Peripheral pulmonary carcinoid tumors.

The light microscopic and ultrastructural features of five asymptomatic peripheral carcinoids presented as distinct pulmonary solitary nodules are described. By conventional microscopy the tumors displayed a variety of histologic patterns, the most unusual one showing tumor cells embedded in a richly vascular hyalinized stroma and forming papillary structures or cystic spaces lined by low cuboidal cells which ultrastructurally bore a strong resemblance to intermediate or transitional forms between types I and II pneumocytes. A striking feature of these tumors was their rich vasculature associated with a marked perivascular sclerosis composed of basement membrane-like material and collagen fibrils most likely produced by the increased numbers of pericytes surrounding these sclerotic vessels. The clinical implications, biologic behavior, and association of these tumors with other pulmonary neoplasms are also discussed.     

肺类癌的治疗与预后

目的 总结肺类癌的临床特点、治疗方法及疗效,评价影响预后的因素。方法 回顾性分析25例肺类癌的临床资料。其中典型类癌（TC）16例,非典型类癌（AC）9例。根据1997年国际抗癌联盟分期,I期15例（TC14例,AC1例）,Ⅱ期4例（TC1例,AC3例）,Ⅲ期6例（TC1例,AC5例）。25例患者均手术治疗,其中18例行单纯手术治疗,5例行术后放射治疗,2例行术后化疗。结果 全组5年和10年生存率分别为87％和72％,单纯手术治疗患者5年生存率为93％,术后辅助治疗的患者无1例生存超过5年。典型类癌的5年生存率为100％,而非典型类部为38％。I期5年生存率为100％、Ⅱ＋Ⅲ期为53％。单因素分析病理类型和分期均为有显著性意义的预后因素。结论 肺类癌以手术治疗为主,对于Ⅲ期肺非典型类癌,推荐术的珩辅助性化疗和(或）放射治疗。多数肺类癌患者可获得长期生存,影响预后的因素主要为病理类型和分期。     

Experience in treatment of metastatic pulmonary carcinoid tumors

Background:The only cure for patients with pulmonarycarcinoids is surgery. In the present paper, we report the results ofmedical treatment of patients with metastatic tumors, their circulatinghormone markers, and immunohistochemical profile of the tumors. Patients and methods/Results:The response to systemicantitumoral treatment was studied in 31 patients with metastaticpulmonary carcinoids. Median survival from treatment start was 25months. Alpha-interferon treatment has resulted in stable disease in 4of 27 patients (median duration 15 months), while 23 patients showedprogressive disease. Somatostatin analogues given as single drugtreatment resulted in progressive disease. Streptozotocin and5-fluorouracil resulted in progressive disease in seven of sevenpatients. Stable disease was obtained for 8 and 10 months respectivelyin two of two patients treated with streptozotocin + doxorubicin. Two ofeight patients treated with cisplatinum + etoposide showed a significantdecrease in tumor size lasting six and eight months respectively, andone displayed stable disease for seven months. Elevation of plasmachromogranin A was seen in 93%. Conclusions:Theresults of systemic antitumoral treatment of pulmonary carcinoids withdistant metastases are generally discouraging. Chemotherapy withcisplatinum + etoposide, or doxorubicin combined with streptozotocin orpaclitaxel may be of value. Alpha-interferon and octreotide offerefficient symptomatic relief, but stabilizes tumor growth in merely15% of the cases. Plasma chromogranin A is the most frequentlyelevated tumor marker.     

Familial occurrence of carcinoid tumors and association with other malignant neoplasms.

