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Patients with carcinoid tumors frequently could benefit from the pharmacologic treatment of depression and anxiety. However, many prescribers avoid serotonergic medications due to the theoretical risk of exacerbating carcinoid syndrome.The authors conducted a retrospective chart review of patients with carcinoid tumors and elevated serotonin levels (as measured by 24-hour urine 5-hydroxyindoleacetic acid [5-HIAA]) at Dana-Farber/Brigham and Women's Cancer Center who initiated treatment with serotonergic antidepressants after a carcinoid diagnosis from 2003 to 2016. Each medication regimen was categorized based on the presence of adverse interactions as defined by clinical worsening of symptoms of carcinoid syndrome in the absence of progressive disease that temporally correlated with a serotonergic medication trial.A total of 73 serotonergic regimens received by 52 patients were included in the primary analysis. Among these medication trials, 8.2% of the regimens (6 regimens) were categorized as being associated with a likely adverse interaction, 61.6% of the regimens (45 regimens) were categorized as having no adverse reaction, 9.6% of the regimens (7 regimens) were categorized as an unlikely adverse reaction, and 20.6% of the regimens (15 regimens) were categorized as unknown. It is interesting to note that none of the 73 trials resulted in a carcinoid crisis requiring emergency care or hospitalization. Only 3 patients discontinued serotonergic medications due to worsening carcinoid syndrome.Serotonergic medications appear to be a safe option for the treatment of depressive and anxiety symptoms in the majority of patients with neuroendocrine tumors and carcinoid syndrome. In the current study,10% of patients developed a combination of flushing, diarrhea, and bloating after the initiation of serotonergic medications. Clinicians can begin with low doses, monitor these symptoms, and reduce the dose or discontinue the medication if necessary. Cancer 2017;123:2735-42. © 2017 American Cancer Society.

BACKGROUND: Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Notch activation has been shown to suppress growth and hormone production in carcinoid cells. METHODS: The purpose of this study was to provide a process for identifying Notch activating compounds via high-throughput screening (HTS) and to validate the effects of the strongest hit from the 7264 compounds analyzed: resveratrol (RESV). RESULTS: Treatment of carcinoid cells with RESV resulted in up-regulation of the Notch signaling pathway as measured by suppression of its downstream target achaete-scute complex-like 1. Luciferase reporter assays incorporating the centromere-binding factor 1 binding site also confirmed the functional activity of RESV-induced Notch. Because activation of the Notch pathway has been shown to suppress carcinoid proliferation, RESV treatment of carcinoid cells led to a dose-dependent inhibition of cellular growth. Immunoblotting revealed phosphorylation of cdc2 (Tyr15) and up-regulation of p21Cip1/Waf, markers of cell cycle arrest, with RESV treatment. Flow cytometry confirmed the mechanism of RESV-induced growth inhibition is S phase cell cycle arrest. Furthermore, because Notch has been shown to inhibit bioactive hormone production from NE tumors, RESV also suppressed expression of the NE peptides/hormones chromogranin A and serotonin. RNA interference assays demonstrated that the hormone suppressing capacity of RESV was due to up-regulation of the Notch2 isoform. CONCLUSIONS: HTS can be used to identify novel Notch activating compounds, which may have the potential to suppress carcinoid tumor growth and the associated endocrinopathies. Cancer 2011. © 2010 American Cancer Society.

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.

Bronchopulmonary neuroendocrine tumors (BP-NETs) comprise approximately 20% of all lung cancers and represent a spectrum of tumors arising from neuroendocrine cells of the BP-epithelium. Although they share structural, morphological, immunohistochemical, and ultrastructural features, they are separated into 4 subgroups: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC), which exhibit considerably different biological characteristics. The clinical presentation includes cough, hemoptysis, and obstructive pneumonia but varies depending on site, size, and growth pattern. Less than 5% of BP-NETs exhibit hormonally related symptoms such as carcinoid syndrome, Cushing, acromegaly, and SIADH. SCLC is the most common BP-NET, while LCNEC is rare, approximately 10% and < or =1%, respectively, of all lung cancers. Both SCLC and LCNEC progress rapidly, are aggressively metastatic, and exhibit a poor prognosis. The incidence of BP-carcinoids (TC and AC) in the US was 1.57 of 100,000 in 2003 (an unexplained and substantial increase over the last 30 years, approximately 6% per year). No curative treatment except for radical surgery (almost never feasible) exists. The slow-growing TC exhibit a fairly good prognosis ( approximately 88%, 5-year survival), whereas AC demonstrate a 5-year survival of approximately 50%, and the highly malignant LCNEC and SCLC5-year survival of 15% to 57% and

BACKGROUND. Currently, no consistently effective therapy is available to inhibit cell proliferation or metastasis of neuroendocrine tumor (NET) disease. The effects of 4 novel peptides were analyzed: a targeted cytotoxic analog of luteinizing hormone-releasing hormone (LH-RH) analog (AN-152), a targeted cytotoxic analog of somatostatin (AN-238), and 2 antagonists of growth hormone-releasing hormone (GH-RH) on 3 NET (carcinoid) cell lines that expressed respective peptide receptors. METHODS. The effects of the compounds were evaluated on cell proliferation in vitro using MTT uptake and Ki67 expression, apoptosis (caspase 3 expression and activity), and cell cycle parameters (DNA distribution). RESULTS. Proliferation of the LH-RH receptor-expressing lung NET, NCI-H720 line, was inhibited 2-fold by AN-152 containing doxorubicin compared with the chemotherapy alone (IC50 of 9.1 nM vs 24 nM). This was associated with a reduction in Ki67 transcript and an increase in both caspase 3 mRNA levels and activity. Proliferation of the GH-RH receptor expressing lung NET, NCI-H727 line, was inhibited by both GH-RH antagonists, the effects being mediated through changes in Ki67 expression, but not in caspase 3-mediated apoptosis. The small intestinal NET, KRJ-I line, was 8× more sensitive to inhibition by AN-238 than to 2-pyrolino-doxorubicin, reflected by increased caspase 3 transcript as well as activity. AN-238-mediated growth inhibition culminated in complete G1 arrest. CONCLUSIONS. The data demonstrate GH-RH antagonists or peptide-linked antineoplastic agents such as AN-152 and AN-238 are effective inhibitors of NET proliferation in vitro. Because peptide receptors such as those for GH-RH, LH-RH, and SST subtypes are commonly expressed by NETs, the development of antineoplastic agents targeted to specific tumor receptors may provide a more efficacious strategy than systemic chemotherapeutic agents currently in use. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND. A comprehensive study of carcinoid tumors from United States-based databases indicated that the small intestine, colon, rectum, and bronchopulmonary system are common locations for carcinoid tumors. In addition, certain carcinoid tumors, such as rectal carcinoids, appeared to be overrepresented in nonwhite populations in the United States. High frequencies of associated noncarcinoid malignancies were reported in some articles. The objective of the current study was to address the organ distribution, frequency of metastasis, and survival rates of carcinoid tumors and the associated noncarcinoid tumors in Taiwanese, Asian populations. METHODS. Two hundred twenty-eight patients with carcinoid tumors were identified and evaluated from the surgical pathology files and medical records of the Veterans General Hospital, Taipei, Taiwan from January 1970 to December 2005. RESULTS. In 228 carcinoid tumors that were analyzed, the rectum (60.5%) was the most common location followed by the lung (20.2%) and the thymus (6.6%). Metastatic lesions were demonstrated in 16.2% of patients. Disease extent was associated with survival. The 5-year survival rates for patients with localized, regional metastatic, and distant metastatic disease were 94.1%, 49.1%, and 0%, respectively (P < .001). Associated noncarcinoid malignancies were noted in 14% of patients with carcinoids, mainly in the gastrointestinal tract (52.9%), lung, and genitourinary system. CONCLUSIONS. A different organ distribution of carcinoids was observed in Taiwanese patients, who had with significantly more carcinoids located in the rectum and thymus compared with patients in Western countries. The patients with carcinoids in the current study had a high possibility of developing associated, noncarcinoid neoplasms. Surveillance of the colon, stomach, lung, and genitourinary system for second malignant tumors is recommended. Cancer 2008. © 2007 American Cancer Society.

