Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma.

Understanding the pathology of familial pancreatic carcinoma may provide important insights into pancreatic tumorigenesis. We now describe in detail the pancreatic pathology of an autosomal dominant pancreatic carcinoma kindred with distinct clinical, genetic, and pathologic manifestations differing from all other reported forms of sporadic or familial pancreatic neoplasia. Affected individuals develop a prodrome of diabetes mellitus, pancreatic exocrine insufficiency, and characteristic pancreatic imaging abnormalities. Eleven family members have undergone total pancreatectomy, revealing a unique and characteristic fibrocystic, lobulocentric pancreatic atrophy. This was patchy to diffuse in distribution and was invariably associated with a nesidioblastosis-like endocrine cell hyperplasia. All but one resected pancreas demonstrated glandular epithelial dysplasia: 10 had low-grade dysplasia (pancreatic intraductal neoplasia grade II of III or PanIN II) and seven also had high-grade dysplasia (pancreatic intraductal neoplasia grade III of III or PanIN III). Dysplasia was multifocal in small-to medium-sized duct-like structures within areas of acinar atrophy, microcystic change, and mucinous hyperplasia. Two pancreata had carcinomas of multiple and unusual histologic subtypes, including small cell undifferentiated carcinoma and giant cell anaplastic carcinoma. The findings in this kindred yield important information on a distinctive and previously unrecognized pancreatic cancer precursor. Recognition of this entity may help identify additional kindreds and perhaps the underlying genetic defect. As is the case for other familial cancers, the as yet unknown specific genetic defect may have wider implications for pancreatic cancer in general.

Neoplasms of the ampulla of vater with concurrent pancreatic intraductal neoplasia: a histological and molecular study.

Adenoma and adenocarcinoma of the ampulla of Vater are uncommon neoplasms of the gastrointestinal tract. Only one report has analyzed the relationship between ampullary adenocarcinoma and pancreatic intraductal neoplasia (PanIN), the precursor lesion of pancreatic adenocarcinoma. An association between PanIN and ampullary adenoma has not been reported previously. Case reports have documented the progression of PanIN to invasive pancreatic adenocarcinoma. We reviewed five resected ampullary adenoma and 17 ampullary adenocarcinoma cases and evaluated the pancreas for PanIN. Pancreatic sections from 35 autopsies were reviewed as a control group. Immunohistochemistry for overexpression of p53 and COX-2 proteins was performed in selected cases, as was PCR analysis for K-ras mutations. Follow-up clinical data were obtained. All 22 ampullary neoplasms were associated with PanIN, which was high grade in two (40%) adenoma cases and seven (41%) adenocarcinoma cases. In 16 (73%) evaluable cases, PanIN extended to the pancreatic resection margin; two of which had high grade PanIN. Among the autopsy controls eight (23%) had low-grade PanIN. Seven of the 22 ampullary cases but none of the autopsy controls had coexistent pancreatitis. A smoking history was present in two of four autopsy cases in which this history was available. Overexpression of the p53 and COX-2 proteins was present in only one case of high-grade PanIN. K-ras mutations were present in four of four of the PanIN lesions evaluated, including one autopsy case. Clinical follow-up revealed no progression of PanIN to invasive carcinoma in the remnant pancreas, although the follow-up period was too short to adequately assess that risk (an average of 3.8 y for adenoma cases and 2.5 y for adenocarcinoma cases). We conclude that adenomas and carcinomas of the ampulla are associated with PanIN, and often high-grade PanIN. Although its malignant potential has not been fully established, PanIN is underreported and often unrecognized. PanIN may be analogous to colorectal adenoma in that both are prevalent in the older adult population, but few progress to carcinoma.

Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.

BACKGROUND: Patients with ulcerative colitis and primary sclerosing cholangitis are at high risk for colonic dysplasia and cancer. This risk approaches 50% after 25 years of colitis. Ursodiol has been shown to protect against development of colorectal neoplasia in animal models. OBJECTIVE: To assess the relationship between ursodiol use and colonic dysplasia, the precursor to colon cancer, in patients with ulcerative colitis and primary sclerosing cholangitis. DESIGN: Cross-sectional study. SETTING: University medical center. PATIENTS: 59 patients with ulcerative colitis and primary sclerosing cholangitis who were undergoing colonoscopic surveillance for colonic dysplasia. MEASUREMENTS: Use of ursodiol was assessed in all patients. The presence or absence of colonic dysplasia was evaluated by colonoscopic surveillance. Other variables assessed were age at onset and duration of ulcerative colitis; duration of primary sclerosing cholangitis; Child-Pugh classification; and use of sulfasalazine, other 5-aminosalicylic acid preparations, prednisone, cyclosporine, azathioprine, and methotrexate. RESULTS: Ursodiol use was strongly associated with decreased prevalence of colonic dysplasia (odds ratio, 0.18 [95% CI, 0.05 to 0.61]; P = 0.005). The association between dysplasia and ursodiol use remained after adjustment for sex, age at onset of colitis, duration of colitis, duration of sclerosing cholangitis, severity of liver disease, and sulfasalazine use (adjusted odds ratio, 0.14 [CI, 0.03 to 0.64]; P = 0.01). Younger age at onset of colitis was associated with an increased risk for dysplasia. CONCLUSIONS: Ursodiol use appears to be associated with a lower frequency of colonic dysplasia in patients with ulcerative colitis and primary sclerosing cholangitis. A randomized trial investigating the chemoprotective effect of ursodiol in patients with ulcerative colitis may be warranted.

