Gastrointestinal carcinoid: epidemiological and survival evidence from a large population-based study (n = 25 531)

BackgroundOwing to its rarity, the published evidence on gastrointestinal (GI) carcinoid is often based on small series of patients or population-based studies regarding all neuroendocrine tumors. Here, we present a comprehensive epidemiological and survival analysis of the largest cohort of patients with GI carcinoid ever reported.Patients and methodsPatients with histological diagnosis of GI carcinoid (n = 25 531) were identified from the Surveillance Epidemiology End Results (SEER) database (including 18 USA cancer registries and spanning the 1973–2009 time frame). Demographic and disease data were used for epidemiological and survival analyses.ResultsThe incidence of GI carcinoid is steadily increasing over the past three decades at a rate higher than any other cancer [annual percentage change (APC) = 4.4, 95% confidence interval (CI) 4.0–4.8]. These patients have a higher risk of further primary tumor (standardized incidence ratio, SIR = 1.15, 95% CI 1.10–1.21), but also a reduced risk of skin melanoma (SIR = 0.64, 95% CI 0.41–0.95). Despite the overall favorable prognosis (5-year disease-specific and relative survival rate: 91.3% and 87.4%, respectively), the mortality rate is increasing over time (APC = 3.5, 95% CI 3.0–4.0) and the 5-year survival rate of patients dying of GI carcinoid (28.5%), though better than that reported for GI cancers in general (8.4%), cannot be considered satisfactory. Finally, a nomogram is provided to predict patient survival on the basis of clinico-pathological factors independently associated with prognosis at multivariate analysis.ConclusionsThese findings can be clinically useful for the management of patients with GI carcinoid and eagerly prompt the continuous effort to develop more effective therapeutic strategies against this slow-growing but chemoresistant tumor.     

Primary carcinoid tumor of the ovary: report of an unusual case

Carcinoid tumors are endocrine malignancies that are often associated with a characteristic syndrome, the malignant carcinoid syndrome, which is most common in patients with small bowel tumors and liver metastases. In the rare instances when the syndrome is present without liver metastases the primary tumor is usually localized to the bronchus or ovary and secretes hormones directly into the systemic circulation. About two thirds of patients with carcinoid syndrome have evidence of carcinoid heart disease. We report on a case of a primary ovarian carcinoid tumor with an unusual clinical presentation.     

The molecular genetics of gastroenteropancreatic neuroendocrine tumors

The pathobiology of neuroendocrine tumors (NETs) is hampered by the lack of scientific tools that define their mechanisms of secretion, proliferation, and metastasis; and, currently, there are no accurate means to assess tumor behavior and disease prognosis. Molecular biologic techniques and genetic analysis may facilitate the delineation of the molecular pathology of NETs and provide novel insights into their cellular mechanisms. The current status and recent advances in assessment of the molecular basis of tumorigenesis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) were reviewed (1981-2004). The objectives of this retrospective study were to provide a cohesive overview of the current state of knowledge and to develop a molecular understanding of these rare tumor entities to facilitate the establishment of therapeutic targets and rational management strategies. Multiple differences in chromosomal aberration patterns were noted between gastrointestinal (GI) neuroendocrine and pancreatic endocrine tumors (PETs). Divergence in gene expression patterns in the development of GI carcinoids and PETs was identified, whereas examination of the PET and GI carcinoid data demonstrated only few areas of overlap in the accumulation of genetic aberrations. These data suggest that the recent World Health Organization classification of GEP-NETs may require updating. In addition, previous assumptions of tumor similarity (pancreatic vs. GI) may be unfounded when they are examined at a molecular level. On the basis of the evolution of genetic information, enteric neuroendocrine lesions (carcinoids) and PETs may need to be classified as two distinct entities rather than grouped together as the single entity "GEP-NETs."     

Different expression levels of lumican in human carcinoid tumor and neuroendocrine cell carcinoma

