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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.

We describe seven patients (three men, four women; ages 27-78) who presented with signs of intestinal ischemia requiring surgical intervention. In each case, the resected colon, small bowel, or both showed striking phlebitis and venulitis affecting veins of the bowel and mesentery and resulting in ischemic injury of the bowel. In each case, this vasculopathy was the only demonstrable cause of ischemia. Arteritis involving the bowel or the mesentery was not found in any patient, and none had clinical evidence or a history of extraintestinal vasculitis. The composition of the inflammatory infiltrate was variable; in four patients, it was predominantly lymphocytic, in two necrotizing and in one lymphocytic/granulomatous. In addition, three patients also had myointimal hyperplasia of the affected mesenteric veins. Six of seven patients recovered uneventfully after surgery, suggesting a self-limited or indolent process, and the seventh died of an unknown cause. We propose the name mesenteric inflammatory veno-occlusive disease (MIVOD) to describe this unusual and previously unrecognized cause of intestinal ischemia. Its etiology is unknown, and MIVOD may represent a precursor of the recently described idiopathic myointimal hyperplasia of mesenteric veins.

Investigation supports the hypothesis that colorectal neoplasms arise by a sequence of events known as neoplastic progression or tumor progression. Evidence shows that the majority, if not all, colorectal adenocarcinomas arise from benign precursor lesions composed of dysplastic epithelium. The dysplastic epithelium may form a polypoid mass, and is designated an adenoma, or may be present in mucosa without a macroscopically visible lesion, whereas it is sometimes called a flat adenoma. Precursor dysplastic lesions rarely progress to invasive adenocarcinoma and later metastasis. Studies supporting tumor progression hypothesis in colorectal neoplasia are derived from histopathologic, clinical, animal model, and molecular biologic spheres of investigation, each of which is reviewed.

The objective of the present study was to determine whether abnormal epithelial DNA content (aneuploidy) in colonic biopsy specimens from ulcerative colitis (UC) patients correlated with and predicted histological progression to dysplasia. Aneuploidy was absent in 20 low-cancer risk patients. In 81 high-cancer risk patients aneuploidy correlated significantly with the severity of histological abnormality (negative, indefinite, dysplasia, or cancer). Statistically our data suggest that many more biopsy specimens than are usually taken are needed to detect focal dysplastic lesions. Prospective study of 25 high risk patients without dysplasia revealed 5 with aneuploidy, all of whom progressed to dysplasia in 1-2.5 years, whereas 19 patients without aneuploidy did not progress to either aneuploidy or dysplasia within 2-9 years. Our data indicate that aneuploidy in mucosal biopsy specimens correlates with histological grade and identifies a subset of patients without dysplasia who are more likely to develop it. It was concluded that more frequent and extensive colonoscopic surveillance of this minority subset of high risk patients and less frequent surveillance in the remaining majority may reduce cost and detect more curable lesions.

Neoplastic progression in patients with chronic ulcerative colitis (UC) is characterized by the development of epithelial dysplasia, which is accompanied by genetic abnormalities that can be detected by flow cytometric and molecular biologic methods. Distribution of and correlation between histologic abnormalities, DNA content, and loss of heterozygosity for a p53 allele (p53 LOH) in the colons of nine UC patients were analyzed. Loss of a p53 allele was found in 85% (22/26) of biopsy specimens classified histologically as carcinoma, 63% (25/40) of biopsy specimens with high grade dysplasia, and 33% (7/21) of biopsy specimens with low grade dysplasia. Loss of heterozygosity for p53 was also found in 9% (5/57) of biopsy specimens indefinite for dysplasia and in 1/18 biopsy specimens negative for dysplasia, showing that this genetic change may occur early in the histological progression towards carcinoma. Aneuploid DNA contents were more common than p53 LOH in regions with negative, indefinite or low grade dysplastic histology; moreover, p53 LOH was detected only in aneuploid cells and not in diploid epithelium. Aneuploidy alone was not as specific a marker for the concomitant presence of dysplasia or carcinoma in a biopsy sample as aneuploidy combined with p53 LOH. These findings show that aneuploidy may precede both p53 LOH and epithelial dysplasia. Two UC patients' colons contained geographically separated clones of cells with different aneuploidies that also showed loss of different p53 alleles, suggesting that neoplasia may arise within different populations of cells in separate areas of the same colon.

