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Introduction: Primary ovarian carcinoids are extremely rare ovarian tumors, and there is limited data available on their clinical characteristics and survival outcomes., Material and Methods: We conducted a historical cohort study of 56 patients to investigate their clinical characteristics. The overall survival, disease-specific survival, recurrence-free survival, and potential prognostic factors of these patients were also evaluated., Results: The median age of these patients was 42.0 years (range: 20-71). The average mass and carcinoid size was 7.3 and 0.4 cm, respectively. Elevated tumor marker levels and ascites were observed in 15 and 10 patients, respectively. In 98.2% of the patients, tumors were confined to the ovary, while only one had metastatic disease. Surgery was the mainstay therapy: 37.5% of the patients underwent unilateral salpingo-oophorectomy, 25.0% underwent hysterectomy with bilateral salpingo-oophorectomy, 21.4% underwent ovarian cystectomy, 10.7% underwent comprehensive staging surgery, and 5.4% underwent bilateral salpingo-oophorectomy. Appendectomy and lymphadenectomy were performed in eight and five patients, respectively, but none showed tumor involvement. Chemotherapy was the only adjuvant treatment utilized, and was administered in four patients. Pathological analysis showed that strumal carcinoid was the most predominant subtype, occurring in 66.1% of the patients. The Ki-67 index was reported in 39 patients, 30 of which had an index of no more than 3%, with a maximum of only 5%. Only one relapse occurred after the initial treatment, and that patient experienced recurrences on two occasions, maintaining stable disease after surgery and octreotide therapy. After a median follow-up of 3.6 years, 96.4% of the patients achieved no evidence of disease, while 3.6% were alive with the disease. The 5-year recurrence-free survival rate was 97.9% and no death occurred. No risk factors for recurrence-free survival, overall survival, or disease-specific survival were identified., Conclusions: The Ki-67 indices were extremely low and prognoses were excellent in patients with primary ovarian carcinoids. Conservative surgery, especially unilateral salpingo-oophorectomy, is preferred. Individualized adjuvant therapy may be considered for patients with metastatic diseases., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Despite a protracted disease course and multiple available therapies, patients with well-differentiated neuroendocrine tumors (NETs) inevitably experience disease progression. Programmed death-ligand 1 (PD-L1) has been associated with NET progression and prognosis. The multicohort, phase 1 KEYNOTE-028 study (ClinicalTrials.gov identifier NCT02054806) evaluated the activity and safety of the anti-programmed cell death protein 1 immunotherapy pembrolizumab in patients with well-differentiated or moderately-differentiated NETs., Methods: Patients with PD-L1-positive, locally advanced or metastatic carcinoid or well-differentiated or moderately-differentiated pancreatic NETs (pNETs) were enrolled into separate cohorts and received pembrolizumab at a dose of 10 mg/kg every 2 weeks for up to 2 years. The objective response rate was the primary endpoint (as per Response Evaluation Criteria in Solid Tumors version 1.1, by investigator review). Safety was a secondary endpoint., Results: Of 170 and 106 patients, respectively, who had evaluable samples among those screened for the carcinoid and pNET cohorts, 21% and 25%, respectively, had PD-L1-positive tumors; of these, 25 and 16 patients, respectively, were eligible and treated. The median follow-up was 20 months (range, 2-35 months) and 21 months (range, 5-32 months), respectively. The objective response rate was 12.0% (95% CI, 2.5%-31.2%) and 6.3% (95% CI, 0.2%-30.2%), respectively; 3 partial responses occurred among the carcinoid cohort and 1 among the pNET cohort. The median duration of response in the carcinoid cohort was 9.2 months (range, 6.9-11.1 months), and was not reached in the pNET cohort. No complete responses occurred. Treatment-related adverse events occurred in 68% and 69% of patients, respectively, most often diarrhea (7 patients in the carcinoid cohort and 4 patients in the pNET cohort) and fatigue (6 patients in each cohort). Hypothyroidism was the most common immune-mediated adverse event (5 patients in the carcinoid cohort and 2 patients in the pNET cohort)., Conclusions: Pembrolizumab demonstrated antitumor activity in a subset of patients with NETs and was well-tolerated., (© 2020 American Cancer Society.)

