Sex Differences in the Survival of Patients with Neuroendocrine Neoplasms: A Comparative Study of Two National Databases.

BACKGROUND: Neuroendocrine neoplasms (NENs) are increasing in incidence globally. Previous analysis of the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed a notable female survival advantage in most tumour sites. This study aims to compare NCRAS to the Surveillance, Epidemiology, and End Results Program (SEER) to validate these results using the same statistical methods. METHODS: A total of 14,834 and 108,399 patients with NENs were extracted from NCRAS and SEER, respectively. Sixty-months survival for both males and females for each anatomical site of NENs were calculated using restricted mean survival time (RMST) and Kaplan-Meier Survival estimates. The sixty-month RMST female survival advantage (FSA) was calculated. RESULTS: FSA was similar in NCRAS and SEER. The highest FSA occurred in lung and stomach NENs. CONCLUSIONS: The data from SEER confirm the findings published by NCRAS. Female survival advantage remains unexplained.

Mixed neuroendocrine and adenocarcinoma of gastrointestinal tract: A complex diagnosis and therapeutic challenge.

In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction. Mixed neuroendocrine and non-neuroendocrine neoplasms of the gastrointestinal system are rare heterogeneous group of tumors characterized by a high malignant potential, rapid growth, and poor prognosis. Due to the rarity of these cancers, the standard therapy is poorly defined. The diagnosis of these tumors is based on combination of morphological features, immunohistochemical and neuroendocrine and epithelial cell markers. Both endocrine and epithelial cell components can act independently of each other and thus, careful grading of each component separately is required. These cancers are aggressive in nature and the potential of each component has paramount importance in the choice of treatment and response. Regardless of the organ of origin, these tumors portend poor prognosis with increased proportion of neuroendocrine component. Multidisciplinary services and strategies are required for the management of these mixed malignancies to provide the best oncological outcomes. The etiopathogenesis of these mixed tumors remains obscure but poses interesting question. We briefly discuss a few salient points in this editorial.

Primary Hepatic Neuroendocrine Carcinoma: A Rare Entity.

Neuroendocrine tumors are typically low-malignancy growths arising from neuroectodermal cells of neural crest origin. Neuroendocrine carcinoma, on the other hand, represents a high-malignancy form of these tumors. While rare in the liver, they often indicate metastasis when present. We present a unique case of incidentally discovered primary hepatic neuroendocrine carcinoma. Initially, the patient's management was based on misleading radiological findings. However, histopathology confirmed the diagnosis, with subsequent imaging ruling out an extrahepatic source. Despite this, the patient opted against surgical intervention, resulting in a fatal outcome. This case underscores the critical importance of prompt diagnosis and intervention to avert adverse outcomes.

CDK4/6 and aromatase inhibitors as first-line treatment in metastatic high-grade neuroendocrine carcinoma of the breast: A case report.

Key Clinical Message: There is no consensus regarding the therapeutic approach of breast neuroendocrine carcinomas (NECs). As most NECs are hormone receptor positive and HER-2 negative, we suggest that endocrine-based strategies may play a leading role. Here, we report a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium. Abstract: Primary neuroendocrine neoplasms of the breast constitute a rare entity. They are characterized by predominant neuroendocrine differentiation and are further divided into well-differentiated neuroendocrine tumors and poorly differentiated (high-grade) neuroendocrine carcinomas (NECs). Regarding their therapeutic approach, there are no standardized guidelines. Herein, we present the first case ever reported, concerning a female patient with de novo metastatic breast NEC who received hormonal therapy, a combination of a CDK4/6 inhibitor palbociclib with letrozole and triptorelin, as first-line treatment with significant clinical and radiological response. As most NECs are estrogen receptor and/or progesterone receptor positive and HER-2 negative, we suggest that hormonal therapy may play a leading role even in the first-line setting. The present report provides a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium of breast NECs.

