Small Cell Neuroendocrine Carcinoma Research Articles

POU2F3-expressing intraepithelial small-cell carcinoma with mixed small-cell carcinoma and conventional-type urothelial carcinoma of the urinary bladder.

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.

CT and MRI findings of small cell neuroendocrine carcinoma of the urinary bladder: comparison with urothelial carcinoma.

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. 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. The maximum diameter (36.5mm vs. 19.0mm, p < 0.01) and height (22.0mm vs. 14.0mm, 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 mm2/s vs. 1.02 × 10-3 mm2/s, p < 0.01). 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.

Pregnancy complicated by small cell neuroendocrine carcinoma of the cervix

Small cell neuroendocrine carcinoma of the cervix (SCNCC) is considered to be an extremely rare, highly invasive and aggressive subtype of squamous cell carcinoma. It is particulary rare during pregnancy. Here we report a case in which a 32-year-old patient who was admitted to our Department at 27 completed weeks of gestation with intermittent vaginal spotting and a large amount of malodorous vaginal discharge. Gynecological examination revealed a 2 cm exophytic polypoid tumor coming out of the cervix. On rectal examination there was no clinically evident parametrial invasion. Biopsy of the cervix was performed and the diagnosis of small cell neuroendocrine carcinoma was established. We reviewed and discussed the features, diagnosis, treatment and prognosis of SCNCC diagnosed during pregnancy.

Abstract 5969: VRK1 can be a therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix

Abstract Objective: Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is extremely rare but highly aggressive and its prognosis is usually poor. Vaccinia-related kinase (VRK)1 is a serine/threonine protein kinase that is involved in cell proliferation by regulating cell-cycle progression and inducing cell-cycle arrest in response to stress signals. VRK2 belongs to the same family as VRK1, and they are paralogs. VRK1 has been reported as a potential therapeutic target in nervous system tumors with low VRK2 expression. Previously, we identified high expression of VRK1 in SCNEC through proteomic analysis of isolated organoids. The objective of the present study is to investigate the effect of VRK1 on the proliferation of SCNEC and its potential as a therapeutic target. Methods: The mRNA and protein expression of VRK1 and VRK2 in ten organoids and two cell lines derived from SCNEC were examined and compared with cervical cancer of other histological subtypes by RNA microarray and western blot analysis. The effect of VRK1 on tumor growth in vitro and in vivo (xenograft model) were evaluated by shRNA-mediated knockdown of VRK1 (shVRK1). RNA-seq was performed from the xenograft tumors. The effects of shVRK1 on cell proliferation were evaluated under various levels of oxidative stress induced by H2O2. Results: VRK1 expression was higher in organoids and cell lines derived from SCNEC than those derived from squamous cell carcinoma and adenocarcinoma, while VRK2 expression was lower in SCNEC. Tumor growth was suppressed significantly by shVRK1 in vivo (mean weight: cell line 1: 0.62 vs 0.06g, p&amp;lt;0.05, 2: 1.79 vs 0.58g, p&amp;lt;0.01). Gene ontology analysis of RNA-seq data suggested that VRK1 is related to cellular responses to stress. Proliferation was slightly suppressed by shVRK1 under normal conditions; however, it was significantly enhanced under oxidative stress (Cell line 1: in shVRK1, -14.0% without oxidative stress vs -54.9% under H2O2 750μM, p&amp;lt;0.01, Cell line 2: similar to Cell line 1). Conclusion: SCNEC exhibited high VRK1 and low VRK2 expression, and the tumor suppressive effect of shVRK1 was more significant in vivo than in vitro. VRK1 may play a role in the tumor microenvironment, including oxidative stress, and is a potential therapeutic target for SCNEC. Citation Format: Mariya Kobayashi, Satoshi Nakagawa, Mizuki Kanda, Yuji Kamei, Masuda Tatsuo, Mamoru Kakuda, Kosuke Hiramatsu, Toshihiro Kimura, Yutaka Ueda, Takayuki Enomoto, Masahiro Inoue, Tadashi Kimura. VRK1 can be a therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5969.