Background: Type-1 gastric neuroendocrine tumors represent a recurring disease and long-acting somatostatin analogs can inhibit both gastrin release and endocrine cell proliferation. The efficacy and timing of this treatment are still unclear. We performed a systematic review of the literature to clarify the role of somatostatin analog treatment in type-1 gastric neuroendocrine tumors., Methods: A computerized literature search was performed using relevant keywords to identify all the pertinent articles published in the last 15 years., Results: Eight studies were included in this systematic review on somatostatin analogs in type-1 gastric neuroendocrine tumors. A complete response rate ranged from 25-100%. When only the six prospective studies were considered, no significant heterogeneity was observed, and the pooled cumulative complete response rate was 84.5% (confidence interval 73.8-92.8). Three studies evaluated the type-1 gastric neuroendocrine tumor recurrence, with a cumulative relapse rate of 30.2% (confidence interval 13.1-50.6) after 34 months., Conclusion: Somatostatin analogs, namely lanreotide and octreotide, have an excellent response rate, with a good safety profile in selected type-1 gastric neuroendocrine tumors, which cannot be safely managed by endoscopic follow-up or resection due to multiple or frequently recurring disease. After therapy discontinuation, the cumulative relapse rate observed after a median 34-month follow-up was relatively high (30.2%).

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (© 2014 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., (Copyright © 2011 American Cancer Society.)

Endocrine tumours derived from the small intestine, ileal carcinoids, produce and secrete the hormones tachykinins and serotonin, which induces the specific symptoms related to the tumour. Because of their low proliferation rate, they are often discovered at late stages when metastases have occurred. The biology that characterizes these tumours differs in many ways from what is generally recognized for other malignancies. In this overview, the current knowledge on the development and progression of ileal carcinoids is described., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

We present an unusual case of primary intracranial carcinoid tumor of the skull base centered at the level of the foramen jugulare, which was proven with surgical biopsy and later with Somatostatin receptor nuclear medicine scan. We present the salient magnetic resonance imaging features of this rare tumor, describe their characteristic nuclear medicine findings, and briefly review the literature., (Copyright © 2008 by the American Society of Neuroimaging.)

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., (2009 American Cancer Society.)

Background: During our daily practice, we observed that cluster designation 23 (CD23) (clone BU38) labels Merkel cells in normal skin. In this study, we examined the expression of CD23 in Merkel cell carcinoma (MCC) and assessed its usefulness in distinguishing MCC from non-cutaneous small cell carcinoma (SMCC)., Methods: Immunohistochemical staining of CD23 was performed on a total of 33 MCCs, 22 SMCCs and 5 carcinoid tumors., Results: CD23 reactivity was present in 32 of 33 (97%) MCCs, 18 of 22 (82%) SMCCs and 5 of 5 (100%) carcinoid tumors. In MCC, 19 cases (59%) showed a predominance of perinuclear dot-like staining similar to cytokeratin 20, 3 (9%) showed mostly cytoplasmic staining and 10 (31%) displayed a combination of perinuclear dot-like and cytoplasmic staining. In contrast, all CD23-positive SMCCs and carcinoid tumors showed a diffuse cytoplasmic staining. There was a significant difference in the CD23 staining patterns between MCC and SMCC (p < 0.0001)., Conclusion: CD23 is expressed in the majority of MCC, SMCC and carcinoid tumor irrespective of clinical outcome. The distinct punctate CD23 staining for MCC may be helpful in differentiating it from SMCC. To our knowledge, this is the first study to show the expression of CD23 in neuroendocrine tumors.

Background: Paraneoplastic neurological syndromes (PNS) are mainly associated with small-cell lung cancer, gynaecological tumours and lymphomas. Few studies report the association of neurological syndromes with a carcinoid, the majority being a serotonin-related myopathy. We report four patients with a PNS associated with carcinoid., Patients and Results: The clinical syndromes were sensory neuropathy, limbic encephalitis, myelopathy and brain stem encephalitis. Two patients had antineuronal autoantibodies (one anti-Hu, one anti-Yo), one patient had antinuclear antibodies, and one patient had no autoantibodies. For two of the carcinoids, expression of HuD in the tumour could be demonstrated., Conclusion: This study demonstrates that carcinoids can also be associated with classical antineuronal antibody-associated PNS.

