Neuroendocrine Carcinoid Tumors Research Articles

D-43 | The Prognostic Value of Invasive Hemodynamic Monitoring in Patients With Carcinoid Heart Disease Needing Bioprosthetic Valve Replacement

Carcinoid heart disease (CnHD) is a serious cause of morbidity and mortality in patients with carcinoid neuroendocrine tumors. Although valve replacement surgery appears to decrease all-cause mortality in patients with advanced CnHD, few studies have investigated the utility of invasive hemodynamic evaluation prior to valvular intervention to predict survivorship. We conducted the first known prospective study of CnHD survival by right heart catheterization (RHC) waveform morphology. 50 patients with symptomatic CnHD met inclusion criteria: having RHC within 3 months prior to bioprosthetic valve replacement. They were categorized into 3 morphologic waveform groups: “Preserved A, V wave,” “tall V wave,” and “ventricularized RV wave.” The 3 groups were evaluated for all-cause mortality. Median follow-up was 29 months and median overall survival was 26 months. Compared to the preserved A&V waveform group, ventricularized RV waveform carried a hazard of death ratio by over four-fold in multivariate Cox regression (HR 4.54, 95%CI 1.03-19.96, p=0.046). Median survival was significantly reduced for ventricularized RV compared to A&V (p=0.046), though there was no significant difference for tall V waveform patients (p=0.724). Our data show that a ventricularized RV waveform on RHC is a significant and independent mortality predictor for CnHD. This may provide unique longitudinal evidence that RHC may be a particularly helpful risk stratification tool for symptomatic CnHD patients needing bioprosthetic valve replacement.

D-43 | Bioprosthetic Valve Monitoring in Patients with Carcinoid Heart Disease

Carcinoid heart disease (CnHD) is a frequent cause of morbidity and mortality in patients with carcinoid neuroendocrine tumors. Although valve replacement surgery appears to decrease all-cause mortality in patients with advanced CnHD, few studies have investigated the outcomes of patients after valve replacement.

Pulmonary neuroendocrine carcinoid tumors: Is there a predictive role to the Ki 67 index?

INTRODUCTION:There are several factors predicting evolution in carcinoid tumors (CT) to date including the Ki67 role.AIMS:The aim of this study is to identify a KI67 cut-off point for a population of CT and determine its prognostic implication in global and disease-free survival.METHODS:Hematoxylin-eosin slides of 102 CT were revised. The percentage of cells expressing Ki 67 was determined manually.STATISTICAL ANALYSIS:The variables were compared with the t-test or the Wilcoxon test according to their distribution, the categorical ones with Chi-square or Fisher's test. The best cut-off point was established by constructing receiver operating characteristic curves, then using that value as a dichotomous variable.RESULTS:72 typical carcinoids (TC) and 30 atypical carcinoids (AC) were analyzed; 66% were female. Median age (TC 38 vs. AC 51, P = 0.001), Ki67 expression (TC 0.63 vs. AC 2, P = 0.003), tumor size (TC 2.5 vs. AC 2.6, P = 0.001), the percentage relapse (TC 3.4% vs. AC 23%, P = 0.006), and the number of deaths (TC 1 vs. AC 4, P = 0.042) were significantly higher in the AC subgroup. The best cut-off point for Ki 67 was 0.755 (area under the curve AUC 0.564, 95% confidence interval 0.270–0.857), with no significant differences found in the disease-free and overall survival curves when considering values < or ≥ at the established cut-off point. The best cut-off point of the Ki-67 when exclusively analyzing AC was 1.18. When using this value as a predictive variable, a marginal statistical association was observed between Ki-67 expression, mortality (P = 0.077), and the frequency of relapses (P = 0.054).CONCLUSIONS:Histological type is the best predictor of prognosis in the carcinoid tumor group. In the AC subgroup, the marginal association between mortality, frequency of relapses and Ki values 67 ≥ 1.18 has clinical relevance future analyses are required to determine the real predictive value of this variable.

