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*

Pulmonary neuroendocrine tumors (PNETs) are a kind of epithelial tumors originating from pulmonary neuroendocrine cells, accounting for about 20% of primary lung tumors, including typical carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma. The morphologic and clinical characteristics of these four types of PNETs are relatively highly heterogeneous. Immune checkpoint inhibitors (ICIs) have been shown robust antitumor activity in a variety of solid tumors. Treatment regimens of advanced PNETs have developed greatly in the past decade, but ICIs are still in their infancy in the field of PNETs. This review focuses on the landscape of current clinical trials and research as well as the situation of ICIs-related biomarkers in PNETs.
.
Carcinoid Tumor ; Carcinoma, Neuroendocrine ; Humans ; Immune Checkpoint Inhibitors ; Lung Neoplasms/drug therapy* ; Neuroectodermal Tumors, Primitive ; Neuroendocrine Tumors/drug therapy*

Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms arising from the pancreatic islet of Langerhans and can be functioning or non-functioning based on the clinical symptoms caused by hormonal secretions. PNETs are the second most common tumor of the pancreas and represent 1–2% of all pancreatic neoplasms. The incidence of pNETs appears to be rising and the prognosis seems to be improving, likely due to the improved treatment options. Recent updates of the World Health Organization classification and grading separate pNETs into 2 broad categories according to the histopathologic criteria, including the Ki-67 proliferative index and mitotic counts: well-differentiated NET and poorly-differentiated neuroendocrine carcinoma (NEC). The classification also incorporates a new subcategory of well-differentiated high-grade NEC (grade 3) to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of the clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. The treatment of advanced or metastatic pNETs may include surgical resection, liver-directed therapies, and/or systemic treatments. In unresectable patients, the goals of these therapies are to palliate the tumor-related symptoms and prolong the lifespan. Systemic therapy consists of the following broad modalities: somatostatin analogues, molecular targeted therapy, systemic chemotherapy, and peptide receptor radionuclide therapy. In conclusion, pNETs are diagnosed increasingly throughout the world, usually with metastatic disease and requiring systemic therapy. Each patient should be evaluated thoroughly and discussed individually by a multidisciplinary and dedicated NET-expert team, which might consider all treatment options, including ongoing clinical trials before selecting the appropriate treatment sequence.
Carcinoma, Neuroendocrine ; Classification ; Drug Therapy ; Humans ; Incidence ; Islets of Langerhans ; Molecular Targeted Therapy ; Neuroectodermal Tumors, Primitive ; Neuroendocrine Tumors ; Pancreas ; Pancreatic Neoplasms ; Patient Care ; Prognosis ; Receptors, Peptide ; Somatostatin ; World Health Organization

A 57-year-old male with periampullary duodenal mass was diagnosed as grade 3 duodenal neuroendocrine carcinoma with multiple liver metastasis. After nine cycles of cisplatin and etoposide, abdominal computed tomography (CT) findings showed complete regression of primary duodenal mass with marked size reduction of liver metastasis. Positron emission tomography findings showed metabolic complete response in both duodenal and liver mass. Pylorus-preserving pancreaticoduodenectomy was done and pathologic finding showed 5 mm sized remnant neuroendocrine tumor. The patient has remained alive with no evidence of disease for 43 months after initial diagnosis. This case suggests the possibility of heterogeneous nature of grade 3 neuroendocrine carcinoma and selected population may have extreme sensitivity to cisplatin and etoposide chemotherapy leading to complete response.
Carcinoma, Neuroendocrine ; Cisplatin ; Diagnosis ; Drug Therapy ; Etoposide ; Humans ; Liver ; Male ; Middle Aged ; Neoplasm Metastasis ; Neuroendocrine Tumors ; Pancreaticoduodenectomy ; Positron-Emission Tomography

Large cell neuroendocrine carcinoma is a rare epithelial neuroendocrine malignancy and is preferentially located in gastrointestinal tract and pancreas. Cases of large cell neuroendocrine carcinoma have been reported in many other locations, including the thymus, gallbladder, prostate, larynx, salivary glands, nasopharynx, tonsil and mastoid. However, primary sinonasal large cell neuroendocrine carcinoma never have been reported in Korea. We experienced a case of primary large cell neuroendocrine carcinoma arising from left maxillary sinus recently. A 82-year-old male patient presented with nasal obstruction and epistaxis. The biopsy revealed large cell neuroendocrine carcinoma with poor differentiation. After a general evaluation, the patient was staged as cT3N0M0. The patient was treated by combined radiotherapy and chemotherapy. We report this rare case with literature review.
Aged, 80 and over ; Biopsy ; Carcinoma, Neuroendocrine ; Drug Therapy ; Epistaxis ; Gallbladder ; Gastrointestinal Tract ; Humans ; Korea ; Larynx ; Male ; Mastoid ; Maxillary Sinus ; Nasal Obstruction ; Nasopharynx ; Palatine Tonsil ; Pancreas ; Prostate ; Radiotherapy ; Salivary Glands ; Thymus Gland

