Joanne Forbes

A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase

BACKGROUND & AIMS Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer. METHODS We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases. RESULTS Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. CONCLUSIONS We found that small intestinal carcinoids can occur as an inherited autosomal-dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis.

Prospective evaluation and treatment of familial carcinoid small intestine neuroendocrine tumors (SI-NETs)

BACKGROUND The aim of this study was to prospectively screen patients with a positive family history of carcinoid small intestine neuroendocrine tumors (SI-NETs) to elucidate the benefits of early detection and operative intervention. METHODS A single-center, prospective trial was conducted from 2008 to 2014 that evaluated patients with 2 or more blood relatives with carcinoid SI-NETs. All eligible patients were screened with urine/serum biochemistries and various imaging modalities. Operative intervention was elected in patients found to have at least 1 positive diagnostic study. RESULTS Twenty-nine patients from 13 families had occult carcinoid SI-NETs (15 female, 14 male). Twenty-four of the 29 patients (83%) had multifocal disease found in either the distal jejunum or ileum. On average, 75.9 cm (range, 13-195) of bowel was resected in 1 segment. Three patients were found to have stage IV disease at operation. All stage I-IIIB patients who had R0 resections have remained disease-free, with a median follow-up of 35 months. CONCLUSION Familial carcinoid SI-NETs often are asymptomatic and can be diagnosed with aggressive screening. With early detection, there may be a window of opportunity for operative resection to change the natural history of this disease and even prove to be curative.

666 Screening for Occult Tumor in Asymptomatic Members of Families With Midgut Carcinoid Tumor (SI-NET) Improves Disease Outcome

BACKGROUND: SI-NETs are rare, indolent, and difficult to diagnose. As a result, patients present late with advanced surgically-incurable disease (dz) and a low 5-year survival rate. Reports of families with ≥2 affected members with multiple primary carcinoid tumors suggest the presence of a familial and possibly hereditary form, in addition to what is generally considered a sporadic dz. Recognition of a familial form of a slow growing tumor and the benefit of early detection of an otherwise treatment-resistant dz suggests that screening may improve dz outcome. AIMS: To prospectively determine whether screening families with SI-NET can detect occult tumor at an early stage and whether surgical intervention can alter the dz outcome. METHODS: A single-center prospective study was conducted from 2008 to 2014 to evaluate asx members of families with ≥2 previously diagnosed (symptomatic, sx) SI-NET cases. Families with other hereditary cancer syndromes were excluded. Asymptomatic (asx) members were screened with biochemical markers (CgA, serotonin, 5-HIAA) and imaging (18-FDOPA PET/CT, CT C/A/P with IV contrast, capsule endoscopy). Positively screened patients underwent ex lap and intraop U/S. Living previously diagnosed sx cases were similarly evaluated or if deceased, by medical records. RESULTS: 15 families with 81 sx cases (mean age 61.0 years; 53% female) and 151 asx members (mean age 52.7 years; 56% female) were evaluated. 36 (24%) asx members (mean age 57.8 years) screened positive. 32 elected for surgery, and 29 had jejunal/ileal carcinoid tumors. Compared to their sx relatives, mean tumor number was 6.5 vs. 6.7, and mean bowel resection was 72.9 vs. 60.6 cm, with the majority having well-differentiated (97% vs. 79% grade I) and multi-focal primary disease (79% vs. 68%) (all p>0.05). Asx members had smaller tumors (mean 8.7 vs. 18.6 mm), earlier disease (7% vs. 68% stage IV), and less nodal involvement (46% vs. 92%) (all p<0.001). All 29 positively screened and surgically confirmed members remain asx, and 27 (93%) have no evidence of dz with a mean follow-up of 39 months. In contrast, 39 (47%) sx deceased relatives had a mean survival of 5.4 yrs, and 42 (53%) are living with disease for 4.4 yrs. Of the 42 living sx relatives, 39 (93%) have stage IIIB (38%) or stage IV (55%) disease. CONCLUSIONS: Asx members of families with ≥2 SI-NET cases are at high risk for occult tumors. Screening detects occult tumors at an early stage. Surgery improves the natural history and may prove to be curative in most cases. Multiple primary tumors appear to be a feature of familial dz and may represent germline/hereditary origin in some families. A careful family history and possibly screening should be performed in families of patients found to have multiple primary SI-NETs.

Sa1143 Comparison of Gallium-68 DOTATATE With 18-Fdopa PET/CT in Patients With Familial Midgut Carcinoid Tumor

as PDNET, and 7 PDNEC based on morphologic features. WDNETs had low-grade cytology and mitotic figures less than 20 per 10 high-power fields. PDNECs demonstrated high grade cytology, sheet-like growth, and higher mitotic activity. PDNETs had intermediate features. Ki-67, p53, and p16 expression data are shown in Table 1. P53 expression in less than 30% of the tumor was considered negative. Conclusion: Tumors with morphologic features of well-differentiated neuroendocrine tumors do not express p53 and rarely express p16. Poorly-differentiated neuroendocrine tumors exhibit Ki-67 indices between 15-40%, with intermediate expression of p53 and p16. Poorly-differentiated neuroendocrine carcinoma with Ki-67 expression greater than 40% had the highest levels of p53 and p16 expression and the worst survival from the time of diagnosis. These data support the hypothesis that patients with neuroendocrine neoplasms of the gastrointestinal tract currently classified as grade 3 (neuroendocrine carcinoma) have variable survival. Further stratification of these patients based on proliferative indices may better predict clinical behavior, and further investigation with larger cohorts is warranted. Moreover, these data suggest expression of p53 and p16 by immunohistochemistry correlate with increasing grade and worse survival, and these markers may be useful in stratifying patients. Table 1

