Urachal mixed adenocarcinoma and small cell neuroendocrine carcinoma with widespread metastasis and resistance to chemotherapy: a case report.

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.

Small cell neuroendocrine carcinoma and poorly differentiated rhabdomyosarcomas of the urinary bladder in adults-A comparative analysis in favor of a common histogenesis.

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.

Advancements in the Understanding of Small-Cell Neuroendocrine Cervical Cancer: Where We Stand and What Lies Ahead.

Small-cell neuroendocrine cervical carcinoma (SCNCC) is a rare yet aggressive gynecological malignancy associated with dismal clinical outcomes. Its rarity has led to a limited number of retrospective studies and an absence of prospective research, posing significant challenges for evidence-based treatment approaches. As a result, most gynecologic oncology centers have limited experience with this tumor, emphasizing the urgent need for a comprehensive review and summary. This article systematically reviews the pathogenesis, immunohistochemical and molecular characteristics, prognostic factors, and clinical management of gynecologic SCNCC. We specifically focused on reviewing the distinct genomic characteristics of SCNCC identified via next-generation sequencing technologies, including loss of heterozygosity (LOH), somatic mutations, structural variations (SVs), and microRNA alterations. The identification of these actionable genomic events offers promise for discovering new molecular targets for drug development and enhancing therapeutic outcomes. Additionally, we delve deeper into key clinical challenges, such as determining the optimal treatment modality between chemoradiation and surgery for International Federation of Gynecology and Obstetrics (FIGO) stage I phase patients within a precision stratification framework, as well as the role of targeted therapy within the homologous recombination (HR) pathway, immune checkpoint inhibitors (ICIs), and prophylactic cranial irradiation (PCI) in the management of SCNCC. Finally, we anticipate the utilization of multiple SCNCC models, including cancer tissue-originated spheroid (CTOS) lines and patient-derived xenografts (PDXs), to decipher driver events and develop individualized therapeutic strategies for clinical application.

Synchronous small cell neuroendocrine carcinoma of the cervix and immature ovarian teratoma: A case report and literature review.

The onset of two synchronous primary malignancies of the female genital tract is uncommon; therefore, the simultaneous occurrence of cervical small cell neuroendocrine carcinoma and ovarian immature teratoma is rare. The present study describes the case of a woman with cervical small cell neuroendocrine carcinoma complicated by ovarian immature teratoma. The clinical manifestations, and the histopathological and immunophenotypic features of the patient are recorded. Furthermore, all PubMed-indexed cases of synchronous primary malignancies in both the cervix and ovary have been briefly summarized.

Advances in combined neuroendocrine carcinoma of lung cancer.

Lung cancer incidence and mortality rates are increasing worldwide, posing a significant public health challenge and an immense burden to affected families. Lung cancer encompasses distinct subtypes, namely, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). In clinical investigations, researchers have observed that neuroendocrine tumors can be classified into four types: typical carcinoid, atypical carcinoid, small-cell carcinoma, and large-cell neuroendocrine carcinoma based on their unique features. However, there exist combined forms of neuroendocrine cancer. This study focuses specifically on combined pulmonary carcinomas with a neuroendocrine component. In this comprehensive review article, the authors provide an overview of combined lung cancers and present two pathological images to visually depict these distinctive subtypes.

Synchronous Double Primary Tumors of Liver (Small Cell Neuroendocrine Carcinoma and Hepatocellular carcinoma): A Case Report.

This study presents a case of dual primary liver cancer involving small cell neuroendocrine carcinoma and hepatocellular carcinoma. The 58-year-old Chinese male patient, who has a medical history of viral hepatitis B, presented with right upper abdominal pain persisting for one month. Imaging studies indicated the presence of multiple liver masses in segments V and VII-VIII, as well as a mass in the left lung. Subsequent hepatic biopsy performed on both segments confirmed the presence of hepatocellular carcinoma in segment V and small cell neuroendocrine carcinoma in segment VII-VIII. After undergoing one cycle of chemotherapy, the lung mass exhibited a reduction in size, while the liver masses showed an inadequate response. Subsequently, the patient underwent Transcatheter Arterial Chemoembolization (TACE) and Hepatic Artery Infusion Chemotherapy (HIAC), resulting in partial remission (PR). However, the patient was diagnosed with brain metastasis and subsequently treated with Sorafenib and Tirelizumab, a Programmed Death 1 (PD-1) immune checkpoint inhibitor. The efficacy evaluation indicated stability, and no severe adverse effects were observed at the time of writing. The patient's survival time was 16 months.