Single-Cell Transcriptome Analysis of Small Cell Neuroendocrine Carcinoma of the Endometrium Reveals ISL1 as a Potential Biomarker for Diagnosis and Treatment.

As a dedifferentiated tumor, small cell endometrial neuroendocrine tumors (NETs) are rare and frequently diagnosed at an advanced stage with a poor prognosis. Current treatment recommendations are often extrapolated from histologically similar tumors in other sites or based on retrospective studies. The exploration for diagnostic and therapeutic markers in small cell NETs is of great significance. In this study, we conducted single-cell RNA sequencing on a specimen obtained from a patient diagnosed with small cell endometrial neuroendocrine carcinoma (SCNEC) based on pathology. We revealed the cell map and intratumoral heterogeneity of the cancer cells through data analysis. Further, we validated the function of ISL LIM Homeobox 1 (ISL1) in vitro in an established neuroendocrine cell line. Finally, we examined the association between ISL1 and tumor staging in small cell lung cancer (SCLC) patient samples. We observed the significant upregulation of ISL1 expression in tumor cells that showed high expression of the neuroepithelial markers. Additionally, in vitro cell function experiments demonstrated that the high ISL1 expression group exhibited markedly higher cell proliferation and migration abilities compared to the low expression group. Finally, we showed that the expression level of ISL1 was correlated with SCLC stages. ISL1 protein in NETs shows promise as a potential biomarker for diagnosis and treatment.

Prognostic factors and treatment impact on overall survival in patients with renal neuroendocrine tumour

AbstractBackgroundRenal neuroendocrine neoplasms (R‐NEN) are exceptionally rare tumours characterized by high mortality rates.ObjectiveThe objective of this study is to analyse prognostic factors and treatment impact on overall survival in patients with R‐NEN.Design, setting and participantsWe identified all patients with R‐NEN in the National Cancer Database (NCDB) from 2004 to 2019 and identified prognostic factors for improved survival.Results and limitationsOf 542 R‐NEN cases, 166 (31%) were neuroendocrine tumour grade 1 (NET‐G1), 14 (3%) were neuroendocrine tumour grade 2 (NET‐G2), 169 (31%) were neuroendocrine carcinoma (NEC‐NOS), 18 (3%) were large cell neuroendocrine carcinoma (LC‐NEC) and 175 (32%) were small cell neuroendocrine carcinoma (SC‐NEC). Median overall survival for all patients in the study was 44.88 months (SE, 4.265; 95% CI, 27.57–62.19). Median overall survival was 7.89 months (SE 0.67; 95% CI, 6.58–9.20) for patients without surgical intervention and 136.61 months (SE 16.44; 95% CI, 104.38–168.84, p &lt; 0.001) for patients who underwent surgery. Increased age (HR, 1.05; 95% CI, 1.03–1.06; p &lt; 0.001), T4 stage disease (HR, 3.17; 95% CI, 1.96–5.1; p &lt; 0.001), NEC‐NOS histology (HR, 2.82; 95% CI, 1.64–4.86; p &lt; 0.001), LC‐NEC histology (HR, 2.73; 95% CI, 1.04–7.17; p = 0.041) and SC‐NEC histology (HR, 5.17; 95% CI, 2.95–9.05; p &lt; 0.001) were all positive predictors of worsening overall survival. The main limitation of the study is its retrospective design.ConclusionR‐NEN is an aggressive tumour characterized by high mortality rates. Surgery continues to be the mainstay of treatment and has shown to provide a survival benefit for most patients.Patient SummaryR‐NEN is composed of several tumour histologies that differ based on their aggressiveness with NEC‐NOS and SC‐NEC being the most lethal. Surgery, predominantly through minimally invasive approaches, is the mainstay of treatment and has a clear survival benefit.