Colorectal large-cell neuroendocrine carcinomas (NECs) are extremely rare and have very poor prognosis compared to adenocarcinomas. A 74-year-old man presented with abdominal pain, diarrhea and hematochezia. The histopathologic report of colonoscopic biopsy performed at a local clinic was a poorly differentiated carcinoma. An abdominopelvic computed scan revealed irregularly enhanced wall thickening at the sigmoid colon with regional fat stranding and lymphnode enlargement. He underwent a laparoscopic high anterior resection with selective peritonectomy for peritoneal carcinomatosis, intraoperative peritoneal irrigation chemotherapy, and early postoperative intraperitoneal chemotherapy for 5 days. The tumor had a high proliferation rate (mitotic count > 50/10 HPFs and 90% of the Ki-67 index) and lymph-node metastases had occurred. On immunohistochemistry, the tumor cells expressed CD56 and synaptophysin. Large-cell NEC was confirmed. Systemic chemotherapy with cisplatin/etoposide was done. The patient is still alive after 3 years with no evidence of recurrence.
Abdominal Pain ; Adenocarcinoma ; Aged ; Biopsy ; Carcinoma* ; Carcinoma, Neuroendocrine* ; Colon* ; Colon, Sigmoid ; Diarrhea ; Drug Therapy ; Gastrointestinal Hemorrhage ; Humans ; Immunohistochemistry ; Neoplasm Metastasis ; Peritoneal Lavage ; Prognosis ; Recurrence ; Synaptophysin

BACKGROUND: To investigate the clinicopathological characteristics of urinary bladder tumors, a rare malignancy, in patients 20 years or younger. METHODS: Using a retrospective chart review among patients who received bladder surgery at 2 institutions between July 1996 and January 2013, we analyzed the clinicopathological characteristics of urinary bladder tumors in 21 pediatric patients (male:female = 4.25:1.00; mean age, 12.1 years). RESULTS: Pathology revealed 9 urothelial tumors, 6 rhabdomyosarcomas, 1 low-grade leiomyosarcoma, 1 large cell neuroendocrine carcinoma, 1 inflammatory myofibroblastic tumor, and 3 cases of chronic inflammation without tumors (including 1 xanthogranulomatous inflammation). Urothelial tumors (mean patient age, 16.0 years) were benign or low-grade; and only transurethral resection of the bladder tumor was necessary for treatment. Patients with rhabdomyosarcomas (mean age, 5 years) underwent radiotherapy (if unresectable) or transurethral resection of the bladder tumor (if resectable), after chemotherapy. Of these patients, 2 underwent radical cystectomy, with the remaining patients not receiving a cystectomy. With the exception of one patient, all patients are currently alive and recurrence-free. CONCLUSION: Urothelial tumors were the most commonly found pediatric bladder tumor, with embryonal rhabdomyosarcoma being the second most common. Urothelial tumors are common in relatively older age. Since urothelial tumors in children typically have a good prognosis and rarely recur, transurethral resection of the bladder tumor is the treatment of choice. Rhabdomyosarcomas are common in younger patients. Since rhabdomyosarcoma is generally chemosensitive, chemotherapy and radiotherapy are the treatment of choice for bladder preservation in these patients.
Carcinoma, Neuroendocrine ; Child ; Cystectomy ; Drug Therapy ; Humans ; Inflammation ; Leiomyosarcoma ; Myofibroblasts ; Pathology ; Prognosis ; Radiotherapy ; Retrospective Studies ; Rhabdomyosarcoma ; Rhabdomyosarcoma, Embryonal ; Urinary Bladder Neoplasms ; Urinary Bladder*