To determine whether or not flow-cytometric evidence of aneuploidy and increased G2/tetraploid fractions predispose to neoplastic progression in Barrett's esophagus, 62 patients with Barrett's esophagus were evaluated prospectively for a mean interval of 34 months. Nine of 13 patients who showed aneuploid or increased G2/tetraploid populations in their initial flow-cytometric analysis developed high-grade dysplasia or adenocarcinoma during follow-up, none of the 49 patients without these abnormalities progressed to high-grade dysplasia or cancer ( P

Barrett's esophagus is a condition in which the normal stratified squamous epithelium is replaced by metaplastic columnar epithelium that predisposes to the development of esophageal adenocarcinoma. Neoplastic progression in Barrett's esophagus occurs by a multistep process associated with genomic instability and the development of aneuploid cell populations. p53 protein overexpression and allelic deletions on chromosome 17p have been shown to be present in some Barrett's adenocarcinomas, but the stage in neoplastic progression at which p53 protein overexpression develops has not been investigated. To determine the stages in neoplastic progression at which p53 protein overexpression could be detected, biopsy specimens from patients with Barrett's esophagus at all stages of histological progression from Barrett's metaplasia negative for dysplasia to esophageal adenocarcinoma were investigated using a multiparameter flow-cytometric assay. p53 protein overexpression was found in 1 of 21 patients (5%) with Barrett's metaplasia negative for dysplasia, 2 of 13 patients (15%) with Barrett's metaplasia with abnormalities in the indefinite/low-grade dysplasia range, 5 of 11 patients (45%) with high-grade dysplasia, and 8 of 15 patients (53%) with Barrett's adenocarcinoma (P less than 0.01). p53 protein overexpression was found in 9% of patients with Barrett's esophagus who had neither high-grade dysplasia nor adenocarcinoma. Whether or not patients whose biopsy specimens show p53 protein overexpression are at increased risk for progression to adenocarcinoma can be determined by prospective endoscopic surveillance.

Flow cytometry was used to detect the presence and assess the distribution of aneuploid cell populations in eight proctocolectomy specimens from patients with ulcerative colitis. Mucosal samples were taken according to a systematic protocol for flow cytometry, the surrounding tissue was examined histologically, and the distributions of flow cytometric and histologic abnormalities were "mapped" within each resected colon. Two resection specimens that were negative for dysplasia lacked aneuploid cell populations. Four resection specimens with final case diagnoses of dysplasia or Dukes' stage A carcinoma had 1–5 regions of aneuploidy or increased 4N (G2/ tetraploid) cell populations located in discrete areas of the colon. Two specimens with dysplasia or Dukes' stage C carcinoma each had 14–15 different, often overlapping, regions of aneuploidy or increased 4N (G2/tetraploid) cell populations involving large portions of the colonic mucosa. Analysis of the DNA content of the invasive portion of the tumor from the specimen with a Dukes' stage C carcinoma showed a single aneuploid cell population. The results show that single or multiple aneuploid cell populations are often present in colons resected for ulcerative colitis with dysplasia or early cancer. The distribution of these aneuploid cell populations suggests that each represents a clone of cells that has expanded to occupy a discrete region of colonic mucosa. Additional genetic errors may result in multiple aneuploid cell populations that may be associated with an increased risk of developing cancer. These data, therefore, are consistent with the hypothesis that genomic instability and clonal evolution are associated with the progression to dysplasia and carcinoma in ulcerative colitis. Because flow cytometry can measure aneuploid cell populations in colonoscopic mucosal biopsies, it may prove to be complementary to histology for detecting patients with ulcerative colitis who are at risk for neoplastic progression.

To assess the incidence of histological esophagitis in infants

Cancer of the colon and rectum is the second most common cancer in men and women in North America. Early diagnosis results in detection of early stage tumours with a high probability of cure. Several studies document the efficacy of screening for the early detection of colorectal cancer; however, its incidence is so high chat screening the entire older adult population is not feasible. Thus, attempts have been made to focus screening on patients at higher than average risk for colorectal carcinoma; these include patients with predisposing conditions or premalignant lesions of the colon. Common predisposing conditions include previous resection of an adenoma or carcinoma, a family history of colorectal carcinoma, and ulcerative colitis of more than IO years' duration. The most important premalignant lesion is the colonic adenoma. Such lesions must be removed in their entirety and examined histologically to exclude the presence of carcinoma. Approximately 51 % of patients with colonic adenomas removed by endoscopic polypectomy will be found to have a carcinoma within the polyp. If a pedunculated adenoma containing invasive carcinoma can be removed with a clear stalk margin, the risk of nodal metastasis is very low, probably less than 2%. In contrast, sessile lesions containing carcinoma already show invasion into the submucosa of the underlying bowel wall with a significant risk of nodal metastasis. Segmental colonic resection is rarely necessary for management of the patient with carcinoma arising in a pedunculated adenoma, but it is often justified for the patient with carcinoma in a sessile lesion. Dysplasia arising in ulcerative colitis is another important premalignant lesion that can be detected by colonoscopy with biopsy. The presence of high grade dysplasia in a patient with longstanding ulcerative colitis is an indication for colectomy.