Carcinoid tumors are generally thought to be sporadic, except for a small proportion that occur as a part of multiple endocrine neoplasia syndromes. Data regarding the familial occurrence of carcinoid as well as its potential association with other neoplasms are limited. A chart review was conducted on patients indexed for malignant carcinoid tumor of the gastrointestinal tract seen at the Mayo Clinic between 1988 and 1996. A survey of family history of malignancies and personal history of other tumors was mailed to all eligible patients. Data for 245 patients were analyzed. Observed rates of carcinoids and other malignancies were compared with Surveillance, Epidemiology, and End Results data. Estimates of the cumulative probability for first-degree relatives developing a carcinoid tumor were calculated. Nine (3.7%) patients with carcinoid tumor had at least one first-degree relative with the same malignancy. The rate of carcinoid tumor in first-degree relatives of probands was higher (P < 0.0001) than expected based on the Surveillance, Epidemiology, and End Results population data. Cumulative probability in a first-degree relative for developing a carcinoid was calculated to be 1.5% at age 80. There was an increased risk for developing a carcinoid tumor among first-degree relatives of patients with carcinoid. Neither patients with carcinoid nor their first-degree relatives had an increased incidence of other malignancies.     

Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors

Objectives

The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined.

Materials and methods

A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990 and 2012.

Results

300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stages I–III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4–32), compared to 3 (1%) patients with typical carcinoid (range, 8–12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum–etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5-year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 month median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 month median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6–72 months).

Conclusions

These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy.     

Familial carcinoid tumors and subsequent cancers: a nation-wide epidemiologic study from Sweden.

Carcinoids are rare neuroendocrine tumors, mainly located in the bowel, stomach and lung. Familial risks in carcinoid tumours are not well known apart from multiple endocrine neoplasia 1 (MEN1). We used the nation-wide Swedish Family-Cancer Database on 10.1 million individuals for assessment. Carcinoid tumors were retrieved from the Cancer Registry covering the years 1958-1998. The offspring generation, aged 0-66 years, accumulated 190 million person-years at risk. The age-adjusted incidence rates were 0.76 for men and 1.29/100,000 for women. Standardized incidence ratios (SIRs) were calculated for offspring when their parents had a carcinoid or any other cancer. When parents presented with carcinoids, SIRs for offspring were 4.35 (n = 8, 95% CI 1.86-7.89) for small intestinal and 4.65 (n = 4, 95% CI 1.21-10.32) for colon carcinoids. If both offspring and parents presented with small intestinal carcinoids, the SIR was 12.31 (n = 4, 95% CI 3.20-27.34). Offspring carcinoids were also increased if parents presented with bladder and endocrine gland tumors, the latter association probably partially due to MEN1. Risks for second cancers were increased, particularly at sites where familial risks were found, including carcinoids in the small intestine.     

Outcome of patients with pulmonary carcinoid tumors receiving chemotherapy or chemoradiotherapy

STUDY OBJECTIVES: To determine the outcome of patients with pulmonary typical and atypical carcinoid tumors treated with chemotherapy with or without radiotherapy. METHODS: Patients with pulmonary neuroendocrine tumors treated at our institution from 1990 to 2001 were identified. The medical records of patients with diagnoses of typical or atypical pulmonary carcinoids were reviewed for the presence of evaluable disease, treatment with chemotherapy with or without radiotherapy, response to these treatments, survival and cause of death. RESULTS: Eighteen patients with typical (n = 8) or atypical (n = 10) pulmonary carcinoid tumors who were treated with chemotherapy with or without radiotherapy were identified. Of these, four received chemotherapy plus chest radiotherapy. Three of these had stable disease and one had a partial response. One of the patients with stable disease to chemoradiotherapy subsequently received chemotherapy alone, to which he had a complete response. Fourteen additional patients were treated with 18 chemotherapy regimens. There were two partial responses, eight stable disease, seven progressive disease and one allergic reaction precluding further treatment. The overall response rate to any chemotherapy was 3/15 (20%, 95% CI 0.07-0.45), and the best overall response rate to chemotherapy with or without chest radiotherapy was 4/18 (22%, 95% CI 0.09-0.45). Median overall survival was 20 months (95% CI 0-51 months). CONCLUSIONS: Patients with typical and atypical pulmonary carcinoid tumors can respond to chemotherapy with or without chest radiotherapy, though with response rates that appear less than those of small cell lung cancers. Further characterization of pulmonary carcinoid tumors and study of treatment alternatives for unresectable disease is warranted.     