Lumican is a member of the small leucine-rich proteoglycan (SLRP) family and participates in the maintenance of tissue structures and tumor growth. Neuroendocrine cell tumors (NETs) including carcinoid tumors and NE cell carcinomas (NECs) possess numerous neuroendocrine (NE) granules, and differences between these tumors are in terms of their biological and metastatic aggressiveness during tumor progression. The purpose of this study was to examine the expression of lumican in NETs, and to determine whether the presence of lumican may be associated with the growth of NETs by comparing its expression between carcinoid tumors and NECs. Immunohistochemically, the positivity rates of lumican expression in the cytoplasm of the tumor cells were 87.5% in carcinoid tumors and 37.5% in NECs. Those of lumican expression in the stroma adjacent to the tumors were 90.1% in carcinoid tumors and 79.2% in NECs. In situ hybridization analysis revealed the lumican mRNA expression in the cytoplasm of carcinoid tumor and NEC cells. Ultrastructurally, the lumican protein was observed in the rough endoplasmic reticulum and NE granules of NETs and interspaces of collagen fibers. Furthermore, RT-PCR analysis revealed the presence of lumican mRNA in NEC cell lines. These results indicate that the higher expression level of cytoplasmic lumican in carcinoid tumors than in NECs may play a role in the slow growth of these tumors.     

10.3760/cma.j.issn.1673-422X.2015.04.019

【Abstract】Gastrointestinal neuroendocrine tumor (GI-NET) originates from peptide neurons and neuroendocrine cells in gastrointestinal tract, and secrets peptide hormones, leading to carcinoid syndrome which rarely happens in clinical practice. Because of the improvement of diagnostic method and understanding of this rare disease, the morbidity is rising in recent years. The main treatments of GI NET are surgery and comprehensive therapy, consisting of chemotherapy and targeted therapy.     

A study of the histopathogenesis of carcinoid tumors of the small intestine and appendix

A specimen from the small intestine with multiple (three) classic carcinoid tumors and one appendiceal carcinoid tumor displaying argentaffinity, argyrophilia (Grimelius stain), and serotonin and neuron specific enolase immunoreactivity was examined by light microscopy with regard to the tumor cell histopathogenesis. The smallest tumor (diameter 0.5 cm) from the small intestine was cut into 512 and the appendiceal tumor into 511 serial sections, which were stained with the argyrophil technique. In the small intestine an increased number of endocrine cells and small proliferating aggregates of endocrine cells were observed among nonendocrine enterocytes in the crypts of Lieberkühn. They seemed to grow initially inside the crypts and to later infiltrate through the basement membrane into the lamina propria of the mucosa. This finding suggests that classic carcinoid tumors of the small intestine develop from mucosal endocrine (enterochromaffin) cells. Since proliferating argentaffin cells were also seen in the mucosal crypts in one of the other two carcinoid tumors (2 cm in diameter) in the same intestine specimen, it is suggested that when multiple carcinoid tumors occur in the small intestine they arise from multiple sites. There was no apparent connection between the mucosal crypts and the carcinoid tumor of the appendix. Thus in this particular case, the appendiceal carcinoid tumor did not appear to derive from the mucosal endocrine cells but from the subepithelial endocrine cells that are present in the lamina propria and submucosa of the appendix wall. Supporting this view is the fact that S-100 protein immunoreactive cells are found both in close relation to subepithelial endocrine cells and as an integral component of appendiceal carcinoid tumors.     

A flow cytometric analysis of 23 carcinoid tumors

Twenty-three carcinoid tumors were investigated from paraffin-embedded tissue with flow cytometry (FCM) in order to correlate the DNA ploidy with clinical variables. DNA aneuploidy was found in ten tumors (45%) and one tumor was classified as tetraploid. Diurnal urinary excretion of 5-hydroxy indolic acetic acid (5-HIAA) was known to be elevated in seven of eight diploid tumors and in four of seven aneuploid carcinoids with distant metastases. Six (55%) of the diploid tumors had not given rise to metastases at the time of diagnosis, compared with three (30%) of the aneuploid tumors. Six of seven patients with an aneuploid tumor and three of five patients with a diploid tumor, observed for at least 10 years, died of the disease. It was concluded that, unlike in earlier studies with static DNA cytometry, DNA aneuploidy is common in human carcinoid tumors and may occur in tumors secreting biogenic amines.     

Clinical and in vitro studies of imatinib in advanced carcinoid tumors.