Gastric Small Cell Neuroendocrine Carcinoma With Loss of Epithelial Markers Expression.

Background/Aim: Given that gastric small cell neuroendocrine carcinoma (SCNEC) is notably more aggressive than conventional adenocarcinoma, and a platinum-based regimen aligned with the treatment for pulmonary SCNEC is advocated when chemotherapy is needed, ensuring an accurate pathological diagnosis is paramount. Case Report: A 63-year-old man, examined for melena, underwent gastroscopy which revealed a total circumferential Borrmann type 3 lesion extending from the pylorus to the antrum of the stomach. He underwent a distal gastrectomy with D2 lymphadenectomy. The microscopic examination revealed SCNEC with a minor adenocarcinoma component. Immunohistochemically, the SCNEC was diffusely positive for synaptophysin, CD56, and INSM1, very focally positive for chromogranin A, and negative for leukocyte common antigen, CD3, and CD20. A significant observation in this case was the complete negativity for epithelial markers including keratin (CK7, CK8, CK20, CAM5.2, and AE1/AE3) and epithelial membrane antigen. Conclusion: Diffuse positivity for neuroendocrine markers, negativity for other lineage markers, and a transition from the adenocarcinoma component, if present, serve as significant diagnostic clues for gastric SCNEC with loss of epithelial markers expression. SCNEC should not be excluded solely based on the negative result for epithelial markers.

A comparative analysis of clinicopathological features of HPV-associated and HPV-independent cervical carcinomas based on P16 INK4a immunohistochemistry: A one-year retrospective study.

The recent WHO classification of female genital tracts recommends cervical carcinomas to be further subtyped as HPV-associated and HPV-independent and accepted p16 immunoreactivity as a surrogate biomarker for HPV testing. This paper presents the clinicopathological spectrum of cervical carcinomas in correlation with p16 immunoreactivity. Aims and Objectives: This study aims to evaluate the immunoreactivity of p16 in cervical carcinoma, subtype them into HPV-associated and HPV-independent based on p16 immunoreactivity, and correlate them with clinicopathological features. Design: A hospital-based retrospective study of one-year duration was done after ethics approval. A total of 124 cases were identified, and various parameters like the presence of mitosis, lymphovascular invasion, tumor budding, tumor-infiltrating lymphocytes, the pattern of stromal invasion, and the pattern of necrosis were recorded and graded. Immunohistochemistry (IHC) with p16 marker was done in 40 cases, and immunoreactivity was correlated with clinical and histopathological parameters. Statistical Analysis: Multivariate analysis was done with Fisher's exact test, and a P value of <0.05 was considered significant. Results: P16 was positive in 36 out of 40 cases which included 35 cases of squamous cell carcinoma (SCC) (keratinizing-14 out of 35 SCC, 11 positive out of these 14, non-keratinizing-21 out of 35 SCC, 20 positive, out of these 21), two cases of adenocarcinoma (both positive), two cases of adenosquamous carcinoma (both positive), and one case of small cell neuroendocrine carcinoma (positive). p16 negative in four cases (10%) (keratinizing type-3, non-keratinizing-1). P value was significant for HPV-independent carcinoma and keratinizing SCC morphology. The P value was not significant when p16 positivity with other parameters. Conclusion: HPV-associated were 90%, HPV-independent were 10%.

Whole exome sequencing identifies common mutational landscape of cervix and endometrium small cell neuroendocrine carcinoma.

