Exocytosis,endocytosis and recycling of secretory vesicles in neuroendocrine cells,and its regulation by cortical actin

The cortical actin network is a mesh of filaments distributed beneath the plasmalemma that dynamically reacts in response to stimuli.This dynamic network of cortical filaments,together with motor myosin partners,adjusts the plasmalemma tension,organizes membrane protein microdomains,remodels the cell surface and drives vesicle motion in order to fine-tune exocytosis,endocytosis and recycling of secretory vesicles.In this review,we discuss how these mechanisms work in secretory cells.

AN IMMUNOHISTOCHEMICAL STUDY OF NEUROENDOCRINE CELLS IN COLONIC CARCINOMA

Seventy-four cases of colonic cancer were studied by immunohistochemistry using anti-Chromogranin A,gastrin, somatostatin, serotonin, glucogon and human chorionic gonadotropin (HCG) to observe the neuroendocrine cell in colonic cancer. It was found that 27of 74 colonic carcinoma showed variable extent of CgA staining (36.5%). Glucagon and HCG was differently the most frequent in hormone antigens in colonic cancer and in metastatic lymph nodes. The endocrine positive colonic carcinomas are more frequent in poorly-differentiated than in well-differentiated (P<0.05). It suggests that there were different NE cells Producing different hormones in colonic cancer. Different hormones may act on different types of colonic cancer.

Gastric neuroendocrine tumors in a BRCA2 germline mutation carrier:A case report

BACKGROUND The molecular changes present in gastric neuroendocrine tumors(NETs)include a loss of heterozygosity or mutation of MEN1,CDKN1B gene mutation,P27 heterozygous mutation,and ATP4A gene missense mutation.We identified and are the first to report a case of type 1 histamine-producing enterochromaffin-like cell NETs(ECL-cell NETs)with a BRCA2 gene germline mutation.CASE SUMMARY The patient had a history of iron-deficient anemia for 5 years,and gastroscopic examination indicated multiple gastric tumors.Then,the patient underwent distal gastrectomy.Microscopically,multifocal tumor cells were found in the mucosa and submucosa;tumor cells were organoid and arranged in nests and cords,and the stroma was rich in sinusoids.The surrounding gastric mucosa showed atrophy with mild intestinal metaplasia or pseudopyloric gland metaplasia.Neuroendocrine cells could be seen with diffuse linear,nodular,and adenomatous hyperplasia.Immunohistochemically,the tumor cells diffusely expressed cytokeratin,chromogranin,synaptophysin,and CD56.Whole-genome highthroughput molecular sequencing revealed a pathogenic germline mutation in the BRCA2 gene,a heterozygous germline frameshift mutation in exon 11,c.6443_6444del(p.S2148Yfs*2).The final diagnosis was gastric type 1 ECL-cell NETs with a BRCA2 gene germline mutation,accompanied by autoimmune gastritis.CONCLUSION This is the first report of a case of type 1 gastric ECL-cell NETs with a pathogenic germline mutation of the BRCA2 gene.The findings of this report will expand the germline mutation spectrum of gastric NETs and increase the understanding of the molecular changes present in these tumors for their improved diagnosis in the future.

Multifocal neuroendocrine cell hyperplasia accompanied by tumorlet formation and pulmonary sclerosing pneumocytoma:A case report

BACKGROUND Pulmonary tumorlets are nodular hyperplastic neuroendocrine cells(NECs)that extend beyond the basement membrane.They often coexist with other lung diseases such as fibrosis and bronchiectasis,but rarely accompanied by pulmonary sclerosing pneumocytoma(PSP),which has not been reported in the literature.CASE SUMMARY A 54-year-old woman was admitted to the hospital because she had symptoms of bloody sputum for more than 4 mo and hemoptysis for 1 wk.Computed tomography images showed atrophy accompanied by infections in the middle lobe of her right lung.Moreover,numerous nodules were identified in the middle lobe of the right lung.The patient underwent thoracoscopic pneumonectomy of the middle lobe of the right lung,and the resected mass was pathologically confirmed to have bronchiectasis,multifocal NEC hyperplasia accompanied by tumorlet,and PSP.CONCLUSION Our report presents a rare clinical case of bronchiectasis complicated with multifocal NEC hyperplasia,tumorlet,and PSP.