Clinicopathologic and Molecular Characterization of Inflammatory Bowel Disease-Associated Neuroendocrine Carcinomas and Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

The pathogenesis of neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) in the gastrointestinal tract remains poorly understood. This study seeks to characterize the clinicopathologic and molecular features of NEC/MiNEN in patients with inflammatory bowel disease (IBD). Eighteen surgically resected IBD-associated intestinal carcinomas with a minimum of 30% neuroendocrine component were collected from 6 academic centers and compared to a control group of 12 IBD-associated carcinomas lacking neuroendocrine differentiation. Both groups exhibited a male predominance and similar age distribution. The NEC/MiNEN group was more likely to have a higher percentage of Crohn's disease (9/18 vs. 1/12, P=0.024), occur in the rectum (9/18 vs. 3/12) and small intestine (4/18 vs. 0/12) (P<0.01), be diagnosed on resection without a preceding biopsy (6/18 vs. 0/12, P=0.057), and have unidentifiable precursor lesions (10/18 vs. 1/12, P=0.018) than the control group. Synchronous carcinoma, advanced tumor stage (pT3 and pT4), and lymph node metastasis occurred at similar rates; however, the NEC/MiNEN group had a higher incidence of angiovascular invasion (14/18 vs. 4/12, P=0.024), distant metastasis (8/18 vs. 1/12, P=0.049), mortality (8/18 vs. 2/12, P=0.058), and worse survival (Kaplan-Meier, P=0.023) than the control group. All tested cases were mismatch repair proficient. A Ki-67 proliferation index ranged from 25% to 100%. Next-generation sequencing in 11 NEC/MiNEN cases revealed low tumor mutational burdens but complex genetic abnormalities commonly involving TP53 (9/11, 82%), FBXW7 (4/11, 36%), and APC (3/11, 27%), with the other genetic alterations randomly occurring in one or two cases. The neuroendocrine component, which shared similar molecular alterations as the non-neuroendocrine component, was subcategorized into intermediate (G3a)- and high-grade (G3b); the higher-grade correlated with more genetic alterations. In conclusion, IBD-associated NEC/MiNEN shows diverse histologic features, variable precursor lesions, intricate genetic abnormalities, and aggressive biologic behavior. The classification and grading of GI-NEC/MiNEN may be refined for better clinical management.

A morphological and immunohistochemical study of ductal carcinoma in situ, invasive breast carcinoma of no special type, and mucinous carcinoma of the breast in comparison with solid papillary carcinoma regarding neuroendocrine marker expression.

The exact relationship between solid papillary carcinoma (SPC) and invasive breast carcinoma of no special type (IBC-NST) with neuroendocrine differentiation and SPC and mucinous carcinoma (MC) of the breast remains unclear. To clarify the relationship, we conducted a comparative study of morphological and neuroendocrine features between ductal carcinoma in situ (DCIS, 72 cases) and SPC in situ (35 cases), and IBC-NST (103 cases) and invasive SPC (92 cases). We also conducted the study between MC associated with and without SPC. Synaptophysin, chromogranin A, and INSM1 were employed for the immunohistochemical study. IBC-NST had occasionally a morphological similarity with invasive SPC. While 123 of 127 cases with SPC demonstrated diffuse staining with one or more of the neuroendocrine markers, the only one case of DCIS and none of IBC-NST showed it. Type B was observed in 16 of 18 cases of MC associated with SPC and in 13 of 33 cases of MC without it. All the cases of MC with SPC and 6 of 33 cases without it showed diffuse staining for at least one of the neuroendocrine markers. In conclusion, a careful distinction between invasive SPC and IBC-NST with neuroendocrine differentiation is required. We assume that SPC in situ is a potential candidate for precursor of IBC-NST with neuroendocrine differentiation. MC of the breast is suggested to have two pathogenetic pathways through SPC in situ or non-SPC in situ. SPC in situ is thought to be less common as a precursor of MC than non-SPC in situ.

Small Cell Carcinoma Prostate: A Case Report with Findings on 18-F FDG PET/CT.

Small-cell carcinoma of the prostate (SCCP) is a rare and very aggressive malignancy with neuroendocrine differentiation. In contrast to conventional prostate adenocarcinoma, SCCP is an aggressive carcinoma and portends to have a poor prognosis. Around 50% of these patients have metastatic disease at the first clinical presentation. We report the findings of 18-F fluorodeoxyglucose positron emission tomography/computed tomography in a case of histologically proven SCCP with an unusual finding of the left internal mammary lymph node.

Efficacy of first-line chemotherapy based on primary site of tumor versus etoposide-platinum in advanced gastroenteropancreatic neuroendocrine carcinoma.

