Large Cell Neuroendocrine Carcinoma Research Articles

Ovarian large cell neuroendocrine carcinoma arising in a mucinous borderline tumour – a case report

Ovarian large cell neuroendocrine carcinoma arising in a mucinous borderline tumour – a case report

A rare primary ovarian large-cell neuroendocrine carcinoma

A rare primary ovarian large-cell neuroendocrine carcinoma

Survival outcomes of surgery and adjuvant chemotherapy in early-stage small cell and large cell lung cancer: a novel focus on tumors less than 1 cm

BackgroundThe role of adjuvant chemotherapy in early-stage small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) remains unclear, particularly for small tumors. This study assesses the survival benefits of adjuvant chemotherapy after surgical resection with a novel focus on tumors less than 1 cm.Materials and methodsData from the National Cancer Database (NCDB) was extracted for patients with SCLC (n = 11,962) and LCNEC (n = 6821) who underwent surgical resection between 2004 and 2020. Exclusion criteria were limited survival (< 30 days), positive lymph nodes, distant metastases, large tumors (> 5 cm), residual microscopic disease, and neoadjuvant therapy. The primary outcome was overall survival (OS) from diagnosis, which was evaluated using Kaplan–Meier methods and multivariate Cox regression analyses. A propensity score matching (PSM) analysis was performed to compare outcomes in patients with SCLC and tumors ≤ 1 cm who received adjuvant chemotherapy versus surgery alone.ResultsThe study involved 4114 SCLC and 3954 LCNEC patients. Adjuvant chemotherapy was associated with a significant increase median OS in both SCLC (6.26 vs. 4.18 years; p < 0.001) and LCNEC (7.02 years vs. 4.89 years; p < 0.001), while also being an independent predictor of better OS in SCLC (HR: 0.74) and LCNEC (HR: 0.75) (p < 0.001). The benefit was more noticeable in tumors ≤ 1 cm, showing a significant OS increase after PSM (median OS 7.34 vs. 5.02 years; p = 0.0048).ConclusionAdjuvant chemotherapy after surgery is associated with improved overall survival in stage I SCLC and LCNEC, particularly in SCLC tumors of 1 cm or less.

The analysis of molecular classification of pulmonary neuroendocrine tumors and relationship between YAP1 and efficacy.

A novel molecular classification for small cell lung cancer (SCLC) has been established utilizing the transcription factors achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). This classification was predicated on the transcription factors. Conversely, there is a paucity of information regarding the distribution of these markers in other subtypes of pulmonary neuroendocrine tumors (PNET). Clinical and survival data for PNET patients were gathered from January 2008 to December 2020. Immunohistochemical analysis was employed to evaluate the expression. The relationship between YAP1 expression and outcomes in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) was examined. Data from low-grade PNET patients who had previously undergone immunotherapy were retrospectively gathered and analyzed. The ASCL1 positive rate was markedly elevated in SCLC (7.1% vs. 60%; P < 0.001) and LCNEC patients (7.1% vs. 38.5%; P = 0.034) compared to PC patients. The YAP1-positive rate was elevated in LCNEC compared to SCLC (43.6% vs. 20%, P = 0.028) and pulmonary carcinoid (PC) patients (43.6% vs. 21.4%; P = 0.021). The DLL3-positive rate in SCLC patients was greater than in SCLC and PC patients (37.1% vs. 23.1% vs. 0%; P = 0.028, P = 0.021). A significant level of tumor heterogeneity was noted, with SCLC and LCNEC patients exhibiting markedly higher heterogeneity than PC patients (65.7% vs. 56.3% vs. 21.4%; P = 0.005, P = 0.025). In patients with LCNEC, YAP1 positivity exhibited no correlation with PD-L1 expression (17.1% vs. 45.7%, P = 0.518). Tumor heterogeneity was also noted in transformed SCLC, with no significant differences in the expression levels of transcription factors between transformed and traditional SCLC. In 13 LCNEC patients with a history of ICI application, YAP1 exhibited no significant effect on PFS (P = 0.331) or OS (P = 0.17) in the subgroup analysis of LCNEC patients. Among the 14 patients with low-grade PNET who underwent immunotherapy, the disease control rate was 85.7%. Patients with high-grade PNET have high levels of expression of ASCL1 and DLL3, whereas patients with LCNEC have high levels of expression of YAP1. With regard to the transcription factor level, it was found that patients with SCLC and LCNEC had a much higher degree of tumor heterogeneity than those with PC. In patients with LCNEC who were receiving monotherapy of ICIs or chemotherapy in combination with ICIs, the expression of YAP1 did not appear to have any clear impact on the prognosis. This is due to the limited sample size of the study, which requires additional investigation. When compared to the expression of TFs in regular SCLC, the expression of TFs in converted SCLC is comparable.

