Pulmonary neuroendocrine/carcinoid tumors

Neuroendocrine tumors are a unique malignant neoplasm that can arise from the respiratory tree. Although well‐differentiated bronchial neuroendocrine tumors (also called carcinoid tumors) are reported to account for approximately 25% of all neuroendocrine tumors, they represent only 1% to 2% of all lung cancers. The epidemiology, clinical behavior, and treatment of neuroendocrine carcinoid tumors differ significantly from other lung malignancies. In this article, the recent data regarding these tumors were reviewed with attention to the treatment modalities used. Although conventional cytotoxic therapy has not been reported to demonstrate much promise in this entity over the past 4 decades, newer molecular targeted agents including those that targeted angiogenesis and the mammalian target of rapamycin (mTOR) pathway have shown encouraging results in early phase trials for advanced carcinoid tumors. Cancer 2009. © 2009 American Cancer Society.     

周围型肺神经内分泌癌的CT征象及强化特点分析

目的分析周围型肺神经内分泌癌(LNEC)的计算机体层摄影(CT)征象及强化特点。方法回顾性分析55例周围型LNEC患者的临床资料。所有患者均接受胸部CT平扫及增强扫描。比较不同类型的周围型LNEC患者的病灶分布情况、病灶大小、CT征象(形态、密度、分叶征、毛刺征、钙化、血管集束征、胸膜凹陷征)及CT值。结果 55例周围型LNEC患者中典型类癌(TC)6例,不典型类癌(AC)5例,大细胞神经内分泌癌(LCNEC)21例,小细胞神经内分泌癌(SCNC)23例。TC、AC、LCNEC、SCNC中均以右肺多见。LCNEC患者的病灶最大径为(42.8±15.6)mm,长于TC患者的(18.3±6.1)mm、AC患者的(22.3±7.6)mm,差异均有统计学意义(P﹤0.05);SCNC患者的病灶最大径为(39.5±11.2)mm,长于TC、AC患者,差异均有统计学意义(P﹤0.05)。TC、AC患者的CT征象以形态规则、密度均匀为主,LCNEC、SCNC患者的CT征象以形态不规则、密度不均匀为主,但TC、AC、LCNEC、SCNC患者病灶的形态、密度比较,差异均无统计学意义(P﹥0.05)。TC、AC、LCNEC、SCNC患者的分叶征、毛刺征、钙化、血管集束征、胸膜凹陷征的比例比较,差异均无统计学意义(P﹥0.05)。TC、AC、LCNEC、SCNC患者CT强化前后差值分别为(50.5±15.6)Hu、(53.5±18.3)Hu、(26.6±8.7)Hu、(28.9±9.6)Hu,组间比较,差异有统计学意义(F=14.434,P﹤0.01)。结论不同类型的周围型LNEC患者的CT平扫及强化的特征具有一定的差异,TC及AC强化明显,而LCNEC及SCNC体积较大,形态不规则、密度不均匀的比例较高。     

The epidemiology of metastases in neuroendocrine tumors

The epidemiology of metastases in neuroendocrine tumors (NETs) is virtually unknown. The present novel approach took use of two nationwide Swedish registers to assess the distribution of metastatic sites in comparison to adenocarcinoma. 7,334 patients with NET were identified from the Swedish Cancer Registry. Metastatic sites were identified from the National Patient and Cause of Death Registries. Sites of metastasis were investigated depending on the primary site of NET. The metastatic potential of NET was assessed. The liver was the most common site of metastasis (82% of patients with metastases), and the small intestine was the most common source of NET metastases. Of all patients with metastatic lung NETs, 66% had liver metastases, whereas the corresponding number for adenocarcinoma of lung was only 20%. The risk of metastasis was highest if the primary was in the small intestine or pancreatohepatobiliary tract, whereas it was lower with appendiceal and rectal NET. Men had more bone metastases compared to women. Patients with metastatic NET had worse prognosis if the primary site was unknown (11 months, 9% of NET patients) compared to those whose primary was known (19 months). The metastatic potential of NETs varies profoundly depending on the primary site. NETs show a clear preference to metastasize to the liver. Surveillance of liver metastases may enable earlier diagnosis and treatment. In liver metastases from NET, the small intestine should be suspected as the primary site, whereas the lung should be suspected in nervous system metastases of NET origin.     

Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas

BACKGROUND:

The current study was conducted to evaluate the efficacy and safety of everolimus in the treatment of patients with nonfunctioning neuroendocrine tumors (NETs) or pheochromocytomas/paragangliomas.

METHODS:

Patients with histologically confirmed nonfunctioning NETs or pheochromocytomas/paragangliomas and with documented disease progression before study enrollment were eligible for the current study. Everolimus was administered daily at a dose of 10 mg for 4 weeks. Response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST; version 1.0) every 8 weeks. The primary endpoint was the 4‐month progression‐free survival rate (PFSR). The hypothesis of the current study was that the 4‐month PFSR would increase from 50% to 65%. Safety was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0).