Genetic characterization of a case of sellar metastasis from bronchial carcinoid neuroendocrine tumor

Background: Metastasis to the pituitary gland from neuroendocrine tumors is a rare occurrence that may originate from primary tumors the lung, gastrointestinal tract, thyroid, and pancreas, among others. Patients may present with signs of endocrine dysfunction secondary to pituitary involvement, as well as mass effect-related symptoms including headaches and visual deficits. Despite a small but accumulating body of literature describing the clinical and histopathological correlates for pituitary metastases from neuroendocrine tumors, the genetic basis underlying this presentation remains poorly characterized.Case Description: We report the case of a 68-year-old with a history of lung carcinoid tumor who developed a suprasellar lesion, causing mild visual deficits but otherwise without clinical or biochemical endocrine abnormalities. She underwent endoscopic endonasal resection of her tumor with final pathology confirming metastasis from her original neuroendocrine tumor. Whole-exome sequencing was performed on the resected sellar tumor and matching blood, revealing increased genomic instability and key mutations in PTCH1 and BCOR that have been previously implicated in both systemic neuroendocrine and primary pituitary tumors with potentially actionable therapeutic targets.Conclusion: This is the first genomic characterization of a metastatic tumor to the sella and reports potential genetic insight, implicating PTCH1 and BCOR mutations, into the pathophysiology of sellar metastasis from primary systemic tumors.

2612 Tumors of the Appendix: Prevalence in Patients with Chronic Pelvic Pain Undergoing Minimally Invasive Excision Surgery with Concomitant Appendectomy for Suspected Endometriosis

Study Objective To determine the prevalence of appendiceal tumors in patients with chronic pelvic pain undergoing excisional surgery. Design Retrospective chart review. Setting Two Large Metropolitan Academic Hospitals. Patients or Participants 135 patients between the ages of 16 to 52 with chronic pelvic pain undergoing minimally invasive excision surgery with concomitant appendectomy for suspected endometriosis from January 2012 to June 2017. Interventions Medical records and postoperative pathology reports were analyzed for all 135 patients for the presence of appendiceal tumors, presence of endometriosis, and age. Measurements and Main Results The prevalence of appendiceal tumors in patients with chronic pelvic pain was 3% (95% CI:0.1-5.8%). Of these cases, three were neuroendocrine carcinoid tumors (0.5 cm, 0.6 cm, and 1.1 cm respectively) and one was a low grade appendiceal mucinous neoplasm (LAMN). Two of the patients had biopsy confirmed endometriosis. The biopsy confirmed endometriosis patients had the 0.6 cm neuroendocrine carcinoid tumor and the LAMN, respectively. Patients with and without appendiceal tumors had mean ages of 26.8±7.1 and 32.6±7.6 years, respectively. Conclusion The 3% prevalence of appendiceal tumors in our sample and the young age of the patients with appendiceal tumors is at odds with the much lower prevalence of appendiceal tumors and much older patient population reported in the literature. This highlights the increased need for research to establish predictive diagnostic criteria for appendiceal tumors and suggests that surgeons consider concomitant appendectomies in patients with chronic pelvic pain.