Background: Primary small cell neuroendocrine carcinomas of the cervix and endometrium are rare gynecological malignancies with limited treatment options. This study aimed to improve the understanding of the carcinogenesis process and identify potential therapeutic targets for these two tumor types by constructing the mutational landscape at the whole exome level. Methods: Primary tumor tissues and their matched blood samples were obtained from 10 patients with small cell cervical neuroendocrine carcinoma (NECC) and five patients with small cell endometrial neuroendocrine carcinoma (NECE). Whole exome sequencing was performed to construct the somatic mutation profiles. Mutational signature and recurrent mutated gene analysis were used to identify tumor subtypes and common carcinogenesis processes. Results: Based on the burden of different mutational signatures, the NECCs in this work can be divided into two subtypes, including the mismatch repair deficiency like (dMMR-like) type (4/10) and the high spontaneous deamination type (6/10). Components of the PI3K/AKT signaling and RAS signaling were exclusively mutated in these two subtypes, respectively. The integration of human papillomavirus made a limited contribution to tumorigenesis in NECC (20%). The dysfunction of the mismatch repair system and microsatellite instability are the major features of NECE. PI3K/AKT, JAK/STAT signaling, and chromatin remodeling activity were the common mutated pathways in NECE. PIK3CA, WNK2, and KMT2B underwent mutations in both the dMMR-like subtype of NECC (50% - 75%) and in NECE (60% - 80%) specimens, while exhibiting infrequent mutational occurrences in publicly available data pertaining to neuroendocrine carcinomas of the lung or bladder (< 10%). Conclusion: We identified the two subtypes of NECC with distinct mutated pathways and potential therapy targets. The dMMR-like type NECC and NECE may share a similar carcinogenesis process that include dysfunction of PI3K/AKT signaling, cell cycle, antiapoptotic processes, and chromatin remodeling activity.

Advances in Research, Diagnosis, and Treatment of Neuroendocrine Cervical Carcinoma: A Review.

Neuroendocrine neoplasms (NENs) were classified separately in the 5th edition (2020) of the World Health Organization (WHO) classification of female genital malignancies. Cervical neuroendocrine carcinoma (NEC) is distinguished by its low incidence, high invasiveness, early local dissemination, and distant metastases. The purpose of this review is to outline the achievements in pathology, diagnostics, gene sequencing, and multi-modality treatment of cervical NEC.

An Unusual Presentation of Occult Small-Cell Neuroendocrine Carcinoma as Acalculous Cholecystitis With Widespread Liver Metastasis.

Small-cell neuroendocrine carcinoma, often classified as small-cell lung carcinoma (SCLC) type, is an aggressive neuroendocrine tumor with early metastatic potential that can lead to unexpected patient presentations. We report the case of a 69-year-old man who presented to the emergency department with worsening right upper abdominal pain, nausea, and vomiting for the past several days. The clinical picture and the workup, including the complete metabolic panel and complete blood count, were highly suggestive of acute cholecystitis with transaminitis and direct hyperbilirubinemia. The ultrasound and magnetic resonance cholangiopancreatography of the abdomen revealed a diffusely hyperdense and hypertrophic liver without evidence of choledocholithiasis. After initial resuscitation, the patient underwent laparoscopic cholecystectomy. Intraoperative findings were consistent with diffuse miliary liver metastatic disease of unknown etiology, rigid liver parenchyma, an extremely frail gallbladder wall, and mild ascites. A biopsy of the liver and cholecystectomy were performed. The final pathology revealed metastatic SCLC to the liver and widespread intravascular tumor emboli, causing diffuse ischemia of the entire gallbladder wall. The patient's postoperative course was marked by the development of foudroyant liver insufficiency and worsening severe type B lactic acidosis.

Surgical Treatment for Metastatic Brain Tumor in the Cerebellar Hemisphere from Small-cell Neuroendocrine Carcinoma of the Urinary Bladder: A Case Report and Review of the Literature.

