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.
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Humans ; Carcinoma, Neuroendocrine/metabolism* ; Signal Transduction ; Animals ; Neoplasm Metastasis ; Neurons/pathology* ; Tumor Microenvironment ; Cell Communication

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.
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Humans ; Oncogene Proteins, Fusion/metabolism* ; Female ; Lung Neoplasms/enzymology* ; Carcinoma, Neuroendocrine/pathology* ; Middle Aged

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*

Objective: To investigate the clinicopathological characteristics of pancreatic lesions in children. Methods: The clinicopathological data of pancreatic lesions in children were analyzed including 42 cases of pancreatic tumors diagnosed from January 2000 to May 2021 in Guangzhou Women's and Children's Medical Center, Guangzhou, China. Histological and immunohistochemical assessments were performed . Related literature was reviewed. Results: The 42 pediatric patients with pancreatic lesions aged 1 day to 12 years (mean, 4.25 years). There were 23 males and 19 females. Clinical presentations included abdominal masses, abdominal pain, vomiting and persistent hypoglycemia after birth. Ultrasound and computerized tomography examination showed space-occupying pancreatic lesions in 31 cases, but no detectable pancreatic lesions in 11 cases. Histologically, among the 42 cases, 22 cases (52.4%) were neoplastic, including 18 cases of epithelial origin. Nine cases of pancreatoblastoma showed that the epithelial tumor cells were arranged in a trabecular pattern, with squamous nests. Six cases of solid-pseudopapillary tumors revealed hemorrhagic and necrotic cysts and monomorphic epithelioid cells arranged in solid sheets, nests or pseudopapillae. Two cases of neuroendocrine tumors showed tumor cells arranged in cords or nests; one case had a mitotic count of about 3/10 high power field, and a Ki-67 index of about 5%, which was consistent with G2 neuroendocrine tumor; the other case showed tumor cells with cytological atypia, brisk mitoses, about 25/10 HPF and a Ki-67 index of about 80%, consistent with small-cell type neuroendocrine carcinoma. The case of acinar cell carcinoma showed high cellularity, tumor cells in solid, cord-like or acinar-like arrangement with little stroma, and monotonous tumor cells with single distinct nucleolus. There were 4 cases of mesenchymal tumors, including 3 cases of Kaposi's hemangioendothelioma and 1 case of inflammatory myofibroblastic tumor. Among the 20 cases (47.6%) of non-neoplastic lesions, there were 11 cases of hyperinsulinism with ATP-sensitive potassium channel abnormality (HAPCA). Severn cases of diffuse type HAPCA in which the islets scattered between the pancreatic acinar tissue, enlarged, and prominent nuclei. Three cases of focal type HAPCA showed pancreatic islet hyperplasia in the form of nested nodules (0.6-1.5 cm). One case of atypical type HAPCA had extensive islet hyperplasia in pancreatic tissue, and scattered proliferation of nest-like nodules was noted. There were also 7 cases of pseudocyst and 2 cases of congenital cyst. Immunohistochemically, pancreatoblastomas were diffusely positive for CKpan, CK8/18, and β-catenin (nuclear staining of squamous nests only). Solid-pseudopapillary tumors expressed CD10, cyclin D1, CD99, vimentin, CD56, and β-catenin (nuclear staining). Neuroendocrine tumors were positive for CK, Syn, NSE, CgA, CD56, and β-catenin (membranous staining). The acinar cell carcinoma was positive for CK8/18, trypsin, and β-catenin (membranous staining). Conclusions: Pancreatic lesions in children have a wide range of histopathological types. HAPCA is the most common lesion of newborns. Pediatric pancreatic tumors are rare and mostly malignant. It is important to recognize them and make correct pathological diagnoses.
Carcinoma, Acinar Cell/pathology* ; Carcinoma, Squamous Cell ; Child ; Female ; Humans ; Hyperplasia ; Infant, Newborn ; Ki-67 Antigen ; Male ; Neuroendocrine Tumors ; Pancreatic Neoplasms/metabolism* ; beta Catenin/analysis*