2618 Should Concomitant Appendectomy be Performed in Patients with Biopsy Proven Endometriosis?

Study Objective To determine the prevalence of appendiceal pathology (i.e. endometriosis, fibrous obliteration, tumor, acute/chronic inflammation) in patients with biopsy proven endometriosis. Design Retrospective chart review. Setting Two Large Metropolitan Academic Hospitals. Patients or Participants 100 patients between the ages of 16 to 51 diagnosed with endometriosis following minimally invasive excision surgery with concomitant appendectomy for suspected endometriosis from February 2012 to June 2017. Interventions Medical records and postoperative pathology reports were analyzed for all 100 patients with biopsy proven endometriosis for the presence of appendiceal pathology. Measurements and Main Results Among the 100 patients with biopsy proven endometriosis and concomitant appendectomy, 42% (95% CI:32.3-51.7%) were diagnosed with appendiceal pathology (i.e. endometriosis, fibrous obliteration, tumor, inflammation). Of these 100 patients, 18% (95% CI:10.5-25.5%) had underlying appendiceal endometriosis and 17% (95% CI: 9.6-24.4%) had underlying fibrous obliteration. Two percent (95% CI:0.0-4.7%) of patients were diagnosed with tumors, which comprised of one neuroendocrine carcinoid tumor (0.6 cm) and one LAMN (low grade appendiceal mucinous neoplasm). Five percent (95% CI:0.7-9.3%) of patients were diagnosed with inflammation, including acute and chronic appendicitis. Conclusion Our findings of a 42% prevalence rate of appendiceal pathology and 18% prevalence of appendiceal endometriosis suggests that surgeons should consider concomitant appendectomies in patients with biopsy proven endometriosis.

2445 Appendiceal Pathology in Women with Endometriosis

Study Objective To report the prevalence of abnormal appendiceal pathology in women with pelvic pain and pathology-confirmed pelvic endometriosis. Design Retrospective case series. Setting Tertiary care referral center. Patients or Participants Forty patients with pelvic pain undergoing laparoscopy for possible endometriosis with concomitant laparoscopic appendectomy during a 5 month period. Interventions Laparoscopic excision of suspected endometriosis with concomitant laparoscopic appendectomy on patients with visible abnormalities of the appendix. Measurements and Main Results Forty patients underwent laparoscopic excision of suspected endometriosis with visible abnormalities involving the appendix and were treated with concomitant laparoscopic appendectomy. Of this subgroup, thirty-eight patients had pelvic endometriosis and eighteen patients (47.3%) had appendiceal pathology: seven (18%) with pathology-confirmed appendiceal endometriosis, three (7.9%) with carcinoid neuroendocrine tumor, two (5.3%) with acute appendicitis, two (5.3%) with mild acute inflammation, two (5.3%) with lymphoid hyperplasia, and two (5.3%) with fibrous obliteration. The prevalence of appendiceal pathology in patients with pelvic endometriosis was 47.3%. Conclusion Appendiceal pathology may be a contributing factor to pelvic pain in women with endometriosis and should be routinely inspected for visible abnormalities.

Primary Typical Carcinoid of The Pleura, A Rare Incidental Finding

Roughly 30% of carcinoids are found in the thoracic cavity, with the overwhelming majority of these being found in the lung parenchyma. We present a case of a rarely found primary pleural carcinoid incidentally diagnosed in a 73 year old male who presented with recalcitrant spontaneous pneumothorax requiring surgical intervention. The patient was taken to the operating room for a right video assisted thoracic surgery, partial pleurectomy, and talc pleurodesis. At the time of the operation, there were no abnormalities noted in the pleura or chest wall, and the patient did well post operatively. Pathologic examination of the pleura revealed a 3mm well differentiated neuroendocrine carcinoid tumor. Laboratory and imaging studies did not indicate another site of tumor. The importance of a multidisciplinary approach to the diagnosis, treatment, and surveillance is emphasized.