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 <5%, respectively. This review provides a broad overview on BP-NETs and focuses on the evolution of the disease, general features, and current diagnostic and therapeutic options., ((Copyright) 2008 American Cancer Society.)

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 8x 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., (Copyright (c) 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.

Background: 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., Methods: 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., Results: 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 and <7% 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 increased >21% (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%)., Conclusions: 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)., (Copyright 2007 American Cancer Society.)

We present a new case of a primary carcinoid tumour of the skin. The mitotic index (4/10 HPF) warrants classification of this case as atypical. The patient was a 58-year-old woman with a 1-year history of a mass on the scalp. Literature review showed this to be only the seventh case of primary carcinoid tumour of the skin. Importantly, the evolution has been favourable in all seven tumours, with a mean follow-up of 2.5 years for the previous six cases. Although the number of cases is too small to draw definitive conclusions, information to date suggests that this type of tumour can be expected to have a benign behaviour, despite the presence in some cases of criteria suggestive of uncertainty, such as the presence of mitosis.

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., (Copyright 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 ( 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

Background: Microsatellite instability (MSI) with concomitant mutations in the coding region of transforming growth factor-beta type II receptor (TGFbetaRII) 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 TGFbetaRII 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 TGFbetaRII and MSH2., Results: Mutational examination of the TFGbetaRII 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 TGFbetaRII immunostaining using AQUA demonstrated that TGFbetaRII 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 TGFbetaRII, 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 TGFbetaRII but were associated with the retention of mismatch repair protein function and a microsatellite-stable phenotype., ((c) 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., ((c) 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., (Copyright 2002 American Cancer Society.)

Background: 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., Methods: 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 was > 10,000/microL., Results: 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)., Conclusions: 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., (Copyright 2001 American Cancer Society.)

Background: 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., Methods: A patient with multiple carcinoids including argyrophilic cell hyperplasia of the duodenum and hypergastrinemia underwent surgery. The resected stomach and duodenum were analyzed histopathologically., Results: 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., Conclusions: 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.

Although cancer is a frequent condition, neoplastic involvement of the peripheral nervous system is rare. The mechanisms are heterogeneous and include lesions within the cerebrospinal fluid (CSF) space, local invasion (e.g. brachial plexus), compression, rarely direct infiltration, perineurial spread and even rarer intranerval metastasis. A 47-year-old woman had been treated for a carcinoid 10 years earlier and had received axillar irradiation. At presentation she suffered from weakness of the biceps brachii and was experiencing pain radiating from the axilla into the forearm and thumb. MR scans of the brachial plexus were negative and her symptoms were primarily considered to stem from a postradiation brachial plexopathy, Because of increasing pain, the brachial plexus was explored and a metastasis in the left musculocutaneous nerve was resected. Several months later, numbness and pain appeared in the ulnar nerve and another intrafascicular metastasis in the ulnar nerve was discovered. Resection with preservation of remaining fascicles was performed. This rare case report demonstrates that multiple mononeuropathies, resembling multiplex neuropathy, may be caused by intranerval metastasis.

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright 2000 American Cancer Society.)

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 < or = 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., (Copyright 2000 American Cancer Society.)

Background: To the authors' knowledge, no study regarding lung carcinoma patients age <30 years has been published. Therefore, this study was undertaken to define the characteristics of lung carcinoma patients age <30 years., Methods: Information regarding 26 patients with primary lung carcinoma who were age <30 years was obtained from 10 medical institutions and reviewed retrospectively. For comparison, 304 patients age > or = 30 years who were admitted to the First Department of Internal Medicine at Toyama Medical and Pharmaceutical University between 1980-1996 were studied., Results: Among the characteristics observed in the group of lung carcinoma patients age <30 years was a high incidence of female gender, no history of smoking, so-called "low grade malignancy," American Joint Committee on Cancer Stage I disease, and previous surgical resection. In addition, a low incidence of squamous cell carcinoma was noted, and a more favorable prognosis was observed., Conclusions: The current study noted clinical features that could be defined clearly in lung carcinoma patients age <30 years.