Although it is known that small intestinal carcinoids are derived from enterochromaffin (EC) cells, these cells remain poorly characterized and little is known of the growth regulatory mechanisms of these neuroendocrine cells. Down-regulation or loss of the transforming growth factor-beta1 (TGFbeta1) cytostatic program and activation of TGFbeta-mediated transcriptional networks is associated with uncontrolled growth and metastasis in other neural tumors, glioblastomas. Whether this phenomenon is common to small intestinal carcinoid tumors was investigated.The effects of TGFbeta1 on cultured normal EC cells (isolated by FACS sorting) and the neoplastic EC cell line, KRJ-I, was assessed using the MTT assay. The TGFbetaRII transcript and protein were identified in tumor cells and the effects of TGFbeta1 on SMAD2 phosphorylation and nuclear translocation quantified. The time-dependent response of SMAD4, SMAD7, c-Myc, and P21(WAF1/CIP1) protein expression and c-Myc and p21(WAF1/CIP1) transcript was measured in response to TGFbeta1 and the transcript expression of candidate downstream targets, MTA1 and E-cadherin, were assessed.TGFbeta1 inhibited normal EC cell proliferation (IC(50) = 17 pM) but stimulated neoplastic EC cell proliferation (EC(50) = 22 pM). In tumor cells, significantly decreased transcript (P.01) of TGFbetaRII was identified, but no receptor mutations were identified and protein expression was evident. TGFbeta1 (1 ng/mL) resulted in SMAD2 phosphorylation and7% nuclear expression compared with 93% in normal EC cells. In neoplastic cells, TGFbeta1 (1 ng/mL) caused a decrease in SMAD4 (16%, P.05), whereas SMAD7 and c-Myc transcript and protein were respectively increased21% (P.05) and approximately 40% (P.002). TGFbeta1 (1 ng/mL) also decreased p21(WAF1/CIP1) transcript by 60% (P.001) and protein that was undetectable at 24 hours. Expression of the downstream targets of the c-Myc pathway, MTA1, was increased (20%) and E-cadherin decreased (30%).The neoplastic EC cell is characterized by loss of TGFbeta-1-mediated growth inhibition and, similar to glioblastomas, utilizes the TGFbeta system to induce gene responses associated with growth promotion (c-Myc and the ERK pathway), invasion (E-cadherin), and metastasis (MTA1).

Current techniques to define gastric neoplasia are limited but molecular genetic signatures can categorize tumors and provide biological rationale for predicting clinical behavior. We identified three gene signatures: Chromogranin A (CgA), MAGE-D2 (adhesion), and MTA1 (metastasis) that define gastrointestinal (GI) carcinoids and hypothesize that their expression can delineate gastric neoplasia. This strategy provides a molecular basis to define neuroendocrine gastric carcinoids (GCs), neuronal stromal tumors (GISTs), or epithelial cell (gastric adenocarcinomas [GCAs])-derived tumors.Total RNA was isolated from 38 GCs: Type I/II (n = 7), Type III/IV (n = 6), GISTs (n = 12), GCAs (n = 13), and normal mucosa (n = 12). Quantitative reverse transcriptase polymerase chain reaction (Q RT-PCR) gene expression was quantified against glyseraldehyde-3-phosphate dehydrogenase (GAPDH) and CgA and MTA1 protein expression levels were analyzed by immunohistochemical analyses of a gastric neoplasia microarray.CgA was elevated in Type I/II (10-fold; P.01) and Type III/IV (100-fold, P.005), decreased in GISTs (100-fold, P.03), and unchanged in GCAs. MAGE-D2 was 5-10-fold elevated (P.05) in Type III/IV, GISTs, and GCAs but not in Type I/II tumors. MTA1 (5-fold, P.01) was elevated in GCs (Type III/IVI/II, P.05), in GISTs (4-fold, P.05), and GCAs. CgA protein levels were elevated in GCs (P.005) but not in GISTs and GCAs. MTA1 levels were elevated in all tumors (P.02) compared with normal, and especially with tumor invasion (P.05).CgA discriminates GCs from other gastric neoplasms; overexpression of MAGE-D2 and MTA1 differentiate Type III/IV from Type I/II GCs. GISTs share similar expression patterns with Type III/IV GCs but have decreased CgA. MTA1 is a marker of tumor invasion.

BACKGROUND The aim of the current study was to clarify the actual clinicopathologic status of extremely rare pancreatic carcinoids. To date, statistical evaluation of such carcinoids has been hampered because an insufficient number of cases has prevented any reliable statistical analyses. METHODS The Niigata Registry for Gut–Pancreatic Endocrinomas contains a total number of 156 cases of pancreatic carcinoids among 165 endocrinocarcinomas registered worldwide. This figure of 156 cases comprises 144 typical and 12 atypical carcinoids, which were compared statistically with carcinoids in other representative sites, according to various clinicopathologic criteria. RESULTS Pancreatic carcinoids made up 1.4% of the total number of registered cases (n = 11,343) and were characteristic in the following five ways. 1) They exhibited a high metastatic rate (66.7%), somewhat lower than that for the ileocecum (76.1%), identical to that for the ileum (66.9%), and far higher than that for the total average of 35.7%. 2) They displayed the largest average tumor size (68.6 mm), followed by that for the ovary (68.2 mm), and ileocecum (46.5 mm) against a total average of 30.2 mm. 3) They revealed a relatively high incidence of the carcinoid syndrome (23.3%), almost equal to that for the ileocecum (24.1%), and exceeded by that for the small intestine (35.8%), when compared with that for the total average of 11.0%. 4) They showed a high rate of immunohistochemical detection for serotonin (92.9%), lower than that for the testicle (100.0%), but higher than the total average of 54.9%. 5) Five-year survival rate was extremely low (28.9% ± 16.7%) compared with those for the appendix (89.7% ± 2.0%) and the small intestine (82.1% ± 3.3%). It was noteworthy that silver impregnations in the pancreatic carcinoid series indicated a result identical to that for the total average: Grimelius argyrophilia, 84.8% versus 85.4%; argyrophil cell type, 59.1% versus 58.5%; and argentaffin cell type, 22.7% versus 22.3%. CONCLUSION It may be said that in the treatment of patients with pancreatic carcinoids, appropriate procedures should be carried out with these distinguishing characteristics always kept in mind. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND The objective of this study was to determine the prognostic variables that influence response and survival in patients with metastatic neuroendocrine tumors who are treated with hepatic arterial embolization (HAE) or chemoembolization (HACE). METHODS Patients with metastatic neuroendocrine tumors who underwent HAE or HACE were included in this retrospective study. Follow-up imaging studies were compared with baseline imaging to determine the radiologic response. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Univariate and multivariate analyses were performed to assess the prognostic variables that affected response and survival. RESULTS The study included 69 patients with carcinoid tumors and 54 patients with pancreatic islet cell carcinomas. Patients who had carcinoid tumors had a higher response rate (66.7% vs. 35.2%; P = 0.0001) and had longer PFS (22.7 mos vs. 16.1 mos; P = 0.046) and OS (33.8 mos vs. 23.2 mos; P = 0.012) compared with patients who had islet cell carcinomas. For patients with carcinoid tumors, multivariate analysis identified male gender as the only independent risk factor for poor survival (P = 0.05). Octreotide was predictive marginally for PFS (P = 0.06). Patients who were treated with HAE had a higher response rate than patients who were treated with HACE (P = 0.004). For patients with islet cell carcinoma, an intact primary tumor, ≥ 75% liver involvement, and extrahepatic metastases were associated with reduced OS in the univariate analysis; the presence of bone metastases was the only risk factor (P = 0.031) in the multivariate analysis. Patients who were treated with HACE had a prolonged OS (31.5 mos vs. 18.2 mos) and improved response (50% vs. 25%) compared with patients who were treated with HAE, although the differences did not reach statistical significance. CONCLUSIONS Patients with carcinoid tumors had better outcomes than patients with islet cell carcinomas. The addition of intraarterial chemotherapy to HAE did not improve the outcome of patients with carcinoid tumors, but it seemed to benefit patients with islet cell carcinomas. In patients who had carcinoid tumors, male gender predicted a poor outcome, and a trend toward prolonged PFS was observed in patients who received concomitant octreotide. An intact primary tumor, extensive liver disease, and bone metastases were associated with reduced survival in patients with islet cell carcinomas. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND Gastrointestinal (GI) carcinoids, considered to be endocrine neoplasms with relatively low levels of malignancy, have never been examined in large, statistically reliable series to determine their true aggressive behavior in the early stage of both minute (≤ 5 mm) or small (5.1–10.0 mm) tumors at a depth of invasion restricted to the mucosa and submucosa (sm carcinoids). METHODS Of a total number of 1914 cases of GI sm carcinoids selected from the Niigata Registry, 1614 with the tumor size recorded on a millimeter scale were categorized in 5-mm size intervals and rates of metastases were calculated for those in each size category. Of statistical significance was confirmation that the rectum (n = 849), the stomach (n = 449), the duodenum (n = 349), and the jejunoileum (n = 149) were among the principal growth sites. The Kaplan–Meier method was used to calculate 5-year-survival rates (5YSRs) and a comparative study was undertaken. RESULTS GI sm carcinoids exhibited a metastasis rate of 16.4% (264 of 1614) as a whole and minute carcinoids (≤ 5 mm) revealed an unexpectedly high metastasis rate of 6.0% (24 of 399) on average, which ranged from 3.7% (8 of 216) in the rectum to 17.2% (5 of 29) in the jejunoileum. Small carcinoids measuring 5.1–10 mm also showed a high metastasis rate of 13.3% (90 of 675) on average, ranging from 9.6% (12 of 125) in the stomach to 41.2% (14 of 34) in the jejunoileum. The combined average metastasis rate for both minute and small carcinoids combined (≤ 10 mm) was as high as 10.6% (114 of 1074). The comparative study confirmed that, in both the stomach and the rectum, the metastasis rate of sm carcinoids was significantly higher than that for ordinary sm carcinomas in tumors > 10 mm. Although most patients (92.8%; 1777 of 1914) underwent an endoscopy and/or a wider resection of the lesions, nonresectable metastases were found in 22 patients (1.1%). Of these, 16 had undergone a laparotomy and 6 had not received surgery. Among 1001 patients with GI sm carcinoids, the 5YSRs after curative resection ranged from 98.3% in the rectum to 89.6% in the stomach (P < 0.05), representing an average of 96.7% for the entire series. CONCLUSIONS Unexpectedly high aggressiveness in metastasis rates in both rectal and gastric sm carcinoids > 10 mm exhibiting values significantly higher than those of sm carcinomas were found in 1914 patients suffering from GI sm carcinoids. However, in sm carcinoids at either the minute or small tumor stage (tumors ≦ 10 mm), the metastasis rates were comparable to those of sm carcinomas. It should be emphasized that the 5YSRs for patients with GI sm carcinoids may be comparable to those with sm carcinomas in certain cases. These points should be taken into consideration when treating patients with GI carcinoids, particularly in the early stage, and even with the depth of invasion confined to the submucosa. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal-dominant syndrome associated with neoplasia of pituitary, pancreas, parathyroid, and foregut lineage neuroendocrine tissue. Although enteropancreatic carcinoid has been well described in patients with MEN 1, it was believed that bronchopulmonary carcinoid was relatively uncommon, occurring in approximately 5% of patients. It is unclear whether the increased screening of asymptomatic patients with MEN 1 will facilitate early diagnosis of this tumor and improve patient prognosis. METHODS The authors reviewed the patient records and, when available, thoracic computed tomographic (CT) images of 129 MEN 1-affected adult members of a single family to determine the prevalence and prognosis of bronchopulmonary nodules and carcinoid. RESULTS Among 129 patients, a diagnosis of bronchopulmonary carcinoid was noted in the records for 6 individuals (1 male and 5 females; 5%). Thoracic CT scans also were available for review from 32 of those patients. Twelve patients (38%) had pulmonary nodules evident on CT scans. Only hypergastrinemia was significantly more common in patients with pulmonary nodules; otherwise, the spectrum of neoplasia was similar between individuals with and without pulmonary lesions. Histologic diagnoses were available in four patients (three female) with abnormal CT images, and carcinoid was confirmed in each patient. No deaths or distant metastases occurred among the patients despite long-term follow-up (mean, 127 months). CONCLUSIONS The findings suggested that bronchopulmonary carcinoid is more prevalent in patients with MEN 1 than was recognized previously. Furthermore, the diagnosis did not appear to portend a poor prognosis in the majority of affected patients. Cancer 2005. © 2004 American Cancer Society.