We performed surgical treatment for cerebellar metastasis of relatively rare small-cell neuroendocrine carcinoma (SCNC) of the urinary bladder. On preoperative imaging, the lesion was solitary, and the edema around the tumor was unremarkable; thus, other differential diagnoses besides a metastatic brain tumor were also considered preoperatively. Intraoperatively, the tumor was soft, and the circumference brain and boundary were indistinct and easily hemorrhagic. The tumor was grossly totally removed, and postoperative radiotherapy was added. The clinical symptoms of the patient were relieved, and he was discharged on foot. Thus far, relatively few reports have described surgical treatment of brain metastases of SCNC of the urinary bladder. We herein report a case of metastatic brain tumor due to SCNC of the urinary bladder that required surgical treatment, along with a review of the previous literature regarding its clinical features and the characteristics of intracranial lesions related to surgery, such as imaging and intraoperative findings.

Equivalent Survival between Gastric Large-Cell Neuroendocrine Carcinoma and Gastric Small-Cell Neuroendocrine Carcinoma.

BACKGROUND: According to the 2019 World Health Organization (WHO) classification of gastric neuroendocrine neoplasms, gastric neuroendocrine carcinoma (GNEC) can be further divided into gastric large-cell neuroendocrine carcinoma (GLNEC) and gastric small-cell neuroendocrine carcinoma (GSNEC). Whether the prognoses of the two types have a discrepancy has long been disputed. METHOD: We collected patients diagnosed with GLNEC or GSNEC in the National Cancer Center of China between January 2000 and December 2020. The characteristics and survival outcomes were compared between the two groups. We further verified our conclusion using the SEER dataset. RESULTS: A total of 114 GNEC patients, including 82 patients with GLNEC and 32 patients with GSNEC, have completed treatment in our hospital. Clinicopathologic differences were not observed between patients with GSNEC and GLNEC concerning the sex, age, body mass index, Charlson Comorbidity Index, tumor location, tumor size, stage, treatment received, the expression of neuroendocrine markers (CD56, Chromogranin A, synaptophysin), and score on the Ki-67 index. The 1-year, 3-year, and 5-year overall survival rates of GLNEC and GSNEC were 89.0%, 60.5%, and 52.4%, and 93.8%, 56.3%, and 52.7%, which showed no statistically significant differences. This result was confirmed further by using the SEER dataset after the inverse probability of treatment weighting. CONCLUSIONS: Although with different cell morphology, the comparison of prognosis between the GLNEC and GSNEC has no significant statistical difference.

Small Cell Neuroendocrine Carcinoma of the Vagina: A Rare Presentation.

Primary small cell neuroendocrine carcinoma of the vagina is a very rare disease. We present a case study of a 52-year-old female who presented to the hospital with complaints of urinary dribbling, burning micturition, pain, and per vaginal bleeding for three to four months. A firm globular mass of approximately 5-6 cm was felt in the anterior vaginal wall per speculum examination. Diagnosis of small cell neuroendocrine carcinoma was made with tissue biopsy and immunohistochemistry. Diagnostic imaging (MRI, positron emission tomography (PET)-CT) plays a vital role in reaching the diagnosis and understanding the treatment response. The patient received six cycles of chemotherapy with cisplatin and etoposide and radiotherapy, achieving a complete response, with complete regression of the lesion. The patient had no sign of tumor recurrence and locoregional or distant metastases after six months of follow-up. Nowadays, there is no need for surgery in the treatment of vaginal small cell neuroendocrine carcinoma, rather radiotherapy and chemotherapy are the treatment of choice. We report a case of neuroendocrine cancer of the vagina treated at our institution.

PD-L1 expression and prognosis in definitive radiotherapy patients with neuroendocrine cervical carcinoma.