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.

A 44-year-old woman with a large benign cartilaginous tumor (chondroma) of the liver is presented. After being followed up by computed tomography for 6 years and with imagining evidence for a recent increase in its size, this asymptomatic tumor was successfully removed at surgery. The resected tumor proved to be chondroma, a benign cartilaginous tumor. A review of the literature showed no previous reports of this type of hepatic neoplasm.

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.

Summary 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.

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.

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 HE 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.

A study was conducted to determine whether laser-induced fluorescence could detect high grade dysplasia in Barrett's esophagus. Four-hundred-ten nm laser light was used to induce autofluorescence of Barrett's mucosa in 36 patients during routine endoscopy. The spectra were analyzed using the Differential Normalized Fluorescence (DNF) Index technique to differentiate high grade dysplasia from either low grade or non-dysplastic mucosa. Each spectrum was classified as either premalignant or benign using two different DNF indices. Analyzing the fluorescence spectra from all patients using one DNF Index, 96% of non- dysplastic Barrett's samples classified as benign tissue. All low grade dysplasia samples classified as benign. Ninety percent of high grade dysplasia samples classified as premalignant. Twenty-eight percent of mixed low grade/focal high grade dysplasia samples classified as premalignant. In summary, high grade dysplasia in Barrett's esophagus patients can be detected by endoscopic laser-induced fluorescence spectroscopy using differential normalized fluorescence technique.

Background & Aims: The DNA mismatch repair gene human MSH2 shows a germline mutation in certain family members with hereditary nonpolyposis colorectal cancer. There is an increased risk of colorectal cancer in patients with ulcerative colitis (UC) with extensive disease of >8 years' duration; however, specific constitutional predisposing genetic abnormalities have not yet been identified. Methods: A germline human MSH2 abnormality was sought in patients with UC with high-grade dysplasia or carcinoma. Results: After direct sequencing of exon 13 and flanking regions of human MSH2 , a germline T to C substitution was shown at the −6 intronic splice acceptor site of exon 13. This substitution was found in 14 of 53 patients with UC with high-grade dysplasia or carcinoma (26%) compared with 4 of 36 high-risk patients with UC without dysplasia or cancer (11%) ( P ≤ 0.04) and in 7 of 80 healthy adult blood donors (9%) ( P ≤ 0.003). The patients with UC who had the substitution were three times more likely to develop neoplasia than patients with UC who did not carry it. Conclusions: An intronic splice-site substitution in the human MSH2 gene is present in the general population but may predispose to cancer in the setting of UC.

In Barrett's esophagus the normal stratified squamous epithelium lining the esophagus becomes replaced by metaplastic columnar epithelium containing goblet cells; it develops as a complication of chronic gastroesophageal reflux disease and predisposes the patient to adenocarcinoma. The frequency with which it leads to adenocarcinoma is not established with certainty, but the reported prevalence averages approximately 10% when the diagnosis of Barrett's esophagus is first made. The estimated incidence of adenocarcinoma varies from one in 152 to one in 441 cases per patient year, or a 30- to 125-fold excess risk. Esophageal adenocarcinoma arises only in patients with metaplastic columnar epithelium. Dysplasia precedes adenocarcinoma in Barrett's esophagus and arises from the metaplastic epithelium; it has been proposed as a marker for detecting patients at high risk for developing carcinoma. Problems with the use of dysplasia as a marker for cancer risk include difficulty in differentiating it from reactive change, variability in diagnosis and grading between observers and when the same observer interprets the sections on different occasions, and lack of understanding of its natural history. Methods other than dysplasia for detecting patients at highest risk for developing carcinoma have been sought, but flow cytometric analysis of DNA content is the only one proven to be valuable to date. Flow cytometric abnormalities correlate well with histological progression in Barrett's esophagus. The prevalence of elevated S phase and G2/tetraploid fractions and of aneuploid cell populations increases with histological progression from metaplasia to indefinite/low grade dysplasia to high grade dysplasia and cancer. Flow cytometric abnormalities in endoscopic biopsy specimens identify those patients with a higher risk of progression to high grade dysplasia or adenocarcinoma.