The Effect of HMGB1 and HMGB2 on Transcriptional Regulation Differs in Neuroendocrine and Adenocarcinoma Models of Prostate Cancer.

Human high-mobility group-B (HMGB) proteins regulate gene expression in prostate cancer (PCa), a leading cause of oncological death in men. Their role in aggressive PCa cancers, which do not respond to hormonal treatment, was analyzed. The effects of HMGB1 and HMGB2 silencing upon the expression of genes previously related to PCa were studied in the PCa cell line PC-3 (selected as a small cell neuroendocrine carcinoma, SCNC, PCa model not responding to hormonal treatment). A total of 72% of genes analyzed, using pre-designed primer panels, were affected. HMGB1 behaved mostly as a repressor, but HMGB2 as an activator. Changes in SERPINE1, CDK1, ZWINT, and FN1 expression were validated using qRT-PCR after HMGB1 silencing or overexpression in PC-3 and LNCaP (selected as an adenocarcinoma model of PCa responding to hormonal treatment) cell lines. Similarly, the regulatory role of HMGB2 upon SERPINE1, ZWINT, FN1, IGFPB3, and TYMS expression was validated, finding differences between cell lines. The correlation between the expression of HMGB1, HMGB2, and their targets was analyzed in PCa patient samples and also in PCa subgroups, classified as neuroendocrine positive or negative, in public databases. These results allow a better understanding of the role of HMGB proteins in PCa and contribute to find specific biomarkers for aggressive PCa.

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

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. 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. 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.

Clinical efficacy of lurbinectedin in metastatic neuroendocrine carcinomas of the genitourinary tract: Multi-institutional real-world experience.

601 Background: Neuroendocrine carcinomas (NEC) of the genitourinary (GU) tract, including small cell (SC) NEC and large cell (LC) NEC, are rare aggressive malignancies. Although highly sensitive to cisplatin-based chemotherapy, GU metastatic NEC (mNEC) have limited data to support next therapies. Lurbinectedin, a marine-derived alkylating drug and a selective inhibitor of oncogenic transcription and DNA repair pathways, is FDA-approved for small cell lung cancer (SCLC) after progression on frontline platinum-based therapy, with a disease control rate (DCR) of 68.6%. It is unknown whether DCR is similar in SCLC and GU mNEC. Methods: We report the first multi-institutional series (n=14) of lurbinectedin in GU mNEC. Imaging-based best overall responses (BOR) were noted as complete (CR), partial (PR), stable (SD), progressive (PD) or non-evaluable (NE). DCR includes CR, PR, and SD. We use the Kaplan-Meier method for overall survival (OS) and progression-free survival (PFS) from lurbinectedin start date. We define duration of response (DoR) from response date to progression or last contact date for patients (pts) with CR or PR. Results: Most pts had a median age at metastasis of 70.5 years (ICR: 64-74.5) [Table]. Primary locations were bladder (7/14, 50%), prostate (5/14, 35.7%) and ureter (2/14, 12.3%). Histology at diagnosis mostly consisted of mixed or pure SCNEC, with one exception of LCNEC. Most pts had visceral disease, prior immunotherapy and at least 2 prior lines of therapy for mNEC before lurbinectedin (8/14, 57.1%). DCR was 6/14 (42.8%), including 5 bladder pts and 1 prostate pt. Among bladder pts, BOR included one CR (1/7, 14.3%) for the LCNEC case, 2 PR (2/7, 28.6%), 2 SD (2/7, 28.6%) and 2 PD (2/7, 28.6%). Most prostate and ureteral pts either progressed on lurbinectedin or were NE (Prostate: 1 PR, 2 PD, and 2 NE; Ureteral: 1 PD and 1 NE). For all 14 pts, median OS was 11.47 months (95% CI: 2.17-13.63) and median PFS was 2.8 mo (1.4-10.9). Median DoR was 7.38 mo (2.3-9.53) for 4 responding pts (CR or PR). Treatment was stopped due to progression (9/14, 64.3%), three adverse events [thrombocytopenia, electrolyte abnormalities, cerebrovascular accident] (3/14, 21.4%), and pt preference (1/14, 7.1%). Conclusions: Lurbinectedin offers encouraging responses (DCR: 5/7, 71.4%) close to those in SCLC, in previously treated bladder mNEC. One CR was noted for a bladder pt with LCNEC. Responses were less appreciated in prostate and ureteral mNEC due to NE responses and limited number. Larger cohorts are needed to confirm survival benefit and genetic analyses are warranted to identify characteristics of responders. [Table: see text]

