Adeline Louie

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.

Hydrogen-1 MR Spectroscopy for Measurement and Diagnosis of Hepatic Steatosis

OBJECTIVE Hydrogen-1 MR spectroscopy ((1)H-MRS) is gaining acceptance as a noninvasive technique for assessment of hepatic steatosis, and the findings have been found to correlate closely with histopathologic grade. The aims of this study were to validate (1)H-MRS performed with a 3-T MRI system for quantifying hepatic steatosis and to determine threshold values of (1)H-MRS proton density fat fraction corresponding to standard histopathologic grade in patients undergoing diagnostic liver biopsy. SUBJECTS AND METHODS We conducted a prospective cross-sectional liver MRS study with 52 subjects undergoing diagnostic liver biopsy. The diagnostic accuracy of (1)H-MRS was evaluated with receiver operating characteristic curves. RESULTS The diagnostic accuracy of (1)H-MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88-1.0). Results were similar for three (1)H-MRS measurements obtained at different locations in the liver, for two independent pathologists, and whether fibrosis was present or absent. One third of participants had elevated transaminase concentrations of unknown cause, and (1)H-MRS estimates of steatosis had perfect agreement with histopathologic grade in this group. Calculated (1)H-MRS proton density fat fraction thresholds for histologic grades were less than 17% for grade 0 or trace steatosis, 17-38.6% for grade 1, and greater than 38.6% for grade 2 or higher. CONCLUSION Hydrogen-1 MR spectroscopy is an effective, noninvasive technique that can be used to diagnose and quantify hepatic steatosis. Hydrogen-1 MR spectroscopy thresholds corresponded with histopathologic grades and may be useful in the workup of patients with elevated transaminase concentrations.

Mesenteric Vasculature-Guided Small Bowel Segmentation on 3-D CT

Due to its importance and possible applications in visualization, tumor detection and preoperative planning, automatic small bowel segmentation is essential for computer-aided diagnosis of small bowel pathology. However, segmenting the small bowel directly on computed tomography (CT) scans is very difficult because of the low image contrast on CT scans and high tortuosity of the small bowel and its close proximity to other abdominal organs. Motivated by the intensity characteristics of abdominal CT images, the anatomic relationship between the mesenteric vasculature and the small bowel, and potential usefulness of the mesenteric vasculature for establishing the path of the small bowel, we propose a novel mesenteric vasculature map-guided method for small bowel segmentation on high-resolution CT angiography scans. The major mesenteric arteries are first segmented using a vessel tracing method based on multi-linear subspace vessel model and Bayesian inference. Second, multi-view, multi-scale vesselness enhancement filters are used to segment small vessels, and vessels directly or indirectly connecting to the superior mesenteric artery are classified as mesenteric vessels. Third, a mesenteric vasculature map is built by linking vessel bifurcation points, and the small bowel is segmented by employing the mesenteric vessel map and fuzzy connectness. The method was evaluated on 11 abdominal CT scans of patients suspected of having carcinoid tumors with manually labeled reference standard. The result, 82.5% volume overlap accuracy compared with the reference standard, shows it is feasible to segment the small bowel on CT scans using the mesenteric vasculature as a roadmap.

CT Colonography Computer-Aided Polyp Detection: Effect on Radiologist Observers of Polyp Identification by CAD on Both the Supine and Prone Scans