Background/Aims: In long-term extensive ulcerative colitis, aneuploidy occurs earlier and loss of heterozygosity for p53 ( p53 LOH) later during histological progression towards carcinoma. This study determined the time of onset of p53 mutation in this progression. Methods: We developed a rapid, sensitive screening assay for p53 mutations at codon 248. The geographic distribution of this p53 mutation was mapped in two fresh colectomy specimens with mutations of codon 248 (1 cancer, 1 dysplasia) and correlated with patterns of clonal expansion, histological progression, and allelic loss. Numerous samples from throughout both colons were analyzed (216 for histology, 142 for DNA content, 104 for mutation, and 41 for p53 LOH). Results: p53 mutation correlated highly with histological grade and was distributed more extensively than p53 LOH. Mutation, but not LOH, was also found in diploid, nondysplastic colonic mucosa adjacent to dysplastic areas. Conclusions: These findings suggest that p53 mutation appears to be an early genetic event that precedes p53 LOH. The very close correlation of p53 mutation with aneuploidy ( P > 0.0001) emphasizes the role of normal p53 at the G 1 checkpoint to help prevent entry of genetically damaged cells into the cell cycle.

A means to monitor intestinal allografts will be crucial for the future success of small bowel transplantation. We have previously demonstrated the ability of high-frequency ultrasound (US) to diagnose porcine intestinal ischemia in vitro. The aim of this study was to compare the histologic appearance of normal porcine small bowel versus bowel undergoing acute rejection, using 8.5-MHz US images. We allowed porcine heterotopic small bowel allograft transplants to reject and then removed, at scheduled intervals from postoperative day 0 to 12, specimens of both the transplanted bowel and the native bowel. We examined the tissues in vitro with an 8.5-MHz linear array US system then studied them histologically. Histologically, the earliest changes of rejection occurred at days 4 to 5, with mild submucosal edema, endotheliitis, and vasculitis affecting the small vessels; the mucosa remained normal. By days 7 to 8, the submucosal endotheliitis became more prominent, with focal thrombosed small vessels; the mucosa now appeared abnormal with flattened villi, erosions, and necrosis. By days 10 to 12, marked submucosal edema, vasculitis, endotheliitis, and necrotic mucosa were present. Ultrasonically, normal intestinal wall has five wall layers, corresponding to mucosa, submucosa, muscularis propria, and subserosal fat. The US criteria for abnormality were loss of folds, decreased numbers of echo layers, discontinuity of layers, and a homogeneous appearance. Using these US criteria, blinded observers differentiated normal from abnormal bowel wall after transplantation with a sensitivity of 84% and a specificity of 81%. Most of the errors occurred with the day 4 and 5 specimens, which appeared nearly normal on US. This study demonstrates that US can potentially differentiate normal from abnormal changes after small bowel transplantation in vitro, and may be useful in monitoring the transplanted intestine. Abnormal US findings might then warrant a biopsy procedure. Further studies are necessary to fully evaluate the potential clinical use of US in intestinal transplantation.

To evaluate the use of ultrasound (US) to detect intestinal wall ischemia, we isolated segments of jejunum on single vascular pedicles in five piglets. We sequentially clamped these segments in intervals of 0 to 6 h, reperfused them for 24 h, and then examined them in vitro histologically and with an 8.5 MHz US scan. All segments were grossly viable except those with 6 h of ischemia. Histologically, mild submucosal edema developed after 1 to 2 h of ischemia; after 3 to 4 h, mucosal necrosis, loss of folds, worsening submucosal edema, and prominent neutrophilic infiltration occurred; after 5 to 6 h, severe mucosal necrosis with hemorrhage and submucosal edema was present. Ultrasonically, we saw five wall layers in the control group corresponding to mucosa, submucosa, muscularis propria, and subserosal fat. After mild (1 to 2 h) ischemia, all layers were present except for a discontinuity in layer 3. After moderate (3 to 4 h) ischemia, the five layers persisted but with a markedly thickened submucosal layer, reduced echogenicity, and flattened mucosal folds. With severe (5 to 6 h) ischemia, we observed a loss of all normal layers with no discernible architecture. Using these US criteria, blinded observers were able to differentiate normal/mild from moderate/severe ischemia with a sensitivity and specificity of 100%. These data suggest that US can differentiate, in vitro, normal from moderate and severe degrees of intestinal wall ischemia that correlates well with the histological appearance. Endoscopic US or surgically implantable US probes can potentially help diagnose clinical intestinal wall ischemia.