High-Grade Sinonasal Small Cell Neuroendocrine Carcinoma in a Patient With Xeroderma Pigmentosum: A Case Report.

Neuroendocrine tumors are rare and highly heterogeneous neoplasms with a wide spectrum of histological differentiation, functional, and biological features. Small cell neuroendocrine carcinomas (SNECs) of the sinonasal tract are particularly rare. Pathological features of SNECs of the nasal cavity and paranasal sinuses, which are aggressive tumors, are similar to those of anaplastic small cell carcinomas of the lung. We present a case of high-grade sinonasal SNECs in a patient with Xeroderma pigmentosum complementation group C (XPC) gene-positive xeroderma, which, to our knowledge, is the first case reported worldwide.

GAD2 Is a Highly Specific Marker for Neuroendocrine Neoplasms of the Pancreas.

Glutamate decarboxylase 2 (GAD2) is the most important inhibitory neurotransmitter and plays a role in insulin-producing β cells of pancreatic islets. The limitation of GAD2 expression to a few normal cell types makes GAD2 a potential immunohistochemical diagnostic marker. To evaluate the diagnostic utility of GAD2 immunohistochemistry, a tissue microarray containing 19,202 samples from 152 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, GAD2 staining was restricted to brain and pancreatic islet cells. GAD2 staining was seen in 20 (13.2%) of 152 tumor categories, including 5 (3.3%) tumor categories containing at least 1 strongly positive case. GAD2 immunostaining was most commonly seen in neuroendocrine carcinomas (58.3%) and neuroendocrine tumors (63.2%) of the pancreas, followed by granular cell tumors (37.0%) and neuroendocrine tumors of the lung (11.1%). GAD2 was only occasionally (<10% of cases) seen in 16 other tumor entities including paraganglioma, medullary thyroid carcinoma, and small cell neuroendocrine carcinoma of the urinary bladder. Data on GAD2 and progesterone receptor (PR) expression (from a previous study) were available for 95 pancreatic and 380 extrapancreatic neuroendocrine neoplasms. For determining a pancreatic origin of a neuroendocrine neoplasm, the sensitivity of GAD2 was 64.2% and specificity 96.3%, while the sensitivity of PR was 56.8% and specificity 92.6%. The combination of PR and GAD2 increased both sensitivity and specificity. GAD2 immunohistochemistry is a highly useful diagnostic tool for the identification of pancreatic origin in case of neuroendocrine neoplasms with unknown site of origin.

Carboplatin and Etoposide for the Treatment of Metastatic Prostate Cancer with or without Neuroendocrine Features: A French Single-Center Experience.

