Humans ; Female ; Uterine Cervical Neoplasms/pathology* ; Carcinoma, Neuroendocrine/pathology* ; Consensus ; Prognosis ; Neoplasm Staging ; Cervix Uteri/pathology*

Neuroendocrine carcinoma (NEC) represents a category of malignant tumors originating from neuroendocrine cells. Given that NEC cells exhibit characteristics of both neural and endocrine cells, they can hijack neuronal signaling pathways and dynamically regulate the expression of neuronal lineage markers during tumor metastasis, thereby constructing a microenvironment conducive to tumor growth and metastasis. Conversely, alterations in the tumor microenvironment can enhance the interactions between neurons and tumor cells, ultimately synergistically promoting the metastasis of NEC. This review highlights recent advancements in the field of cancer neuroscience, uncovering neuronal lineage markers in NEC that facilitate tumor dissemination through mediating crosstalk, bidirectional communication, and synergistic interactions between tumor cells and the nervous system. Consequently, the latest findings in tumor neuroscience have enriched our understanding of the biological mechanisms underlying tumor metastasis, opening new research avenues for a deeper comprehension of the complex biological processes involved in tumor metastasis, particularly brain metastasis. This review provides a comprehensive review of the crosstalk between tumor cells and neural signaling in the metastasis of NEC.
.
Humans ; Carcinoma, Neuroendocrine/metabolism* ; Signal Transduction ; Animals ; Neoplasm Metastasis ; Neurons/pathology* ; Tumor Microenvironment ; Cell Communication

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine tumor with unique characteristics, and its treatment regimens are primarily derived from those for small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In recent years, the incidence rate has been on the rise, and the prognosis are affected by the interaction of multiple factors such as individual, clinical stage and treatment mode, and the heterogeneity is significant. In the study of molecular subtypes, multiple subgroups were divided according to key gene mutations such as RB1 and TP53, and genomic subtypes were associated with survival, chemotherapy response, and efficacy of precision therapy. Targeted therapy excavates multiple targets, and the efficacy of drugs is different. Immunotherapy has made remarkable progress, and immune checkpoint inhibitors (ICIs) have been effective in all stages of chemotherapy alone or in combination with chemotherapy or radiation therapy, but there is a risk of hyperprogressive diseases, and accurate prognostic markers need to be explored urgently. This review reviews the latest research progress in the study of molecular subtypes and precision therapies such as targeted therapy and immunotherapy of pulmonary LCNEC, and points out that pulmonary LCNEC treatment will develop in the direction of precision and individualization in the future.
.
Humans ; Lung Neoplasms/drug therapy* ; Carcinoma, Neuroendocrine/drug therapy* ; Precision Medicine ; Immunotherapy ; Carcinoma, Large Cell/drug therapy*

Neuroendocrine carcinoma (NEC), a subtype of neuroendocrine tumors with high proliferative activity, is characterized by strong invasiveness and poor prognosis. This article reports a previously healthy female non-smoker who developed NEC occurring sequentially in different lobes of both lungs. The lesions were pathologically diagnosed by hematoxylin-eosin (HE) staining as large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC), respectively. Next-generation sequencing (NGS) performed on both lesions revealed the presence of echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion mutations in both lesions. Notably, the patient achieved a significant therapeutic response to ALK-tyrosine kinase inhibitors (TKIs) targeted therapy.
.
Humans ; Oncogene Proteins, Fusion/metabolism* ; Female ; Lung Neoplasms/enzymology* ; Carcinoma, Neuroendocrine/pathology* ; Middle Aged