Bronchial carcinoid tumors.

Twenty-eight pulmonary carcinoid tumors were reviewed histologically and clinically. Hematoxylin-and-eosin-stained sections were utilized, as well as special stains, including the argyrophil and argentaffin reactions. The 22 tumors located centrally, at the level of primary or segmental bronchi, had a microscopic appearance distinct from those located more peripherally. One peripheral tumor that was large in size appeared much more aggressive histologically, and was designated an atypical carcinoid. The origin of carcinoid tumors from Kulchitsky cells in the lung, the distinction of peripheral tumors from chemodectomas, and the relationship of bronchial carcinoids to bronchial epithelial hyperplasias and oat cell carcinomas are discussed.     

Familial gastrointestinal carcinoid tumours and associated cancers

BackgroundCarcinoid tumours are neuroendocrine neoplasms mainly located in the gastrointestinal tract and bronchopulmonary system. Our study's aim was to characterise the familial nature of gastrointestinal carcinoid tumours using the Swedish Family-Cancer Database, which includes >11.5 million individuals.MethodsFamilial relative risks (RRs) of carcinoid tumours were estimated for individuals with family history of invasive cancers. RRs of invasive cancers for the offspring of patients with carcinoid tumours were calculated as well. RRs were based on Poisson regression.ResultsThe risk of carcinoid tumours was significantly increased among individuals with a parental history of carcinoid tumours (RR 4.33). An association was also found between carcinoid tumours in the offspring and parental invasive cancers of the brain, breast, liver, endocrine glands and urinary organs. In addition, parental invasive cancers of the kidney as well as squamous cell skin cancer associated with small intestinal carcinoids in the offspring. The risk of carcinoid tumours was elevated among those whose siblings were affected by colon and rectal cancers.ConclusionThe results describe the familial aggregation of carcinoid tumours with other noncarcinoid malignancies. Carcinoid tumours are rare and translating these results into screening programmes needs more research; however, gene finding studies should be stimulated.     

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.     

Bronchial carcinoid tumors in children

Carcinoid tumors are the most common endobronchial tumors in the pediatric population, and represent a rare cause of airway obstruction. Clinical manifestations are unspecific, and diagnosis is often delayed due to low clinical suspicion. These tumors are considered low-grade malignant neoplasms, and their evolution is usually favorable after surgery. However, local recurrence and/or metastases can occur with both typical and atypical carcinoid tumors, justifying the need of prompt diagnosis and long-term follow-up.     

Treatment of advanced carcinoid tumors

PURPOSE OF REVIEW: Carcinoid tumors often present with metastatic disease. Generally, these tumors can be treated conservatively. New evidence exists, however, that stage IV disease may be better managed with more aggressive medical and surgical treatment. Headway is also being made into understanding the associated fibrosis seen with advanced disease and in better understanding signaling pathways with the hope of offering future treatment options. RECENT FINDINGS: Recent literature has advocated for more aggressive surgical treatment of carcinoid tumors, especially in the setting of hepatic metastases and peritoneal carcinomatosis. Octreotide and lanreotide are further being described for treating metastatic carcinoids. Radiolabeled somatostatin analogues may prove to be as effective for treating carcinoids as for visualizing them. Other potential treatment modalities include pharmacologic activation of signaling pathways to control excess hormone production. Research into fibrosis - a cause of pain, bowel obstruction, retroperitoneal vascular constriction and right heart failure - has shown that serotonin and tachykinins may be the key mediators. SUMMARY: Patients with stage IV carcinoid tumors may benefit from more aggressive surgical management and new treatment modalities. The growing body of knowledge regarding important molecular signaling pathway may lead to new medical therapies and further understanding of the sequelae of excess hormone production.     