Carcinoid tumors represent an unusual and complex disease spectrum with protean clinical manifestations. This compilation of several large United States-based databases comprising patients from 1950 to 1999 examines 13,715 carcinoid tumors and provides epidemiologic information regarding the natural history and evolution of the detection and diagnosis of this entity.The authors evaluated 10,878 carcinoid tumors that were identified by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI) from 1973 to 1999 in addition to 2837 carcinoid tumors that were registered previously by two earlier NCI programs. To the authors' knowledge, this represents the largest current epidemiology series addressing carcinoid tumors to date.Specific trends in incidence for carcinoid tumors of certain sites were identified. Among the most recently collected subset of data, sites that demonstrated the greatest incidence of carcinoids were the gastrointestinal tract (67.5%) and the bronchopulmonary system (25.3%). Within the gastrointestinal tract, most carcinoid tumors occurred in the small intestine (41.8%), rectum (27.4%), and stomach (8.7%). For all sites, age-adjusted incidence rates were highest in black males (4.48 per 100,000 population per year). Associated noncarcinoid tumors were frequent in conjunction with small intestinal (29.0%), gastric (20.5%), colonic (20.0%), and appendiceal (18.2%) carcinoids. The highest percentages of nonlocalized lesions were noted for cecal (81.5-83.2%) and pancreatic (71.9-81.3%) carcinoids, whereas the highest percentage of localized disease was found among rectal (81.7%), gastric (67.5%), and bronchopulmonary (65.4%) carcinoids. The best 5-year survival rates were recorded for patients with rectal (88.3%), bronchopulmonary (73.5%), and appendiceal (71.0%) carcinoids; these tumors exhibited invasive growth or metastatic spread in 3.9%, 27.5%, and 38.8% of patients, respectively.Carcinoids appear to have increased in overall incidence over the past 30 years; for some sites, this trend has been evident for nearly half a century. Recent marked increases in gastric and rectal carcinoids and a concomitant decrease in appendiceal carcinoid incidence may be due in part to varying rules of registration among the compiled databases examined in this report or to improvements in diagnostic technology; increased awareness of and about carcinoid tumors also may play a significant role. In 12.9% of all patients with carcinoid, distant metastases already were evident at the time of diagnosis; the overall 5-year survival rate for all carcinoid tumors, regardless of site, was 67.2%. These findings bring into question the widely promulgated relative benignity of carcinoid disease. Certain carcinoid tumors, such as those of the rectum, appear to be over-represented among the black and Asian populations within the United States, suggesting the role of genetics in the development of this intriguing disease.

Version 2 of the Collaborative Stage Data Collection System (CSv2) became effective with cases diagnosed in 2010. This report focuses on the CSv2 components required to derive the American Joint Committee on Cancer (AJCC) stage for prostate cancer and on the site-specific factors for prostate cancer captured in CSv2. The report also highlights differences between the AJCC 6th and 7th editions for classifying prostate cancer stage.Data from 18 Surveillance, Epidemiology, and End Results (SEER) Program population-based registries (SEER-18) were analyzed for the years 2004-2010, which included 400,591 prostate cancer cases.CSv2 provides specificity with regard to the Gleason grading system by distinguishing between clinical and pathologic patterns and scores. The AJCC 7th edition incorporates prostate-specific antigen values into staging, subdivides stage II into IIA and IIB, and reclassifies extraprostatic invasion with microscopic bladder neck invasion from T4 in the 6th edition to T3a; this latter change affected the AJCC stage of 283 cases in 2010. Of the 44,578 prostate cancer cases diagnosed in 2010 that would have been classified as stage II in the AJCC 6th edition, 32.7%, 27.5%, and 39.8% are classified as stages I, IIA, and IIB, respectively, in the 7th edition.CSv2 provides more information than was previously available to researchers using SEER prostate data. The absence of a clearly defined clinical stage for each prostate case is the overriding limitation that researchers face in relying on Collaborative Stage information to analyze prostate cancer data.

BACKGROUND Diagnostic difficulties in pulmonary cytology may be compounded by other medical problems, lack of pertinent information, and the presence of rare tumors. In the current study, the authors describe six cases of lower respiratory tract cytology that presented particular diagnostic challenges or pitfalls. METHODS Three lung fine-needle aspiration biopsies (FNAB) from three patients, four bronchoalveolar lavages from two patients, and one bronchial washing from one patient, each with histologic confirmation, were reviewed. Cytologic material included direct smears, ThinPrep® slides, and cell blocks. Cytologic findings were compared with established cytologic criteria for each final diagnosis. RESULTS Two cases with Aspergillus infection that demonstrated reactive atypical cells were misinterpreted as squamous cell carcinoma and nonsmall cell carcinoma. Two cases diagnosed as significant atypia and negative, respectively, subsequently were found to show bronchioloalveolar carcinoma (as well as lymphangioleiomyomatosis, which was suspected clinically) and bronchogenic adenocarcinoma, respectively. One lung FNAB from a patient subsequently confirmed to have bronchiolitis obliterans-organizing pneumonia (BOOP) showed reactive pneumocytes that initially were misinterpreted as being suspicious for carcinoid. These reactive pneumocytes were identified histologically in the area of BOOP. The last case was an FNAB of a well differentiated fetal-type adenocarcinoma, an unusual variant of adenocarcinoma that to the authors' knowledge rarely is described in the cytology literature. CONCLUSIONS Cytomorphologic features of lower respiratory tract pathology combined with appropriate clinical information and diagnostic discretion usually allow accurate diagnoses and should decrease both false-positive and false-negative result rates. Clinical information and radiologic findings may be invaluable, but may not always parallel the cytologic diagnosis. Cancer (Cancer Cytopathol) 2001;93:364–75. © 2001 American Cancer Society.

