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.

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.

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.

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.

Epidermoid cyst of the breast: Mammography, ultrasound, MRI.

Epidermal cysts are common cysts located cutaneously or subcutaneously in the head, neck, and trunk. However, deep epidermal cysts of the breast are very rare, and are frequently associated with traumatic implantation. We present the case of a 62-year-old woman with a palpable mass in the right breast. The patient was evaluated using mammography, ultrasound, and MRI, which uniquely characterized the mass and revealed a second mass. Histological analysis revealed fragments of an epidermoid cyst. The origin of the cysts and location deep within the breast tissue likely were due to a previous bilateral-reduction mammoplasty.

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.

Conspicuity of colorectal polyps at CT colonography: visual assessment, CAD performance, and the important role of polyp height.

RATIONALE AND OBJECTIVES: The factors that influence the conspicuity of polyps on computed tomographic (CT) colonography (CTC) are poorly understood. The aim of this study is to compare radiologists' visual assessment of polyp conspicuity to quantitative image features and show the relationship between visual conspicuity and the detection of colonic polyps by computer-aided detection (CAD) on CTC. METHODS: One polyp (size range 6-10 mm) was selected from the CTC examination of each of 29 patients from a larger cohort. All patients underwent oral contrast-enhanced CTC with same-day optical colonoscopy with segmental unblinding. The polyps were analyzed by a previously validated CAD system and placed into one of two groups (detected [n = 12] or not detected [n = 17] by CAD). The study population was intentionally enriched with polyps that were not detected by the CAD system. Four board-certified radiologists, blinded to the CAD results, reviewed two- and three-dimensional CTC images of the polyps and scored the conspicuity of the polyps using a 4-point scale (0 = least conspicuous, 3 = most conspicuous). Polyp height and width were measured by a trained observer. A t-test (two-tailed, unpaired equal variance) was done to determine statistical significance. Intra- and interobserver variabilities of the conspicuity scores were assessed using the weighted kappa test. Regression analysis was used to investigate the relationship of conspicuity to polyp height and width. RESULTS: A statistically significant difference was found between the average conspicuity scores for polyps that were detected by CAD compared to those that were not (2.3 +/- 0.6 vs. 1.4 +/- 0.8) (P = .004). There was moderate intraobserver agreement of the conspicuity scores (weighted kappa 0.57 +/- 0.09). Interobserver agreement was fair (average weighted kappa for six pair-wise comparisons, 0.38 +/- 0.15). Conspicuity was correlated with manual measurement of polyp height (r(2) = 0.38-0.56, P < .001). CONCLUSIONS: This CAD system tends to detect 6-10 mm polyps that are more visually conspicuous. Polyp height is a major determinant of visual conspicuity. The generalizability of these findings to other CAD systems is currently unknown. Nevertheless, CAD developers may need to specifically target flatter and less conspicuous polyps for CAD to better assist the radiologist to find polyps in this clinically important size category.

CT colonography with computer-aided detection as a second reader: observer performance study.

PURPOSE: To evaluate the effect of computer-aided detection (CAD) as second reader on radiologists' diagnostic performance in interpreting computed tomographic (CT) colonographic examinations by using a primary two-dimensional (2D) approach, with segmental, unblinded optical colonoscopy as the reference standard. MATERIALS AND METHODS: This HIPAA-compliant study was IRB-approved with written informed consent. Four board-certified radiologists analyzed 60 CT examinations with a commercially available review system. Two-dimensional transverse views were used for initial polyp detection, while three-dimensional (3D) endoluminal and 2D multiplanar views were available for problem solving. After initial review without CAD, the reader was shown CAD-identified polyp candidates. The readers were then allowed to add to or modify their original diagnoses. Polyp location, CT Colonography Reporting and Data System categorization, and reader confidence as to the likelihood of a candidate being a polyp were recorded before and after CAD reading. The area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, and specificity were estimated for CT examinations with and without CAD readings by using multireader multicase analysis. RESULTS: Use of CAD led to nonsignificant average reader AUC increases of 0.03, 0.03, and 0.04 for patients with adenomatous polyps 6 mm or larger, 6-9 mm, and 10 mm or larger, respectively (P > or = .25); likewise, CAD increased average reader sensitivity by 0.15, 0.16, and 0.14 for those respective groups, with a corresponding decrease in specificity of 0.14. These changes achieved significance for the 6 mm or larger group (P < .01), 6-9 mm group (P < .02), and for specificity (P < .01), but not for the 10 mm or larger group (P > .16). The average reading time was 5.1 minutes +/- 3.4 (standard deviation) without CAD. CAD added an average of 3.1 minutes +/- 4.3 (62%) to each reading (supine and prone positions combined); average total reading time, 8.2 minutes +/- 5.8. CONCLUSION: Use of CAD led to a significant increase in sensitivity for detecting polyps in the 6 mm or larger and 6-9 mm groups at the expense of a similar significant reduction in specificity.

Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1.

Little is known of the natural history of thymic carcinoids in multiple endocrine neoplasia type 1 (MEN1). This is important because in 1993 they were identified as a frequent cause of death, yet only small retrospective studies and case reports exist. We report results of a prospective study of 85 patients with MEN1 evaluated for pancreatic endocrine tumors and followed over a mean of 8 yr with serial chest computed tomography, magnetic resonance imaging (MRI), chest x-ray, and, since 1994, octreoscans [somatostatin receptor scintigraphy (SRS)]. Seven patients (8%) developed thymic carcinoids. Patients with and without carcinoids did not differ in clinical, laboratory, or MEN1 tumor features, except for male gender and the presence of a gastric carcinoid. All thymic tumors were hormonally inactive. Four thymic carcinoids lacked 11q loss of heterozygosity, although it was found in three pancreatic endocrine tumors. Computed tomography and/or MRI were more sensitive than SRS or chest x-ray in detecting tumors initially or with recurrence. All patients underwent resection of the thymic carcinoid, and in all patients followed more than 1 yr, the tumor recurred. Bone metastases developed in two patients and were detected early only on MRI, not SRS. This study provides information on early thymic carcinoids and allows modifications of existing guidelines to be recommended for their diagnosis, surveillance, and treatment.

Primary acinic cell carcinoma of the breast.

Acinic cell carcinoma (ACC) is an uncommon neoplasm of the salivary glands with low malignant potential. Even rarer is the occurrence of primary ACC of the breast, there is only one previously documented case. We now describe the second case of a primary carcinoma of the breast with morphological, ultrastructural, and immunohistochemical features consistent with an ACC. In contrast to the previous case report we report the lack of encapsulation of the tumor and a spectrum of cell types within the tumor including cells resembling well-differentiated infiltrating ductal carcinoma. Additionally we did not observe the abundant nuclear abnormalities noted in the previously published case. We report for the first time the mucicarmine-staining pattern of this tumor as well as immunohistochemistry directed against cytokeratin 7, the estrogen receptor, and the progesterone receptor.

Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma.

BACKGROUND: Malignant pancreatic endocrine tumors (PETs) have a poor prognosis and existing antitumor treatments are unsatisfactory. Recent studies have shown somatostatin analogues to have antitumor growth effects in patients with malignant PETs; however, to the authors' knowledge, little information exists regarding their efficacy or effect on survival in patients with progressive malignant gastrinoma, the most common symptomatic malignant PET. The purpose of the current study was to study prospectively the efficacy, safety, and effect on survival of long-term treatment with octreotide in consecutive patients with progressive malignant gastrinoma. METHODS: Fifteen consecutive patients with malignant gastrinoma with progressive hepatic metastases were studied. All patients underwent conventional imaging studies (computed tomography scan, magnetic resonance imaging, ultrasound, and, if needed, selective angiography) and somatostatin receptor scintigraphy prior to treatment and at 3-6-month intervals while receiving treatment. The patients all were treated initially with octreotide, 200 microg every 12 hours, and at last follow-up were being maintained on long-acting release octreotide, 20-30 mg every month. Tumor size and/or number were used to classify patient responses as either no tumor response or tumor response (stabilization or decrease in size). Treatment response was correlated with tumor and clinical characteristics. RESULTS: Tumors in 8 of the 15 patients studied (53%) responded at 3 months, with 47% (7 of 15 patients) demonstrating tumor stabilization and 6% (1 of 15 patients) demonstrating a decrease in tumor size. The mean duration of response was 25.0+/-6.1 months (range, 5.5-54.1 months). Six of the eight responders were continuing to respond at the time of last follow-up. Tumor response did not correlate with any clinical parameter (e.g., tumor extent, fasting gastrin, or acid secretory rates). However, slow-growing tumors were more likely to respond prior to treatment (86% vs. 0%) (P < 0.0014). During follow-up (range, 4-8 years), 25% of the responders died compared with 71% of the nonresponders, a difference that approached statistical significance (P = 0.10). Two patients (13%) developed serious side effects that required the withdrawal of octreotide. CONCLUSIONS: Octreotide is an effective antitumor treatment in patients with progressive malignant gastrinoma. In approximately 50% of these patients octreotide has an antigrowth effect; treatment is associated with a low incidence of serious side effects compared with other antitumor treatments commonly used and, in contrast to many studies, the growth response is long-lasting. The results of the current study suggest that octreotide treatment should replace chemotherapy as the standard treatment for these patients, especially those patients with slow-growing tumors. Additional studies involving larger numbers of patients will be needed to determine a convincing effect on survival.