Intranodular Thyroid Metastasis of a Large Cell Neuroendocrine Carcinoma of the Endometrium.

A 64-year-old woman underwent initial 18F-FDG PET/CT staging for a suspicious endometrial mass, which showed high uptake in the endometrial mass and a focal uptake in a known left thyroid nodule. Histology revealed a high-grade large cell neuroendocrine carcinoma of the endometrium with FIGO (International Federation of Gynecology and Obstetrics) stage Ib. Further explorations revealed a synchronous thyroid metastasis. Patient then received adjuvant immunochemotherapy. This case showed a potential pitfall in the initial assessment of this rare and aggressive malignancy on which the therapeutic approach greatly depends.

The International Association for the Study of Lung Cancer Staging Project: The Database and Proposal for the Revision of the Staging of Pulmonary Neuroendocrine Carcinoma in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer.

Pulmonary high-grade neuroendocrine carcinoma (NEC) includes small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). The seventh and eighth editions of the TNM classification for lung cancer confirmed the applicability of this staging system for SCLC. With the proposal of N2 and M1c subcategories for the ninth edition classification, we assessed the applicability to NECs. The database included NEC cases diagnosed between January 2011 and December 2019. Eligible cases, with valid survival time and eighth edition TNM stage, were classified as pure SCLC, combined SCLC/non-small cell carcinoma and LCNEC. Survival was calculated by the Kaplan-Meier method, pairwise differences using log-rank test, and prognostic groups by a Cox regression analysis. There were 6181 pure/combined SCLC and 697 LCNEC cases available. For SCLC, survival outcome analyses included 4453 with clinical stage, and 583 with pathologic stage data. The corresponding numbers for LCNEC were 585 and 508. The SCLC data validated the ninth edition classification for lung cancer, including the proposed new subcategories, N2a, single-station ipsilateral mediastinal/subcarinal lymph node involvement, and N2b, involvement of multiple ipsilateral/subcarinal stations. The data also validated the subcategorization of M1c into M1c1 (multiple lesions in a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems). The LCNEC data were insufficient for complete survival analysis, but the available data showed decreasing survival with increasing clinical and pathological stages. The ninth edition TNM classification applies to patients with NEC and is the appropriate standard for use in clinical practice.

Diagnostic relevance of p53 and Rb status in neuroendocrine tumors G3 from different organs: an immunohistochemical study of 465 high-grade neuroendocrine neoplasms.

The double inactivation of TP53 and RB1 is considered typical of neuroendocrine carcinomas (NECs) but is assumed to be rare in high-grade neuroendocrine tumors (NETs). The immunohistochemical determination of the p53 and Rb status has therefore been proposed as a diagnostic tool. We studied this status in a large series of high-grade neuroendocrine neoplasms, from multiple origins, in order to (a) assess the patterns observed in the different histopathological categories, (b) compare them between the various anatomic sites, and (c) evaluate their possible diagnostic relevance. Four hundred sixty-five cases from 9 organ systems (142 high-grade NETs -NET-G3-, 162 large-cell NECs -LCNEC-, 144 small-cell NECs -SCNEC-) and 60 cases of NET G1/G2 were included. The expression of both proteins was normal in 96.7% of NET G1/G2, 76.7% of NET-G3, and 5.8% of all NECs. p53 expression was abnormal in 12.7% of NET-G3 and 91.5% of NECs. Rb expression was lost in 10.6% of NET-G3 and 68.3% of NECs. Rb loss was significantly less frequent in LCNEC than in SCNEC (57.3% versus 80.6%); abnormal p53 expression was comparable in the two categories. Patterns were comparable between primary sites, except for head and neck NECs. For diagnostic purposes, taking into account, Rb status improved, but only marginally, the performances of p53 status. In conclusion, our study underlines the molecular heterogeneity of NET-G3 and LCNEC, irrespectively of the primary, and provides further insight on the diagnostic relevance of p53/Rb immunodetection in high-grade neuroendocrine neoplasms.