PRIMARY TYPICAL CARCINOID OF THE PLEURA: A RARE INCIDENTAL FINDING

SESSION TITLE: Disorders of the Pleura 1 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: Carcinoid tumors are a rare occurrence of the thoracic cavity, constituting roughly 0.5 to 2.5% of all pulmonary neoplasms. This case discusses an incidental finding of a primary pleural carcinoid in a patient presenting with spontaneous pneumothorax requiring operative management. CASE PRESENTATION: A 73 year old male with a history of COPD presented with a shortness of breath and was transferred to our facility for a persistent spontaneous right pneumothorax. A CT scan was obtained showing multiple bilateral emphysematous blebs, but no pulmonary or chest wall lesions (Figure 1). The patient was taken to the operating room for a right VATS, partial pleurectomy, and talc pleurodesis after a persistent pneumothorax despite multiple chest tubes. Intraoperatively, no abnormalities were noted in the pleura or chest wall at the time of pleurectomy. Two chest tubes were positioned intraoperatively and placed to waterseal on POD3. They were removed on POD5 and patient was discharged POD7. The parietal pleural specimen was described as an irregularly shaped yellow membrane measuring 14.5X0.5X0.1 cm. There were no gross lesions. Microscopy revealed a well differentiated neuroendocrine carcinoid tumor with a maximum diameter of 3mm. Nests of neuroendocrine cells were present and stained positive for CD-56, CK7, synaptophysin, and CEA. ERG, CK20, WT-1, cam 5.2, TTF-1, CDX-2, and calretinin were negative (Figure 2). Follow-up PET-CT at clinic revealed no evidence of residual disease (Figure 3). DISCUSSION: The most common primary location of carcinoid tumors is the small intestine (30.4%), followed by pulmonary (29.8%) and colon (9.2%). A majority of reported pleural cases are of metastatic disease. Therefore, primary pleural carcinoid disease is a rarity. CT imaging can identify thoracic or gastrointestinal primary carcinoid tumors. In a retrospective review of 50 patients with carcinoid syndrome, Moss et al. identified pleural thickening in nine patients, of which 4 had a primary tumor. Presentation of these patients with primary pleural carcinoid is usually due to mass effect or as an incidental finding on imaging. In this case report, the patient was found to have a 3 mm focus in a pleurectomy specimen. Given the rarity of primary pleural carcinoid, this finding warranted further investigation to ensure that this was not metastatic disease. CONCLUSIONS: A multidisciplinary approach to these rare cases with pathology and radiology cannot be stressed enough. The first step is to rule out other more common pleural malignancies though a panel of histologic stains. Further imaging, including a PET CT, is suggested to identify FDG avid lesions that can be the primary origin. Reference #1: Bertino EM, Confer PD, Colonna JE, Ross P, Otterson GA. Pulmonary neuroendocrine/carcinoid tumors. Cancer. 2009;115:4434-4441. Reference #2: Townshend AP, Lakshminarayanan B, Ucar AE, Chaudry ZR, Duffy JP. Rare pleural recurrence of typical pulmonary carcinoid tumor 30 years after lobectomy. The Annals of thoracic surgery. 2007;83:1523-1524. Reference #3: Moss SF, Lehner PJ, Gilbey SG, et al. Pleural involvement in the carcinoid syndrome. QJM: An International Journal of Medicine. 1993;86:49-53. DISCLOSURES: No relevant relationships by Ernest Chan, source=Web Response No relevant relationships by Lawrence Crist, source=Web Response No relevant relationships by Rajeev Dhupar, source=Web Response I own stock in this company relationship with Inntuitive SUrgical Please note: $20001 - $100000 Added 03/03/2018 by James Luketich, source=Web Response, value=None, I purchsed my self as an stock holder relationship with johnson and Johnson Please note: $20001 - $100000 Added 03/03/2018 by James Luketich, source=Web Response, value=none, I purchsed myself as an no disclosure on file for Anupama Sharma; no disclosure on file for Diane Strollo

Pediatric neuroendocrine carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center.