Chemotherapy using carboplatin and etoposide (CE) is frequently pragmatically proposed to treat metastatic prostate cancer (mPC), both primary small-cell neuroendocrine (PSC-NE) carcinoma and adenocarcinoma with or without neuroendocrine (NE) marker elevation. However, the real benefit of CE is poorly reported in the recent therapeutic context. We retrospectively analyzed the efficacy and tolerance of CE chemotherapy in these three different groups of mPC patients. Efficacy endpoints included radiological response, progression-free survival (PFS), and overall survival (OS), as well as PSA response and PFS2/PFS1 ratio in patients with adenocarcinoma. Sixty-nine patients were included in this single-center study (N = 18 with PSC-NE carcinoma and 51 with adenocarcinoma with (N = 18) or without (N = 33) NE marker elevation). Patients with adenocarcinoma were highly pretreated with next-generation hormonal agents (NHAs) and taxanes. In patients with adenocarcinoma, a PSA response ≥50% was observed in six patients (15.8%), four of whom had NE marker elevation. The radiological response was higher in PSC-NE and tended to be higher in adenocarcinoma when NE marker elevation was present. Comparing patients with adenocarcinoma with vs. without NE marker elevation, the median PFS was 3.7 and 2.1 months and the median OS was 7.7 and 4.7 months, respectively. Overall, 62.3% of patients experienced grade 3-4 adverse events (mainly hematological), and three treatment-related deaths were recorded. Reports of the clinical results of CE suggest that we should not mix PSC-NE and castration-resistant adenocarcinoma of the prostate. In patients with heavily pretreated adenocarcinoma, the benefit/risk ratio of CE chemotherapy seems unfavorable due to poor response and high toxicity.

Japan Society of Gynecologic Oncology 2022 guidelines for uterine cervical neoplasm treatment.

The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2022 for the Treatment of Uterine Cervical Cancer are revised from the 2017 guideline. This guideline aimed to provide standard care for cervical cancer, indicate appropriate current treatment methods for cervical cancer, minimize variances in treatment methods among institutions, improve disease prognosis and treatment safety, reduce the economic and psychosomatic burden of patients by promoting the performance of appropriate treatment, and enhance mutual understanding between patients and healthcare professionals. The guidelines were prepared through the consensus of the JSGO Guideline Committee, based on a careful review of evidence gathered through the literature searches and the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise seven chapters and 5 algorithms. The main features of the 2022 revision are as follows: 1) added discussed points at the final consensus meeting; 2) revised the treatment methods based on the International Federation of Gynecology and Obstetrics 2018 staging system; 3) examined minimally invasive surgery based on Laparoscopic Approach to Cervical Cancer trial; 4) added clinical question (CQ) for treatments of rare histological types, gastric type, and small-cell neuroendocrine carcinoma; 5) added CQ for intensity-modulated radiation therapy; 6) added CQ for cancer genomic profiling test; and 7) added CQ for cancer survivorship. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2022 for the Treatment of Uterine Cervical Cancer.

The impact of neo/adjuvant treatment choices on prognosis for surgically treated small-cell neuroendocrine carcinoma of the cervix.

Small-cell neuroendocrine carcinoma of the cervix (SCNCC) is a rare and aggressive tumor with a poor prognosis. Surgical resection followed by adjuvant therapy is the standard treatment for early-stage disease but the influence of different neo/adjuvant treatment approaches remains unclear. Retrospectively, we collected patients' characteristics and treatments in two medical centers. Disease status and survival outcomes were renewed through follow-up. Statistics analysis mainly included Kaplan-Meier methods for survival curve estimation, log-rank test for survival curve comparison, and Cox proportional hazards models for independent prognostic factors prediction. Finally, 51 patients treated by radical surgery between January 2010 and April 2020 were enrolled with a median age of 50 years (range: 32-68). 12 (23.5%) patients were at stage IIIC1 according to the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging systems and the rest were at the early stage. The mean tumor size was 3.6±1.3 cm. Pathological examination found 24 cases with pure SCNCC and 27 cases with admixed SCCC. 29 (56.9%) patients had deep stromal infiltration and 19 (37.3%) patients had lymphovascular space invasion. 34 (66.7%) patients received neo/adjuvant chemotherapy and pelvic radiation was conducted in 41 (80.39%) patients with a median dose of 46 Gy (range: 40-50.4 Gy). The median follow-up time was 25.0 months. The median disease-free survival (DFS) time was 23.0 months. 27 (52.9%) patients developed distant metastasis and 14 (27.5%) experienced local failure. The median overall survival (OS) was 32.0 months. Univariate and multivariate analysis showed neoadjuvant chemotherapy as negative (HR=2.081, 95% CI 1.030-4.203, p=0.041) and adjuvant chemotherapy (HR=0.409, 95% CI 0.213-0.784, p=0.020) as positive independent prognostic factor for DFS. For OS, only lymph node metastasis was confirmed as an independent prognostic factor in both univariate analysis (HR=1.528, 95% CI 1.011-2.308, p=0.044) and multivariate analysis (HR=1.697, 95% CI 1.041-2.768, p=0.034). In conclusion, for surgically treated SCNCC, adjuvant chemotherapy showed a positive influence on DFS while neoadjuvant chemotherapy harmed DFS. OS was unaffected by either treatment choice.