BACKGROUND: Classification of the pulmonary neuroendocrine tumor (pNET) categories is a step-wise process identified by the presence of necrosis and number of mitoses per 2 mm. In neuroendocrine tumor pathology, Ki-67 was first described as a prognostic factor in the pancreas and incorporated into the grading system of digestive tract neuroendocrine neoplasms in the 2010 WHO classification. However, the significance of Ki-67 in pNETs was still a controversial issue. This study was to investigate the potentially diagnostic value of Ki-67 in pNETs. METHODS: We retrieved 159 surgical specimens of pNETs, including 35 typical carcinoids (TCs), 2 atypical carcinoid (ACs), 28 large-cell neuroendocrine carcinomas (LCNECs), 94 small-cell lung cancers (SCLCs). Manual conventional method (MCM) and computer-assisted image analysis method (CIAM) were used to calculate the Ki-67 proliferative index. In CIAM, 6 equivalent fields (500 × 500 μm) at 10× magnification were manually annotated for digital image analysis. RESULTS: The Ki-67 index among the 4 groups with ranges of 0.38% to 12.66% for TC, 4.34% to 29.48% for AC, 30.67% to 93.74% for LCNEC, and 40.71% to 96.87% for SCLC. The cutoff value of Ki-67 index to distinguish low grade with high grade was 30.07%. For the univariate survival analyses in pNETs, both the overall survival and progression-free survival correlated with Ki-67 index. In addition, the Ki-67 index performed by CIAM was proved to be of great positive correlation with MCM. CONCLUSIONS Ki-67 index counted by CIAM is a reliable method and can be a useful adjunct to classify the low- and high-grade NETs.
Adult ; Aged ; Aged, 80 and over ; Carcinoma, Neuroendocrine ; metabolism ; pathology ; Female ; Humans ; Immunohistochemistry ; Ki-67 Antigen ; metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell ; metabolism ; pathology ; Male ; Middle Aged ; Neuroendocrine Tumors ; metabolism ; pathology ; Prognosis ; World Health Organization

Carcinoma, Medullary ; metabolism ; Carcinoma, Neuroendocrine ; Humans ; NAD(P)H Dehydrogenase (Quinone) ; metabolism ; NADP ; metabolism ; Neoplasm Proteins ; metabolism ; Prognosis ; Thyroid Neoplasms ; metabolism

Sunitinib is a multi-target tyrosine kinase inhibitor used to treat gastrointestinal stromal tumors, renal cell carcinoma, and pancreatic neuroendocrine tumors. The most common adverse reactions are known to be nausea, fatigue, diarrhea, stomatitis, esophagitis, hypertension, skin toxicity (hand-foot syndrome), hypothyroidism, and reduction in the cardiac output of the left ventricle. Herein, we report the case of a 57 year-old female who visited our hospital complaining of epigastric pain. She had been taking sunitinib at 25 mg/day to treat a metastatic pancreatic neuroendocrine tumor. Upon computed tomography performed on admission, we observed that fluid had collected around the pancreas. Laboratory analysis revealed hypertriglyceridemia (triglycerides 993 mg/dL). Tyrosine kinase inhibitors are known to have limited effects on lipid metabolism. In this case, we suggest that hyperglycemia seems to have had a limited effect on lipid levels. We are rather of the view that hyperglycemia, a history of distal pancreatectomy, and hypothyrodisim, indirectly caused the observed hypertriglyceridemia.
Carcinoma, Renal Cell ; Cardiac Output ; Diarrhea ; Esophagitis ; Fatigue ; Female ; Gastrointestinal Stromal Tumors ; Heart Ventricles ; Humans ; Hyperglycemia ; Hypertension ; Hypertriglyceridemia* ; Hypothyroidism ; Lipid Metabolism ; Nausea ; Neuroendocrine Tumors* ; Pancreas ; Pancreatectomy ; Protein-Tyrosine Kinases ; Skin ; Stomatitis

OBJECTIVETo analyze the clinicopathological features of pancreatic neuroendocrine neoplasms (P-NENs).

METHODSFrom January 2006 to December 2010, 64 patients with P-NENs were diagnosed in the Department of Pathology, West China Hospital, Sichuan University. Immunohistochemical staining of neuroendocrine markers, synaptophysin (Syn) and chromogranin A (CgA), were first made to determine whether the tumor had neuroendocrine properties, then the P-NENs were classified as neuroendocrine tumor (NET), neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC, G3) according to the morphological changes and proliferative activity (Ki 67 expression).

RESULTSOf all the 64 cases detected, 60 were NETs and four were NEC. Most of the tumors were single solitary masses, and more than half of the tumors arose in the head of the pancreas, while about one third in the tail. The positive rates of CgA and Syn immunostaining were 96.9% and 95.3%, respectively. The tumor stages of the 64 patients were as follows: stage I, 44 cases; stage II, 11 cases; stage III, one case; and stage IV, 8 cases. The median age of patients in the study was 45.56 years. Of all the P-NENs, 38 cases were functional ones, presenting with characteristic clinical syndrome owing to hormone hypersecretion, while 26 cases were nonfunctional ones with no distinct clinical syndrome. 58 patients underwent surgical operation. The 5-year progression-free survival rate was 91.4%.