The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia.

Cyclooxygenase 2 (COX-2) overexpression has been described in sporadic colonic neoplasia, but its role in ulcerative colitis (UC) neoplastic progression remains unexplored. Although the specific role of cyclooxygenase in colonic neoplasia is uncertain, its inhibition by nonsteroidal anti-inflammatory drugs decreases the risk of sporadic colonic adenocarcinoma and causes regression of adenomas in familial adenomatous polyposis. To investigate the role of COX-2 in UC-associated neoplasia, we assessed COX-2 protein and mRNA expression throughout the spectrum of UC-associated neoplastic lesions in four total colectomy specimens, using immunocytochemistry and a novel TaqMan reverse transcriptase-polymerase chain reaction assay. The findings were correlated with DNA ploidy and inflammatory activity. We found COX-2 overexpression throughout the neoplastic spectrum in UC (P: < 0.0001, R:(2)=0.53), even in diploid samples that were negative for dysplasia. Overall, neoplastic change explained 53% of the variation in COX-2 expression, whereas inflammatory activity explained only 11%. COX-2 was overexpressed in all aneuploid samples and in 38% of diploid samples (P: = 0.0074). cDNA representational difference analysis was also performed and revealed that COX-2 mRNA was an up-regulated cDNA representational difference analysis difference product. COX-2 overexpression occurs early in UC-associated neoplasia, and the increase cannot be explained by inflammatory activity alone. The data suggest that COX-2-specific inhibitors may have a chemopreventative role in UC but the possibility that they could exacerbate UC inflammatory activity needs to be tested.

Primary alveolar soft part sarcoma of the stomach: a case report and review.

Alveolar soft part sarcoma (ASPS) is a rare tumor typically located in skeletal muscles and muscolofascial planes. Isolated cases of ASPS have been described as arising in the viscera. We report a mesenchymal tumor of the stomach in a 54-year-old Italian woman without evidence of primary neoplasm elsewhere ten years following the initial diagnosis. The histologic, histochemical, immunohistochemical, and electron microscopic findings were all consistent with the diagnosis of ASPS and allowed differentiating it from morphologically similar and more common tumors, such as metastatic renal cell carcinoma and paraganglioma. The patient is alive and well ten years following the initial presentation.

Effect of segment length on risk for neoplastic progression in patients with Barrett esophagus.

BACKGROUND: The increased risk for esophageal adenocarcinoma associated with long-segment (> or =3 cm) Barrett esophagus is well recognized. Recent studies suggest that short-segment (<3 cm) Barrett esophagus is substantially more common; however, the risk for neoplastic progression in patients with this disorder is largely unknown. OBJECTIVE: To examine the relation between segment length and risk for aneuploidy and esophageal adenocarcinoma in patients with Barrett esophagus. DESIGN: Prospective cohort study. SETTING: University medical center in Seattle, Washington. PATIENTS: 309 patients with Barrett esophagus. MEASUREMENTS: Patients were monitored for progression to aneuploidy and adenocarcinoma by repeated endoscopy with biopsy for an average of 3.8 years. Cox proportional hazards analysis was used to calculate adjusted relative risks and 95% Cls. RESULTS: After adjustment for histologic diagnosis at study entry, segment length was not related to risk for cancer in the full cohort (P > 0.2 for trend). When patients with high-grade dysplasia at baseline were excluded, however, a nonsignificant trend was observed; based on a linear model, a 5-cm difference in segment length was associated with a 1.7-fold (95% CI, 0.8-fold to 3.8-fold) increase in cancer risk. Among all eligible patients, a 5-cm difference in segment length was associated with a small increase in the risk for aneuploidy (relative risk, 1.4 [CI, 1.0 to 2.1]; P = 0.06 for trend). A similar trend was observed among patients without high-grade dysplasia at baseline. CONCLUSIONS: The risk for esophageal adenocarcinoma in patients with short-segment Barrett esophagus was not substantially lower than that in patients with longer segments. Although our results suggest a small increase in risk for neoplastic progression with increasing segment length, additional follow-up is needed to determine whether the patterns of risk occurred by chance or represent true differences. Until more data are available, the frequency of endoscopic surveillance should be selected without regard to segment length.