Clonal Origin and Lineage Ambiguity in Mixed Neuroendocrine Carcinoma of the Uterine Cervix

Small cell neuroendocrine carcinoma of the cervix (SCNEC/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. In this study, a panel of organoid lines from patients with SCNEC/cervix was established and 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. By tracking single cells, the existence of cells with bipotential differentiation towards SCNEC and adenocarcinomas was revealed. 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 KRT19 expression, changes in the differentiation of each cell were revealed 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.

Claudin 18.2 expression in digestive neuroendocrine neoplasms: a clinicopathological study.

Claudin 18.2-targeted therapy has shown significant efficacy in treating claudin 18.2-positive cancers. However, limited systematic studies have investigated characteristics of claudin 18.2 expression in neuroendocrine neoplasms (NENs). Data and specimens from 403 cases of digestive NENs were retrospectively collected, and claudin 18.2 expression was detected using immunochemical staining. Claudin 18.2 was positive in 19.6% (79/403) of the digestive NENs. The highest positive rate of claudin 18.2 was observed in gastric NENs (72/259, 27.8%), accounting for 91.1% (72/79) of all positive cases. The positivity rate was significantly higher in gastric NENs compared to pancreatic (2/78, 2.6%) or colorectal NENs (2/38, 5.3%; p < 0.05). For digestive NENs, claudin 18.2 positivity was significantly higher in neuroendocrine carcinomas (NECs) (37/144, 25.7%) than in neuroendocrine tumours (NETs; 14/160, 8.8%; p < 0.001), but no significant difference was found between gastric NECs (59/213, 27.7%) and gastric NETs (13/46, 28.3%; p > 0.05). The positivity was significantly higher in large-cell NECs (LCNECs; 28/79, 35.4%) and MiNEN (mixed neuroendocrine-non- neuroendocrine neoplasms)-LCNECs (23/66, 34.8%) compared to small-cell NECs (SCNECs; 9/65, 13.8%) and MiNEN-SCNECs (5/33, 15.2%; p < 0.05). Claudin 18.2 expression was more prevalent in gastric NENs than in pancreatic (12.5 ×; p = 0.001) and colorectal NENs (5.9 ×; p = 0.021). Claudin 18.2 staining was a useful method for identify the gastric origins of NETs, with a sensitivity of 28.3% and a specificity of 99.1%. The expression characteristics of claudin 18.2 in NENs were characterized, which may provide a clinicopathological reference for targeted therapies in patients with NENs.

Imaging PARP Upregulation with [123I]I-PARPi SPECT/CT in Small Cell Neuroendocrine Carcinoma.

Imaging PARP Upregulation with [123I]I-PARPi SPECT/CT in Small Cell Neuroendocrine Carcinoma.