CONCLUSIONSP-NENs may occur anywhere in the pancreas, and the clinical manifestations may not be easy to distinguish from other diseases. Diagnosis depends on pathological examination. Surgery is the major approach option, and the clinical prognosis is rather good. The tumor histological grade and distant metastasis are independent prognostic factors in P-NENs.

Adult ; Aged ; Carcinoma, Neuroendocrine ; metabolism ; pathology ; secondary ; surgery ; therapy ; Chemoembolization, Therapeutic ; Chromogranin A ; metabolism ; Disease-Free Survival ; Female ; Humans ; Liver Neoplasms ; secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Neuroendocrine Tumors ; metabolism ; pathology ; secondary ; surgery ; therapy ; Pancreatic Neoplasms ; metabolism ; pathology ; surgery ; therapy ; Retrospective Studies ; Survival Rate ; Synaptophysin ; metabolism ; Young Adult

Adult ; CD56 Antigen ; metabolism ; Carcinoma, Neuroendocrine ; metabolism ; pathology ; surgery ; Humans ; Ki-67 Antigen ; metabolism ; Male ; Mediastinal Neoplasms ; metabolism ; pathology ; surgery ; Mediastinum ; pathology ; surgery ; Phosphopyruvate Hydratase ; metabolism ; Synaptophysin ; metabolism

OBJECTIVETo study the clinicopathologic characteristics of parathyroid carcinoma (PTC).

METHODSEleven cases of PTC encountered during the period from 1994 to 2012 were enrolled into the study. Forty cases of parathyroid adenoma (PA) were also retrieved for comparison. The clinical manifestations, laboratory results and pathologic features were analyzed, with literature review.

RESULTSThe main clinical manifestations of PTC included neck mass (11/11), hypercalcemia (11/11) and hyperparathyroidism (11/11). Most patients also had osteoporosis (10/11). In contrast, PA often manifested as hypercalcemia (40/40) and hyperparathyroidism (40/40). Histologic examination of PTC showed that the tumor cells contained clear to eosinophilic cytoplasm and separated by dense bands of fibrosis. The tumor mass was surrounded by thick fibrous capsule. Foci of capsular invasion and vascular permeation were identified at the tumor periphery in all cases. Cellular atypia was not conspicuous but mitotic figures and coagulative necrosis were easily identified. On the other hand, PA were composed of tumor cells with clear to eosinophilic cytoplasm, forming glands, trabeculae or nests. Most of them (35/40) had intact fibrous capsule. Mitotic figures were rarely encountered and tumor necrosis was absent. Immunohistochemical study showed that the tumor cells in PTC were positive for CK19 (11/11), chromogranin A (9/11), synaptophysin (7/11) and parathyroid hormone (11/11). They were negative for thyroglobulin, TTF-1 and calcitonin. The Ki-67 index was less than 10% (range = 2% to 9%). In contrast, the tumor cells in PA were positive (40/40) for CK19, chromogranin A, synaptophysin and parathyroid hormone. They were negative for thyroglobulin, TTF-1 and calcitonin. The Ki-67 index was less than 3%. Follow up-data were available in 9 cases of PTC (duration of follow up = 11 months to 224 months) and 7 of the patients were still alive. Follow up of all PA cases showed no evidence of recurrence.

CONCLUSIONSPTC is a rare malignant endocrine tumor presenting as neck mass. Histologic features suggestive of malignant behavior include presence of coagulative tumor necrosis and capsular/vascular invasion. It needs to be distinguished from other entities such as parathyroid adenoma, papillary thyroid carcinoma and medullary thyroid carcinoma.

Adenoma ; metabolism ; pathology ; Adult ; Carcinoma ; metabolism ; pathology ; Carcinoma, Neuroendocrine ; Carcinoma, Papillary ; Chromogranin A ; metabolism ; Diagnosis, Differential ; Female ; Follow-Up Studies ; Humans ; Hypercalcemia ; etiology ; Hyperparathyroidism ; etiology ; Immunohistochemistry ; Keratin-19 ; metabolism ; Male ; Middle Aged ; Osteoporosis ; etiology ; Parathyroid Hormone ; metabolism ; Parathyroid Neoplasms ; complications ; metabolism ; pathology ; surgery ; Synaptophysin ; metabolism ; Thyroid Neoplasms ; metabolism ; pathology