Familial pediatric endocrine tumors

Pediatric endocrine tumors are rare but have fairly characteristic presentations. We describe an approach to diagnosis and management of five of the most common presentations including gonadoblastoma, paraganglioma, medullary thyroid cancer, adrenal cancer, and pituitary adenoma. Genetic testing can aid in the early detection and prevention and management of tumors in patients and in other family members.     

Diagnosis and treatment of carcinoid tumors

Carcinoid tumors belong to the family of neuroendocrine tumors, which are usually slow growing with distinct biological and clinical characteristics. The incidence of these tumors is approximately 2.5 in 100,000 people per year. The former classification system of foregut, midgut and hindgut tumors is still used in clinical routine, although there is a new World Health Organization classification. Determination of the histopathology of carcinoid tumors is of utmost importance and involves specific immunohistochemical staining for chromogranin A, synaptophysin, serotonin and gastrin. Proliferation capacity measured by Ki67 is used to guide forthcoming medical treatment. Localization procedures include computerized tomography, ultrasound, magnetic resonance imaging, somatostatin receptor scintigraphy and positron emission tomography. Surgery remains the cornerstone of treatment and provides the only chance of a cure. Other cytoreductive procedures include radiofrequency ablation, laser treatment and chemoembolization. Biological treatment includes cytotoxic agents, such as somatostatin analogs and interferon-alpha, which should be applied in slow-growing neoplasms. Combination regimens including cisplatin, etoposide, streptozotocin and 5-fluorouracil should be reserved for treatment of highly proliferating tumors. Future therapy of carcinoid tumors will be based on the specific tumor biology and treatment will be customized for each individual patient. New therapies, such as antiangiogenic agents and new, long-acting somatostatin analogs, together with further development of tumor-targeted treatments, will come into clinical use in the near future.     

Inhibition of mTOR in carcinoid tumors

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumors, whose incidence and prevalence are increasing. The clinical behavior of NEN is variable, ranging from well-differentiated slow growing tumors to highly aggressive poorly differentiated neuroendocrine carcinomas. The term carcinoid is commonly used for the more benign variants of these neoplasms. Most frequently, carcinoids have their origin in the small intestine, followed by in the lung and other sites. Some of these tumors are associated with the carcinoid syndrome. The use of somatostatin analogs has revolutionized the clinical management of patients with carcinoids. However, although symptomatic relief and stabilization of tumor growth for various periods of time are observed in many patients treated with somatostatin analogs, tumor regression is rare. Currently, there is no other powerful antiproliferative agent available for carcinoids. Mammalian target of rapamycin (mTOR), a main protein kinase in the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway, is an important intracellular mediator involved in multiple cellular functions including proliferation, differentiation, apoptosis, tumorigenesis, and angiogenesis. Alterations of the normal activity of mTOR and of mTOR-related kinases in this pathway have been found in a diversity of human tumors, including NEN; therefore, mTOR pathway represents an attractive target for new anticancer therapies. While mTOR inhibitors, such as everolimus, are established therapy in pancreatic NEN, results from recent clinical trials indicate that mTOR inhibitors may be also of value in the management of carcinoids. However, further clinical trials will have to confirm efficacy and elucidate, in which subtypes and in which setting, these drugs might be most usefully applied.     