Pure large cell neuroendocrine carcinoma originating from the endometrium: A case report

BACKGROUND Large cell neuroendocrine carcinoma(LCNEC)of the endometrium is an uncommon and highly aggressive tumor that has not been comprehensively characterized.We report a case of pure endometrial LCNEC and review the current literature of similar cases to raise awareness of the histological features,treatment,and prognosis of this tumor.CASE SUMMARY We report the case of a 73-year-old woman who presented with irregular postmenopausal vaginal bleeding.Ultrasonography showed an enlarged uterus and a 5.1 cm×3.3 cm area of medium and low echogenicity in the uterine cavity.Biopsy by dilatation and curettage suggested poorly differentiated carcinoma.Magnetic resonance imaging revealed a heterogeneously enhanced uterine tumor with diffuse infiltration of the posterior wall of the uterine myometrium and enlarged pelvic lymph nodes.The patient underwent a hysterectomy and bilateral adnexal resection.Gross observation revealed an ill-defined white solid mass of the posterior wall of the uterus infiltrating into the serosa with multiple solid nodules on the serous surface.Microscopically,the tumor cells showed neuroendocrine morphology(organoid nesting).Immunohistochemistry revealed the tumor cells were diffusely positive for the neuroendocrine markers CD56,chromogranin A,and synaptophysin.Thus,the tumor was diagnosed as stage IIIC endometrial LCNEC.CONCLUSION Pathologic findings and immunohistochemistry are essential in making a diagnosis of endometrial LCNEC.

Large cell neuroendocrine carcinoma of the ampulla of Vater

BACKGROUND: Neuroendocrine tumors of the ampulla of Vater are extremely rare, and few cases of large cell neuroendocrine carcinoma (LCNEC) of the ampulla have been reported. METHODS: A 48-year-old male with obstructive jaundice was admitted to our hospital. On examination the patient was found to have a periampullary growth and subsequently underwent the Whipple's procedure. RESULTS: Histopathological examination and immunohistochemistry revealed features of LCNEC of the ampulla of Vater. The patient developed multiple liver metastases 6 months after Whipple's procedure. CONCLUSION: LCNEC of the ampulla of Vater is rare and highly aggressive, with a dismal prognosis.

Silent advanced large cell neuroendocrine carcinoma with synchronous adenocarcinoma of the colon:A case report

BACKGROUND Large cell neuroendocrine carcinoma(LCNEC)accounts for about 0.25%of colorectal cancer patients.Furthermore,synchronous LCNEC and adenocarcinoma coexistence in the colon is very rare.LCNEC are usually aggressive and have a poor prognosis.Usually,colorectal LCNEC patients complain of abdominal symptoms such as pain,diarrhea or hematochezia because it is often diagnosed as an advanced disease that accompanies metastatic lesions.CASE SUMMARY We describe a case of relatively asymptomatic synchronous LCNEC and colon adenocarcinoma.A 62-year-old male patient visited our hospital due to anemia detected by a local health check-up.He did not complain of melena,hematochezia or abdominal pain.Physical examination was unremarkable and his abdomen was soft,nontender and nondistended with no palpable mass.Laboratory tests revealed anemia with hemoglobin 5.1 g/dL.Colonoscopy revealed an ulcerofungating lesion in the ascending colon and about a 1.5 cm-sized large sessile polyp in the sigmoid colon.Endoscopic biopsy of the ascending colon lesion revealed the ulcerofungating mass that was LCNEC and endoscopic mucosal resection at the sigmoid colon lesion showed a large polypoid lesion that was adenocarcinoma.Multiple liver,lung,bone and lymph nodes metastasis was found on chest/abdominal computed tomography and positron emission tomography.The patient was diagnosed with advanced colorectal LCNEC with liver,lung,bone and lymph node metastasis(stage IV)and synchronous colonic adenocarcinoma metastasis.In this case,no specific symptom except anemia was observed despite the multiple metastases.The patient refused systemic chemotherapy and was discharged after transfusion.CONCLUSION We report a case of silent LCNEC of the colon despite the advanced state and synchronous adenocarcinoma.

Solitary pituitary metastasis resulting from pulmonary large cell neuroendocrine carcinoma

Solitary pituitary metastasis is a rare phenomenon in human neoplasms. We report a case of lung cancer with the initial manifestation of endocrinopathy resulting from pituitary metastasis. The patient's initial diagnosis was a poorly differentiated carcinoma, however, morbid anatomy revealed a definite diagnosis of large cell neuroendocrine carcinoma(LCNEC). Clinical physicians should be aware of potential initial manifestations such as endocrine abnormalities including panhypopituitarism and diabetes insipidus due to solitary pituitary metastasis. This case demonstrates that an endocrine abnormality such as panhypopituitarism could be an initial manifestation of LCNEC.

Case report of a mixed pulmonary large cell neuroendocrine carcinoma

A 57 year-old male patient was found to have a lesion in the middle lobe of his right lung using chest computed tomography(CT).Tumor cells were detected,and surgical excision was performed.The patient was diagnosed with mixed large cell neuroendocrine carcinoma,and underwent six cycles of a chemotherapy regimen comprising etoposide combined with cisplatin.Genetic testing revealed an EGFR mutation,which prompted oxitinib-targeted therapy.To date,no signs of recurrence or metastasis have been reported.