Evaluation of a subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonic acid oil derived from Mortierella alpina in rats.

Arachidonic acid oil (ARA-oil) derived from the fungus Mortierella alpina for use in infant nutrition was tested in a subchronic (13-week) oral toxicity study in rats, preceded by an in utero exposure phase. The ARA-oil was administered as admixture to the rodent diet at dose levels of 3000 ppm, 15,000 ppm and 75,000 ppm. An additional high-dose group received 75,000 ppm ARA-oil in combination with 55,000 ppm fish oil containing docosahexaenoic acid (DHA), at a ratio of ARA to DHA, comparable to the ratio in mother's milk of 2:1. The total levels of fat in each diet were kept constant by adding the appropriate amounts of corn oil. A concurrent control group received 130,000 ppm corn oil in the diet. An additional carrier control group was fed unsupplemented rodent diet. Administration of the test substances from 4 weeks prior to mating, throughout mating, gestation, lactation of parental (F(0)) animals and weaning of the F(1) pups did not affect fertility or reproductive performance, nor the general condition of pups, viability, sex ratio or number of pups. Pup weight gain in the ARA/DHA-oil group was lower than the controls administered equal amounts of corn oil. In the subsequent subchronic study survival, clinical signs, body weight gain and food consumption were not adversely affected by the test substances. Ophthalmoscopic examination did not reveal any treatment-related changes. There were no treatment-related effects observed up to dietary test substance concentrations of 15,000 ppm. The following statistically significant differences were found in the ARA high-dose group and /or in the ARA/DHA group compared to the corn oil control group: decreased alkaline phosphatase activity, decreases in cholesterol, triglycerides and phospholipids concentrations, increased creatinine and urea concentrations. Furthermore, these groups showed increased adrenal, spleen and liver weights. The incidence of hepatocellular vacuolation was increased in females of the ARA high-dose group and the ARA/DHA group. Oil droplets were observed in the mesenteric lymph nodes and in the intestinal villi in the ARA high-dose group and the ARA/DHA group. In addition, lipogranulomas were observed in the mesenteric lymph nodes in these groups. The observed changes in the high-dose groups may be effects of the high intake of high-fat levels, rather than specific effects of the ARA-oil. The no-observed-effect level in this study was placed at 15,000 ppm ARA-oil. This level is equivalent to approximately 970mg ARA-oil/kg body weight/day.

Histopathology of reflux-induced esophageal and supraesophageal injuries.

As many as half of patients who have symptoms and objective evidence of gastroesophageal reflux disease (GERD) will have normal mucosa or only hyperemia at endoscopy. Because inflamed esophageal mucosa may appear normal endoscopically, and because hyperemia may or may not reflect histologic espophagitis, biopsy to document tissue injury in symptomatic patients with these minimal endoscopic findings may be helpful. Reflux may induce inflammation in the squamous mucosa of the esophagus, but in many patients only hyperplasia of the epithelium is seen. This hyperplasia is defined by a basal zone that exceeds 15% of the thickness of the mucosa and subepithelial papillae that exceed 67% of the thickness of the mucosa. Because these changes may be present normally in the distal 2.5 cm of the esophagus, and because they may be distributed over the distal 8 cm in a patchy fashion, multiple biopsies taken more than 2.5 cm above the esophagogastric junction are necessary to detect them reliably. Supraesophageal complications of GERD include posterior laryngitis, inflammatory polyp of the larynx (contact ulcer or laryngeal granuloma), subglottic stenosis and laryngeal squamous cell carcinoma.

The pathologic spectrum of gastrointestinal and hepatic histoplasmosis.