BACKGROUND To the authors' knowledge, no study regarding lung carcinoma patients age

BACKGROUND Despite the generally successful scintigraphic detection of endocrine tumors with [111In]-DTPA-D-[Phe1]-octreotide (OctreoScan®, Mallinckrodt Medical, Petten, The Netherlands), its intraoperative application awaits the development of suitable gamma detectors. This study describes a novel probe (H-probe2) and its ex vivo efficacy for the detection of midgut carcinoid tumors. METHODS The probe measures 180 mm × 24 mm, and contains a bismuth germinate crystal connected to a photomultiplicator tube, a lead shield, and a tantalum collimator with an angled, 3-mm wide opening. It was characterized in a test bench utilizing solublilized 111In and 99mTc, and 8 fresh operative specimens containing 26 histologically verified midgut carcinoid tumors (2-40 mm) from patients exposed to OctreoScan®. Measurements were made at 2.5-mm intervals over the entire specimens and presented three dimensionally. RESULTS The test bench analysis supported efficient shielding, and a total collimation of 27 ° for 111In and 20 ° for 99mTc. In addition to 18 palpable tumors, 4 of 6 surgically occult tumors (2-3 mm in dimension) could be discovered with H-probe2. Small tumors in close apposition to a large tumor could not be separated. Wellcounter examination showed that tumors detected with the H-probe2 exhibited 1.7-84.1 times higher radionuclide uptake than the surrounding normal tissue. CONCLUSION Ex vivo analysis of H-probe2 supported detection of tumors inaccessible to surgical palpation, but its clinical efficiency awaits intraoperative evaluation. Cancer 1997; 80:2495-500. © 1997 American Cancer Society.

Background. Carcinoid tumors of the gastrointestinal tract are most common localized in the appendix, followed by the small intestine, the rectum, and the stomach. The localization of these tumors at the ampulla of Vater is extremely seldom. Methods. In the present study the authors describe two patients with carcinoid tumors of the ampulla Vater and review 71 previously published cases. Results. Most patients presented with jaundice, but without carcinoid syndrome. Because the tumor grows submucosally, preoperative diagnosis was correct only in 15%. Most tumors were around 2 cm in size. Metastasis to lymph nodes and/or liver was present in 45%. Standard treatment is Whipple resection or local excision in small tumors. Conclusions. Carcinoid tumors of the ampulla of Vater are an extremely rare clinical entity. Generally, the prognosis is good with a 5-year survival period of 90%.

Background. Peptide hormone synthesis in neuroendocrine tumors is a well-recognized phenomenon. However, production in neuroendocrine tumors of atrial natriuretic polypeptide (ANP), a newly discovered peptide hormone from the heart, has not been studied extensively. Methods. The presence of immunoreactive human ANP (IR-hANP) in neuroendocrine tumors was determined using a specific human ANP radioimmunoassay. Neuroendocrine tumors examined included 9 small cell carcinomas of the uterus, 28 small cell carcinomas of the lung, 20 carcinoid tumors, 54 pancreatic endocrine tumors, 17 neuroblastic tumors, 14 pheochromocytomas, and 14 medullary carcinomas of the thyroid. Twenty atrial tissues also were examined as the control. Molecular size of IR-hANP in the extracts of atrial and tumor tissues was determined by gel chromatography. Results. IR-hANP was detected in the extracts of small cell carcinoma of the uterus, small cell carcinoma of the lung, and carcinoid tumor, with concentrations ranging from 3.1 to 210 ng/g wet weight tissue. No IR-hANP was detected in the extracts of pancreatic endocrine tumor, neuroblastic tumor, pheochromocytoma, and medullary carcinoma of the thyroid. The frequency of production of IR-hANP in neuroendocrine tumors was highest in small cell carcinoma of the uterus (44%), followed by small cell carcinoma of the lung (18%) and carcinoid tumor (15%). IR-hANP present in the extracts of small cell carcinomas of the uterus had molecular size heterogeneity, with three fragments in addition to α-, β-and γ-human ANP. Conclusions. These results indicate that IR-hANP is produced by neuroendocrine tumors and that the molecular size of IR-hANP in tumor tissues is different from that in atrial tissues. Cancer 1994; 73:1292–6.

BACKGROUND: Neuroendocrine tumor (NET) cell lines frequently express both insulin-like growth factor (IGF) ligand and the cognate IGF-1 receptor (IGF-1R) and, as such, potentially depend on the activation of IGF-1R and its downstream effectors for growth and survival. Preclinical studies suggest that somatostatin analogs and mammalian target of rapamycin (mTOR) inhibitors exhibit antitumor activity against NETs through inhibition of IGF-1-dependent signaling, suggesting that IGF-1R inhibition may be a promising therapeutic approach to NETs. Therefore, the authors of this report evaluated the safety and efficacy of MK-0646, a fully human monoclonal antibody (MoAb) that binds to the IGF-1R, as monotherapy in patients with metastatic, well-differentiated NETs. METHODS: A phase 2 study was performed in which patients received intravenous MK-0646 10 mg/kg once weekly over 1 hour. Archived pretreatment tumor tissue was obtained and genotyped for v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-3-kinase, catalytic, alpha polypeptide (PIK3CA); and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, and immunohistochemistry was performed to measure the expression IGF-1R. RESULTS: Twenty-five patients received treatment (40% women; median age, 61 years; age range, 37-83 years), including 15 patients with carcinoid tumors and 10 patients with pancreatic NETs. No partial or complete responses were observed. The median progression-free survival was 4.2 months in the pancreatic NET cohort (range, 0.7-6.7 months) and 2.7 months in the carcinoid cohort (range, 2-3 months). Serious adverse events that were potentially related to MK-0646 included grade 3/4 hyperglycemia in 8 of 25 patients (32%), grade 2 hypersensitivity reaction in 1 of 24 patients (4%), and grade 3 lipase elevation in 1 of 25 patients (4%). CONCLUSIONS: Despite a compelling preclinical rationale, MK-0646 was inactive as a single agent in well-differentiated NETs. Further studies of MK-0646 as a monotherapy in unselected NETs are unwarranted. Cancer 2012. © 2012 American Cancer Society.

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.

A solitary hepatic tumor in a 50-year-old woman, which was observed as a hemangioma, ultimately was resected because it increased in size. The tumor volume doubling time was 28.8 months over the observed period of 30 months. The histologic diagnosis was carcinoid tumor. Immunohistochemical staining showed strong focal reactivity for gastrin and diffuse reactivity for pancreatic polypeptide, vasointestinal polypeptide, calcitonin, and parathormone. Preoperative gastric hyperacidity with diarrhea and a body weight loss of 7 kg, moderately controlled by cimetidine on admission, suggested high serum gastrin levels produced by the tumor. Her symptoms resolved after surgery, and she had a normal serum gastrin level with negative secretin stimulation test results. A review of six cases of hepatic gastrinoma suggests that surgical resection, if feasible, would be the treatment of choice.

Background. Although patients with neuroendocrine tumors typically exhibit an indolent clinical course, the pace of disease accelerates and the prognosis deteriorates once objective progression of disease begins. Thirty-four patients with advanced neuroendocrine tumors were treated with octreotide as antineoplastic therapy. This treatment was begun only after documentation of clear objective progression of disease. Methods. A Phase II trial was performed at a tertiary comprehensive cancer center. Results. The median survival for this patient population from the start of octreotide therapy has not been reached, with a median follow-up of 29 months (range, 1–47 months). No major objective tumor regressions were seen. Seventeen patients (50%) experienced a computed tomography-documented stabilization of disease that was maintainable for a minimum of 2 months (median, 5 months; range, 0–27 months). Of the 34 patients, 20 patients received octreotide as their first antineoplastic therapy. The median survival for these 20 patients has not been reached, with a median follow-up also of 29 months (range, 12–41 months). Conclusions. Octreotide may influence the natural history of neuroendocrine tumors. The survival in patients treated with octreotide, as measured from the time of progression of disease, compares favorably with that of historical controls. Proof of a survival advantage for patients treated with octreotide would require a multicenter, randomized trial.

Five patients with ovarian carcinoid who had severe constipation for a long period preoperatively showed marked reduction of this symptom postoperatively. Because this phenomenon was believed to be caused by some biologically active substance rather than a mechanical effect of the tumor, reactivity to 17 amine and peptide hormones was studied immunohistochemically in these patients. Numerous peptide YY (PYY)-positive cells were detected, with PYY-positive cells representing more than 50% of all carcinoid tumor cells in each patient. PYY, which has a pharmacologic inhibitory action on intestinal motility, was presumably the cause of the constipation in these patients.