Primary large cell neuroendocrine carcinoma of the bladder:A case report

BACKGROUND Large cell neuroendocrine carcinoma(LCNEC)of the bladder is a rare nonurothelial tumor of the bladder.The treatment of LCNEC of the bladder is different from that of urothelial carcinoma(UC);therefore,early and accurate diagnosis is particularly important.As LCNEC of the bladder is rare and its clinical symptoms and radiographic features are similar to those of urothelial tumors,the clinical diagnosis of the disease remains challenging.CASE SUMMARY We report a 72-year-old female patient who presented with gross hematuria for 3 mo.A solitary tumor located in the anterior wall of the bladder was found by cystoscopy.Pathological examination after biopsy suggested UC of the bladder in the absence of immunohistochemical assessment.The patient underwent partial cystectomy and was finally diagnosed with LCNEC(pT2bN0M0)based on the results of postoperative immunohistochemical examination.During the 10-mo follow-up,no signs of tumor recurrence or metastasis were found.CONCLUSION Immunohistochemical examination is essential for diagnosing LCNEC of the bladder.Accurate diagnosis and multidisciplinary treatment in the early stage of the disease are crucial for improving the prognosis.

Large cell neuroendocrine carcinoma transformation:A novel acquired drug resistance mechanism in colorectal adenocarcinoma

Acquired resistance is a major problem limiting the clinical efficacy of treatments for metastatic colorectal cancer(mCRC).Histological transformation is an important mechanism underlying the acquired resistance of non-small cell lung cancer and prostate cancer to targeted therapy.However,no report has examined the role of histological transformation in mCRC.Here,we report the first case of histologically transformed large cell neuroendocrine carcinoma from primary colon adenocarcinoma during antiangiogenesis and anti-PD-1 combination therapy.The histologic conversion was confirmed by the observation that the transformed large cell neuroendocrine carcinoma lesion retained the original mutational signature found in the primary tumor.Sequential tumor biopsy and dynamic changes in tumor markers demonstrated the transformed process.The histological transformation not only resulted in discordant responses to the same treatment but also significantly shortened overall survival.This case calls for more attention to histological transformation in mCRC.Tumor rebiopsy upon disease progression and monitoring dynamic changes in tumor markers would help to identify such cases.

Biological characteristics of breast carcinomas with neuroendocrine cell differentiation

Background The aim of this study was to investigate DNA content and expression of c-erbB-2, PS2, and prostate-specific antigen (PSA) proteins in breast carcinomas with neuroendocrine (NE) cell differentiation.Methods Chromogranin, c-erbB-2, PS2, and PSA in 131 samples of breast cancer were detected immunohistochemically. Classic Feulgen staining image analysis techniques were used to quantify DNA content in 81 of the breast cancer samples.Results The c-erbB-2 positive rate in breast carcinoma samples containing neuroendocrine cells was 37.5% and the rate of high expression of c-erbB-2 (++ or +++) was 33.3%, both significantly lower than that in breast carcinomas without neuroendocrine cells (62.6% and 68.7%, respectively, P<0.05). The rates of positive PS2 and PSA expression in breast carcinoma samples containing neuroendocrine cells were 72.2% and 55.0%, respectively, both significantly higher than that in breast carcinoma samples without neuroendocrine cells (45.0% and 16.4%, respectively, P<0.05). In NE (+) samples, the integral optical density, DNA index, DNA stemline peak, > 5c aneuploidy cells, and rate of aneuploidy among cells were all lower than that in NE (-) breast carcinomas (P<0.01). In NE (+) grade I or II breast carcinomas, these indices were also all lower than that in the NE (-) breast carcinoma samples (P<0.01).Conclusion Breast carcinomas with neuroendocrine differentiation have a lower rate of malignancy. Neuroendocrine differentiation could serve as a prognostic marker in clinical practice.

A case of large-cell neuroendocrine carcinoma harboring rare ALK fusion with initial response to the ALK inhibitor crizotinib and acquired F1174L mutation after resistance

A 51-year-old,male,non-smoker with a 3.4 cm mass in the right middle lobe was diagnosed with large cell neuroendocrine carcinoma(LCNEC).Fluorescence in situ hybridization revealed anaplastic lymphoma kinase(ALK)gene translocation,in agreement with the immunohistochemistry result obtained with use of ALK-Ventana.Radiographic examinations showed both bone and brain metastasis.After two cycles of chemotherapy consisting of etoposide and cisplatin,the patient achieved stable disease,and was subsequently switched to crizotinib.Both computed tomography and magnetic resonance imaging revealed partial response after 4 months of crizotinib,but progressed after treatment for 10 months,when several hard lymph nodes were palpable in the left supraclavicular fossa.Lymph node biopsy showed similar histology of tumor cells and targeted next-generation sequencing revealed ALK F1174L on exon 23 with two rare forms of ALK rearrangements.This case provides evidence of responsiveness of ALK inhibitors for a rare pattern of ALK-rearranged LCNEC,and suggests that F1174L,a common resistant mutation found in non-small-cell lung cancer,also causes crizotinib resistance in LCNEC.