Fine Needle Aspiration Cytological Diagnosis of Primary Breast Large-Cell Neuroendocrine Carcinoma/Squamous Cell Carcinoma.

Primary breast large-cell neuroendocrine carcinoma (LCNEC)/squamous cell carcinoma (SCC), also referred to as mixed neuroendocrine/non-neuroendocrine neoplasms of the breast (Br-MiNENs), represents an exceedingly rare malignancy. We report the first case of primary breast LCNEC/SCC diagnosed via ultrasound-guided fine-needle aspiration (FNA) biopsy of the left supraclavicular and left internal mammary lymph nodes. The patient, a 40-year-old female, underwent a lumpectomy followed by breast-conserving surgery and was diagnosed with primary breast LCNEC. Notably, within merely four months following the breast-conserving surgery, PET-CT revealed lymph node enlargement, prompting the performance of FNA. FNA cytology of metastatic lymph nodes revealed two distinct tumor components, allowing for clear differentiation between LCNEC and SCC in the smear. The diagnosis was further corroborated by immunocytochemical (ICC) staining of the cell blocks. Subsequently, histopathological re-examination of the breast mass revealed occult SCC components comprising less than 1% of the tumor cells. Additionally, the case exhibited triple-negative breast cancer, with PIK3CA, TP53, RB1, and BCL2L11 mutations identified through next-generation sequencing (NGS). Br-MiNEN is exceedingly rare, and its cytological diagnosis poses significant challenges. It is recommended that a detailed and objective description of each tumor component and its proportion be provided. This report provides the first detailed description of the FNA cytology of LCNEC/SCC, thereby enhancing cytopathologists' comprehension of this tumor. Auxiliary studies, including ICC staining and molecular biology assays, are crucial for accurate diagnosis, therapy, and prognosis.

Methylation status of selected genes in non-small cell lung carcinoma - current knowledge and future perspectives.

DNA methylation is recognized as an early event in cancer initiation and progression. This review aimed to compare the methylation status of promoter regions in selected genes across different histological subtypes of non-small cell lung cancer (NSCLC), including adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and the rare but highly aggressive large-cell neuroendocrine carcinoma (LCNEC). A comprehensive literature search was conducted in the PubMed database until August 17, 2024, using standardized keywords to identify reports on promoter methylation in NSCLC. Seventy-five studies were reviewed, focusing on the promoter methylation of key genes, such as APC, BRCA1, CDH1, CDH13, DAPK1, DLEC1, FHIT, GSTP1, hMLH1, MGMT, CDKN2A, RARβ, RASSF1, RUNX3, and TIMP3. These studies explored diagnostic, prognostic, epidemiological, and therapeutic aspects across NSCLC subtypes. Additionally, mutational profiles of TP53, RB1, KEAP1, and STK11 and expression patterns of ASCL1, DLL3, and NOTCH were analyzed. The findings suggest that LCNEC may serve as a biological bridge between non-small cell and small-cell lung carcinoma. Our analysis highlights that the methylation status of selected genes could enhance diagnosis, prognosis, and personalized treatment strategies in patients with NSCLC, particularly those with LCNEC.

Clinicopathological Features of Epstein-Barr Virus-Positive Neuroendocrine Carcinoma: Analysis of Twenty-Two Cases.