RATIONALE AND OBJECTIVES To determine whether the display of computer-aided detection (CAD) marks on individual polyps on both the supine and prone scans leads to improved polyp detection by radiologists compared to the display of CAD marks on individual polyps on either the supine or the prone scan, but not both. MATERIALS AND METHODS The acquisition of patient data for this study was approved by the Institutional Review Board and was Health Insurance Portability and Accountability Act-compliant. Subsequently, the use of the data was declared exempt from further institutional review board review. Four radiologists interpreted 33 computed tomography colonography cases, 21 of which had one adenoma 6-9 mm in size, with the assistance of a CAD system in the first reader mode (ie, the radiologists reviewed only the CAD marks). The radiologists were shown each case twice, with different sets of CAD marks for each of the two readings. In one reading, a true-positive CAD mark for the same polyp was displayed on both the supine and prone scans (a double-mark reading). In the other reading, a true-positive CAD mark was displayed either on the supine or prone scan, but not both (a single-mark reading). True-positive marks were randomized between readings and there was at least a 1-month delay between readings to minimize recall bias. Sensitivity and specificity were determined and receiver operating characteristic (ROC) and multiple-reader multiple-case analyses were performed. RESULTS The average per polyp sensitivities were 60% (38%-81%) versus 71% (52%-91%) (P = .03) for single-mark and double-mark readings, respectively. The areas (95% confidence intervals) under the ROC curves were 0.76 (0.62-0.88) and 0.79 (0.58-0.96), respectively (P = NS). Specificities were similar for the single-mark compared with the double-mark readings. CONCLUSION The display of CAD marks on a polyp on both the supine and prone scans led to more frequent detection of polyps by radiologists without adversely affecting specificity for detecting 6-9 mm adenomas.

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.

Mesenteric vasculature-guided small bowel segmentation on high-resolution 3D CT angiography scans

Due to the low image contrast and high tortuosity of the small bowel on CT scans, it is difficult for even experienced radiologists to localize small bowel. To facilitate this, we propose a novel mesenteric vasculature-guided method for small bowel region segmentation on high-resolution contrast-enhanced CT angiography (CTA) scans. It is essential and useful for further localizing small bowel tumors. The mesenteric vasculature is first segmented using multi-view multi-scale vesselness enhancement filters on maximum intensity projection images. Second, the small bowel region is automatically segmented based on the map of mesenteric vasculature and its relationship to the small bowel. The method is applied to high-resolution contrast-enhanced abdominal CTA scans of patients suspected of having carcinoid tumors. The result, 79.3% volume overlap accuracy compared with the reference standard, shows it is feasible to segment the small bowel using the mesenteric vasculature as a roadmap on CTA scans.

Case of the Season: A Giant Fibroadenoma in the Guise of a Phyllodes Tumor; Characterization Role of MRI

A 25 year old Caucasian female presented with a painless enlarging mass in the right breast. She first noticed it 18 to 24 months ago when her right breast became firmer and larger. She was seen by her primary care provider who attributed it to hormonal changes, and continued to only observe it. Three months ago she noticed another but smaller breast mass superficial to the first mass. In addition, she has noted a 10 to 15 pound weight loss over the year. She denied any breast pain, skin thickening, nipple discharge or other nipple changes. Family history was negative for breast and ovarian cancer. On physical examination, the right breast was approximately twice as large as the left breast with distended veins seen at the medial aspect of the right breast. A large soft mass associated with 2 smaller superficial masses occupied most of the right breast. No lymph nodes were palpated. X-ray mammography, ultrasound (US) and magnetic resonance imaging (MRI) examinations were performed.

Computer-aided mesenteric small vessel segmentation on high-resolution 3D contrast-enhanced CT angiography scans

Segmentation of the mesenteric vasculature has important applications for evaluation of the small bowel. In particular, it may be useful for small bowel path reconstruction and precise localization of small bowel tumors such as carcinoid. Segmentation of the mesenteric vasculature is very challenging, even for manual labeling, because of the low contrast and tortuosity of the small blood vessels. Many vessel segmentation methods have been proposed. However, most of them are designed for segmenting large vessels. We propose a semi-automated method to extract the mesenteric vasculature on contrast-enhanced abdominal CT scans. First, the internal abdominal region of the body is automatically identified. Second, the major vascular branches are segmented using a multi-linear vessel tracing method. Third, small mesenteric vessels are segmented using multi-view multi-scale vesselness enhancement filters. The method is insensitive to image contrast, variations of vessel shape and small occlusions due to overlapping. The method could automatically detect mesenteric vessels with diameters as small as 1 mm. Compared with the standard-of-reference manually labeled by an expert radiologist, the segmentation accuracy (recall rate) for the whole mesenteric vasculature was 82.3% with a 3.6% false positive rate.

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.

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.