Background: Although ampullary carcinoid tumors (ACs) are often categorized clinically as duodenal carcinoid tumors (DCs), there are distinct clinical and pathologic differences., Methods: Clinical, histopathologic, and immunohistochemical features of 12 ACs were compared with those of 53 DCs that did not involve the ampulla., Results: 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 (P < 0.001)., Conclusions: Carcinoid tumors of the ampulla differ clinically, histologically, and immunohistochemically from carcinoid tumors elsewhere in the duodenum.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: [(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., Methods: 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., Results: Disregarding liver metastases, a total of 34 of 60 abdominal tumors were detected by SPECT; however, SPECT failed to visualize any tumor < 9 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 those > 5 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., Conclusions: 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 size > 5 mm in greatest dimension could be identified.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: The purpose of this study was to determine the clinical course, effects of specific tumor histopathologic characteristics, and extent of surgical treatment on the metastatic rate in patients with rectal carcinoids., Methods: Medical records of 44 patients who presented with rectal carcinoids were retrospectively reviewed. Primary tumors were classified by size (< 1 cm, 1-2 cm, and > 2 cm), and tumor histopathologic features (atypical or typical). Extensive surgery was defined as abdominoperineal or low anterior resection of the rectum or laparotomy with intent of curative resection., Results: Median follow-up for patients who presented without metastasis was 84 months. Thirteen of the 44 patients (30%) presented with metastatic disease. The 5-year metastasis free survival rates for those patients presenting without metastatic disease were 100% for patients with tumors < 1 cm (n = 16), 73% for those with tumors 1-2 cm (n = 8), and 25% for those with tumors > 2 cm (n = 4) (P = 0.04 comparing < 1 cm with 1-2 cm and P = 0.05 comparing 1-2 cm with > 2 cm); tumor size data were not available for 3 patients. The 5-year metastasis free survival rate for patients presenting without metastatic disease with typical histology (n = 20), regardless of size, was 100%, compared with 50% for patients with tumors with atypical histology (n = 11) (P = 0.001). Nine patients underwent extensive surgery for rectal carcinoid tumors but no survival benefit was demonstrated., Conclusions: Atypical histopathologic features and a tumor size > 1 cm are associated with aggressive behavior of rectal carcinoid tumors. Extensive surgery offers no survival advantage over local excision for patients with rectal carcinoid tumors.

Background: Carcinoid tumors of the gastrointestinal tract differ in their clinical and histopathologic features, depending on the site of origin. There are few clinicopathologic studies that specifically describe jejunoileal carcinoid tumors., Methods: One hundred sixty-seven ileal and jejunal carcinoids were retrospectively studied with emphasis on clinical, pathologic, immunohistochemical, and prognostic features., Results: The mean age of patients at the time of presentation was 62 +/- 12 years (range, 13-93 years). Eight patients had carcinoid syndrome (5%) and 1 had Zollinger-Ellison syndrome. Twenty-six percent of tumors were multiple, and 77% were transmurally invasive; 31% had regional lymph node metastases only, and 32% had liver or mesenteric metastases. Ninety-three percent of tumors had an insular growth pattern. Serotonin was expressed in 86% of tumors (86 of 102), chromogranin in 92%, and neuron specific enolase in 95%. Twenty percent of tumors (10 of 51) expressed prostatic acid phosphatase; 96% were argyrophil, and 98% argentaffin. Of 80 cases with follow-up data (mean follow-up, 52 +/- 5 months), 21% were dead of disease, 16% were dead of other causes, 19% were alive with disease, and 44% had no evidence of disease at last follow-up. The 5-year Kaplan-Meier survival estimate for all cases was 58%. By univariate analysis, survival was negatively correlated with distant metastases at the time of surgery (P = 0.002), mitotic rate (P = 0.01), tumor multiplicity (P = 0.01), the presence of carcinoid syndrome (P = 0.02), depth of invasion (P = 0.03), and female gender (P = 0.05); by multivariate analysis, survival was negatively associated with distant metastasis (P = 0.002), carcinoid syndrome (P = 0.01), and female gender (P = 0.03)., Conclusions: Jejunoileal carcinoid tumors have a relatively high rate of transmural invasion and aggressive clinical behavior. They are usually insular and largely argentaffin, with a high rate of chromogranin and serotonin positivity. These features differentiate jejunoileal carcinoids from other gastrointestinal carcinoids.