Epstein-Barr Virus (EBV)-positive neuroendocrine carcinoma (NEC) is a rare neoplasm with limited histopathological and therapeutic data. This report presents 22 cases of EBV-positive NEC, analyzing age distribution, morphology, and immunophenotype. The median patient age was 47years (range: 27-67years), with a male-to-female ratio of 17:5. Most cases (86%, 19/22) were localized to the nasal cavity or nasopharynx, while the remaining three (14%, 3/22) involved the lung, eyelid, and chest wall. Tumors were identified as small cell neuroendocrine carcinoma (SCNEC) or large cell neuroendocrine carcinoma (LCNEC) based on cellular morphology. Immunohistochemical analysis showed positivity for at least one, but generally, two neuroendocrine markers and INI1, while negativity for NUT and squamous cell carcinoma markers, such as p63, p40, and CK5/6. In situ hybridization consistently revealed EBV early RNAs (EBERs) in all cases. Notably, eight patients benefited from chemoradiotherapy. Recognizing this rare tumor is essential for optimizing treatment strategies.

Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms.

Delta-like Ligand 3 (DLL3) targeting therapies are promising in small cell lung cancer (SCLC) treatment. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized. We describe the landscape of DLL3 at the mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer. Additionally, we explore its expression in extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 expression is enriched in SCLC, LCNEC along with combined histology lung cancers. Moreover, we find a wide range of DLL3 expression in high-grade EP-NEN. We describe heterogenous DLL3 expression not only in SCLC but also in different NEN types. This comprehensive characterization of DLL3 can help guide future clinical trial design targeting DLL3 in NEN including LCNEC and EP-NEN that are lacking standard of care treatment options.

Neuroendocrine Tumors in Horseshoe Kidneys: A Review of the Literature With Report of a Novel Finding Expanding Their Morphologic Spectrum

Horseshoe kidney is a rare congenital anomaly with an unusually higher frequency of neuroendocrine tumors. Symptoms are rare, and, in most of the cases, are incidentally diagnosed. The clinical behavior of these tumors is heterogeneous and can be difficult to predict based on histology alone. Necrosis and percentage of Ki-67 may have a role in prognosis. Almost all tumors are carcinoids (well-differentiated neuroendocrine tumors) observed at an early age and with no sex dominance. It is not known the reason for the higher frequency of neuroendocrine tumors in horseshoe kidneys and the histogenesis is unknown. One of the hypotheses supports that renal carcinoid tumors may arise from neuroendocrine cells within foci of metaplastic or teratomatous epithelium within the kidney. With consonance with this hypothesis, there are reports of carcinoids in horseshoe kidneys associated with a cystic lesion lined by the intestinal epithelium, with mucinous differentiation and osseous metaplasia, arising in a mature teratoma of the kidney, arising within mature teratoma and clear cell renal cell carcinoma, with a mucinous cystadenoma element, and arising within mature cystic teratoma synchronous with primary adenocarcinoma. There is only one reported large cell neuroendocrine carcinoma of a horseshoe kidney in a 57-year-old Chinese woman. Herein, we report a patient that to the best of our knowledge is the first case of a combined well-differentiated neuroendocrine tumor and large-cell neuroendocrine carcinoma with rhabdoid features in horseshoe kidney. The histologic component of rhabdoid features expands the morphologic spectrum of neuroendocrine tumors in the horseshoe kidney. We provide a comprehensive review of the literature summarizing pertinent key clinical and pathologic aspects.

Neuroendocrine carcinomas of the gastrointestinal tract : Morphology, molecular pathology, cellular origin