Background: Neuroendocrine carcinoma of the cervix (NECC) is more prone to lymphatic infiltration, lymph node involvement, local recurrence, and distant metastasis. Using concurrent chemoradiotherapy (CCRT) with or without adjuvant chemotherapy as the standard treatment for locally advanced NECCs and CCRT for patients with early lesions confined to the cervix. However, the prognosis of NECC patients treated with definitive radiotherapy (RT) is unknown. Immune checkpoint inhibitors are a promising therapeutic strategy for locally advanced cervical cancer. Some reports suggest that the expression of PD-L1 in solid tumors correlates with prognosis. Aim: This study investigates prognostic factors for survival in patients with neuroendocrine cervical carcinoma (NECC) treated with definitive RT and the relationship between PD-L1 expression and prognosis in these patients. Methods: This retrospective study included 66 patients with histologically confirmed NECC who received RT with or without chemotherapy. From January 2015 to December 2020, patients received routine extended-field irradiation (EFI), and PD-L1 expression was assessed by immunohistochemistry. The most commonly used chemotherapy agents were etoposide-platinum and paclitaxel-platinum. Results: PD-L1 expression was positive in 17 of 45 (37.8%) patients. There were 52 cases of pure NECC and 14 cases of mixed carcinoma. Sixty stage IB-III patients received definitive RT. The 3- and 5-year progression-free survival (PFS) was 39.8% and 34.1%, and 3- and 5-year overall survival (OS) was 48.0% and 40.2%, respectively. There was no significant difference in 3 and 5-year PFS and 3 and 5-year OS between patients with pure and mixed carcinoma. Positive PD-L1 expression was associated with higher 3-year PFS in patients with mixed histology. Univariate analysis showed that lymph node metastasis (LNM) and the International Federation of Gynecology and Obstetrics stages predicted 3- and 5-year PFS in patients who received definitive RT. The median OS in patients receiving less than four cycles and at least four cycles of chemotherapy (CT) was 26.0 and 44.0 months, respectively (P = 0.038); moreover, 3- and 5-year PFS was 34.1% and 25.7% in the former and 46.4% and 40.4% in the latter. There were no significant differences in OS and PFS between pelvic irradiation and prophylactic EFI in patients treated with definitive RT. There were no significant differences in para-aortic failure rate after concurrent chemoradiotherapy between patients who underwent pelvic irradiation or prophylactic EFI (P = 0.147). Conclusion: In patients with mixed NECC, positive PD-L1 expression is correlated with higher 3-year PFS. Chemoradiotherapy was effective for NECCs. The LNM and stage predicted PFS. Four or more cycles of chemotherapy improve prognosis. Prophylactic EFI did not significantly improve PFS and OS. Relevance for Patients: This study is relevant to patients as it confirms that chemoradiotherapy is effective for both early and locally advanced NECC and that four or more cycles of chemotherapy improved prognosis. The regimen should be carefully evaluated to ensure that patients receive the most effective radiation therapy for the prophylactic of para-aortic LNM. Potential risk factors for the recurrence of radical radiotherapy should be fully understood to minimize these risks. This study observed that PD-L1 expression positive in patients with mixed NECC types is correlated with higher 3-year PFS.

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

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

Small cell neuroendocrine carcinoma of the cervix: From molecular basis to therapeutic advances.

Small cell neuroendocrine carcinoma of the cervix (SCNECC) is an uncommon but aggressive uterine malignancy, the cause of which is generally associated with human papillomavirus (HPV) infection. A lack of clinical trials and evidence-based treatment guidelines poses therapeutic challenges to this rare tumor. At present, published data remain limited to case series and case reports. While clinical management has traditionally followed those of small cell neuroendocrine (SCNE) lung cancer relying on surgery, chemoradiation, and systemic chemotherapy, the prognosis remains dismal. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies that target programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1), atezolizumab and durvalumab have proven effective in extensive-stage SCNE lung cancer. Moreover, pembrolizumab has also proven beneficial effects when added onto chemotherapy in metastatic and recurrent HPV-associated non-SCNE cervical cancer. It holds promise to use ICIs in combination with chemoradiation to improve the clinical outcomes of patients with SCNECC. Future advances in our understanding of SCNECC biology - associated with the study of its genomic and molecular aberrations as well as knowledge from SCNE of lung and other extrapulmonary sites- would be helpful in discovering new molecular targets for drug development. Collaborative efforts and establishment of a SCNECC-specific biobank will be essential to achieve this goal.