Nonthrombotic occlusion or stenosis of the mesenteric veins is a rare cause of intestinal ischemia that usually occurs in association with systemic vasculitis. The current report includes four male patients with segmental ischemic colitis caused by idiopathic myointimal hyperplasia in the small mesenteric veins and their intramural branches; neither vasculitis nor arterial involvement were present. Three of the four patients were less than or equal to 38 years of age; the fourth was 67. All four patients were previously healthy and had no history of drug use of any kind. Clinical findings included abdominal pain, diarrhea, bloody stools, and colonic strictures discovered by barium enema. The intima of the mesenteric and intestinal mural veins was focally thickened by a marked increase in cells and matrix between the endothelium and internal elastic lamina, whereas the vessel walls external to the thickened intima appeared normal. Histochemistry and immunoreactivity with antibodies to muscle-specific actins (HHF-35) disclosed that the intimal thickening was caused by proliferation of smooth muscle cells in a proteoglycan matrix. All patients recovered completely after segmental resection of the ischemic portion of the colon and had no recurrence of intestinal symptoms on follow-up of up to 7 years. These unusual venous lesions do not appear to have been previously described; their etiology and pathogenesis remain unknown.

Mutations in the first exon of the c-Ki-ras protooncogene were analyzed in carcinomas and dysplasias from patients with sporadic colon cancer and chronic ulcerative colitis by a combination of histological enrichment, cell sorting, polymerase catalyzed chain reaction, and direct sequencing. In contrast to sporadic colon carcinomas, where 52% (11 of 21) contained mutations in codon 12, only 1 of 28 samples of ulcerative colitis associated carcinoma or dysplasia contained a c-Ki-ras mutation, despite the presence of aneuploid cell populations. These results suggest that a different genetic pathway for tumor progression may exist between sporadic colon carcinoma and carcinomas arising in chronic ulcerative colitis.

Five patients with maturity-onset diabetes mellitus and hepatomegaly were studied. This group included moderately obese females in whom hepatomegaly and abnormal liver studies were associated with a marked elevation in the erythrocyte sedimentation rate. Liver biopsies from all 5 showed fatty steatosis and pericentral fibrosis. In 3 of the 5, fibrous bridging between central veins and portal tracts was present. Collagen surrounded swollen hepatocytes, some of which contained intracellular hyalin indistinguishable from Mallory's hyalin. Polymorphonuclear neutrophils and regenerating nodules were not present. None of the patients had a history of alcohol use, and in 2 followed closely for 2 yr, alcohol was never detected in random blood samples. The recognition of this morphologic lesion may help to clarify the significance of this finding as an intermediate lesion between fatty steatosis and cirrhosis in diabetics.

Barrett's esophagus develops as a complication of chronic gastroesophageal reflux and predisposes patients to the development of dysplasia and adenocarcinoma of the esophagus. Because light microscopy of dysplasia in Barrett's esophagus shows diminished or absent mucus, we used transmission electron microscopy to compare cytoplasmic organelles required for mucus production in dysplastic and nondysplastic esophageal columnar epithelium. These observations of the rough endoplasmic reticulum, Golgi apparatus, and secretory granules were correlated with histologic interpretations and flow cytometric measurements of abnormalities of DNA content. Ultrastructural abnormalities included depletion and alteration of organelles required for mucus biosynthesis. These abnormalities often were accompanied by cells with markedly distended rough endoplasmic reticulum and massive accumulation of cytoplasmic glycogen aggregates. All 9 patients who had Barrett's dysplasia with or without early adenocarcinoma had ultrastructural abnormalities, as did 3 of 8 patients whose biopsy histology was indefinite for dysplasia. Abnormalities measured by flow cytometry correlated well with the presence of these ultrastructural aberrations. All 9 patients with Barrett's dysplasia with or without early adenocarcinoma had abnormalities observed by electron microscopy and aneuploidy or increased G2ltetraploid fractions measured by flow cytometry. Two of the 3 patients whose biopsies were indefinite for dysplasia and who had ultrastructural abnormalities also had aneuploidy or increased G 2 /tetraploid fractions. Neither ultrastructural nor flow cytometric abnormalities were found in the remaining 5 patients whose biopsies were indefinite for dysplasia, in 19 of 22 patients with Barrett's specialized metaplasia, or in any of the 7 patients with gastroesophageal reflux disease without Barrett's specialized meta plasia. Two of the 22 patients with Barrett's specialized metaplasia had distended rough endoplasmic reticulum in rare cells, and one other had an aneuploid cell population. We conclude that neoplastic progression in Barrett's esophagus is associated with abnormalities of cytoplasmic organelles required for mucus production. With few exceptions, these ultrastructural aberrations correspond to the presence of dysplasia or of aneuploidy or increased G 2 /tetraploid fractions. Electron microscopy and flow cytometry detect abnormalities associated with the development of dysplasia and cancer in Barrett's esophagus that may be biologically significant.