Neuroendocrine carcinomas (NEC) are poorly differentiated neuroendocrine neoplasms that can occur ubiquitously in the mucosa-bearing organs of the gastrointestinal tract. Based on their morphology, they are classified into large cell (LCNEC) and small cell NEC (SCNEC). The most common form of mixed differentiation is the combination with an adenocarcinoma, referred to as mixed adenoneuroendocrine carcinoma (MANEC). NEC/MANEC exhibit asignificantly poorer prognosis than the adenocarcinomas of their respective primary sites, which is inextricably linked to their typical histomorphology. Adenocarcinomas with aberrant expression of neuroendocrine markers do not show aworse clinical course. Molecularly, NEC/MANEC have aprofile comparable to the adenocarcinomas of their site of origin and aprofile divergent from neuroendocrine tumors. Analyses of gastric NEC/MANEC have shown frequent MYC amplifications, which are reflected in MYC signatures in various transcriptome analyses.The cellular origin of NEC remains asubject of controversial discussion. New insights are provided by aMYC-driven, genetically modified mouse model that led to the development of large gastric tumors. These tumors were histologically identified as LCNEC and were accompanied by both neuroendocrine and non-neuroendocrine precursor lesions. Using immunofluorescence, aderivation from resident neuroendocrine cells in the gastric corpus was demonstrated, suggesting that at least aportion of LCNEC may originate directly from neuroendocrine cells.

Breast metastasis from large cell neuroendocrine carcinoma of the lung: a case report

BackgroundPrimary breast carcinoma is far more common than breast metastases. Common breast metastases usually come from lymphoma, leukemia, melanoma, and ovarian cancers. Breast metastases from neuroendocrine carcinomas are considered an exceeding rare entity. It has been reported in the literature that the pathological presentation of this particular metastatic tumor is very challenging as it shares many morphological characteristics with primary breast carcinoma.Case presentationWe report a case of a patient with large cell neuroendocrine carcinoma of the lung metastasizes to both breasts. The patient was initially presented with brain metastasis of unknown origin. Further radiological imaging workup showed multiple bilateral breast masses and bilateral lymphadenopathy, which raised concern for secondary lymphoma of the breast. The histopathology of this case was challenging, particularly when triple negative invasive ductal carcinoma diagnosis had been made. Multidisciplinary meetings between medical oncologists, radiologists, and pathologists profoundly helped confirming the diagnosis of metastatic large cell neuroendocrine tumor to the breast.ConclusionLarge cell neuroendocrine carcinoma of the lung is a relatively uncommon diagnosis with generally poor prognosis. Large cell neuroendocrine carcinoma that metastasizes to the breast is even scarcer. Correlation between clinical assessment, radiological imaging, and pathological evaluation is the key in making such an unusual and complex diagnosis. Additionally, radiologists should be aware of metastatic presentations of the breast and avoid confusion with mimicking benign entities or primary breast carcinomas.

Utility of patient-derived xenografts to evaluate drug sensitivity and select optimal treatments for individual non-small-cell lung cancer patients

BackgroundPatient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens.MethodsHistopathological examination, immunohistochemistry and whole-exome sequencing confirmed similarity between our PDX tumors and primary tumors in terms of morphology and genetic characteristics. The drug reactivity of the PDX tumor was validated in vivo. The mechanisms of acquired resistance to Osimertinib PDX tumors were investigated by WES and WB.ResultsWe successfully established 13 NSCLC-PDXs derived from 62 patients, including eight adenocarcinomas, four squamous-cell carcinoma, and one large-cell neuroendocrine carcinoma. Histological subtype and clinical stage were significant factors affecting the successful PDXs establishment. The treatment responses to conventional chemotherapy in PDXs were entirely consistent with that of their corresponding patients. According to the genetic status of tumors, more appropriate targeted agents were selected in PDXs for their corresponding patients as alternative treatment options. In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure.

Histological transformation in lung adenocarcinoma: Insights of mechanisms and therapeutic windows.

Histological transformation from lung adenocarcinoma (ADC) to small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC), squamous cell carcinoma (SCC), and sarcomatoid carcinoma (PSC) after targeted therapies is recognized as a mechanism of resistance in ADC treatments. Patients with transformed lung cancer typically experience a poor prognosis and short survival time. However, effective treatment options for these patients are currently lacking. Therefore, understanding the mechanisms underlying histological transformation is crucial for the development of effective therapies. Hypotheses including intratumoral heterogeneity, cancer stem cells, and alteration of suppressor genes have been proposed to explain the mechanism of histological transformation. In this review, we provide a comprehensive overview of the known molecular features and signaling pathways of transformed tumors, and summarized potential therapies based on previous findings.

The prognostic implications of podoplanin in cancer-associated fibroblasts and PD-L1 expression in high-grade neuroendocrine carcinoma of the lung.

