmonary and urinary HGNEC exhibited several different CK7 staining patterns, including negative staining (n=28), dot-like staining (n=73), partial membranous staining (n=26), and complete membranous staining (n=60). Overall, 88.9% (44/49) of pulmonary SmCC and 88.0% (44/50) of urinary SmCC showed negative or dot-like patterns for CK7, while 90.8% (59/65) of pulmonary LCNEC and 72.7% (16/22) of urinary LCNEC showed partial or complete membranous patterns for CK7 (χ 2 =105.05, P <0.0001). The distinct staining patterns were also present in those mixed SmCC and LCNEC. In addition, the specimen types or fixation did not affect CK7 staining patterns. In conclusion, CK7 has a high differential value for SmCC and LCNEC and could help guide personalized treatment for patients.

This study sought to reveal the clinicopathologic characteristics of large cell neuroendocrine carcinoma (LCNEC) of the skin/conjunctiva. The retrieved patients included 3 men and 3 women with a median age of 85 (63-95) years. All lesions occurred on the face, including the ears, with a median tumor size of 11.5 (7-65) mm. Lymph node metastasis was observed in 5 (83%) of 6 cases, and distant metastasis was noted in 2 (33%). One patient (17%) who had a 13-mm-sized tumor died of the tumor 13 months after excision. All tumors were mainly located in the dermis, and one of them also exhibited intraepithelial spreading. The cytology resembled that of an LCNEC in other organs. No adnexal differentiation was observed. Five cases were of the pure type, but one had a component of squamous cell carcinoma. Immunoreactivities for CAM5.2, CK7, CK19, BerEP4, epithelial membrane antigen, neuron-specific enolase, synaptophysin, c-KIT, GATA3, and bcl-2 were frequently present, but CK20, neurofilament, Merkel cell polyomavirus large T antigen, mammaglobin, estrogen receptor, HER2, and TTF1 were completely negative in all cases. Mutant-pattern immunostaining of p53, PTEN, and Rb was frequently observed. The Ki67 rate exceeded 70% in all cases. LCNEC of the skin/conjunctiva is a morphologically-defined group of primary cutaneous/conjunctival neuroendocrine neoplasm, although it may be heterogeneous similar to other-site LCNEC or Merkel cell carcinoma. This study highlighted the predominant location for the face, high metastatic and lethal potential, possible combination with other tumor components, and frequent mutant-type immunoexpressions of p53, PTEN, and Rb in this tumor group.