Six cases of primary hepatic carcinoid tumors were studied with combined immunocytochemical and electron microscopic techniques. Positive tumor immunostaining with PHE5, LK2H10, neuron-specific enolase (NSE), serotonin, gastrin, and insulin antibodies was observed. At the ultrastructural level, cytoplasmic dense granules were seen in all the cases tested. This finding supports a putative origin of these carcinoids found in the liver from a pluripotential stem cell. The clinical course and follow-up of these cases suggests that this unusual hepatic neoplasm has a more favorable prognosis than other forms of hepatic cancer.

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.” Cancer 2005. © 2005 American Cancer Society.

BACKGROUND To the authors' knowledge, little is known regarding the role of E-cadherin/β-catenin system dysregulation in pulmonary neuroendocrine tumors. METHODS E-cadherin and β-catenin immunoreactivity was evaluated in 10 hyperplastic neuroendocrine tumorlets and 210 neuroendocrine tumors, including 96 typical carcinoids (CTs), 35 atypical carcinoids (ACTs), 49 large cell neuroendocrine carcinomas (LCNECs), and 30 small cell lung carcinomas (SCLCs). RESULTS Normal and hyperplastic bronchial neuroendocrine cells expressed E-cadherin/β-catenin with an orderly distribution along the cell membrane. Neuroendocrine tumors retained β-catenin expression in all tumors and E-cadherin in most tumors, with the exception of 2% of LCNECs, 3% of SCLCs and 9% of ACTs. E-cadherin showed a prevalent membrane-associated, linear immunoreactivity in CTs, whereas membrane-disarrayed and cytoplasmic staining was seen in most ACTs, LCNECs, and SCLCs (P < 0.001). β-Catenin exhibited similar immunoreactivity patterns according to tumor type and a close association with E-cadherin subcellular distribution (P < 0.001). Nuclear accumulation of β-catenin was found only in seven LCNECs and in two SCLCs. In ACTs, disarrayed immunoreactivity for E-cadherin and/or β-catenin was associated with a nontrabecular growth pattern, altered expression of the cell-motility marker fascin, and lymph node metastases. Furthermore, a disarrayed E-cadherin distribution pattern was associated with the pathologic lymph node classification and the number of involved lymph nodes. Multivariate analysis confirmed that a disarrayed E-cadherin or β-catenin pattern was an independent predictor of lymph node metastases in patients with ACT. CONCLUSIONS The subcellular compartmentalization of the E-cadherin/β-catenin complex was altered in pulmonary neuroendocrine tumors. This likely affects the tumor growth pattern and cell motility of ACT and was correlated with the occurrence of lymph node metastases. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND Microsatellite instability (MSI) with concomitant mutations in the coding region of transforming growth factor-beta type II receptor (TGFβRII) results in an aberrant growth-regulatory phenotype in colorectal carcinomas. The authors postulated that a similar mechanism occurred during the malignant evolution of small bowel carcinoid tumors. METHODS Mutational analysis of two coding regions in the TGFβRII gene associated with MSI and BAT-26 within intron 5 of the mismatch repair gene, hMSH2, was undertaken in small bowel carcinoids (n = 14), lymph node metasasis (n = 1) and liver metastases (n = 5). Quantitative PCR analysis [TAQMAN, Applied Biosystems, Foster City, CA] was then undertaken to examine gene alterations in mismatch repair genes (hMLH1 and hMSH2) in small bowel carcinoids (n = 7) and matched normal mucosa (n = 5). Staining was then analyzed using quantitative tissue array profiling (AQUA analysis) in a small bowel EC carcinoid tissue microarray (n = 55 tumors) with immunostaining against TGFβRII and MSH2. RESULTS Mutational examination of the TFGβRII gene and BAT-26 demonstrated that MSI was not present in any carcinoid material. Q RT-PCR analysis demonstrated statistically significant increased message levels of hMSH2 but not hMLH1 in carcinoid tumors. Quantitative analysis of membrane TGFβRII immunostaining using AQUA demonstrated that TGFβRII expression was down-regulated (P < 0.0002) in thirty-three primary small bowel carcinoids that exhibited lymph node and liver metastases compared to normal mucosa. AQUA analysis of nuclear MSH2 immunostaining demonstrated no differences for MSH2 between normal tissue and carcinoid tumor metastasis. Small bowel carcinoids characterized by variable expression of TGFβRII, did not exhibit MSI and had no differences in MSH2 expression. CONCLUSIONS The molecular events leading to the formation of carcinoid tumors in the small bowel were different from those resulting in epithelial carcinomas. The usually slow-growing and relatively nonaggressive carcinoid tumors had variable expression of TGFβRII but were associated with the retention of mismatch repair protein function and a microsatellite-stable phenotype. Cancer 2005. © 2004 American Cancer Society.

BACKGROUND Carcinoid tumors rarely metastasize to the brain. The objectives of the current study were to assess the frequency of brain metastasis from carcinoid tumors, determine correlates of survival, and describe treatment modalities and their outcomes. METHODS Between January 1977 and December 2003, 1633 patients with a carcinoid tumor were registered at The University of Texas M. D. Anderson Cancer Center. Of those, 24 patients (1.5%) had a diagnosis of brain metastasis. The authors collected demographic and clinical data and performed a statistical analysis. RESULTS The median age at the time patients were diagnosed with brain metastasis was 60 years. The metastases were treated with whole-brain radiotherapy (WBRT) alone in 7 patients (29%), and 12 patients (50%) underwent surgical resection, 7 of whom (29%) also received WBRT. The median survival time for the entire cohort after diagnosis of the primary tumor was 2.3 years (95% confidence interval [CI], 0.5–4.1 years), and the median survival time after the diagnosis of brain metastasis was 10.0 months (95% CI, 4.0–16.0 months). The longest median survival observed after the diagnosis of brain metastasis (3.2 years) occurred in patients who underwent resection and received WBRT. In the multivariate analysis, the adjusted rate ratio for comparison of all treatments versus combination of neurosurgical intervention and WBRT was 5.7 (95% CI, 1.3–26.1; P = 0.024). A positive effect of surgery followed by WBRT on the duration of survival was detected in patients with a single metastasis (P = 0.084) as well as in those with multiple metastases (P = 0.018). CONCLUSIONS Prolonged survival was observed in patients < 65 years old as well as in those who underwent surgery and received WBRT in comparison with other treatments. Whenever feasible, neurosurgical resection followed by WBRT seems to be the indicated treatment in patients with brain metastases from carcinoid tumors. Cancer 2004. © 2004 American Cancer Society.

BACKGROUND. Carcinoids and small cell lung carcinomas stimulate their growth in an autocrine manner by releasing serotonin, an effect that is blocked by selective serotonergic receptor antagonists that, unfortunately, exert undesirable side effects on serotonergic central nervous function. Moreover, conventional chemotherapeutic agents, such as streptozocin, fluorouracil, cyclophosphamide, and doxorubicin, which target tumor cells directly, have produced disappointing results in the treatment of patients with these tumors in the advanced stage. Therefore, there is still a need for more specific and potent chemotherapeutic agents in the fight against serotonin-producing tumors. METHODS. The authors synthesized 7-hydroxytryptophan to test its chemotherapeutic value in cell culture, using a system consisting of serotonin-producing and nonproducing cell lines. RESULTS. The authors chose tryptophan hydroxylase, the rate-limiting enzyme of serotonin biosynthesis, which is expressed highly in small cell lung carcinomas and carcinoids, as a target for the induction of cellular suicide by chemotherapy. They found that this otherwise substrate specific enzyme was capable of metabolizing in situ a harmless tryptophan analogue, 7-hydroxytryptophan, to a potent toxin, 5,7-dihydroxytryptamine, a conversion blocked by the specific tryptophan hydroxylase inhibitor parachlorophenylalanine. CONCLUSIONS. These data suggest that 7-hydroxytryptophan may be a highly specific chemotherapeutic compound against serotonin-producing tumors that also interferes with the autocrine capabilities of serotonin synthesis.

Background. Carcinoid tumors of the esophagus are rare. Most reported cases have had a poor prognosis. The authors report the case of a 64-year-old man with a 4-cm carcinoid tumor of the lower esophagus. Methods. Following endoscopic resection of an argyrophilic, nonargentaffin, carcinoid tumor of the lower esophagus, endosonography showed residual tumor, suggestive of a metastatic lymph node. The findings were confirmed at transhiatal esophagectomy. Results. No recurrence has been observed along the current 5-year follow-up. Conclusions. Lymph node metastasis does not rule out the possibility of prolonged survival in esophageal carcinoids. Endosonography is strongly advisable for preoperative evaluation. Cancer 1993; 72:2320-2.