Background: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) constitute a rare and aggressive group of malignancies usually with widespread disease. There are limited studies on GEP-NECs, and therefore, we aim to acquire more information on the clinical features, treatment regimens, and prognosis. Methods: Data from advanced GEP-NECs patients who had not previously received systemic treatment for advanced disease at The First Affiliated Hospital of Nanjing Medical University from 2010 to 2022 were retrospectively collected. Relationships between clinical-pathological features, treatment regimens, and prognosis were investigated using Kaplan-Meier curves and cox regression models. Results: A total of fifty-four patients were enrolled in the study. The median age was 65.5 years and 79.6% were male. At diagnosis, 51.9% and 3.7% of patients developed liver and brain metastasis respectively. Sixteen (29.6%) patients received chemotherapy according to primary site of tumor (PST), while thirty-eight (70.4%) were treated with etoposide-platinum (EP) regimen, which based on the first-line treatment of advanced small cell lung cancer (SCLC). No significant differences on progression-free survival (PFS) and response rate were observed between these two groups. Univariate survival analysis showed that liver metastasis, elevated baseline serum carcinoembryonic antigen, elevated baseline serum neuron-specific enolase, elevated baseline serum lactate dehydrogenase, and elevated baseline serum neutrophil-to-lymphocyte ratio (NLR) were associated with shorter PFS. After multivariate analysis, elevated NLR was the only factor that remained significantly associated with shorter PFS (P=0.01). Conclusions: GEP-NECs are aggressive neoplasms, of which elevated NLR is proven to be an independent negative predictor. Treatment regimens based on PST are not inferior to regiments based on SCLC (EP) for GEP-NECs patients. Large-scale, prospective randomized controlled trials are required to establish the standard of care.

Case report: A challenging case of severe Cushing's syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor.

Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%-10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.

EBV-positive small cell neuroendocrine carcinoma of nasopharynx as a probably unique subtype of neuroendocrine carcinoma: a clinicopathologic study of three cases and literature review.

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

Clinicopathologic characteristics and prognostic factors of patients with surgically treated high-grade neuroendocrine carcinoma of the cervix: A multicenter retrospective study.

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

Corrigendum: Cardiac infarction caused by PD-1 inhibitor during small cell neuroendocrine carcinoma of the ureter treatment: a case report.

[This corrects the article DOI: 10.3389/fonc.2023.1114397.].

Complete response induced by nivolumab monotherapy in gastric neuroendocrine carcinoma: a case report.

No standard treatment has been established for gastric neuroendocrine carcinoma (G-NEC). We present the case of a patient with recurrent G-NEC who achieved a complete response (CR) with nivolumab. A woman in her 70 s, with no significant medical or family history of illness, underwent an upper gastrointestinal endoscopy, which revealed a Borrmann type 2 tumor in the gastric antrum. Malignant tumor cells were not detected in the endoscopic biopsy samples; however, a malignant gastric tumor was strongly suspected. Therefore, surgical resection was performed, and the tumor was pathologically diagnosed as a G-NEC with liver metastases. Adjuvant etoposide plus carboplatin was administered for four cycles, but recurrence in the liver was observed 5 months after the completion of adjuvant chemotherapy. Ramucirumab plus paclitaxel and irinotecan were introduced as second and third-line treatments. After these treatments, the mesenteric lymph node metastases expanded. Tumor mutation burden (TMB) was low (five mutations/megabase), and microsatellite instability remained stable. However, programmed death-ligand 1 Combined Positive Score (CPS) was ≥ 5 in the resected sample. Therefore, nivolumab monotherapy was introduced as a fourth-line treatment. The mesenteric lymph node metastases exhibited swelling 3 weeks after the initiation of nivolumab; however, they rapidly shrank, and CR was later achieved. Treatment with nivolumab is currently ongoing for 12 months. This is the first report of nivolumab monotherapy in a patient with G-NEC who showed pseudo-progression. Even in TMB-low and microsatellite stable cases, nivolumab may be a viable option for patients with G-NEC.