PURPOSE: Effective systemic therapy options for carcinoid tumors are lacking. We conducted in vitro studies and a phase II clinical trial to explore the activity of imatinib in carcinoid tumors. EXPERIMENTAL DESIGN: Cells of the human bronchial carcinoid cell line NCI-H727 and the human pancreatic carcinoid cell line BON-1 were treated with increasing concentrations of imatinib using standard procedures to assess in vitro growth-inhibitory activity. A clinical trial using a two-stage phase II design to assess the response rate and safety profile of imatinib at a dose of 400 mg given twice daily in patients with advanced carcinoid tumors was completed. RESULTS: In both cell lines, there was a dose- and time-dependent cytotoxic effect. The clinical trial enrolled 27 evaluable patients. Median duration on trial was 16 weeks. One patient had a partial response, 17 had stable disease, and 9 had progressive disease by the Response Evaluation Criteria in Solid Tumors criteria. Median progression-free survival time was 24 weeks. Median overall survival is 36 months. Seven patients who achieved a biochemical response had a superior progression-free survival time compared with patients without biochemical response (115 weeks compared with 24 weeks; P = 0.003). An increase in plasma basic fibroblast growth factor was associated with a shorter progression-free survival duration (P = 0.02). CONCLUSIONS: Our data suggest that imatinib is active in vitro and has a modest clinical activity in carcinoid patients. Changes in tumor markers may help select patients who are likely to benefit from therapy.     

Treatment of malignant carcinoid tumors with recombinant interferon alfa-2b: development of neutralizing interferon antibodies and possible loss of antitumor activity

Twenty patients with malignant carcinoid tumors were treated for 6 months with recombinant interferon alfa-2b (IFN alpha-2b; Intron-A; Schering Corp., Bloomfield, NJ) at a mean dose of 5.9 megaunits three times per week. Eleven of the 20 patients (55%) had a greater than 50% reduction of tumor markers (urinary 5-hydroxyindoleacetic acid or plasma neuropeptide K), showing objective tumor response. Six patients (30%) had stable disease with no significant change in tumor markers or tumor size, and three (15%) had progressive disease with an increase in tumor markers and size. These results are similar to those reported earlier for treatment with natural leukocyte IFN in patients with carcinoid tumors. Only two patients (35%) had a slight reduction of tumor size after 6 months of treatment. Three patients developed neutralizing antibodies to IFN alpha-2b. Two of these patients initially showed an objective response, which lasted until IFN antibodies developed. In one of these patients, a change to human leukocyte IFN resulted in normalization of antibody titers within 3 months, and the patient had a second objective clinical response. There was no correlation between development of IFN antibodies and development of autoimmune phenomena such as increased titers of antinuclear antibodies or thyroid autoantibodies. IFN alpha-2b seems to be as potent as human leukocyte IFN in the treatment of patients with malignant carcinoid tumors, but it is important to recognize that antibodies neutralizing IFN may develop in some patients, with concomitant loss of antitumor effects. A change to natural leukocyte IFN might be beneficial in these patients.     

Systemic therapy for advanced pancreatic neuroendocrine tumors: an update

Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (pancNETs). Although these tumors share many morphologic and clinical characteristics, carcinoid tumors appear to be far less sensitive to therapeutic agents than pancNETs, and recent advances approved for pancNETs have not been submitted for FDA approval in patients with carcinoid tumors. Treatment options for patients with advanced pancNETs are multidisciplinary and include surgical resection, liver-directed therapies, and systemic therapies. Cytotoxic therapies, such as temozolomide, fluorouracil, oxaliplatin, and streptozocin-based chemotherapy regimens, are active against some pancNETs, and can play a role in the palliation of patients with advanced disease and symptoms related to tumor bulk. Two therapies were recently approved for progressive well-differentiated pancNETs: sunitinib and everolimus. Both agents showed improved progression-free survival in patients with progressive pancNETs, but can also result in nontrivial toxicities, and therefore should only be considered in patients with progressing and advanced or symptomatic disease. This article discusses these recent trials and provides an update of systemic treatment options in patients with well-differentiated pancNETs.     

Appendiceal malignancies

Malignancies of the appendix are extremely rare. Of the reported cases, carcinoid tumors are most common, with mucinous cystadenocarcinomas and adenocarcinomas next in frequency. Adenocarcinoids, which share morphologic and clinical features that are a composite of adenocarcinomas and carcinoids, have been described. Concomitant second malignancies, most often in the GI tract, occur with greater than expected frequency in patients with appendiceal tumors. Treatment and prognosis are markedly different for each of the histologic variants of appendiceal malignancy. In general, carcinoid tumors (smaller than 2 cm in diameter) may be treated by appendectomy alone and are associated with long term survival. Adenocarcinomas, unless well differentiated and extremely superficial and localized, required hemicolectomy and confer a prognosis that is, stage for stage, similar to that of adenocarcinoma of the colon. Mucinous cystadenocarcinomas may spread widely through the abdomen, resulting in P peritonei, but can be associated with long survival duration if surgical treatment is aggressive. There is evidence that adenocarcinoids develop from simultaneous neoplastic change in two stem cell populations. Metastases may show histologic features of adenocarcinomas alone, of carcinoid tumors alone, or may resemble a composite neoplasm. The prognosis is variable and treatment recommendations are not well defined.     