Neoplasms characterized by the expression of markers of neuroendocrine differentiation in neoplastic cells are defined as neuroendocrine neoplasms. A case of neuroendocrine carcinomas (NECs) with a small amount of papillary adenocarcinoma and significantly vacuolar nucleus at the esophagogastric junction was reported in this article. A 77-year-old male had dysphagia for one week. Endoscopy revealed early-stage esophagogastric junction carcinoma, and biopsy was diagnosed as poorly differentiated carcinoma. Endoscopic submucosal dissection was performed. Histologically, the papillary adenocarcinoma progresses from typically branching papillary structures (well-differentiated) to hyperplasia of the lining epithelium of the papilla to form a cribriform structure (moderately differentiated), to solid area lacking papillary structures (poorly differentiated). There was a continuous process, and during this process, the vacuoles in the nuclei of tumor cells showed progressive changes from mild to obvious and finally to significant vacuoles. The tumor was mainly composed of solid areas (about 95%), with single cell, large cell, round or oval to irregular nuclei, and significantly vacuolar nuclei, nuclei with larger vacuoles appeared in a loop, a few thin weakly basophilic or weakly eosinophilic fine particles could be seen in the vacuoles, and the vacuoles had rough edges. The nucleus chromatin at the outer edge of the vacuoles was fine particles, and mitosis was common (20-30/mm²), atypical mitosis could be seen, and nucleoli could be seen easily, the cytoplasm was weakly eosinophilic, and the boundaries of cells were unclear. The cells were arranged in a nested, trabecular, or diffuse sheet shape, with some arranged in a glandular tube shape. Tumor thrombus was found in the vein of submucosa; the interstitial tissue rich in capillaries within the tumor was accompanied by a large number of neutrophil infiltration. Immunohistochemical staining showed that the solid area of the tumor was positive for synaptophysin (Syn) and chromogranin A (CgA), while papillary adenocarcinoma was negative. Mucin 5AC (MUC5AC) was diffusely positive in papillary adenocarcinoma, while the proportion of positive cells in the solid area of the tumor was about 10% to 15%. In a word, this case showed the extreme situation of the vacuolar nuclear characteristics of NECs, extremely rare, in a sense, this case expanded the boundary of the morphological spectrum of NECs. Understanding the extreme vacuolar features of this nucleus is helpful to make a correct pathological diagnosis.
Humans ; Male ; Esophagogastric Junction/pathology* ; Aged ; Carcinoma, Neuroendocrine/pathology* ; Vacuoles/pathology* ; Esophageal Neoplasms/pathology* ; Cell Nucleus/pathology* ; Adenocarcinoma, Papillary/pathology* ; Stomach Neoplasms/pathology*

Humans ; Herpesvirus 4, Human ; Epstein-Barr Virus Infections ; Carcinoma, Small Cell ; Nasopharynx/pathology* ; Carcinoma, Neuroendocrine/pathology* ; Nasopharyngeal Neoplasms/pathology*

Objective To investigate the clinicopathological features,immunohistochemical features,diagnosis,and relationship with sporadic prostate cancer in primary small cell neuroendocrine carcinoma of the bladder. Methods We retrospectively analyzed the clinical characteristics of 12 patients with primary small cell neuroendocrine carcinoma of the bladder diagnosed at Beijing Chao-Yang Hospital affiliated to Capital Medical University from January 2013 to September 2022.The histological features of primary small cell neuroendocrine carcinoma of the bladder were re-evaluated by two pathologists according to the 2022 revision of the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs.Electronic medical records were retrieved,and telephone follow-up was conducted from the time of histopathological diagnosis to the death or the end of the last follow-up until January 31,2023. Results The 12 patients include 7 patients in pT3 stage and 1 patient in pT4 stage.Eight patients were complicated with other types of tumors,such as high-grade urothelial carcinoma of the bladder and squamous cell carcinoma.Five patients had sporadic prostate cancer.Immunohistochemical staining showed that 12 (100.0%),10 (83.3%),and 8 (66.7%) patients were tested positive for CD56,Syn,and CgA,respectively.The Ki67 proliferation index ranged from 80% to 90%.Five patients with urothelial carcinoma were tested positive for CK20,GATA3,and CK7.P504S was positive in all the 5 patients with prostate cancer,while P63 and 34βE12 were negative.The follow-up of the 12 patients lasted for 3-60 months.Eight of these patients died during follow-up,with the median survival of 15.5 months.Four patients survived. Conclusions Primary small cell neuroendocrine carcinoma of the bladder is a rare urological tumor with high aggressiveness and poor prognosis.In male patients with bladder prostatectomy,all prostate tissue should be sampled.If prostate cancer is detected,the prostate-specific antigen level should be monitored.
Humans ; Male ; Carcinoma, Transitional Cell/pathology* ; Carcinoma, Neuroendocrine/pathology* ; Urinary Bladder Neoplasms/pathology* ; Urinary Bladder/pathology* ; Retrospective Studies ; Prostatic Neoplasms ; Biomarkers, Tumor