Podoplanin (PDPN) expression in cancer-associated fibroblasts (CAFs) (CAF-PDPN) is considered a poor prognostic factor in nonsmall cell lung cancer, but little is known about its clinical significance in high-grade neuroendocrine carcinoma of the lung (HGNEC). This study examines the association between CAF-PDPN and stromal programmed death-ligand 1 (PD-L1) expression and the prognostic implications of CAF-PDPN and PD-L1 expression status in surgically resected HGNEC patients. Immunohistochemical analyses were performed on 121 resected HGNEC specimens using antibodies against PDPN and PD-L1. Correlations between CAF-PDPN, stromal PD-L1 expression, and clinicopathologic features and their implications for survival were analyzed statistically. There were substantially more large-cell neuroendocrine carcinomas in the stromal PD-L1-positive group and more vascular invasion in the tumoral PD-L1-positive group. PDPN expression in CAF was moderately correlated with stromal PD-L1 expression (ρ = 0.567, p < 0.001). In a survival analysis combining CAF-PDPN and stromal PD-L1 status, the 5-year RFS rates for Group A: CAF-PDPN (+)/stromal PD-L1 (+), Group B: CAF-PDPN (+)/stromal PD-L1 (-), Group C: CAF-PDPN (-)/stromal PD-L1 (+), and Group D: CAF-PDPN (-)/stromal PD-L1 (-) were 62.0%, 46.8%, 17.5%, and 20.2%, respectively, with corresponding 5-year OS rates of 76.6%, 69.2%, 27.0%, and 25.3%. The log-rank test showed statistically significant differences among the groups in RFS (p < 0.001) and OS (p < 0.001). There is a correlation between CAF-PDPN and tumoral/stromal PD-L1 expression, and positive status for either CAF-PDPN or stromal PD-L1 expression could be an independent favorable prognostic factor in surgically resected HGNEC patients.

Large cell neuroendocrine carcinoma in pancreatoblastoma with TP53 and SMAD4 mutations: a clinicopathologic study of a rare entity

Abstract Pancreatoblastoma, a rare pancreatic tumor, exhibits diverse differentiation pathways, including acinar, ductal, and neuroendocrine lineages, often with distinct squamoid nests [3]. We present a notable case of pancreatoblastoma coexisting with large cell neuroendocrine carcinoma in a 10-year-old boy, presenting with abdominal discomfort, weight loss, and lesions in the pancreas, spleen, and liver visible on imaging. A liver biopsy revealed a poorly differentiated carcinoma with neuroendocrine features, while a splenic biopsy showed acinar cell differentiation, raising possible diagnoses of pancreatoblastoma or acinar cell carcinoma. Subsequent surgical resection after chemotherapy revealed diverse components within the pancreatoblastoma, including well-differentiated acinar and neuroendocrine cells, squamoid nests, and a high-grade neuroendocrine carcinoma. Genetic analysis detected pathogenic variants in TP53 and SMAD4, rarely found in pancreatoblastomas. This juxtaposition of large cell neuroendocrine carcinoma and pancreatoblastoma suggests a potential evolution from well-differentiated neuroendocrine tumors to poorly-differentiated carcinomas within pancreatoblastomas.

Analysis of ASCL1/NEUROD1/POU2F3/YAP1 Yields Novel Insights for the Diagnosis of Olfactory Neuroblastoma and Identifies Sinonasal Tuft Cell-like Carcinoma