A RARE PRESENTATION OF SMALL CELL LUNG CARCINOMA METASTASIZING TO PHEOCHROMOCYTOMA

Abstract Introduction/Objective Tumor-to-tumor metastasis is a rare phenomenon in which primary tumor cells metastasize hematogenously into another unrelated tumor. We report an interesting case of a tumor-to-tumor metastasis of small cell lung carcinoma to pheochromocytoma of the adrenal gland. Methods/Case Report A 75-year-old female former cigarette smoker with a past medical history of hypertension presented with a two-day history of dyspnea and epigastric pain. Physical examination demonstrated elevated blood pressure only. A computerized axial tomography scan of the chest and abdomen showed an incidental 3.1 cm right adrenal mass and right hilar lymphadenopathy. Detailed biochemical workup showed elevated serum epinephrine, norepinephrine, and 24-hour urine metanephrine. Adrenalectomy showed a 5.8 cm tumor mass with solid lobulated yellow to pink-tan and focally hemorrhagic cut surfaces. Microscopic examination showed a neoplasm composed of two distinct components. The predominant component consisted of nests ("zellballen") of large polygonal cells with variable nuclear pleomorphism, abundant amphophilic to basophilic cytoplasm, and a delicate intervening fibrovascular stroma, without significant mitotic activity. The minor component was characterized by sheets and nests of "small blue cells" with round to ovoid nuclei, stippled nuclear chromatin pattern, scanty cytoplasm, patchy necrosis, and high mitotic activity (&amp;gt;20 mitoses per 10 HPF). Foci of small cell carcinoma deposits were also present in the lymphatic channels of pheochromocytoma. Immunohistochemical stains demonstrated cytoplasmic staining of predominant component tumor cells for synaptophysin, chromogranin, and the absence of staining for TTF-1, CK CAM 5.2, and Ki-67. However, minor component tumor cells demonstrated cytoplasmic staining for synaptophysin, membranous staining for CK CAM 5.2, and nuclear staining for TTF-1 and Ki-67(60%). A final diagnosis of composite pheochromocytoma (predominant) and small cell neuroendocrine carcinoma (minor) was rendered. The possibility of a” collision” tumor comprising primary small cell carcinoma of pulmonary origin metastatic to an adrenal pheochromocytoma in light of the patient's cigarette smoking history and the presence of right hilar lymphadenopathy was favored. The subsequent biopsy of the right subcarinal adenopathy showed small cell carcinoma. Results (if a Case Study enter NA) NA Conclusion To the best of our knowledge, this is the only case of metastasis to a pheochromocytoma from a small cell neuroendocrine lung carcinoma.

Primary Small Cell Neuroendocrine Carcinoma of the Tonsil: A Rare Case Report and Review of Literature

Neuroendocrine tumors of the head and neck region are extremely infrequent. Small cell neuroendocrine carcinoma (NEC) of the tonsil is almost unheard of and carries a poor prognosis. There is no standard treatment protocol with regard to this tumor type. We present a 74-year-old male with complaints of odynophagia and swelling on the right side of the neck for one month. Physical examination showed a right neck level II lymph node with an ulceroproliferative mass involving the (R) tonsillar fossa, uvula, soft palate, and obstructing the oropharynx. MRI showed a right tonsillar mass measuring 3.4 × 3.3 × 1.4 cm with an ipsilateral level II lymph node measuring 2.7 × 1.9 cm. PET-CT scan showed a metabolically active right tonsillar lesion with a right level II lymph node. Histopathological examination revealed small cell NEC. On immunohistochemistry, tumor cells were strongly positive for PanCK, synaptophysin, chromogranin, CD56, and p16. Tumor cells were negative for CD45, CK7, CK20, and EBV-LMP. Ki-67 was 80%. The patient was treated with cisplatin and etoposide-based chemotherapy, and the tumor showed a very good response.

Small Cell Neuroendocrine Carcinoma of Bladder

Being a very rare histopathological type, neuroendocrine tumors are rather aggressive tumors that are usually diagnosed at an advanced stage. Neuroendocrine bladder tumor represents less than 1% of all bladder cancers. Though diagnosed in similar age period of 6th to 8th decade like urothelial carcinoma, its histopathological features and its poor prognosis are apart and rather similar to the small cell cancer of the lung. In this case report, we present a case of high-grade small cell neuroendocrine carcinoma of bladder in an elderly man.