Carcinoid tumor presenting as central nervous system symptoms. Case report and review of the literature

Carcinoid tumors are relatively uncommon. They are known for their slow growing behavior and unique symptoms. Patients with carcinoid tumors usually present with signs and symptoms due either to local disease or to the carcinoid syndrome. During the course of these tumors, they tend to metastasize to different sites, including regional lymph nodes, lungs, liver, and bone. They rarely metastasize to the central nervous system (CNS) and very rarely present with signs and symptoms related to CNS metastasis. We report a patient who presented with CNS symptoms and was found to have a pulmonary carcinoid tumor involving the liver and the dura mater. In this article, CNS involvement in carcinoid tumors is discussed, and the literature is reviewed.     

The limitation of liver function tests in metastatic carcinoid tumors

To evaluate the utility of liver function tests (LFT) as indicators of metastatic carcinoid tumors, a retrospective study was performed. The LFT results of 17 patients with carcinoid tumors metastatic to the liver were compared with 17 patients with other malignant tumors. In the noncarcinoid group, 82.4% of the patients had elevated alkaline phosphatase (AP) or gamma glutamyl transpeptidase (GGTP), whereas only 28.6% of carcinoid patients had abnormal enzymes. The medians of all LFT values were significantly higher in noncarcinoid patients than in the carcinoid group, except for glutamic pyruvic transaminase (SGPT). Our data indicate that LFT are helpful in screening for liver metastases in patients with noncarcinoid tumors, but are unreliable in carcinoid tumors. Imaging tests should be used to rule out liver metastases in carcinoid tumors, irrespective of LFT results.     

Recent advances in carcinoid pathogenesis, diagnosis and management

Carcinoid tumors usually present as diagnostic dilemmas due to obscure or nonspecific symptomatology. Advances in molecular biology are allowing the investigation of molecular markers of aggressiveness, better serum tumor markers, as well as the molecular pathogenesis of carcinoid heart disease. Somatostatin receptor scintigraphy (SRS) and whole body positron emission tomography (PET) are providing much improved sensitivity in localization of both primary and metastatic tumors. Long acting depot somatostatin analogues are combining effectiveness and ease of use for medical management of carcinoid syndrome. An additional benefit may be tumor growth suppression.     

Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice

An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC.     

支气管肺类癌导致的异位ACTH综合征

目的通过对支气管肺类癌引起的异位ACTH综合征患者的临床资料分析,总结其临床特点,以提高对该病的认识和诊治水平。方法回顾性分析北京协和医院1984～2009年经病理证实的13例支气管肺类癌引起的异位ACTH综合征患者的临床资料。结果13例患者就诊时的平均年龄35．4岁,就诊时的病程为19．9±18．3个月（1．3～60个月）,从初诊至发现肺部占位的时间为15．6±36．1个月（1．0—132个月）。11例（84．6％）患者存在低血钾（2．60±0．61mmol／L）。4例（30．8％）患者大剂量地塞米松抑制试验不被抑制。11例（91．7％）患者初诊时进行了肺CT检查发现了肺部病变。肿瘤平均直径为2．1cm。结论支气管肺类癌是导致隐性异位ACTH综合征的常见原因,但在临床上有时与库欣病很难鉴别。因此对于ACTH依赖的库欣综合征应常规筛查肺部病变,对可疑病例进行全面检查以明确肿瘤定位。     

原发性肺类癌的治疗进展与展望

原发性肺类癌(pulmonary carcinoid,PC)是一种较为少见的肺部肿瘤。在2015年世界卫生组织(WHO)最新的肿瘤分类中,PC包括典型类癌(typical carcinoid,TC)和非典型类癌(atypical carcinoid,AC)。PC与大细胞神经内分泌癌(large cell neuroendo? crine carcinoma,LCNEC)和小细胞肺癌(small cell lung carcinoma,SCLC)均属于肺部神经内分泌肿瘤(neuroendocrine tumor,NET)。由于发病率较低,且缺乏特异性的临床表现,PC的诊断和管理相对较复杂。对于整体健康状况和肺储备可以耐受手术的早期局限型PC患者,外科手术切除是首选的治疗方法。而晚期或不可切除PC患者,目前各种指南推荐的标准系统治疗缺乏统一的共识。本文拟对PC最新的诊断及多学科治疗进展进行综述。