Epithelioid hemangioendothelioma (EH) is a vascular neoplasm that occurs predominantly in soft tissue and is not infrequently misdiagnosed as an epithelial neoplasm or angiosarcoma. Only a few cases of hepatic EH have been described, and a relationship to oral contraceptive (OC) use in patients with the hepatic lesions has not generally been recognized. We present a series of five patients with malignant epithelioid hemangioendothelioma of the liver. Confirmation of the endothelial origin of these tumors was provided by positive immunoperoxidase staining for Factor-VIII-related antigen in the four cases studied by that technique, and by the demonstration of Weibel-Palade bodies in two tumors examined by electron microscopy. All five patients were young women (mean age 33 years) and all five gave a history of OC use of 4-7 years' duration. The clinical course varied from indolent but progressive to rapid death. One patient who underwent resection of the primary tumor has survived 3 years without evidence of disease, and one patient with metastatic disease who was treated with radiation and chemotherapy has survived for 8 years with disease. Three patients with extrahepatic spread have died of the tumor. Early diagnosis of this distinctive tumor might offer the hope of salvage by resection or liver transplantation.

Four case reports of patients with tumors of the esophagus resembling those of salivary gland origin are presented with a review of the cases published to date. These tumors arise in the submucosal glands in the esophagus and are histologically similar to adenoid cystic and mucoepidermoid carcinomas of the salivary glands. The mucoepidermoid variety occurs more frequently in men than in women, and the adenoid cystic carcinomas are equally distributed between the sexes. In most of the cases reported the tumors were resectable but the overall survival rate is poor and is similar to the rates found with the more frequent squamous cell cancer of the esophagus.

The value of endoscopic surveillance biopsy for dysplasia and carcinoma in patients with Barrett's esophagus is controversial. One reason is that the available histologic criteria are not adequate to separate patients with lesser degrees of dysplasia or predysplastic changes who are at increased risk for carcinoma and therefore require more frequent surveillance from those patients who are not at increased risk. We used flow cytometry and histology to evaluate 317 biopsy specimens from 64 consecutive patients who were in a cancer surveillance program for Barrett's esophagus and 3 additional patients with adenocarcinoma in Barrett's esophagus. Specimens from 10 patients had aneuploid cells; 9 of these had dysplasia or carcinoma, or both, but 1 patient had only specialized metaplastic epithelium. Twenty specimens ahd G2/tetraploid fractions greater than 6%; all 20 came from patients who had cancer or dysplasia, or were indefinite for dysplasia. All patients with dysplasia or adenocarcinoma had evidence of genomic instability (aneuploidy) or abnormalities of mucosal proliferation by flow cytometry, even when the dysplasia was focal or difficult to recognize histologically. In a small subset of patients with specialized metaplastic epithelium whose specimens were histologically negative or indefinite for dysplasia, the mucosa had aneuploid cell populations or proliferative abnormalities that were otherwise found only in dysplasia or carcinoma. Additional study may prove that this subset of patients merits more frequent endoscopic biopsy surveillance because of an increased risk for developing carcinoma. Because the abnormalities we have detected by flow cytometry correlate well with the conventional histologic diagnoses of dysplasia and carcinoma, they may prove to be a valuable objective adjunct in the diagnosis of dysplasia and carcinoma in Barrett's esophagus.