While neuroendocrine (carcinoid) tumors are increasingly recognized in the adult population, they are often not suspected in children. Retrospective review of all well-differentiated neuroendocrine (carcinoid) tumors was performed based on pathology reports from a quaternary pediatric medical center between January 2003 and June 2016. Clinical presentations, treatment approaches, imaging findings, and outcomes were reviewed and analyzed. A total of 45 cases of pathology-proven carcinoid tumor were reported with an average age of 14.1 years (range: 7-21 years, SD: 2.8 years). Of these cases, 80% (36) were appendiceal, 11% (5) bronchial, 2% (1) colonic, 2% (1) gastric, 2% (1) enteric, and 2% (1) testicular. Metastases were observed in one (3%) appendiceal, one (100%) enteric, and two (40%) bronchial cases. No recurrence was demonstrated in any appendiceal carcinoid cases. Recurrence was seen in one of three extra-appendiceal gastrointestinal tumors. Tumor site and size significantly correlated with metastases and recurrence. Contrary to recent epidemiological investigations in adults, appendiceal carcinoid tumors remain the most common site for pediatric carcinoid tumors. Appendiceal carcinoid tumors exhibited benign clinical courses without recurrence during short-term follow-up. Extra-appendiceal gastrointestinal carcinoid tumors exhibited much more aggressive behavior with greater metastases and recurrence. Bronchial carcinoid tumors demonstrated good clinical response to resection even in cases with mediastinal lymph node involvement. While increased use of urine 5-HIAA levels and somatostatin receptor-specific imaging might improve detection and guide management of extra-appendiceal carcinoid tumors, longer-term follow-up is needed.

Pediatric Neuroendocrine Carcinoid Tumors: Review of Diagnostic Imaging Findings and Recent Advances.

Although rare, pediatric neuroendocrine tumors including carcinoid tumor have increased in incidence over the past few decades. Despite increased recognition, survival rates have not significantly improved. Earlier detection of these tumors is necessary to improve clinical outcomes. This article discusses imaging approaches for detecting pediatric carcinoid tumors including anatomic imaging methods such as CT and MRI as well as functional imaging methods targeting the somatostatin receptor including 111In-labeled octreotide and newer 68Ga-based radiotracers that may hold promise in hybrid PET/CT or PET/MRI. Improvements in functional imaging with novel somatostatin receptor-specific radiotracers along with fused functional and anatomic imaging have substantially improved the clinical detection of carcinoid tumors. Although rare, these tumors are encountered in children, and an awareness of the appropriate use of various imaging methods is essential for pediatric specialists. Further research is needed to ascertain the diagnostic value of newer imaging methods and radiotracer-based treatment approaches, especially in the pediatric population.

Rare Cases of Synchronous Colon Adenocarcinoma and Rectal Carcinoid Tumor

Colorectal cancer is the fourth and the third most common cancer in men and women, respectively, worldwide. Carcinoid of the rectum is the second most common site for gastrointestinal neuroendocrine tumors (NET). Concurrent colon adenocarcinoma and rectal carcinoid has not been reported. Here, we report two rare cases of synchronous colon adenocarcinoma and rectal carcinoid. Case Presentations Case #1 A 40 year old white male presented with hematochezia and abdominal pain. A CT of the abdomen and pelvis revealed focal segment of the sigmoid colon with thick wall, surrounding fat stranding and prominent lymph nodes. Follow up colonoscopy revealed a friable, ulcerated mass with biopsies revealing moderately differentiated adenocarcinoma. A rectal polyp was resected with biopsy revealing well-differentiated neuroendocrine carcinoid tumor. Computerized scan of the chest was negative for any metastasis. Patient underwent laparoscopic sigmoidectomy. Pathologic examination revealed moderately differentiated adenocarcinoma invading the peri-colonic fat. Adjuvant chemotherapy was started 4 weeks post operatively. Case #2 A 70 year old man with history of stage III adenocarcinoma of the colon was also found to have a rectal polyp consistent with carcinoid. The patient underwent trans anal resection and received adjuvant chemotherapy. Recent follow up colonoscopy was negative for malignancy. Discussion: NETs are rare and only represent 0.5% of all newly diagnosed cancer. Rectal carcinoids accounts for only 1-2% of all rectal tumors. We report cases of synchronous colorectal adenocarcinoma and rectal carcinoid. There was one case report of synchronous well-differentiated adenocarcinoma of the sigmoid colon and malignant ileal carcinoid tumor. While rectal carcinoids are typically nonfunctioning and asymptomatic, their presence should raise awareness of a potential synchronous cancer as observed in our cases. Conclusion: Synchronous colon adenocarcinoma and rectal carcinoid are rare but can be diagnosed with colonoscopy. The detection of rectal carcinoid necessitates thorough evaluation of the remainder of the colon for cancer so that timely treatment can be carried out.

