Clear cell change in colonic tubular adenoma and corresponding colonic clear cell adenocarcinoma is associated with an altered mucin core protein profile.

Clear cell change is seen in <1% of colonic tubular adenomas (TAs) and remains incompletely characterized. Associated adenocarcinomas can also demonstrate a clear cell phenotype. Eleven TAs with at least focal clear cell change with or without associated invasive adenocarcinoma, from 10 patients were studied. The lesions were stained with periodic acid-Schiff (PAS)/PAS-diastase and immunolabeled with antibodies to MUC2, MUC5AC, MUC6, CK7, CK20, and CDX2. Eight of 11 (77%) TAs with clear cell change had focal to extensive high-grade dysplasia. Two were associated with invasive clear cell adenocarcinoma. The adenomas and adenocarcinomas ranged from 0.5 to 3.5 cm. PAS/PAS-diastase stains showed minimal PAS(+) material in the clear cells. On immunohistochemical studies, the clear cells had decreased MUC2 labeling compared with the surrounding conventional adenoma in 9 of 11 (88%) cases, including the 2 clear cell adenocarcinomas. In 3 of the 11 lesions, the background TA showed at least focal MUC5 immunoreactivity, their associated clear cell area had decreased MUC5 labeling in all 3 cases. No immunoreactivity to MUC6 was observed in the background TAs and clear cells in all cases. Compared with background TA, both increased and decreased expression of CK7, CK20 (in quantity), and CDX2 (in intensity) were observed in the clear cells of TAs and adenocarcinomas. One of the clear cell adenocarcinomas was CK20, CK7, CDX2 and the other was CK20, CK7, CDX2-focal positive. Thus, although the clear cells have different MUC protein profiles than the background adenomatous epithelium, invasive clear cell adenocarcinomas retained the typical CK20(+)/CK7(-) profile of conventional adenocarcinomas. Our results indicate that clear cell adenocarcinomas can be primary to the colorectum with identifiable precursors. Awareness of them and their immunoprofile allows distinction from clear cell lesions from other sites.

Sclerosing mesenteritis involving the pancreas: a mimicker of pancreatic cancer.

Sclerosing mesenteritis (SM), also known as mesenteric lipodystrophy, rarely involves the parenchyma of the pancreas. When SM does involve the pancreas, it can mimic pancreatic carcinoma both clinically and radiographically with pain, obstructive jaundice, a mass lesion, and even the appearance of vascular invasion. We report 6 patients with SM involving the pancreas (mean age 43.2 y, 5 female), and review their clinical presentation, radiographic findings, pathology, and outcome. Five of these 6 patients were originally thought to have a primary pancreatic neoplasm. Initial presenting clinical information was available for each patient: all 6 reported abdominal or epigastric pain, 3 reported weight loss, and 2 reported one or more of the following: back pain, fever, abdominal bloating/distention, nausea with/without vomiting, and anorexia. The lesions formed masses with an infiltrative pattern and all had 3 key histologic features: fibrosis, chronic inflammation, and fat necrosis-without a known etiology. The inflammatory infiltrate was composed of a mixture of lymphocytes, plasma cells, and scattered eosinophils. Of the 5 patients with post-treatment clinical information available, 4 had at least a partial response to treatment with steroids, tamoxifen, azathioprine, resection, or a combination of these, and 1 did not respond. A dramatic response to immunosuppressive therapy is illustrated by the case of a 46-year-old woman who presented with the presumptive diagnosis of an unresectable pancreatic cancer. Distinguishing SM from pancreatic carcinoma is crucial to appropriate management, as patients with SM may benefit from immunosuppressive therapy.

Mycophenolic acid (cellcept and myofortic) induced injury of the upper GI tract.