The presence of argyrophil cells in the proliferative compartment of noncarcinoid carcinomas of the GI tract is well-documented; however, their prevalence and prognostic significance in colorectal carcinomas have never been systematically investigated and reported in the English literature. We applied the Churukian-Schenk argyrophil stain, a histochemical technique previously shown to be the most effective for demonstrating argyrophil cells, to 94 carcinomas of the colon and rectum from patients in whom a minimum 5-year follow-up was available. The 94 cases included 25 nonmucinous colonic and 25 nonmucinous rectal adenocarcinomas; 25 mucinous adenocarcinomas from all sites; and 19 undifferentiated carcinomas from all sites. Twenty control colorectal carcinoids all gave a positive argyrophil stain. Nineteen (20%) of the 94 carcinomas contained argyrophil cells as follows: adenocarcinoma of the colon, 52%; adenocarcinoma of the rectum, 16%; mucinous adenocarcinoma, 4%; and undifferentiated carcinoma, 5%. Crude 5-year survival rates were: carcinoids 80%; all carcinomas containing argyrophil cells, 37%; all without argyrophil cells, 27%. Chi-square between the later two groups was 0.723 (p less than 0.5). Because of the intrinsically poorer prognosis of mucinous and undifferentiated carcinomas, a comparison of survival rates was made excluding these tumors; chi-square was 0.095 (p less than 0.8). We conclude that argyrophil cells are commonly present in nonmucinous adenocarcinoma of the colon, but are less common in nonmucinous adenocarcinomas of the rectum and rare in mucinous and undifferentiated carcinomas. The presence of argyrophil cells did not influence prognosis in this series of cases.

Ten patients with Crohn’s disease of the upper gastrointestinal tract were studied. All patients had either gastric or duodenal involvement, or both, and all had typical Crohn’s disease elsewhere. In one patient, an esophageal lesion of Crohn’s type was present. Upper abdominal pain and nausea and vomiting were the predominant clinical symptoms; signs of gastric outlet obstruction signalled the onset of gastroduodenal involvement. In four patients not previously known to have Crohn’s disease, gastric outlet obstruction was the initial sign of the disease, but all four proved to have concurrent disease of the ileum or colon. The histologic changes in the upper gastrointestinal lesions were similar to those in the ileum and included transmural chronic inflammation, granulomas, and marked submucosal fibrosis. Other disease processes known to produce similar changes were carefully excluded.

A 21-year-old woman with Gardner's syndrome (colonic polyposis with soft tissue and bone tumors) and bilateral fibromatosis of the breast is presented. Six other members of her family had polyposis of the colon, and 4 of them had 2 or more manifestations of Gardner's syndrome. One patient, a 21-year-old man, had an osteochondroma of the femur. Fibromatosis of the breast and osteochondroma are unusual findings in patients with familial polyposis. The colons were compared to those from 8 patients with polyposis without soft tissue or bone tumors, and no differences were observed. Gardner's syndrome and familial polyposis may be produced by a single pleiotropic gene with varying expressivity.

Six normal and 16 neoplastic colorectal specimens were examined with 8.5-MHz ultrasound (US). An articulated system facilitated precise spatial correlation between US and histologic sections. Images were blindly interpreted and then compared with histologic results. All six normal specimen showed five distinct echo layers and were distinguished from neoplastic specimens by all the observers. The central echogenic layer, corresponding to the submucosa, is useful in determining the depth of origin of a neoplasm and the presence of submucosal invasion. US had an accuracy of 92.5% in demonstrating invasion of the submucosa and 77% for invasion of the muscularis externa. For mucosal neoplasms with invasion through the muscularis externa and extension into the subserosal tissues, nearly 90% of US interpretations were correct. High-frequency US may be useful in determining the depth of invasion of mucosal tumors with respect to the submucosa and in differentiating mucosal from extramural masses.

Hereditary gastrointestinal polyposis syndromes can be divided into adenomatous and hamartomatous types. Familial adenomatous polyposis coli (FAPC) is the prototype adenomatous polyposis syndrome and is defined by the autosomal dominant transmission of multiple (more than 100) colorectal adenomas. Virtually all affected patients develop colorectal carcinoma if untreated. Adenomas may develop also in the stomach and small bowel in FAPC patients, but the incidence of carcinoma in these sites is low. A variety of extracolonic manifestations has been reported in FAPC, with the name Gardner's syndrome applied to kindreds with osteomas of the skull and mandible, multiple epidermal cysts, and other skin and soft-tissue lesions. In Turcot's syndrome, brain tumors are present. The distinction between Gardner's and Turcot's syndromes and classical FAPC has become blurred because of marked overlap between them; some authorities consider them to be varying manifestations of a single genetic defect. The hamartomatous polyposes include Peutz-Jeghers syndrome, familial juvenile polyposis, Cowden's disease, intestinal ganglioneuromatosis, and the Ruvalcaba-Myrhe-Smith syndrome. The incidence of gastrointestinal cancer in patients with Peutz-Jeghers syndrome and familial juvenile polyposis exceeds that in the normal population, but is relatively low. In Cowden's disease, the gastrointestinal tract may be the site of multiple hamartomas, but there is no associated increase in the incidence of gastrointestinal cancers; instead, there is an increased incidence of carcinoma of the breast and thyroid. Intestinal ganglioneuromatosis occurs in von Recklinghausen's disease, in association with multiple endocrine neoplasia, type 2b, or as an isolated abnormality. Patients with ganglioneuromatosis do not appear to have an increased risk of developing gastrointestinal cancer. Ruvalcaba-Myrhe-Smith syndrome comprises macrocephaly, mental deficiency, an unusual craniofacial appearance, hamartomatous intestinal polyposis, and pigmented macules on the penis. No increased risk of developing cancer has been identified in the few reported cases.