Diagnosis and treatment of carcinoid tumors

Carcinoid tumors belong to the family of neuroendocrine tumors, which are usually slow growing with distinct biological and clinical characteristics. The incidence of these tumors is approximately 2.5 in 100,000 people per year. The former classification system of foregut, midgut and hindgut tumors is still used in clinical routine, although there is a new World Health Organization classification. Determination of the histopathology of carcinoid tumors is of utmost importance and involves specific immunohistochemical staining for chromogranin A, synaptophysin, serotonin and gastrin. Proliferation capacity measured by Ki67 is used to guide forthcoming medical treatment. Localization procedures include computerized tomography, ultrasound, magnetic resonance imaging, somatostatin receptor scintigraphy and positron emission tomography. Surgery remains the cornerstone of treatment and provides the only chance of a cure. Other cytoreductive procedures include radiofrequency ablation, laser treatment and chemoembolization. Biological treatment includes cytotoxic agents, such as somatostatin analogs and interferon-α, which should be applied in slow-growing neoplasms. Combination regimens including cisplatin, etoposide, streptozotocin and 5-fluorouracil should be reserved for treatment of highly proliferating tumors. Future therapy of carcinoid tumors will be based on the specific tumor biology and treatment will be customized for each individual patient. New therapies, such as antiangiogenic agents and new, long-acting somatostatin analogs, together with further development of tumor-targeted treatments, will come into clinical use in the near future.     

Growth characteristics of rectal carcinoid tumors

PURPOSE: Tissue growth depends on both cell proliferation and cell death. This study was designed to examine the growth characteristics of rectal carcinoid tumors. METHODS: Fifty rectal carcinoid tumors were studied clinicopathologically and experimentally. Expression of Ki-67, TGF-alpha, p53, and bcl-2 was examined immunohistochemically, and apoptotic cells were identified by the in situ DNA nick end labeling method. EGF receptor expression was examined by a colorimetric in situ mRNA hybridization technique. RESULTS: The median Ki-67 labeling index (LI) in all lesions was 0.62 +/- 0.59%. Ki-67 LI was significantly (p < 0.01) higher in lesions larger than 5 mm than in lesions smaller than 5 mm. TGF-alpha was expressed more frequently (p < 0.01) in lesions larger than 5 mm (100%) than in lesions smaller than 5 mm (65.2%). Ki-67 LI was significantly (p < 0. 05) higher in lesions with TGF-alpha expression than in lesions without TGF-alpha expression. The in situ hybridization revealed EGF receptor expression in all 46 lesions with intact mRNA (100%), and coexpression of TGF-alpha and EGF receptor was found in 39 of the 46 (84.8%) lesions. The median apoptotic index (AI) in all lesions was 0.15 +/- 0.12%. AI has increased with tumor size and was significantly (p < 0.05) higher in lesions with a higher Ki-67 LI than in lesions with a lower Ki-67 LI. p53 protein was detected in only 1 patient who had liver metastases, and the gene mutation was confirmed by polymerase chain reaction and single-strand conformation polymorphism analysis. bcl-2 expression was absent in all lesions. CONCLUSIONS: The Ki-67 LI indicated a low cellular proliferative activity in rectal carcinoid tumors. AI was very low, and was significantly correlated with proliferative rate. Inhibition of apoptosis by mutated p53 or bcl-2 may not have occurred in most of these tumors. TGF-alpha/EGF receptor autocrine mechanisms may play a possible role in tumor growth, and the cellular proliferative activity may increase as tumors grow larger.     

Metastatic carcinoid tumors: a clinical review

Carcinoid tumors are neuroendocrine tumors derived from enterochromaffin cells, which are widely distributed in the body. They can originate from any location in the body, but they are traditionally described as originating from the foregut, midgut, and hindgut. Although the overall incidence of carcinoid tumors appears to have increased in the past decades, the prognosis for patients with metastatic carcinoid tumors has improved during the last decade. Due to longer survival times, complications, such as carcinoid heart disease, and new metastatic patterns, like skin and bone metastases, may become more important features of carcinoid disease. Therapy focused on these complications should be part of the management. Combining new diagnostic and treatment modalities in metastatic carcinoid patients may result in better quality of life and longer survival times. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach, with decisions made in multidisciplinary meetings focused on "tailor-made" therapy based on patients' specific conditions. Because carcinoid tumors are uncommon, effort should be made to treat these patients in specialized centers and for these centers to join together in multicenter studies.