We characterized the pathologic spectrum of lesions in gastrointestinal and hepatic histoplasmosis by studying cases of disseminated disease in immunocompromised and immunocompetent patients from endemic and nonendemic areas. We evaluated 56 specimens from 52 patients with H&E and silver stains. Of these patients, 43% presented with gastrointestinal rather than pulmonary symptoms. Thirty-one percent had gastrointestinal lesions, 10% had liver lesions, and 43% had both. Gross gastrointestinal features included ulcers (49% of patients), nodules (21%), hemorrhage (13%), obstructive masses (6%) and normal mucosa (23%). Microscopic gastrointestinal findings included diffuse lymphohistiocytic infiltration (83%), ulceration (45%), lymphohistiocytic nodules (25%), or minimal inflammatory reaction (15%) but only rare well-formed granulomas (8.5%). The most common hepatic finding was portal lymphohistiocytic inflammation; discrete hepatic granulomas were seen in less than 20% of involved livers. The pathologist must be aware of the broad range of gastrointestinal and hepatic lesions produced by histoplasmosis and, in particular, that well-formed granulomas are rare. Given the appropriate clinical context, histoplasmosis should be considered in both immunocompetent and immunocompromised patients, regardless of pulmonary symptoms, in nonendemic as well as endemic areas.

Safety and toxicity of nonoxynol-9 gel as a rectal microbicide.

BACKGROUND AND OBJECTIVES: Methods of HIV and STD prevention, which can be controlled by the receptive partner, are a high priority for research and development. Studies on the safety of Nonoxynol-9 (N-9) on the vaginal mucosa have yielded conflicting results. No Phase I study has evaluated the effect of N-9 on the rectal mucosa. GOALS: To assess the safety of 52.5 mg of N-9 in a 1.5-g gel when applied one to four applicators per day to the rectum and penis. STUDY DESIGN: The study included 25 HIV-negative and 10 HIV-positive, monogamous gay male couples in which each partner was exclusively insertive or receptive while using N-9 gel. Each participant served as his own control during placebo gel use compared to during N-9 gel use. Receptive partners underwent anoscopic examination after 1 week of placebo use and after 2, 5, and 6 weeks of N-9 gel use, with rectal biopsies obtained after 1 week of placebo use and after 5 and 6 weeks of N-9 gel use. Insertive partners had safety monitoring after 1 week of placebo use and after 2, 5, and 6 weeks of N-9. RESULTS: No rectal ulcers were detected; superficial rectal erosions were noted in two HIV-negative participants. Abnormal or slightly abnormal histologic abnormalities of rectal biopsies were detected in 31 (89%) receptive participants after N-9 gel use compared to 24 (69%) participants after 1 week of placebo gel use. Meatal ulceration, not caused by herpes simplex virus, was detected in one HIV-negative participant. CONCLUSION: Low-dose N-9 gel was not associated with macroscopic rectal and penile epithelial disruption or inflammation, but histologic abnormalities were commonly observed during N-9 gel as well as during placebo gel use.

Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis.

Patients with long-standing ulcerative colitis (UC) are at increased risk for colon cancer. These cancers are thought to arise from preexisting dysplasia in a field of abnormal cells that often exhibits aneuploidy and p53 abnormalities. Using dual color fluorescence in situ hybridization with centromere probes and locus-specific arm probes for chromosomes 8, 11, 17, and 18, we demonstrate that chromosomal instability (CIN) is present throughout the colon of UC patients with high-grade dysplasia or cancer. In rectal biopsies that were negative for dysplasia, abnormalities in chromosomal arms, especially losses, were most common, whereas centromere gains were most common in dysplasia and cancer. The frequency and type of abnormalities varied between the chromosomes examined; chromosome 8 was the least affected, and 17p loss was found to be an early and frequent event. Chromosomal arm instability showed 100% sensitivity and specificity for distinguishing control biopsies from histologically negative rectal biopsies from these UC patients, raising the possibility that a screen for CIN might detect the subset of UC patients who are at greatest risk for development of dysplasia and cancer. These results suggest that dysplasia and cancer in UC arise from a process of CIN that affects the entire colon; this may provide the mutator phenotype that predisposes to loss of tumor suppressor genes and evolution of cancer.

Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer.

BACKGROUND: Pancreatic cancer, the fourth most common cause of cancer death in the United States, is hereditary in an estimated 10% of cases. Surveillance of patients with a familial predisposition for pancreatic cancer has not been systematically evaluated. OBJECTIVE: To develop a surveillance program that can identify and treat patients who have precancerous conditions of the pancreas and a family history of pancreatic cancer. DESIGN: Prospective cohort study. SETTING: University medical center. PATIENTS: 14 patients from three kindreds with a history of pancreatic cancer. INTERVENTIONS: Endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography (ERCP), spiral computed tomography, and serum carcinoembryonic antigen and CA19-9 analysis were performed in all patients. Four affected patients were tested for the K-ras mutation. MAIN OUTCOME MEASUREMENT: Pancreatic dysplasia was determined by histologic evaluation. RESULTS: Seven of the 14 patients were believed to have dysplasia on the basis of clinical history and abnormalities on endoscopic ultrasonography and ERCP and were referred for pancreatectomy. All 7 patients had histologic evidence of dysplasia in pancreatectomy specimens. Findings on endoscopic ultrasonography were subtle, nonspecific, and similar to those seen in patients with chronic pancreatitis. Findings on ERCP ranged from mild and focal side-branch duct irregularities and small sacculations to main-duct strictures and grapelike clusters of saccules. Some of these changes are typical of chronic pancreatitis, but others are more distinctive. Spiral computed tomography and serum tumor markers had low sensitivity in the detection of pancreatic dysplasia. Analysis for the K-ras mutation yielded positive results in 3 of 4 patients with dysplasia. CONCLUSIONS: Thorough screening of patients with a family history of pancreatic cancer is feasible. Clinical data combined with imaging studies (endoscopic ultrasonography and ERCP) can be used to identify high-risk patients who have dysplasia. The role of molecular genetic testing is uncertain at this time.