RESULTS:

A total of 34 patients were enrolled. Of these, 27 patients had nonfunctioning NETs, 5 had pheochromocytomas, and 2 had paragangliomas. The 4‐month PFSR was 78%. Partial response (PR) was observed in 3 patients. Twenty‐eight patients had stable disease (SD) and 2 patients developed progressive disease (PD). The response rate (RR) and overall disease control rate (DCR) were 9.0% (95% confidence interval [95% CI], 0%‐18.6%) and 93.9% (95% CI, 85.8%‐100%), respectively. The PFS was 15.3 months (95% CI, 4.6 months‐26.0 months). Of the patients with nonfunctioning NETs, 3 achieved a PR and 23 had SD (RR, 11.1%; DCR, 100%); the PFS was 17.1 months (95% CI, 11.1 months‐23.0 months) and the 4‐month PFSR was 90.0%. Twenty‐one patients (80.8%) demonstrated tumor shrinkage. In 7 patients with pheochromocytomas/paragangliomas, 5 achieved SD, and 2 developed PD. The PFS was 3.8 months (95% CI, 0.5 months‐7.0 months) and the 4‐month PFSR was 42.9%. Four patients demonstrated tumor shrinkage. The major grade 3/4 adverse events were thrombocytopenia (14.7%), hyperglycemia (5.9%), stomatitis (5.9%), and anemia (5.9%).

CONCLUSIONS:

Everolimus was associated with high therapeutic efficacy and tolerability in patients with nonfunctioning NETs, and demonstrated modest efficacy in patients with pheochromocytomas/paragangliomas. Cancer 2012. © 2012 American Cancer Society.     

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity

BACKGROUND:

Normal adult lungs contain pulmonary neuroendocrine cells (PNECs). PNEC hyperplasia may be either reactive or idiopathic, and the idiopathic type is defined as diffuse idiopathic PNEC hyperplasia (DIPNECH). It is believed that DIPNECH is a neuroendocrine proliferative process associated with carcinoid tumors. The available data regarding this rare condition are very limited. The objective of the current study was to describe the clinical, radiologic, and pathologic characteristics of patients with DIPNECH and the effect of various therapeutic modalities on patient well being.

METHODS:

The authors retrospectively studied 11 consecutive patients with DIPNECH who were followed at 2 referral centers in Israel between 2000 and 2010.

RESULTS:

All patients were women, and their median age was 62.8 years. Six patients presented with respiratory symptoms, such as prolonged dyspnea, wheezing, and cough. All patients had carcinoid tumor together with multiple, small pulmonary nodules observed on thoracic high‐resolution computerized tomography images. The mean size of the dominant lesion was 19.4 ± 9.6 mm. Nine patients underwent thoracotomy and resection of the dominant lesion. The disease was stable in 5 of 11 patients; in 6 of 10 patients, it progressed, and the patients received treatment with somatostatin analogs, which induced disease stabilization in all patients. Metastatic disease was diagnosed in 3 of 11 patients (36%). All patients were alive at the end of follow‐up (mean, 4.63 ± 2.04 years; ongoing).

CONCLUSIONS:

The association of lung neuroendocrine tumor with multiple nodules in women, together with complains of chronic cough and wheezing, should raise suspicion of DIPNECH. Whenever possible, these patients should undergo surgical excision of the dominant lesion, and somatostatin analogs may be considered for symptomatic or tumor control in patients with progressive disease. Cancer 2012;. © 2011 American Cancer Society.     

Making progress against rare cancers: A case study on neuroendocrine tumors

In April 2023, the National Cancer Institute offered a roadmap for cancer research to achieve Cancer Moonshot goals. To reach these goals requires making progress for all cancers, not just those that are most common. Achieving progress against rare cancers, as well as common cancers, requires involvement of large clinical research networks. In 2020, the Patient-Centered Outcomes Research Institute (PCORI) launched an initiative on Conducting Rare Disease Research using PCORnet, the National Patient-Centered Clinical Research Network. The purpose of this commentary is to introduce the broader community of cancer researchers to the PCORnet NET-PRO study (comparing the effects of different treatment approaches for neuroendocrine tumors on patient-reported outcomes) thereby demonstrating how researchers can use the PCORnet infrastructure to conduct large-scale patient-centered studies of rare cancers.     