Endoscopic ultrasound imaging has potential for improving the diagnosis of gastrointestinal disease. However, the anatomic correlates of gastrointestinal ultrasound images have not been precisely defined. We have compared ultrasound images with the corresponding histologic sections of 81 specimens of resected and postmortem, normal and diseased gastrointestinal tissue. The five layers seen on ultrasound images of the normal gastrointestinal tract correspond to (1) superficial mucosa, (2) deep mucosa, (3) submucosa plus the acoustical interface between the submucosa and muscularis propria, (4) muscularis propria minus the acoustical interface between the submucosa and muscularis propria, and (5) serosa and subserosal fat. This interpretation takes into consideration the echoes produced by the tissue layers and the echoes produced by the interfaces between layers. Abnormal findings on ultrasound images of neoplastic and inflammatory diseases correspond to histologic tissue structure. When properly interpreted, ultrasound images of the gastrointestinal wall can provide potentially useful diagnostic information.

Generic stains for secretory granules in carcinoid tumors often yield inconsistent and unpredictable results. Consequently, these techniques have been modified and new ones devised; however, very few studies comparing the efficacy of the various methods have been published. To determine which method would most consistently demonstrate carcinoid granules, we applied a battery of six stains to 73 tumors, all morphologically identified as carcinoids, from various sites (17 pulmonary, 13 small intestinal, 20 appendiceal, 18 rectal, five miscellaneous). Stains employed included four argyrophil (Sevier-Munger, Grimelius, Pascual, Churukian-Schenk), one argentaffin (Fontana-Masson), and one non-silver technique (lead hematoxylin). Of the 73 carcinoids, 97% stained positively with the Churukian-Schenk, 82% with the Pascual, 79% with the Grimelius, 74% with the Sevier-Munger, 67% with lead hematoxylin, and 51% with the Fontana-Masson technique. The two cases negative by the Churukian-Schenk technique were also negative with all other stains; thus, this technique most consistently demonstrated secretory granules in carcinoids, including all 18 rectal tumors. The Churukian-Schenk method achieves its superior results by reducing background staining and nonspecific precipitation to a level that permits sparse, small granules to be readily identified. In control sections of normal mucosa and in some tumors, this stain revealed more than one population of argyrophil cells as identified by the size, color, and staining intensity of the granules.

We describe the normal gross anatomy and histology of the colon, with emphasis on the appearance of the mucosa as seen in the endoscopic biopsies. Various artifacts that may be encountered as a result of trauma from the biopsy forceps, incorrect orientation of the tissue, fixation, and the effects of laxatives and enemas are described and illustrated. Recommendations for optimum handling of biopsies are made.

Abnormalities in cellular DNA content and proliferative rate are observed not only in cancer, but may be seen in premalignant disease as part of the multistep process of progression towards malignancy during carcinogenesis. Flow cytometry can be used to document these premalignant changes. Several gastrointestinal diseases provide good models for studying these abnormalities as early detectors which may select those patients at greatest risk for progression to cancer.

The degree of fibrosis in both the inner and outer medullae of the kidney was semiquantitated in 100 unselected autopsies in a blind study. A statistically significant relationship between renal medullary fibrosis in both zones, hypertension, and renal arterio- and arteriolar sclerosis was observed. The part medullary fibrosis plays in this relationship was not indicated by this study, but it most likely is secondary to the renal arterial disease. Renal medullary fibrosis adds another relationship between the renal medulla and the hypertensive state. Since there is experimental evidence in support of an antihypertensive function exerted by the renal medulla, renal medullary fibrosis could be an index of the loss of such function.