Leukotrienes in ulcerative colitis: results of a multicenter trial of a leukotriene biosynthesis inhibitor, MK-591.

BACKGROUND & AIMS: Leukotrienes (LTs) are believed to be important in the pathogenesis of ulcerative colitis (UC). The aim of this study was to determine whether inhibition of LT biosynthesis with a 5-lipoxygenase inhibitor (MK-591) induces remission in patients with mild to moderate UC. METHODS: One hundred eighty-three patients with mild to moderately active UC enrolled in this randomized parallel group, double-blind study. Patients received placebo or MK-591 at a dose of 12.5, 50, or 100 mg twice daily for 8 weeks. A subset of patients underwent rectal dialysis to determine LTB4 concentration. RESULTS: MK-591 reduced LTB4 concentrations in rectal dialysate at the final determination. The median percent of baseline LTB4 concentration for 100 mg taken twice daily was 1.4% (n = 4); for 50 mg taken twice daily, 16.5% (n = 6); for 12.5 mg taken twice daily, 12% (n = 6); and for placebo, 78% (n = 6). There was no correlation between reduction of LTB4 and remission. Patients in remission at week 8 were as follows: placebo, 9 of 44 (20.5%); 100 mg taken twice daily, 11 of 43 (25.6%); 50 mg taken twice daily, 8 of 49 (16.3%); and 12.5 mg taken twice daily, 4 of 47 (8.5%) (P > 0.10). CONCLUSIONS: MK-591 markedly inhibited LT biosynthesis, but it did not differ significantly from placebo in clinical efficacy. Inhibition of LT biosynthesis was not effective as a single therapeutic modality in active UC.

Endoscopic fluorescence detection of high-grade dysplasia in Barrett's esophagus.

BACKGROUND & AIMS: Early detection and treatment of esophageal cancer in Barrett's esophagus may improve patient survival if dysplasia is effectively detected at endoscopy. Typically, four-quadrant pinch biopsy specimens are taken at 2-cm intervals. This study was conducted to determine whether laser-induced fluorescence spectroscopy could be used to detect high-grade dysplasia in patients with Barrett's esophagus. METHODS: Four hundred ten-naonometer laser light was used to induce autofluorescence of Barrett's mucosa in 36 patients. The spectra were analyzed using the differential normalized fluorescence (DNF) index technique to differentiate high-grade dysplasia from either low-grade or nondysplastic mucosa. Each spectrum was classified as either premalignant or benign using two different DNF indices. RESULTS: Analysis of the fluorescence spectra from all patients collectively using the DNF intensity at 480 nm (DNF480) index showed that 96% of nondysplastic Barrett's esophagus samples were classified as benign, all low-grade dysplasia samples as benign, 90% of high-grade dysplasia samples as premalignant, and 28% of low-grade with focal high-grade dysplasia samples as premalignant. Using the two DNF indices concurrently, all patients with any high-grade dysplasia were classified correctly. CONCLUSIONS: Laser-induced fluorescence spectroscopy has great potential to detect high-grade dysplasia in Barrett's esophagus when using the DNF technique.

Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis.

Microsatellite instability (MIN) has been detected in many cancer types; however, recently we also observed it in the nonneoplastic but inflammatory setting of pancreatitis. Consequently, we sought to examine whether MIN was present in another inflammatory condition, ulcerative colitis (UC). MIN was found in 50% of UC patients whose colonic mucosa was negative for dysplasia, 46% of those with high-grade dysplasia, and 40% of those with cancer but in none of the ischemic or infectious colitis controls (P<0.03). Thus, UC patients may have MIN within mucosa that has no histological evidence of neoplastic change. MIN in this setting may reflect the inability of DNA repair mechanisms to compensate for the stress of chronic inflammation, and may be one mechanism for the heightened neoplastic risk in UC.