Background: Carcinoid tumors are unusual and most reports are anecdotal or limited in number. A series of 2837 cases was published in 1975. No recent large series is available., Methods: The authors evaluated 5468 cases identified by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI) from 1973 to 1991 together with 2837 carcinoid cases previously registered by 2 earlier NCI programs. To the authors' knowledge, the 8305 carcinoid tumors analyzed represent the largest current epidemiology series to date., Results: The most frequent sites for carcinoids were the gastrointestinal (GI) tract (73.7%) and the bronchopulmonary system (25.1%). Within the GI tract, most occurred in the small bowel (28.7%), appendix (18.9%), and rectum (12.6%). For all sites, age-adjusted incidence rates were highest in African American males (2.12 per 100,000 population per year). Associated noncarcinoid tumors were frequent in conjunction with small intestinal (16.6%), appendiceal (14.6%), and colonic carcinoids (13.1%). The highest percentage of nonlocalized lesions were noted for pancreatic (76.1%), colonic (71.2%), and small intestinal carcinoids (70.7%) and this corresponded to their poor 5-year survival rates (34.1%, 41.6%, and 55.4%, respectively). The best 5-year survival rates were recorded for appendiceal (85.9%), bronchopulmonary (76.6%), and rectal carcinoids (72.2%). These exhibited invasive growth or metastatic spread in only 35.4%, 27.2%, and 14.2% of cases, respectively., Conclusions: Carcinoids appear to have increased in incidence in the past 20 years. In part, this may be due to different surgical rules of the various registries, improved diagnostic technology, and increased awareness. A cumulative analysis of all types of carcinoid tumors in the SEER group indicates that in 45.3% metastases are already evident at the time of diagnosis. The overall 5-year survival rate of all carcinoid tumors regardless of site was 50.4% +/- 6.4%.

Background: Peritoneal carcinomatosis (PC) in patients with digestive endocrine tumors (DET) is considered rare but its prevalence is unknown. The objectives of this study were to assess the prevalence and prognostic implications of PC in patients with various types of DET., Methods: One hundred and sixteen consecutive patients with DET seen over a 3-year period were studied. Fifty-nine had gastrinomas, 30 had carcinoid tumors, and 27 had other types of endocrine tumors, mainly nonfunctioning ones. Diagnosis of PC was based on clinical symptoms (ascites and König's syndrome), findings of computed tomography scans that were performed at least yearly, and pathologic confirmation of tumor nodules or positive cytology in the peritoneal fluid. Factors associated with PC were investigated and the influence of PC on patients' survival was assessed., Results: PC was found in 11 patients (overall PC prevalence: 10%; with 27% in patients with carcinoid tumors, 11% in those with nongastrinoma pancreatic endocrine tumors, and 0% in patients with gastrinomas). Nine of 11 patients with PC also had liver metastases. PC was metachronous to detection of the primary tumor in 7 of 11 patients, occurring 54 months (range, 23-273 months) after the diagnosis. In addition to the nature of the primary tumor, a greatest dimension of more than 5 cm was associated with the presence of PC in two of three patients with pancreatic endocrine tumors. In patients with carcinoid tumors, an ileal primary tumor occurred more frequently in patients with PC (87.5%) than in those without PC (50%). Prevalence of liver and other metastases was not significantly increased in patients with PC. Although five patients died of their disease, no deaths were related to PC. Actuarial survival rates at 5 years were 64% and 84% in patients with and without PC, respectively (P = not significant), whereas they were 73% and 93% in patients with and without liver metastases, respectively (P < 0.02)., Conclusions: PC is not a rare event in the course of DET, especially in patients with carcinoid tumors. It did not occur in the patient population with gastrinomas, which are less often malignant but may also differ from the other types of DET by several cell characteristics. In contrast to liver metastases, PC is not associated with a significant decrease in life expectancy.