Large cell neuroendocrine carcinoma (LCNEC) of the gallbladder is extremely rare and usually combined with other type of malignancy, mostly adenocarcinoma. We report an unusual case of combined adenosquamous carcinoma and LCNEC of the gallbladder in a 54-year-old woman. A radical cholecystectomy specimen revealed a 4.3×4.0 cm polypoid mass in the fundus with infiltration of adjacent liver parenchyma. Microscopically, the tumor consisted of two distinct components. Adenosquamous carcinoma was predominant and abrupt transition from adenocarcinoma to squamous cell carcinoma was observed. LCNEC showed round cells with large, vesicular nuclei, abundant mitotic figures, and occasional pseudorosette formation. The patient received adjuvant chemotherapy. However, multiple liver metastases were identified at 3-month follow-up. Metastatic nodules were composed of LCNEC and squamous cell carcinoma components. Detecting LCNEC component is important in gallbladder cancer, because the tumor may require a different chemotherapy regimen and show early metastasis and poor prognosis.
Adenocarcinoma ; Carcinoma, Adenosquamous ; Carcinoma, Neuroendocrine ; Carcinoma, Squamous Cell ; Chemotherapy, Adjuvant ; Cholecystectomy ; Drug Therapy ; Female ; Follow-Up Studies ; Gallbladder Neoplasms ; Gallbladder ; Humans ; Liver ; Middle Aged ; Neoplasm Metastasis ; Prognosis

Primary neuroendocrine tumors originating from the extrahepatic bile duct are rare. Among these tumors, large cell neuroendocrine carcinomas (NECs) are extremely rare. A 59-year-old man was admitted to Sanggye Paik Hospital with jaundice that started 10 days previously. He had a history of laparoscopic cholecystectomy, which he had undergone 12 years previously due to chronic calculous cholecystitis. Laboratory data showed abnormally elevated levels of total bilirubin 15.3 mg/dL (normal 0.2–1.2 mg/dL), AST 200 IU (normal 0–40 IU), ALT 390 IU (normal 0–40 IU), and gamma-glutamyl transferase 1,288 U/L (normal 0–60 U/L). Serum CEA was normal, but CA 19-9 was elevated 5,863 U/mL (normal 0–37 U/mL). Abdominal CT revealed a 4.5 cm sized mass involving the common bile duct and liver hilum and dilatation of both intrahepatic ducts. Percutaneous transhepatic drainage in the left hepatic duct was performed for preoperative biliary drainage. The patient underwent radical common bile duct and Roux-en-Y hepaticojejunostomy for histopathological diagnosis and surgical excision. On histopathological examination, the tumor exhibited large cell NEC (mitotic index >20/10 high-power field, Ki-67 index >20%, CD56 [+], synaptophysin [+], chromogranin [+]). Adjuvant concurrent chemotherapy and radiotherapy were started because the tumor had invaded the proximal resection margin. No recurrence was detected at 10 months by follow-up CT.
Bile Duct Neoplasms ; Bile Ducts, Extrahepatic* ; Bilirubin ; Carcinoma, Neuroendocrine* ; Cholecystectomy, Laparoscopic ; Cholecystitis ; Common Bile Duct ; Diagnosis ; Dilatation ; Drainage ; Drug Therapy ; Follow-Up Studies ; Hepatic Duct, Common ; Humans ; Jaundice ; Liver ; Middle Aged ; Neuroendocrine Tumors ; Radiotherapy ; Recurrence ; Synaptophysin ; Tomography, X-Ray Computed ; Transferases

Neuroendocrine tumors (NETs) of the esophagus are extremely rare, aggressive and have a poor prognosis. Combined therapy using chemotherapy, radiotherapy and/or surgery appear effective. Here, we present a patient with a complaint of dysphagia who was diagnosed with this rare tumor. Upper gastrointestinal endoscope of a 46-year-old female revealed a localized ulcerative lesion in the middle esophagus. Histologic exam of biopsy specimens indicated a neuroendocrine carcinoma. The tumor cells were arranged in microtubular structures, with small and round cells containing scanty cytoplasm. They were positive for synaptophysin and chromogranin A on immunohistochemical staining. A computed tomography scan showed an esophageal tumor with enlarged superior mediastinal lymph nodes and about 1.2 cm sized liver metastasis, similar to findings in PET-CT scanning. The patient was prescribed chemotherapy consisting of etoposide and cisplatin, which led to regression of disease on follow-up imaging study. She continues under clinical observation. We seek to increase awareness of this exceedingly rare but hazardous disease by sharing our unexpected finding.
Biopsy ; Carcinoma, Neuroendocrine ; Chromogranin A ; Cisplatin ; Cytoplasm ; Deglutition Disorders ; Drug Therapy ; Endoscopes, Gastrointestinal ; Endoscopy ; Esophageal Neoplasms ; Esophagus ; Etoposide ; Female ; Follow-Up Studies ; Humans ; Liver ; Lymph Nodes ; Middle Aged ; Neoplasm Metastasis ; Neuroendocrine Tumors* ; Prognosis ; Radiotherapy ; Synaptophysin ; Ulcer