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population‐based study

Most gastrointestinal stromal tumors (GISTs) are considered nonhereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies at increased frequencies. It was hypothesized that greater insight could be gained into possible associations between GISTs and other malignancies with a national cancer database inquiry. Patients diagnosed with GISTs (2001-2011) in the Surveillance, Epidemiology, and End Results database were included. Standardized prevalence ratios (SPRs) and standardized incidence ratios (SIRs) were used to quantify cancer risks incurred by GIST patients before and after GIST diagnoses, respectively, in comparison with the general US population. There were 6112 GIST patients, and 1047 (17.1%) had additional cancers. There were significant increases in overall cancer rates: 44% (SPR, 1.44) before the GIST diagnosis and 66% (SIR, 1.66) after the GIST diagnosis. Malignancies with significantly increased occurrence both before and after diagnoses included other sarcomas (SPR, 5.24; SIR, 4.02), neuroendocrine-carcinoid tumors (SPR, 3.56; SIR, 4.79), non-Hodgkin lymphoma (SPR, 1.69; SIR, 1.76), and colorectal adenocarcinoma (SPR, 1.51; SIR, 2.16). Esophageal adenocarcinoma (SPR, 12.0), bladder adenocarcinoma (SPR, 7.51), melanoma (SPR, 1.46), and prostate adenocarcinoma (SPR, 1.20) were significantly more common only before the GIST diagnosis. Ovarian carcinoma (SIR, 8.72), small intestine adenocarcinoma (SIR, 5.89), papillary thyroid cancer (SIR, 5.16), renal cell carcinoma (SIR, 4.46), hepatobiliary adenocarcinoma (SIR, 3.10), gastric adenocarcinoma (SIR, 2.70), pancreatic adenocarcinoma (SIR, 2.03), uterine adenocarcinoma (SIR, 1.96), non-small cell lung cancer (SIR, 1.74), and transitional cell carcinoma of the bladder (SIR, 1.65) were significantly more common only after the GIST diagnosis. This is the first population-based study to characterize the associations and temporal relations between GISTs and other cancers by both site and histological type. These associations may carry important clinical implications for future cancer screening and treatment strategies.

Abstract LB-171: Concordance between protein expression and mRNA expression in the large cohort of cancer patients

Abstract Introduction: Immunohistochemical (IHC) analysis of protein expression in clinical specimens has been invaluable in diagnosing, monitoring and guiding treatment in cancer patients. This approach, however, has its limitations including the difficulty to obtain robust and reliable antibodies, the semi quantitative nature of the assay, subjectivity of intensity call, and the lack of specificity to detect clinically relevant isoform expression in tumor specimen. In light of these limitations, RNA expression may be a useful replacement or a complementary approach to IHC in clinical settings. In this study, we compared the concordance between IHC and mRNA expression levels as measured by microarray using a large cohort of cancer patients spanning multiple lineages. Methods: 10246 patient samples that included 40 tumor types were utilized in this study. Transcript and protein expression levels were measured for ESR1, AR, KIT, ERBB2 (Her2), RRM1, and ERCC1. Transcript levels were measured by Illumina's HumanHT-12 microarray (v4), and IHC was performed using the following antibodies: SP1 (ESR1), AR27 (AR), 4B5 (Her2), 8F1 (ERCC1), anti-CD117 polyclonal (KIT), and 10526-1-AP (RRM1). Results: We observed a significant correlation between ERBB2, ESR1, and KIT with IHC data. Of the 3 probes on the microarray measuring ERBB2, only one probe mapping to the 3’ end of the two ERBB2 isoforms showed significant association with IHC data. For KIT, IHC and mRNA expression correlated well across, thymic carcinomas, poorly differentiated neuroendocrine tumors, melanoma, GIST, and head and neck cancer. For ESR1, significant correlations were observed for uterine sarcoma, endometrial carcinoma, and breast adenocarcinoma. Cervical cancers and ovarian surface epithelial carcinomas showed diminished association, and there was a lack of association in NSCLC and neuroendocrine carcinoid tumors. For AR, we observed strong correlation only in prostate tumors. ERCC1 and RRM1 mRNA expressions did not correlate well with protein expression in any of the tumor lineages examined. Conclusion: These observations suggest that measuring mRNA via microarray has the potential to serve as a surrogate for IHC in clinical setting. The mixed associations observed for some of the genes exhibited lineage specificity suggesting that the relation between microarray results and IHC may be driven by the tissue-specific expression of isoforms, differential expression of genes in the stromal cells, and the technical limitations of each platform including the specificity of either the probes used to measure mRNA or antibodies used to measure protein expression. As such, combining the two platforms in the clinical setting may provide a more complete assessment of gene expression in tumor samples. Citation Format: Anatole Ghazalpour, Wangjuh Sting Chen, Wenhsiang Wen, Zoran Gatalica, Ryan Bender. Concordance between protein expression and mRNA expression in the large cohort of cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-171. doi:10.1158/1538-7445.AM2014-LB-171