Tu1096 Utility of Neuroendocrine Biomarkers in Screening for Occult Familial Midgut Carcinoid Tumor in Asymptomatic High Risk Individuals: Results of a Prospective Study

Background: The incidence of gastric neuroendocrine tumors (NETs) has increased ten-fold since the 1970s. The majority of type I gastric NETs arise from enterochromaffin-like cell hyperplasia in the setting of atrophic gastritis and pernicious anemia. Studies on type I gastric NETs have been limited, and consensus over their management and long-term outcomes remains elusive. Aim: The primary aim was to describe the clinicopathologic characteristics, management, and outcome of type I gastric NETs for this patient population at The Mount Sinai Hospital. Methods: From existing databases of the Mount Sinai Division of Gastrointestinal Pathology and the Carcinoid Cancer Foundation, we identified 56 patients with type I gastric NETs seen at The Mount Sinai Hospital from 1993 to 2012. A comprehensive dataset encompassing demographic, clinical, endoscopic and pathologic factors was generated. Overall survival information was determined from medical records and confirmed using the Social Security Death Index. Tumor-Node-Metastasis (TNM) staging was conducted according to tumor size, depth of invasion, presence of nodal involvement and presence of metastasis. Tumors were graded based on mitotic counts and Ki67 index. Statistical analysis was performed using SPSS. Results: The median age was 63.3 years (range: 37.2-89.4); 80.4% were female. Upon initial presentation, 70.3% exhibited abdominal pain and 24.3% unintentional weight loss. Two-thirds and one-third of patients tested positive for parietal cell and intrinsic factor antibodies, respectively, while median gastric pH was 6.9. Median carcinoid size was 3.0 mm (range: 0.8-25.0), with 55.8% displaying multifocal disease (Table 1). Stage I-IV disease was observed in 83.8%, 10.8%, 5.4% and 0%, respectively. Tumors were either low (69.7%) or intermediate (30.3%) grade. Furthermore, 7.3% of patients exhibited gastric dysplasia, whereas 5.5% developed gastric adenocarcinoma. Patients received a mean 1.15 endoscopies per year, while 28.6% underwent polypectomy, 32.7% somatostatin therapy and 46.4% laparoscopic antrectomy (Table 2). The 5and 10-year disease-specific survival rates were 100%. There were two patient deaths unrelated to NET disease. Conclusion: Most type I gastric NET patients developed multiple, small, benign, indolent lesions. The majority of patients underwent EGD surveillance annually, with a minority receiving somatostatin-based or surgical intervention. We discovered a very low but real rate of regional lymph node involvement; however, these occurred in the complete absence of distant metastasis. This was unexpected given the generally indolent behavior of type I gastric NETs. Interestingly, several patients demonstrated concurrent dysplasia or adenocarcinoma, underscoring the efficacy of regular endoscopic management not only for gastric NETs, but also for dysplasia and adenocarcinoma.

1065 Screening for Occult Midgut Carcinoid Tumor in High Risk Individuals Using Functional and Anatomic Imaging Modalities: Results of a Prospective Study

Background: Carcinoid tumors of the small intestine are rare, often presenting with late stage disease not amenable to treatment, while early stage disease is surgically curable. Familial midgut carcinoid tumor has been described in rare case reports. However, the recent development of a relatively large cohort of high-risk asymptomatic members of familial midgut carcinoid tumor families has exposed the need for effective screening for occult tumor. Aim: Compare the utility of imaging modalities for the detection of occult midgut carcinoid tumor in an asymptomatic, high-risk cohort. Methods: This was a single center, prospective, natural history study. First-degree family members of affected individuals in families with at least two known cases of midgut carcinoid tumor were screened with computed tomography enterography (CTE), magnetic resonance imaging (MRI), [18F]fluorodihydroxyphenylalanine (FDOPA) positron emission tomography (PET), and (111)Inpentetreotide scintigraphy (SRS). Individuals with a family history of multiple endocrine neoplasia-1, multiple endocrine neoplasia-2, neurofibromatosis, or von Hippel Lindau, or any other known familial tumor syndrome were excluded. Patients with findings consistent with carcinoid tumor were referred for exploratory laparotomy and small bowel resection. Results: One-hundred-seven high-risk, asymptomatic patients underwent screening. A total of 20 patients were referred for surgery for abnormal small bowel findings. In patients referred for surgery, CTE was abnormal in 15 of 20 cases, MRI was abnormal in 2 of 20 cases, FDOPA-PET was abnormal in 14 of 20 cases, and SRS was abnormal in 1 of 20 cases. A total of 17 patients (16% yield of screening) were confirmed to have midgut carcinoid tumor. Median age of diagnosis was 56 (range 44-74) years. Nine of 17 patients were found with either stage 1 or 2 disease, while 8 of 17 patients were found with stage 3 or 4 disease. The positive predictive value of multi-modality screening for carcinoid tumor was 85%. The three falsely positive patients were found to have a lymphangioma, large lymphoid aggregates, or a lymphocele of the distal small bowel. Fifteen of 16 occult carcinoid patients have shown no evidence of disease on a median follow-up of 26 (range 3-35) months. Conclusions: Screening of asymptomatic, high risk individuals with multi-modality imaging diagnosed a high proportion of early stage midgut carcinoid tumors compared to previously reported series. CT and FDOPA-PET were most sensitive compared to MRI and SRS, both of which were of limited value. Sensitive diagnostic imaging appears promising for the detection of early disease and therefore may improve the surgical outcome of individuals at risk for midgut carcinoid.