BACKGROUND: Carcinoids are rare indolent neuroendocrine tumors, mainly located in bowel, stomach, and lung. Their etiology is virtually unknown although a family history is a minor cause.METHODS: Site specific incidence trends and several risk factors of carcinoid tumors were studied based on the nationwide Swedish Family-Cancer Database of 10.2 million individuals and their more than 1 million tumors. Data on a total of 5184 carcinoid tumors were retrieved from the Cancer Registry covering years 1958-1998.RESULTS: The overall age-adjusted incidence rates were 2.0 for men and 2.4/100,000 for women in 1983-1998. Appendix was the main site for women whereas small intestine was the main site for men. The incidence of all carcinoids, including those at the main sites increased during the follow-up period but appeared to plateau in the middle of the 1980s. Appendiceal carcinoids showed an unusually early onset with a maximum incidence at age 15-19 years for women and 20-29 years for men. Among women, parity was not related to the age specific incidence of carcinoid tumors. A Poisson regression analysis showed that family history of carcinoids in first-degree relatives (relative risk, 3.6), well educated social background (relative risk for professionals, 2.8), and birth in large cities were risk factors.CONCLUSIONS: The data suggest that the increase in carcinoid tumors may be largely ascribed to the application of advanced medical viewing techniques that detect asymptomatic tumors. However, the difference in incidence between men and women in appendiceal tumor may be real and independent of parity. (Less)

Pulmonary carcinoid tumors are rare and usually occur sporadically. Infrequently, they arise in association with multiple endocrine neoplasia type 1 (MEN1). Familial pulmonary carcinoid tumors not associated with MEN1 have not been described.Two sets of first-degree relatives diagnosed with primary pulmonary carcinoid tumors with no clinical features of MEN1 were identified in a pair of siblings and in a mother and daughter. Mutations in the MEN1 gene were sought using polymerase chain reaction analysis on paraffin embedded tissue from two members of one of the families.Histopathologic and immunohistochemical studies confirmed the diagnoses of carcinoid tumors. None of these patients and no family members had features of MEN1. DNA analysis did not detect germline mutations in the MEN1 gene.The occurrence of familial pulmonary carcinoid tumors in the absence of MEN1 suggests a novel, rare germline mutation specific to the development of pulmonary carcinoids.

New agents with antitumor activity in patients with neuroendocrine tumors are sorely needed. A Phase II study of high-dose paclitaxel in patients with metastatic carcinoid and islet cell tumors was performed at the Mayo Clinic. Granulocyte-colony-stimulating factor (GCSF) also was administered to ameliorate neutropenia.Twenty-four patients (14 with carcinoid tumors, 9 with islet cell tumors, and 1 with an anaplastic tumor) were enrolled on this Phase II study of paclitaxel given as a 24-hour continuous infusion at a dose of 250 mg/m(2) every 3 weeks plus GCSF at a dose of 5 microg/kg/day subcutaneously, beginning 24 hours after the completion of the paclitaxel dose and continuing until the absolute neutrophil count was10,000/microL.All 24 patients were evaluable for analysis. The overall response rate was 8% (95% confidence interval [95% CI], 0-0.11). At last follow-up all patients except 1 had developed disease progression, with an estimated median time to disease progression of 3.2 months (95% CI, 1.6-6.0 months). The estimated median survival was 1.5 years (95% CI, 1.0-1.8 years). Hematologic toxicity was significant with 12 of 24 patients developing Grade 4 (according to the National Cancer Institute Common Toxicity Criteria scale) neutropenia; however, there were no septic deaths reported. There were 17 episodes of Grade 4 neutropenia in these 12 patients and the duration of these events ranged from 2-5 days. More common nonhematologic toxicities included arthralgia (21 patients), anorexia (15 patients), nausea (15 patients), diarrhea (12 patients), and allergic reactions (2 patients).Given the lack of antitumor activity of paclitaxel and the significant hematologic toxicity observed despite the use of GCSF support in the current study cohort of patients with neuroendocrine tumors, further studies of this combination in this particular patient population are not recommended.

To the authors' knowledge, multiple carcinoid tumors of the duodenum have not been reported previously. However, multiple carcinoids in the stomach, ileum, and rectum, which were accompanied by the proliferation of endocrine cells, have been reported in the published literature.A patient with multiple carcinoids including argyrophilic cell hyperplasia of the duodenum and hypergastrinemia underwent surgery. The resected stomach and duodenum were analyzed histopathologically.There were 11 carcinoid lesions, each of which was accompanied by peripheral endocrine cell micronests (ECMs). Increasing gastrin positive cells in the antral region and chronic duodenitis in the duodenal bulb also were observed. The peripheral ECMs usually were adjacent to proliferating argyrophilic cells in the Brunner gland ducts or the crypts of Lieberkühn, which showed focal pyloric gland metaplasia.In the case presented in the current study, the development of the multiple carcinoid lesions may be strongly related to the presence of multifocal pyloric gland metaplasia, as well as to the trophic action of gastrin, which is present at high levels in the setting of chronic duodenitis.

The nosology of neuroendocrine neoplasia has evolved substantially in recent years. The aim of this study was to review the authors' institutional experience and diagnostic accuracy for cytologic specimens of neuroendocrine carcinoma (NEC) and to identify features most suggestive of neuroendocrine differentiation.The cytologic and histologic findings of 29 archival NEC in which cytology preceded biopsy or resection were compared. The study was comprised of 6 carcinoid tumors, 3 atypical carcinoid tumors, 17 high grade NEC (5 small cell, 9 large cell, and 3 mixed small/large cell), and 3 combined NEC/nonneuroendocrine carcinomas. Cytologic material was derived from 21 fine-needle aspirates (FNA), 6 bronchial brushing/washings, and 2 gastrointestinal tract brushings.Of the 29 cases, the correct cytologic diagnosis was rendered in 11. Two cases were identified as NEC but were graded incorrectly. The remaining 16 cases were interpreted as nonsmall cell carcinoma (8 cases); diagnostic or suspicious of carcinoma, not otherwise specified (7 cases); and atypical, indeterminate for malignancy (1 case). On review, neuroendocrine features were identified in 14 of the latter 16 cases.The cytologic diagnosis of NEC, both high and low grade, can be difficult. Because of acinus-like formations and columnar cell shapes, low grade NEC may be mistaken for adenocarcinoma. Small cell carcinomas, especially in bronchial brush and wash preparations, may be difficult to classify beyond malignant. Large cell NEC may be confused with nonneuroendocrine carcinomas because of abundant cytoplasm and nucleoli. Attention to the presence of loose cell aggregates in a background of singly dispersed cells; feathery patterns created by tumor cells clinging to capillaries; rosette formations; delicate, granular cytoplasm; inconspicuous nucleoli; molding in high grade tumors; and, most important, speckled or dusty chromatin patterns are useful in identifying neuroendocrine differentiation in cytologic specimens.

BACKGROUND Bronchopulmonary carcinoid tumors can be divided into typical and atypical carcinoids according to their histologic and clinical features. Atypical carcinoids tend to have less predictable biologic behavior and are associated with a worse prognosis than typical carcinoids. The authors examined apoptosis and the expression of apoptosis regulating proteins Bcl-2, Bax, Bak, and Mcl-1 in 21 typical and 10 atypical bronchopulmonary carcinoid tumors. To find features distinguishing the growth of these types of tumors, the expression of p53 protein and the proliferation marker Ki-67 were also investigated. Finally, the parameters were compared with clinical follow-up data. METHODS Thirty-one bronchopulmonary carcinoid tumors were examined by using in situ 3′-end labeling of DNA (TUNEL) for apoptosis and immunohistochemical staining methods for Bcl-2, Bax, Bak, Mcl-1, p53, and Ki-67 in formalin fixed, paraffin embedded tissue specimens. RESULTS The apoptotic indices (AIs) were low in general (mean 0.18%), but higher AIs (> 0.5%) were observed significantly more often in atypical than in typical carcinoids (P < 0.008) in association with shortened survival (P < 0.008). No relation between apoptosis and Bcl-2, Bax, Bak, or Mcl-1 expression was found. Expression of p53 protein was detected in only three atypical carcinoids, which also had significantly higher AIs than p53 negative tumors (P < 0.03). Proliferation rates measured by Ki-67 index were unusually low; the highest proliferation rates were observed in atypical carcinoids. There was a positive correlation between AI and Ki-67 indices (P < 0.01). CONCLUSIONS This study suggests that the extent of apoptosis in bronchopulmonary carcinoid tumors is low. This, together with a low proliferation rate and an apparent absence of p53 mutation, enables a benign growth pattern. Some atypical carcinoids with enhanced apoptosis are associated with shortened survival, clearly deviating from typical carcinoids. Cancer 2000;88:1590–8. © 2000 American Cancer Society.