Background: The prostatic neuroendocrine cell is a regulatory cell that produces serotonin and peptide hormones. This cell is part of a more widely dispersed diffuse neuroendocrine regulatory system known as the APUD system. Focal neuroendocrine differentiation is seen in virtually all prostate carcinomas to one degree or another. Specific malignancies that are purely neuroendocrine include small cell carcinoma and carcinoid/carcinoid-like tumors. A variety of studies suggest a possible prognostic significance of neuroendocrine differentiation in prostate carcinoma., Methods: The literature on the prostatic neuroendocrine cell and neuroendocrine differentiation in prostate carcinoma is reviewed., Results: Based on analogy with other better studied elements of the diffuse neuroendocrine regulatory system or APUD system, as well as the morphology and specific products produced by neuroendocrine cells, it is likely that they play an important regulatory role in the prostate. Neuroendocrine differentiation may be of prognostic significance in prostate carcinoma. Mechanisms are not well characterized at this point, but the known growth factor activity of the neuroendocrine cell products, an increase in proliferation in cells surrounding neuroendocrine cells, and a lack of androgen receptor expression in neuroendocrine cells, suggest mechanisms by which they may be of prognostic significance., Conclusions: Neuroendocrine differentiation in prostate carcinoma may be of prognostic significance, but better methods to define neuroendocrine, differentiation are necessary. The therapeutic implications of neuroendocrine differentiation in prostate carcinoma may be of significance and need to be explored further.

Background: Gastric carcinoids are uncommon, and are unlike carcinoids at other gastrointestinal sites, clinically and pathologically., Methods: The authors studied specimens from 104 patients with gastric carcinoid, with study emphasis being placed on pathologic features, immunohistochemistry, clinical associations, and prognostic factors., Results: The average age of the 47 male patients and 57 female patients was 61 years. Twenty-seven patients had chronic atrophic gastritis, 12 had pernicious anemia, and 6 had hypergastrinemia; no patient had carcinoid syndrome. Most of the tumors were confined to the mucosa and submucosa. Lymph node metastases were present in only one patient. The tumors were argyrophilic in 84% and argentaffin in 14%. Chromogranin tested positive in all patients; serotonin was detected in one-third; other hormones were much less common. Gastrin-positive tumors were antral. Of the 62 patients with follow-up, 44 were alive without disease, 4 were alive with disease, and 14 were dead (4 died of carcinoid-related disease). None of the deceased had pernicious anemia or hypergastrinemia. The tumors in patients with a fatal outcome were 2 cm or larger., Conclusion: Gastric carcinoids generally are indolent tumors, particularly when associated with pernicious anemia or hypergastrinemia or when smaller than 2 cm. Chromogranin is the most sensitive marker.

Primary ovarian carcinoid tumors are uncommon, and carcinoid heart disease is a rare complication. Although carcinoid syndrome and carcinoid heart disease typically occur in the setting of metastatic carcinoid tumor, particularly involving the liver, this is not necessarily the case in patients with primary ovarian carcinoid tumors. After surgical resection of an ovarian carcinoid tumor, the prognosis is excellent; however, carcinoid heart disease can continue to progress. The following is a case report of a patient who, despite having complete resection of a primary ovarian carcinoid tumor, went on to develop progressive, debilitating carcinoid heart disease. This is an important scenario to recognize, because proper management and surgical intervention in carcinoid heart disease can be lifesaving.