Chemoembolization as a locoregional treatment for metastatic disease on a liver transplant from a bronchial carcinoid neuroendocrine tumor

Chemoembolization as a locoregional treatment for metastatic disease on a liver transplant from a bronchial carcinoid neuroendocrine tumor

Circulating Serotonin and Bone Density, Structure, and Turnover in Carcinoid Syndrome

Gut-derived serotonin has been proposed as a regulator of bone formation, and inhibition of gut serotonin synthesis increases bone formation in rodents. Carcinoid neuroendocrine tumors can produce very high levels of circulating serotonin and so offer a model of serotonin excess in humans. The objective of the study was to determine whether patients with carcinoid syndrome have lower bone formation markers, lower bone density, or poor bone structure compared with healthy controls. We conducted a cross-sectional study of 25 patients with carcinoid syndrome and 25 healthy controls, individually matched to carcinoid patients by gender, age, height, and body mass index. We measured circulating serotonin in blood and plasma and 5-hydroxyindoleacetic acid (5HIAA) in plasma and urine. We measured lumbar spine and hip bone mineral density by dual-energy x-ray absorptiometry, the distal radius and tibia with high-resolution peripheral quantitative computed tomography, and bone turnover with serum osteocalcin, amino-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (CTX). All measures of serotonin and 5HIAA were higher in carcinoid patients than in controls. No measures of bone density or bone structure differed significantly between cases and controls. Osteocalcin was higher in the cases than controls (26.0 vs 21.1 ng/mL, P = .02). PINP and CTX did not differ between cases and controls. In patients with carcinoid syndrome, plasma 5HIAA was positively correlated with osteocalcin. In controls, whole-blood serotonin was positively correlated with osteocalcin, PINP, and CTX (R values = 0.40-0.47, all P < .05.). High circulating serotonin in carcinoid syndrome is not associated with clinically significant lower bone density, poorer bone structure, or lower bone formation markers.

Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors

Neuroendocrine (carcinoid) tumors (NETs) are endocrine neoplasms occurring most frequently in gastrointestinal and bronchopulmonary (BP) systems. The majority of patients present with advanced disease for which few treatment options exist. We assessed 104 NETs (74 cases) for biomarkers targeted by anticancer drugs under development for other forms of cancer. Activating mutations were assessed in epidermal growth factor receptor (EGFR), stem cell factor receptor (KIT), and platelet-derived growth factor receptor alpha (PDGFRA), as well as non-response mutations in KRAS. Copy number of EGFR and HER-2/neu was quantified with fluorescence in situ hybridization. Immunohistochemical analyses were performed for EGFR, KIT, PDGFRA, somatostatin receptor subtypes 2A and 5 (SSTR5), vascular endothelial growth factor receptor 1, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF1R), heat shock protein 90 (Hsp90), and transforming growth factor-beta receptor 1 (TGFBR1). NETs lacked HER2-overexpression predictive of anti-HER2 response and KIT and PDGFRA activating mutations indicative of imatinib sensitivity. High EGFR aneusomy (20% of all cases) and elevated EGFR copy number (39%) were found, but few KRAS mutations associated with non-response to anti-EGFR therapy (3%). Hsp90, TGFBR1, IGF1R, and SSTR5 exhibited highest levels of immunohistochemical staining in the largest percents of tumors. In subsequent in vitro studies, anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) (targeting Hsp90) inhibited proliferation of BP NET lines NCI-H727, NCI-H720, and NCI-H835 with IC(50) values of 70.4, 310, and 788 nM respectively; BMS-754807 (targeting IGF1R/IR) inhibited growth with IC(50) values of 428 nM, 2.8 microM, and 1 microM. At growth-inhibiting concentrations, 17-AAG (24 h) induced loss of EGFR and IGF1R in the IGF1R-expressing NCI-H727 line, and BMS-754807 (24 h) inhibited constitutive IGF1R autophosphorylation. Our results support further research into Hsp90, IGF1R, and EGFR as targets for developing new anticancer therapeutics for some NETs.

Gammagrafía con análogos de la somatostatina en el diagnóstico y el seguimiento del carcinoide bronquial pediátrico

Carcinoid tumor is a rare neuroendocrine neoplasm with different locations, the most frequent ones during the pediatric age being the appendix and lung. Scintigraphy with (111)In-DTPA-d-Phe(1)-octreotide has led to an importance advance in the diagnosis of extension in carcinoid tumor patients. We present three pediatric patients with bronchial carcinoid studied with somatostatin analogue scintigraphy (SSRS). The first patient (9 years) was studied using the SSRS after surgery due to carcinoid tumor in the right lower lobe in which tumor remains was observed (this being clearer in the tomography study). The second patient (10 years) presented due to endobronchial tumor in the left lower lobe together with atelectasis of the LUL and emphysema of the LLL. Radiology imaging techniques suggested the differential diagnosis between the endobronchial carcinoid tumor or plasma cells or foreign body gramuloma. The SSRS showed an abnormal deposit of activity in the left hemithorax consisted with carcinoid tumor. No other areas suggesting metastasis were observed. After the surgery (endobronchial resection), new controls with SSRS showed absence of disease. The third patient (12 years) came after a lobectomy (RUL) due to bronchial carcinoid. The SSRS did not show any abnormal areas of activity. In the subsequent control (3 months), a deposit of activity was observed in the middle third of the right hemithorax, after which a lobectomy was performed (RLL and ML) that showed small remains of neuroendocrine carcinoid. Subsequent controls were negative. The SSRS has demonstrated great utility in the diagnosis, follow-up and staging of pediatric patients, carriers of neuroendocrine carcinoid tumors.

Ovarian hyperstimulation secondary to ectopic secretion of follicle-stimulating hormone. Literature review prompted by a case

To present an exceptional clinical case of functional follicle-stimulating gonadotropin secretion by a thorax neuroendocrine carcinoid tumor. Case report. Department of Obstetrics and Gynecology, Cruces University Hospital, Vizcaya, Spain. A 26-year-old woman with ovarian hyperstimulation. Diagnosis algorithm. Successful management of ovarian hyperstimulation. A 26-year-old woman seen with abdominal pain and swelling had bilateral multicystic ovaries. The diagnosis algorithm revealed the presence of ovarian hyperstimulation but with no due etiology. On the basis of the persistence of high levels of FSH a computed tomographic scan was taken looking for an FSH-producing neuroendocrine tumor. In idiopathic ovarian hyperstimulation secondary to supraphysiologic secretion of FSH, the presence of an FSH-producing neuroendocrine tumor should be considered. As far as we know, there are no similar cases with a confirmed diagnosis published in the literature.

Pulmonary neuroendocrine/carcinoid tumors

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