Objective: To investigate the clinicopathological characteristics of superior mediastinal lymph node metastases (sMLNM) in medullary thyroid carcinoma (MTC). Methods: This retrospective analysis enrolled the patients who were treated for sMLNM of MTC in our hospital from May 2012 to January 2021. All patients were suspected of sMLNM due to preoperative imaging. According to the pathological results, the patients were divided into two groups named sMLNM group and the negative superior-mediastinal-lymph-node group. We collected and analyzed the clinical features, pathological features, pre- and post-operative calcitonin (Ctn), and carcinoembryonic antigen (CEA) levels of the two groups. Logistic regression analysis was used to analyze risk factors, and receiver operation characteristic (ROC) curves were drawn to determine the optimal cut-off values of preoperative Ctn and preoperative CEA for predicting sMLNM. Results: Among the 94 patients, 69 cases were in the sMLNM group and 25 cases were in the non-SMLNM group. Preoperative Ctn level (P=0.003), preoperative CEA level (P=0.010), distant metastasis (P=0.022), extracapsular lymph node invasion (P=0.013), the number of central lymph node metastases (P=0.002) were related to sMLNM, but the multivariate analysis did not find any independent risk factors. The optimal threshold for predicting sMLNM by pre-operative Ctn is 1500 pg/ml and AUC is 0.759 (95% CI: 0.646, 0.872). The sensitivity, specificity, positive predictive value, and negative predictive value of diagnosis are 61.2%, 77.3%, 89.1%, 39.5%, respectively. In patients who underwent mediastinal lymph node dissection through transsternal approach, the metastatic possibility of different levels from high to low were level 2R (82.3%, 28/34), level 2L (58.8%, 20/34), level 4R (58.8%, 20/34), level 3 (23.5%, 8/34), level 4L (11.8%, 4/34). Postoperative complications occurred in 41 cases (43.6%), and there was no perioperative death in all cases. 14.8% (12/81) of the patients achieved biochemical complete response (Ctn≤12 pg/ml) one month after surgery, 5 of these patients were in sMLNM group. Conclusions: For patients who have highly suspicious sMLNM through imaging, combining with preoperative Ctn diagnosis can improve the accuracy of diagnosis, especially for patients with preoperative Ctn over 1 500 pg/ml. The superior mediastinal lymph node dissection for the primary sternotomy should include at least the superior mediastinal levels 2-4 to avoid residual lesions. The strategy of surgery needs to be cautiously performed. Although the probability of biochemical cure in sMLNM cases is low, nearly 40% of patients can still benefit from the operation at the biochemical level.
Humans ; Carcinoembryonic Antigen ; Lymphatic Metastasis/pathology* ; Retrospective Studies ; Lymph Nodes/pathology* ; Thyroid Neoplasms/pathology* ; Carcinoma, Neuroendocrine/pathology* ; Lymph Node Excision/methods*

Objective: To investigate the clinicopathological features, treatment and prognosis of maxillofacial neuroendocrine carcinoma. Methods: A total of 11 patients with maxillofacial neuroendocrine carcinoma diagnosed in the Department of Pathology of The First Affiliated Hospital of Zhengzhou University from December 2010 to July 2022 were retrospectively enrolled, including 8 males and 3 females, aged (65.2±9.5) years (ranged from 49 to 87 years), with a disease course of 0.5 to 6.0 months. The clinicopathological data including head and neck CT, MRI and treatment methods were analyzed. Results: Submandibular gland and maxilla were involved in 3 cases, parapharynx in 2 cases, and face, tongue root and soft palate in 1 case respectively. Clinically, the initial symptom is a rapidly growing painless or tender mass, which may be accompanied by restricted mouth opening, dysphagia, and local numbness after invasion of masticatory muscles and nerves. The tumors were all invasive and low-density, with unclear boundaries from the surrounding tissues. Among the patients, 9 received surgical treatment, and 5 received adjuvant treatment after surgery (2 received chemotherapy, 3 received radiotherapy+chemotherapy). According to the 5th edition of the World Health Organization classification of head and neck tumors in 2022, there were 1 case (1/11) with poorly differentiated large cells and 10 cases (10/11) with poorly differentiated small cells. Histologically, the macrocell type is composed of large cells with rough chromatin, obvious vacuolar nucleolus, protruding nucleolus, and necrosis. The small cell type is dominated by small blue round cells with neuroendocrine characteristics, with active growth and multifocal necrosis. Immunohistochemical staining showed that cytokeratin (CK), epithelial membrane antigen (EMA) and synaptophysin (Syn) were diffusively expressed, 10 cases expressed CD56, 8 cases expressed p63, 6 cases expressed weakly punctated chromograin-A (CgA), and S-100 was not expressed. The Ki-67 index ranges from 20 to 90 percent. By the end of follow-up (0.5 to 127.0 months), 3 patients were alive, and the mean progression-free survival (21.0 months) of postoperative chemoradiotherapy patients was significantly longer than that of surgery and/or chemotherapy alone (3.3 months). Conclusions: Maxillofacial neuroendocrine carcinoma is characterized by low differentiation of small cells, high degree of malignancy and poor prognosis. Radical surgery combined with chemoradiotherapy has better local control effect.
Male ; Female ; Humans ; Carcinoma, Small Cell/therapy* ; Retrospective Studies ; Carcinoma, Neuroendocrine/pathology* ; Prognosis ; Tongue

The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK^6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK^6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK^6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK^6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK^6/7 in cells. These results suggested that FAK^6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.
Female ; Humans ; Alternative Splicing ; Breast Neoplasms/metabolism* ; Carcinoma, Pancreatic Ductal/pathology* ; Focal Adhesion Protein-Tyrosine Kinases/therapeutic use* ; Nerve Tissue Proteins/genetics* ; Neuroendocrine Tumors/genetics* ; Oncogenes ; Pancreatic Neoplasms/metabolism*