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: Ultrasound-guided percutaneous alcohol injection (PAI) is used in the treatment of hepatocellular carcinoma. The aim of this study is to evaluate the results of treatment with PAI of liver metastases (LM) that measure fewer than 5 cm in diameter, where three or less lesions are present., Methods: Between December 1987 and November 1992, 40 patients were treated for one or more liver tumors (n < or = 3). These 40 patients had a total of 55 lesions. There were 55 LM: 32 cases of colorectal origin, 9 cases of mammary origin, 5 cases with a carcinoid tumor, 4 with an undifferentiated tumor, 3 with cancer of the uterus, 1 with an epidermoid cancer of the esophagus, and 1 with a bronchogenic carcinoma. The tumor has been considered spherical and the total volume of alcohol used depends on the diameter of the tumor. The volume was calculated using the formula V = 4/3 pi [r + 0.5]3; this volume was injected during several sessions, not more than 10 ml per injection. The injections were performed once a week until the calculated volume was reached., Results: Of the 55 tumors treated, there was a complete necrosis in 31 cases (56.3%). The median survival of the 40 patients was 21 months, with a 3-year actuarial survival of 39%. Among patients with LM of colorectal origin, the median survival was increased when the total necrosis was obtained (38 months versus 21 months, P < 0.04)., Conclusion: PAI seems to be a therapeutic alterative when surgery is contraindicated or when LM are resistant to chemotherapy.

Background: Using a wide range of interferon (IFN) doses and schedules, a number of authors have found them to be active against neuroendocrine tumors., Methods: To verify the clinical activity of IFN, 49 evaluable patients with advanced stage low- and intermediate-grade neuroendocrine tumors were treated with recombinant IFN-alpha-2a at a daily dose of 6 x 10(6) IU intramuscularly for 8 weeks, and 3 times weekly thereafter. The predominant histotype was carcinoid, although a few cases had malignant islet cell tumors, medullary thyroid carcinoma, Merkel cell carcinoma, or other neuroendocrine tumors. All of the patients had measurable lesions and most had multiple sites. Carcinoid syndrome was present in 14 cases., Results: After a median treatment duration of 6 months, complete regression was achieved in 1 of the 7 cases of medullary thyroid carcinoma, and partial response was observed in 4 of 34 carcinoids. Response duration ranged from 1-11 months. Control of the syndrome was obtained in nine patients and a greater than or equal to 50% reduction of 5-hydroxyindoleacetic acid in eight patients. The treatment was well-tolerated. The most frequently observed side effects were fever, flu-like syndrome, and leukopenia. After 12 months of recombinant IFN-alpha-2a, 15 cases in progression and 4 with stable disease or partial response received another treatment (either radiometabolic therapy with I131 metaiodobenzylguanidine or polychemotherapy with streptozotocin plus epirubicin)., Conclusions: The use of recombinant IFN-alpha-2a at these doses is well-tolerated and effective in controlling carcinoid syndrome (complete remission plus partial remission, 64%), although it has limited activity on tumor growth inhibition. No definitive data can be given for the other protocol treatments.

Background: Primary carcinoid tumor of the kidney is rare; only 18 patients have been reported. Because of the rarity of the lesion, its prognosis and clinicopathologic features are not well characterized, and its histogenesis is unknown., Methods: Clinicopathologic, immunohistochemical, and ultrastructural studies were performed on five patients with primary carcinoid tumor of the kidney., Results: Age of the patients ranged from 42 to 63 years, with a mean of 53.2 years. Only one patient had a carcinoid syndrome. Three were men, and two were women. In each patient, the tumor was solitary and confined to the kidney. All tumors had histologic features identical to those of carcinoid tumors affecting other sites. The cytoplasmic granules of the tumor cells were reactive with Grimelius stain in all patients. All tumors also were immunoreactive for keratin, neuron-specific enolase, and chromogranin, but only two patients had tumors that reacted for serotonin, pancreatic polypeptide, and vasoactive intestinal polypeptide. Ultrastructural studies showed numerous intracytoplasmic neuroendocrine granules in four tumors. One patient had Robson Stage I cancer, and two each had Stage II and IV cancer. The two patients with Stage IV tumor died of disease at 36 months and 28 months after diagnosis; one patient with Stage II carcinoid is alive without clinical evidence of residual disease 8 years after control of metastases; the other patient with Stage II and the patient with Stage I cancer are alive and well without evidence of disease at 36 months, and 2 months, respectively., Conclusion: Tumor stage at presentation appears to be the most important factor in determining outcome. The number of mitoses and degree of cellular atypia appear to be important pathologic parameters in predicting prognosis, despite the limited number of patients reported in this report.

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.