Clinical Challenges and Management Strategies in Pulmonary Large-Cell Neuroendocrine Carcinoma.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare but aggressive malignancy of the lung. Its nonspecific presentation and propensity for severe disease at the time of diagnosis create challenges in treatment. We report a case of an asymptomatic 61-year-old female who was incidentally found to have a pulmonary nodule after a fall. Upon further workup, she was found to have an aggressive LCNEC. The patient underwent a robotic-assisted left upper lobectomy, which was complicated by left lower lobe bronchus kinking and post-obstructive atelectasis, warranting further management by thoracic surgery. The patient additionally underwent video-assisted thoracoscopic surgery (VATS), open thoracotomy, pneumopexy, and bronchial stenting. This case highlights the need for strategies for early detection in at-risk populations. A multidisciplinary approach, which may involve both medical and surgical subspecialties, is essential in the management of this complex disease from the time of diagnosis to follow-up postoperatively to achieve the best clinical outcome.

Update in the management of gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine neoplasms are a diverse group of neoplasms that can occur in various areas throughout the body. Well-differentiated neuroendocrine tumors (NETs) most often arise in the gastrointestinal tract, termed gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Although GEP-NETs are still uncommon, their incidence and prevalence have been steadily increasing over the past decades. The primary treatment for GEP-NETs is surgery, which offers the best chance for a cure. However, because GEP-NETs are often slow-growing and do not cause symptoms until they have spread widely, curative surgery is not always an option. Significant advances have been made in systemic and locoregional treatment options in recent years, including peptide-receptor radionuclide therapy with α and ß emitters, somatostatin analogs, chemotherapy, and targeted molecular therapies.

State of the art of cervical cancer treatment in rare histologies.

The objective of this review is to summarize the current scientific evidence to formulate clinical recommendations regarding the classification, diagnostic approach, and treatment of rare histological subtypes of cervical cancer; neuroendocrine carcinoma, gastric-type mucinous adenocarcinoma, and glassy cell adenocarcinoma. These histological subtypes are generally characterized by their low frequency, aggressive biological behavior, certain chemoradioresistance, and consequently, high recurrence rates with a deleterious impact on survival. Molecular studies have identified several associated mutations in neuroendocrine carcinoma (PIK3CA, MYC, TP53, PTEN, ARID1A, KRAS, BRCA2) and gastric-type adenocarcinoma (KRAS, ARID1A, PTEN) that may serve as molecular targets. While adenocarcinomas are typically treated and classified based on squamous histology across early, locally advanced, and advanced stages, the treatment strategies for neuroendocrine carcinomas in early stages or locally advanced cases differ, particularly in the sequencing of administering chemotherapy, chemoradiotherapy, or surgery. The chemotherapy regimen is based on etoposide plus cisplatin (EP). Unlike squamous cell carcinomas, immune checkpoint inhibitors are yet to establish a standard role in the treatment of recurrent neuroendocrine carcinomas due to the absence of clinical trials. Regarding glassy cell adenocarcinomas and gastric-type adenocarcinoma, the potential use of immunotherapy in advanced stages/disease requires further evaluation through international collaborations, given the limited number of cases.

An elderly case of paraneoplastic anti-NMDA receptor encephalitis associated with large cell neuroendocrine carcinoma of the lung.

BACKGROUND: Recent studies have suggested that N-methyl-D-aspartate (NMDA) receptors are involved in the cell proliferation in several tumors. However, there have been no reports demonstrating the expression of NR1 subunit of the NMDA receptor in large cell neuroendocrine carcinoma (LCNEC). CASE PRESENTATION: Here, we report the first elderly case of paraneoplastic anti-NMDA receptor encephalitis associated with LCNEC of the lung with NR1 expression. Of note, NR1 subunit expression in the tumor cells of the present case was confirmed by immunohistochemistry (IHC). Radiation therapy and immunotherapies, such as corticosteroids and intravenous immunoglobulin (IVIG), shrank the tumors and improved neurological symptoms in the present case. Additionally, we also confirmed the expression of NR1 in the tumor cells obtained from three other cases with LCNEC of the lung at our hospital by IHC. CONCLUSION: Our IHC results indicate that LCNEC generally expresses NR1 subunit and NMDA receptor may be involved in the tumor development and growth.

Differential NEUROD1, ASCL1, and POU2F3 Expression Defines Molecular Subsets of Bladder Small Cell/Neuroendocrine Carcinoma with Prognostic Implications.