Gastric neuroendocrine tumor: A practical literature review

Gastric neuroendocrine tumors are gastric neoplasms originating from enterochromaffin type cells and are inserted in a larger group, named gastroenteropancreatic neuroendocrine tumors. They are considered rare and variable in terms of their clinical, morphological and functional characteristics and may be indolent or aggressive. They are classified into types I, II and III, according to their pathophysiology, behavior and treatment. Their diagnosis occurs, in most cases, incidentally during upper digestive endoscopies, presenting as simple gastric polyps. Most cases (type I and type II) are related to hypergastrinemia, can be multiple and are treated by endoscopic resection, whenever possible. The use of somatostatin analogs for tumor control may be one of the options for therapy, in addition to total or subtotal gastrectomy for selected cases. Adjuvant chemotherapy is only reserved for poorly differentiated neuroendocrine carcinomas. Although rare, gastric neuroendocrine tumors have an increasing incidence over the years, therefore deserving more comprehensive studies on its adequate treatment. The present study reviews and updates management recommendations for gastric neuroendocrine tumors.     

Pancreatic neuroendocrine tumors: a comprehensive review

Pancreatic neuroendocrine tumors (NETs) are a heterogeneous group of tumors. Despite being relatively rare, representing just 1–2% of all pancreatic neoplasms, the incidence of pancreatic NET has increased over the past two decades. Although the primary treatment for localized NET is surgical resection, there is still a lack of effective therapeutic options for patients with advanced unresectable pancreatic NET. Recently, the targeted agents sunitinib malate (SUTENT®, Pfizer Inc, NYC) and everolimus (AFINITOR®, Novartis, Basel, Switzerland)—both with different mechanisms of action—received United States Food and Drug Administration approval for the treatment of progressive, well‐differentiated, pancreatic NET in patients with unresectable, locally advanced or metastatic disease. SUTENT® also received approval for this indication by the European Commission in 2010. Our article presents an overview of pancreatic NET, with a focus on their diagnostic work‐up, clinical presentation and treatment options. Topics for further investigation of targeted therapy are also discussed.     

Gastrointestinal neuroendocrine tumors in 2020

Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence within the last few decades. They contain chromogranin A, synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor. Ki-67 index and mitotic index correlate with cellular proliferation. Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors. Most of the gastrointestinal neuroendocrine tumors are non-functional. World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm. Gastric neuroendocrine tumors arise from enterochromaffin like cells. They are classified into 4 types. Only type I and type II are gastrin dependent. Small intestinal neuroendocrine tumor is the most common small bowel malignancy. More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve. Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs. Duodenal and jejuno-ileal neuroendocrine tumors are distinct biologically and clinically. Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver. Appendiceal neuroendocrine tumors are generally detected after appendectomy. Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis. Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000. Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy, endoscopic ultrasound, serology of biomarkers, imaging studies and functional somatostatin scans. Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.     

Everolimus in advanced,progressive, well‐differentiated,non‐functional neuroendocrine tumors: RADIANT‐4 lung subgroup analysis

In the phase III RADIANT‐4 study, everolimus improved median progression‐free survival (PFS) by 7.1 months in patients with advanced, progressive, well‐differentiated (grade 1 or grade 2), non‐functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35‐0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT‐4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8‐10.9) months in the everolimus arm vs 3.6 (1.9‐5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28‐0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3‐4 drug‐related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well‐differentiated, non‐functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT‐4 cohort. These results support the use of everolimus in patients with advanced, non‐functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783).     

Gastroenteropancreatic neuroendocrine tumors: incidence and treatment outcome in a single institution in Korea

Aim: We studied to identify the clinicopathological features, treatment outcome, and prognostic factors for patients with gastrointestinal and hepatopancreaticobiliary neuroendocrine tumor (NET). Method: Between February 2001 and May 2006, a total of 470 patients were diagnosed with NET arising from the gastrointestinal tract, pancreas, and hepatobiliary system. The retrospective patient cohort was obtained and analyzed. Results: The male to female ratio was 1.5:1, and the median age was 55 years (range, 16–81). The most common primary site was the rectum (55.8%). Overall 29 (6.2%) originated from the hepatobiliary system. At initial presentation, 60 patients (12.8%) showed distant metastases. Curative surgery or endoscopic resection was performed in 401 patients. Histopathological distributions were as follows: well differentiated tumor (82.1%), well differentiated carcinoma (10.2%) and poorly differentiated carcinoma (7.7%). The frequency of the poorly differentiated type was somewhat higher in the hepatobiliary system than in the pancreas and gastrointestinal tract (44.8, 15.4 and 2.8%, respectively, P < 0.05). The estimated 5‐year overall survival rate for all patients was 89.6%. Multivariate analysis showed that distant metastases (P = 0.018), origin from the hepatobiliary system (P < 0.001) and poorly differentiated neuroendocrine carcinoma (P < 0.001) were independent predictors for poor survival outcome. Conclusion: Patients with locoregional NET had a favorable long‐term survival after curative resection. Distant metastases, hepatobiliary localization and a poor degree of tumor cell differentiation were poor prognostic factors. Further investigational approaches for treatment of advanced disease are needed.