In the current study the authors report a 57-year-old woman with a scalp tumor and cervical lymphadenopathy who had a previously resected duodenal carcinoid. Histologic and immunophenotypic characteristics of the duodenal carcinoid differed from those of the scalp and cervical lymph node tumors, prompting the use of molecular methodologies to make the diagnosis.Paraffin embedded tissues from the duodenal carcinoid, scalp, and lymph node tumors were dissected using microscopic visualization and laser capture microdissection. DNA was extracted and polymerase chain reaction (PCR) was performed to evaluate loss of heterozygosity and microsatellite alterations using primers flanking 22 polymorphic microsatellite markers from 9 chromosomal regions, including genes associated with MEN-1 (11q), CDKN2 (9p), p53 (17p), and bronchial carcinoid (3p). Microdissected lymphocytes from the three tissues were used as source of constitutional DNA (controls).Fourteen of the 22 markers were informative (heterozygous in control lymphocytes). A marker on 3p12 showed loss of the same parental allele in the three tumors. A different marker on 3p14.2 showed an identical shifted band in the three tumors indicative of a common microsatellite alteration.The shared molecular abnormalities among the three tumors indicated a common clonal origin, leading to a diagnosis of primary duodenal carcinoid with clear cell metastases to the scalp and cervical lymph nodes. These findings led to radiation therapy and immunotherapy rather than chemotherapy. This case illustrates the novel application of laser capture microdissection combined with PCR-based analyses of genomic markers for the identification of the origin of metastatic disease.

BACKGROUND Neuroendocrine neoplasms of the lung represent a wide spectrum of phenotypically and biologically distinct entities. Their histopathologic diagnosis, which carries therapeutic and prognostic significance, may sometimes be difficult because of their overlapping features. We previously demonstrated that large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs) failed to show positive nuclear staining of RB protein (RB−), whereas typical and atypical carcinoids (TCs and ACs) showed nuclear RB immunostaining (RB+). METHODS In the current study, a series of 58 surgically resected lung tumors, of which 33 tumors were initially diagnosed as SCLCs and 25 as TCs or ACs, were studied for RB and p16 protein expression by immunohistochemistry. They were also reviewed for their pathologic diagnosis; the reviewers were blinded to the RB and p16 protein status. RESULTS Nineteen tumors were diagnosed as TCs, 5 as ACs, 7 as LCNECs, and 27 as SCLCs. Three of seven LCNECs were RB+, whereas the other four were RB−. In contrast, all 19 TCs were RB+ and all 27 SCLCs were RB−. In addition, two of five ACs were RB+, whereas the other three were RB−. Interestingly, all 3 RB+ LCNECs and the 1 RB+ AC tested failed to show nuclear staining of p16 protein in any tumor cells (p16−), although some normal stromal cells showed nuclear staining of p16 protein (p16+) as positive internal controls, indicating loss of p16 function in these tumors. It is also noteworthy that the three RB+ LCNECs were initially diagnosed as SCLCs and one of the RB− ACs was initially considered a TC. With the exception of TCs, tumors were significantly more prevalent among heavy smokers with >20 pack-years compared with nonsmokers and light smokers with ≤20 pack-years (P < 0.01). CONCLUSIONS These findings suggest that all SCLCs and LCNECs have abnormalities in the p16:RB pathway, as do at least certain ACs, whereas the p16:RB pathway is normal in TCs. Cancer 2000;88:550–56. © 2000 American Cancer Society.

Carcinoid tumors of the extrahepatic bile duct are rare and account for 0.2-2% of all gastrointestinal carcinoids. Similar to other tumors of the bile duct, these lesions are difficult to diagnose preoperatively and nearly impossible to distinguish from cholangiocarcinoma.The authors retrospectively analyzed all reported cases of carcinoid tumor of the bile duct and report on two additional cases.Thirty cases of carcinoid tumor of the bile duct have been reported. Among this group were 20 women and 9 men (female-to-male ratio, 2.2:1) with an overall mean age of 47 years (range, 19-79 years). The most common anatomic sites for extrahepatic carcinoid tumors were the common bile duct (58%), perihilar region (28%), cystic duct (11%), and common hepatic duct (3%). Jaundice was the most common presenting complaint (55%). Sixty-nine percent of patients with extrahepatic biliary carcinoids had disease confined to the bile duct, whereas 31% had evidence of distant metastases. All patients who presented with localized disease remain disease free with a mean follow-up of 32 months (range, 3 months to 20 years).Carcinoid tumor of the bile duct is a rare form of malignant biliary obstruction. Unlike cholangiocarcinoma, biliary carcinoids occur more commonly in younger patients and in women. Aggressive local invasion by the primary tumor is rare, and metastases occur in less than one-third of patients. All patients who underwent a curative surgical resection were alive and disease free at time of published report, implying a more favorable prognosis. Aggressive surgical resection is recommended.

Serum chromogranin A levels (CgA) are reported by some authors to be of clinical utility for assessing the presence or absence of a pancreatic endocrine tumor and tumor extent or growth. The aim of the current study was to assess this finding and compare the results with those from serum gastrin determinations (FSG) in a large cohort of patients with gastrinomas.In 112 consecutive patients with the Zollinger-Ellison syndrome serum CgA and FSG levels were measured and correlated with disease activity, extent of disease, and the presence of multiple endocrine neoplasia type-1 (MEN-1) or gastric carcinoid tumors.Serum CgA levels drawn on 2 consecutive days correlated closely (P0.00001) as did serum gastrin levels. Serum CgA levels correlated significantly with FSG levels (P0.00001). Serum CgA and FSG levels were significantly higher in patients with active disease than in disease free patients (P0.00001). The sensitivity for the presence of disease was higher for CgA compared with FSG (92% vs. 80%; P = 0.021). However, the specificity of CgA was 67%. Serum CgA levels were not significantly different in the four disease categories (stable extrahepatic disease, increasing extrahepatic disease, stable liver metastases, and increasing liver metastases). FSG levels were significantly lower in patients with stable extrahepatic disease compared with those with increasing extrahepatic disease. However, both tumor markers decreased significantly with a gastrinoma resection in five patients. The presence of MEN-1 or a gastric carcinoid tumor did not influence the results.The results of the current study showed that serum CgA and FSG levels both are sensitive tumor markers for the detection of a gastrinoma; however, CgA levels have a relatively low specificity. Neither the magnitude of the serum CgA nor gastrin level correlated with tumor growth or tumor extent and therefore cannot be used to determine these variables. However, in contrast to some other studies, the results of the current study show that changes in serum CgA or gastrin in a given patient with time are related to the tumor extent and not to gastric mucosal changes due to hypergastrinemia.

Although ampullary carcinoid tumors (ACs) are often categorized clinically as duodenal carcinoid tumors (DCs), there are distinct clinical and pathologic differences.Clinical, histopathologic, and immunohistochemical features of 12 ACs were compared with those of 53 DCs that did not involve the ampulla.Patients with AC were ages 28-74 years (mean, 54.9 years); 8 were males and 4 were females. Five were white and three were black; the race of four patients was not known. The size of ACs ranged from 0.2 to 5.0 cm in greatest dimension. There were no significant differences between AC patients and DC patients with respect to male predominance, race, tumor size, and mitotic rate. The insular growth pattern was more common in AC; the cribriform type was more common in DC. Four of 12 ACs contained psammoma bodies, versus none of 53 DCs (P = 0.001). The rate of metastasis was similar in patients with AC (4 of 12, 33%) compared with DC patients (14 of 53, 26%). In DC patients, involvement of the muscularis propria, a size greater than 2 cm, and mitotic activity were significantly correlated with metastatic risk. In AC patients, tumor size and mitotic activity had no correlation with metastatic potential. One AC had features of an atypical carcinoid tumor; there were none in the duodenal group. One-half of patients with AC presented with jaundice versus 7% of patients with DC (P = 0.005). Three patients (25%) with AC had von Recklinghausen disease versus 0 of 53 patients with DC (P = 0.003). Immunohistochemically, tumor cells expressed somatostatin in 67%, serotonin and cholecystokinin in 17%, insulin in 25%, and glucagon and gastrin in 0% of ACs. In contrast, 56% of DCs expressed gastrin (P0.001).Carcinoid tumors of the ampulla differ clinically, histologically, and immunohistochemically from carcinoid tumors elsewhere in the duodenum.