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and pro-metastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell neuroendocrine carcinomas (LCNEC) assembled in tissue microarrays. Co-expression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified five distinct molecular subtypes in bladder SMC based on expression of ASCL1, NEUROD1 and POU2F3: ASCL1+/NEUROD1- (n=33; 34%), ASCL1-/NEUROD1+ (n=21; 21%), ASCL1+/NEUROD1+ (n=17; 17%), POU2F3+ (n=22, 22%), and ASCL1-/NEUROD1-/POU2F3- (n=5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (p < 0.001). DLL3 expression was high in both SMC (n=72, 82%) and LCNEC (n=11, 85%). YAP1 expression was enriched in non- neuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (p<0.05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1 and POU2F3. POU2F3 expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter recurrence-free and overall survival. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.

Dermoscopic characteristics of Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous tumour with high mortality and frequently delayed diagnosis. Clinically, it often manifests as a rapidly growing erythematous to purple nodule usually located on the lower extremities or face and scalp of elderly patients. There is limited available data on the dermoscopic findings of MCC, and there are no specific features that can be used to definitively diagnose MCC. AIM OF THE STUDY: Here, we aimed to summarize existing published literature on dermatoscopic and reflectance confocal microscopy (RCM) features of MCC. MATERIALS AND METHODS: To find relevant studies, we searched the PubMed and Scopus databases from inception to April 12, 2023. Our goal was to identify all pertinent research that had been written in English. The following search strategy was employed: (" dermoscopy" OR " dermatoscopy" OR " videodermoscopy" OR " videodermatoscopy" OR " reflectance confocal microscopy") AND " Merkel cell carcinoma". Two dermatologists, DK and GE, evaluated the titles and abstracts separately for eligibility. For inclusion, only works written in English were taken into account. RESULTS: In total 16 articles were retrieved (68 cases). The main dermoscopic findings of MCC are a polymorphous vascular pattern including linear irregular, arborizing, glomerular, and dotted vessels on a milky red background, with shiny or non-shiny white areas. Pigmentation was lacking in all cases. The RCM images showed a thin and disarranged epidermis, and small hypo-reflective cells that resembled lymphocytes arranged in solid aggregates outlined by fibrous tissue in the dermis. Additionally, there were larger polymorphic hyper-reflective cells that likely represented highly proliferative cells. CONCLUSION: Dermoscopic findings of MCC may play a valuable role in evaluating MCC, aiding in the early detection and differentiation from other skin lesions. Further prospective case-control studies are needed to validate these results.

Distinctive phenotypic and microenvironmental characteristics of neuroendocrine carcinoma and adenocarcinoma component in gastric mixed adenoneuroendocrine carcinoma.

This study aimed to conduct an in-depth examination of gene expression and microenvironmental profiles of gastric neuroendocrine carcinoma (NEC) and mixed adeno-neuroendocrine carcinoma (MANEC). Tissue microarrays from 55 patients with gastric MANEC (N=32) or NEC (N=23) were analysed using digital spatial profiling (GeoMx® DSP). Representative regions of interest (ROIs) were selected from the adenocarcinoma portion (ADC-MANEC) and neuroendocrine carcinoma portion (NEC-MANEC) of the MANEC cores, and pure NEC (pNEC) cores. All ROIs were separated into epithelial components and stromal components by the masking procedure in GeoMx® platform, followed by transcriptome analysis. Comparison of gene expression between ADC-MANEC and NEC-MANEC/pNEC identified several differentially expressed genes in the epithelial (including PEG10, MAP1B, STMN3, and AKT3) and stromal (FN1, COL1A1, SPARC, and BGN) components. Gene set enrichment analysis revealed that pathways related to the E2F target and G2M checkpoint were more enriched in NEC-MANEC and pNEC than in ADC-MANEC. Deconvolution analysis showed that the microenvironmental profile varied according to histologic differentiation. In ADC-MANEC, intraepithelial infiltrating immune cells were relatively more numerous, while fibroblasts in the stroma were more abundant in NEC-MANEC and pNEC. This study confirmed the distinct expression profile of each histological component of MANEC according to its tumour versus stromal compartment using the DSP platform. Although each component of MANEC shares the same genetic origin, distinctive phenotypes should not be overlooked when managing patients with MANEC. This study provides a useful validation dataset for future studies.