The diagnosis and treatment of sinonasal small round epithelial/neuroepithelial malignancies depends on the expression of conventional neuroendocrine markers (cNEM), such as synaptophysin, chromogranin-A, INSM1, and CD56/NCAM1. However, these tumors remain diagnostically challenging due to overlapping histologic and immunohistochemical features. The transcriptional regulators ASLC1, NEUROD1, POU2F3 and YAP1 are novel NEM (nNEM) used for subtyping of small-cell lung cancer (SCLC). Herein, we assessed the immunoexpression of nNEM in 76 sinonasal malignancies including 27 olfactory neuroblastomas (ONB), 14 small-cell (SCNEC) and 2 large-cell neuroendocrine carcinomas (LCNEC), 12 sinonasal undifferentiated carcinomas (SNUC), 7 olfactory carcinomas (OC), 11 SWI/SNF-deficient carcinomas, and 3 neuroendocrine tumors (NET). We correlated nNEM expression with the extent of neuroendocrine differentiation defined by averaged cNEM expression (NE-high: H-score≥150, NE-low: H-score<150). Dominant NE subtypes were defined by the nNEM with the highest H-score. Co-expression of two nNEM with <100 H-score difference defined a co-dominant NE subtype. NE differentiation positively correlated with NEUROD1 and negatively with YAP1 expression (p<0.0001). ONB were NE-high (96%) and all were NEUROD1-dominant/POU2F3-negative/ASCL1-negative(low)/YAP1-negative(low). In contrast to ONB, all OC were NE-low, mostly (71%) co-dominant subtypes, and NEUROD1-low(negative) (100%, p=0.0001) and YAP1-high (71%, p=0.0001). Most notably, all SNUC were POU2F3-(co)dominant/NEUROD1-negative irrespective of the IDH2 mutations. Sinonasal tumors with high POU2F3 expression showed enrichment for “tuft cell carcinoma” and tuft cell signatures (p=0.009). Similar to SCLC, SCNEC was heterogeneous in terms of nNEM expression comprising several molecular subtypes including ASCL1-(co)dominant (43%) cases. All SWI/SNF-deficient carcinomas were consistently ASLC1/NEUROD1/POU2F3-negative and YAP1-positive. ASLC1/NEUROD1/POU2F3/YAP1 are useful markers in differential diagnosis of ONB, SNUC, OC and SWI/SNF-deficient carcinomas. Subsets of SNUC and LCNEC may represent tuft cell-like carcinomas suggesting that the tuft cell could be explored as the cell of origin for these tumors. The therapeutic vulnerabilities associated with POU2F3 expression in SCLC suggest that a similar approach might be considered for POU2F3-positive carcinomas of the sinonasal tract. Given their diagnostic and possible therapeutic relevance, nNEM have potential to transform the way we approach the diagnosis and management of sinonasal small round epithelial/neuroepithelial malignancies.

Neuroendocrine Neoplasms of the Breast: Current Insights and Future Directions.

The breast neuroendocrine neoplasms (NENs) represent a heterogeneous group of tumors and account for less than 1% of all NENs. The 5th edition of the WHO Classification of Breast Tumors in 2019 introduced a more stringent definition for breast NENs including neuroendocrine tumors (NETs) (G1, G2) and neuroendocrine carcinomas (NECs) (small cell carcinoma, large cell neuroendocrine carcinoma). While the diagnostic criteria and treatment of breast NENs still have some unsolved issues. We aim to discuss the diagnosis, treatment progress, existing problems, and future development direction of breast NENs. We provide a comprehensive review and evaluation of the diagnostic criteria, pathological features, utilization of immunohistochemical markers, molecular characteristics, pathogenesis, clinical significance, treatment options for breast NENs. (1) Under the new definition, "pure" breast NENs are extremely rare. (2) Breast NETs are graded according to Nottingham grading System. Grading criteria utilized in other systems for NENs, such as mitotic count, ki67 proliferation index, and necrosis, have not been applied to breast NENs. (3) The WHO has not yet acknowledged the existence of NET G3 clearly. (4) The expression of NE markers may differ in breast NECs. (5) The treatment of breast NENs is still based on IBCs-NST, and without any difference from invasive carcinoma with NE features. (6) The prognosis of breast NENs remains unclear, while the prognosis for NECs is significantly poorer than invasive breast carcinomas of no special type (IBCs-NST) has been confirmed. Strict adherence to criteria is the key to correctly diagnose breast NENs with the exclusion of metastasis from other sites. Further exploration is required to determine the tissue origin of breast NENs and understand the pathogenesis. Efforts are still needed to establish unified diagnostic criteria and a unique diagnosis and treatment consensus for breast NENs.