Recent classifications identify four categories of neuroendocrine (NE) tumors of the lung: low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC), and high grade large cell neuroendocrine carcinoma (LC-NEC) and small cell lung carcinoma (SCLC).The authors studied the molecular changes present in 59 archival NE tumors (10TCs, 11 ACs, 18 LNECs, and 20 SCLCs). Utilizing microdissection and polymerase chain reaction-based assays, the authors examined loss of heterozygosity (LOH) at ten chromosomal regions frequently deleted in lung tumors (3p, 5q, 11q, 13q, and 17p) and for mutations at the p53 and ras genes.With the exception of ras gene mutations, the majority of these changes frequently were present in carcinomas and were present at lower frequencies in carcinoids. LOH at one or more 3p regions was the most frequent change found in the carcinoids. A relatively high incidence of LOH at the MEN1 gene was common in all NE lung tumors. The incidence of LOH and p53 gene abnormalities progressively increased with increasing severity of tumor type. The patterns of p53 gene mutations were different between AC and high grade NE tumors. LOH at 5q21 was correlated with poor survival in the carcinoid group.Although NE lung tumors have varied etiologies, the results of the current study support the clinicopathologic concept that they represent a spectrum ranging from low grade TC to the highly malignant NE carcinomas.

Patients with neuroendocrine gastrointestinal tumors usually present with inoperable metastatic disease and severe hormonal symptoms. Specific chemotherapy, interferon-alpha (IFN), and somatostatin analogs are established therapies for these patients, but all of them eventually fail. Hepatic arterial embolization can provide reduction of both hormonal symptoms and tumor burden in these patients.Between 1981 and 1995, a total of 55 liver embolizations with gel foam powder were performed on 41 patients with histopathologically verified neuroendocrine tumors; 29 had carcinoid tumors and 12 had endocrine pancreatic tumors (EPTs). All patients had received medical treatment, including chemotherapy (n = 18), IFN (n = 31), and octreotide (n = 19), and were experiencing treatment failure when liver embolization was performed at a median of 37 months after diagnosis of liver metastases. Medical treatment was continued after embolization.An overall objective response was noted in 15 of 29 patients with carcinoid tumors (52%). The median duration of effect was 12 months in patients with midgut carcinoid tumors. An overall objective response was observed in 6 of 12 patients with EPTs (50%), with a median duration of effect of 10 months. Adverse events were observed, and, in agreement with earlier reports, the rate of serious complications was 10%. Survival analyses showed a median survival of 80 months and a 5-year survival rate of 60% from the performance of embolization on patients with midgut carcinoid tumors, whereas for patients with EPTs the median survival from embolization was only 20 months.Liver embolizations performed relatively late in the clinical course in our series appeared to be as effective as "early" embolizations in other series of patients with carcinoid tumors. The results for those with EPTs were poorer, and earlier embolizations may result in better outcomes for these patients. Considering the morbidity associated with the procedure, it is imperative to select patients according to extent of liver involvement, severity of carcinoid heart disease, and somatostatin receptor status.

The origins of and interrelations between low grade and high grade neuroendocrine lung tumors, typical and atypical carcinoids, and small cell lung carcinoma (SCLC) have not been elucidated. Karyotypic and molecular genetic studies have demonstrated deletions in 3p in 100% of SCLCs and the candidate lung tumor suppressor gene, FHIT, at 3p14.2 is not expressed in the majority of SCLCs. Similar studies of typical and atypical carcinoids could clarify the interrelations among these tumors.For molecular genetic analyses, archival carcinoids and paired normal cells were microdissected from paraffin sections, deparaffinized, and DNA prepared. Oligonucleotide primer pairs for 12 microsatellite markers mapping between 3p14.2 and 3p21.3 were used to amplify allelic DNA fragments from 13 typical and 6 atypical carcinoids. In addition, an independent series of archival sections of carcinoids and SCLCs was tested by immunohistochemistry for expression of Fhit protein.Of the six atypical carcinoids examined, three had lost an allele at all informative markers, whereas one had lost alleles in two distinct regions and two showed allele loss in a subregion of the chromosome region tested. Of the 13 typical carcinoids, 3 showed allele loss at only 1 or 2 loci each. Typical carcinoids, similar to normal lung epithelia, were strongly positive for the cytoplasmic Fhit protein, SCLCs were uniformly negative, and atypical carcinoids appeared to express an intermediate level of Fhit protein.Loss of heterozygosity at 3p14.2-p21.3 is significantly more extensive in all atypical carcinoids. Atypical carcinoids, which exhibit clinicopathologic features intermediate between typical carcinoids and small cell carcinomas and have been considered well differentiated neuroendocrine carcinomas, also are intermediate between typical carcinoids and SCLC on the basis of extent of loss of 3p alleles and reduced expression of Fhit protein.

Small bowel carcinoma is uncommon. However, hereditary nonpolyposis colorectal carcinoma (HNPCC) patients are at increased risk of small bowel carcinoma. The purpose of this study was to characterize small bowel tumors in HNPCC patients.A questionnaire was mailed to the members of International Collaborative Group on HNPCC (ICG-HNPCC) requesting clinicopathologic data in their registries on HNPCC patients with small bowel carcinoma. Survival was estimated utilizing the Kaplan-Meier method.Forty-two individuals from 40 HNPCC families developed 42 primary and 7 metachronous small bowel tumors. There were 46 adenocarcinomas and 3 carcinoid tumors. The median age at diagnosis of the index small bowel tumor was 49 years. Mismatch repair gene mutations were present in 15 of 42 patients (36%). There were nine hMLH1 and six hMSH2 mutations. The small bowel was the first site of carcinoma in 24 patients (57%). The median survival for the 42 patients was 47 months (range, 0-447 months). The overall 5- and 10-year survival rates were 44% and 33%, respectively.Small bowel tumors can be the presenting neoplasms in HNPCC patients. Similar to colorectal carcinoma in HNPCC, small bowel adenocarcinomas in HNPCC patients occur at an earlier age and appear to have a better prognosis than those occurring in the general population.

[(111)In]-diethylenetriamine pentaacetic acid (DTPA)-D-[Phe1]-octreotide (OctreoScan, Mallinckrodt Medical, Petten, The Netherlands), combined with single photon emission computed tomography (SPECT), has limited possibilities to detect small abdominal endocrine tumors. This study explores the efficacy of OctreoScan and a newly developed handheld gamma detector probe (H-probe2) for the localization of neuroendocrine abdominal tumors.Twenty-one patients with endocrine pancreatic or midgut carcinoid tumors were given 100-200 megabecquerels (MBq) [(111)In]-DTPA-D-[Phe1]-octreotide and underwent preoperative SPECT examination, after which time surgery was undertaken within 24-48 hours. Intraoperatively the radioactivity of tumors and normal tissues was measured with the H-probe2 connected to a portable personal computer. Resected intestinal specimens of ten patients with carcinoid tumors were examined by gamma camera ex vivo. Biopsies of all tumors subsequently were investigated in a wellcounter and by routine histopathology.Disregarding liver metastases, a total of 34 of 60 abdominal tumors were detected by SPECT; however, SPECT failed to visualize any tumor9 mm. The shielding of the manual probe allowed intraoperative examination despite the substantial radiation energy of (111)In. The H-probe2 detected 91% of the tumors investigated, and these included all those5 mm. In the wellcounter the H-probe2-detected tumors exhibited 4.7-157.7 times higher radionuclide uptake than the surrounding normal tissues. The gamma camera analysis detected 68% of tumors in the resected specimens.The intraoperative H-probe2 examination provided substantial improvement in the detection of small endocrine lesions accumulating [(111)In]-DTPA-D-[Phe1]-octreotide and all lesions with a size5 mm in greatest dimension could be identified.

Although carcinoid tumors of the gastrointestinal tract are relatively common, their occurrence in the esophagus is exceedingly rare. The authors report a case of an atypical carcinoid presenting in the cervical esophagus of an 82-year-old woman.The tumor was studied with routine, silver, and immunohistochemical techniques for cytokeratin, chromogranin, and various secretory products. In addition, the literature was reviewed for carcinoid tumors of the esophagus and the findings summarized.The esophageal tumor showed focal necrosis, atypical cytologic features, and increased mitotic activity. It stained diffusely for chromogranin and focally for serotonin; thus it was considered an atypical carcinoid. The patient was free of disease 9 months after excision. On review of the literature, 13 additional cases of esophageal carcinoid were found. The average age of the patients was 60 years with a male predominance of 6:1; the most common presenting symptoms included dysphagia and weight loss. The majority of tumors occurred in the submucosa of the lower esophagus, and ranged in size from 1 to 12 cm. All patients except one had surgical treatment, three received adjuvant radiotherapy or chemotherapy. Although follow-up was limited, survival correlated with stage; seven of ten Stage I or II patients were disease free whereas three of four Stage III or IV patients had died of disease; the fourth patient is alive with brain metastases.Esophageal carcinoid tumors are exceedingly rare neoplasms. They usually occur in the lower esophagus of males who present with dysphagia. Survival statistics are limited, but appear best correlated with disease stage.