BACKGROUND: Mycophenolic acid (MPA) is an immunosuppressant drug commonly used in patients undergoing solid organ transplant. Although its pattern of inducing injury in the colon is well-known and features prominent crypt apoptosis that mimics graft-versus-host-disease, the injury pattern in the upper gastrointestinal (GI) tract is less extensively documented. We studied the pattern of upper GI tract injury in symptomatic patients taking MPA. DESIGN: Twenty solid organ transplant patients who were taking MPA and had concurrent upper GI tract biopsies were identified on a laboratory information system search. From these 20 patients, 17 duodenal, 18 gastric, and 7 esophageal biopsies were examined. All patients were symptomatic. Apoptosis and patterns of chronic and active injuries were assessed on standard hematoxylin and eosin, periodic acid-Schiff/Alcian blue, and Diff-Quik stained slides. To measure the significance of apoptosis, we standardized the apoptotic counts in normal biopsies using duodenal, gastric, and esophageal biopsies from 45 normal cases and performed statistical analysis. For the purposes of this study, we regarded apoptotic counts higher than the mean plus 2 SDs as significant. Thus the cut-off values for apoptosis were > or =2 apoptotic bodies/100 crypts for duodenum, > or =3/100 glands for stomach, and > or =2/10 high-power field for esophagus. RESULTS: GI-related symptoms and abnormalities manifested between 1 month and 10 years posttransplant and included diarrhea (55%); nausea (45%); abdominal pain (35%); vomiting (25%); GI bleeding (15%); dysphagia (10%); dyspepsia, anemia, and hematemesis (5% for each). Most (14 out of 17, 82%) duodenal biopsies showed apoptotic counts of > or =2/100 crypts, 28% (5 out of 18) of gastric biopsies showed apoptotic counts of > or =3/100 glands, and 57% (4 out of 7) of esophageal biopsies showed apoptotic counts of > or =2/10 high-power field. Four gastric biopsies showed a previously undescribed injury pattern of parietal cells resembling the ballooning degeneration. Additional pathologic findings included: chronic peptic duodenitis (6 out of 17, 35%), active duodenitis (1 out of 17, 6%), and celiac-like features (2 out of 17, 12%) in the duodenum; chemical gastropathy (3 out of 18, 17%), active chronic gastritis without Helicobacter pylori (2 out of 18, 11%), and erosion (1/18,6%) in the stomach; reactive epithelial change (3 out of 7, 43%), active esophagitis (3 out of 7, 43%), ulceration (2 out of 7, 29%), and erosion (1 out of 7, 14%) in the esophagus. Serum MPA levels were available in 7 patients, 6 of whom had abnormal duodenal apoptotic counts. On follow-up, available for 16 patients, symptoms improved in all the patients whose dose was decreased or whose medication was withdrawn (10 out of 10) and symptoms persisted in all the patients whose dose was not altered (6 out of 6). Follow-up biopsies after reduction of the medication dose were available for 1 patient and showed substantial reduction in apoptosis. In contrast, follow-up biopsies from 1 patient whose dosage was not altered showed persistent abnormal apoptotic counts in the duodenum. CONCLUSIONS: As noted by others (Parfitt JR, Jayakumar S, Driman DK. Am J Surg Pathol. 2008; 32:1367-1372), mycophenolate mofetil-associated injury of the upper GI tract, like that in the colon, is characterized by prominent apoptosis similar to that of mild or grade I graft-versus-host-disease injury. We offer apoptotic count guidelines, which we hope will facilitate recognition of mycophenolate mofetil-associated injury in the upper GI tract.

Selected topics in the evaluation of pediatric gastrointestinal mucosal biopsies.

The practice of pediatric gastrointestinal pathology provides specific challenges to the pathologist. Often the clinical information accompanying a biopsy specimen will read simply, "failure to thrive." Other situations, such as the evaluation of a neonate's rectal suction biopsy for Hirschsprung disease, are notorious for providing diagnostic challenges in high-pressure situations. In this review, we will discuss several commonly encountered situations in pediatric pathology: the evaluation of pediatric esophageal eosinophilia, a child who has swallowed a non food item, caustic substance, or hot liquid, the evaluation of a pediatric colorectal biopsy with focal active colitis, and the evaluation of rectal suction biopsies for Hirschsprung disease. With each topic, we will discuss a general approach to the case, diagnostic tips, and how to avoid commonly encountered pitfalls. Finally, we highlight key references pertinent to these issues that can he used to help convey pathologic findings to pediatric gastroenterologists.

Successful liver transplantation for Budd-Chiari syndrome in a patient with paroxysmal nocturnal hemoglobinuria treated with the anti-complement antibody eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hemolytic anemia caused by somatic mutations in the phosphatidylinositol glycan-complementation class A gene and the resulting absence of a key complement regulatory protein, CD59. Affected red blood cells in patients with PNH undergo intravascular complement-mediated lysis with resulting anemia, hemoglobinuria, and venous thromboses. Hepatic venous outflow thrombosis [Budd-Chiari syndrome (BCS)] is especially common in PNH patients and often fatal. The few case reports of outcomes in patients undergoing liver transplant for BCS secondary to PNH detail instances of recurrent BCS as well as early thrombotic portal vein occlusion and hepatic artery thrombosis requiring retransplantation. PNH is therefore generally considered a contraindication to liver transplantation. Here we present the first report of a patient with PNH and BCS undergoing successful liver transplantation while receiving eculizumab, a humanized monoclonal antibody that blocks the activation of the terminal complement at C5.

New treatments, new challenges: pathology's perspective on esophageal carcinoma.

While frank esophageal carcinoma rarely presents a diagnostic challenge, early lesions are often tricky to assess. This difficulty stems in part from drawbacks in the classification systems designed to stratify early lesions as a guide for deciding treatment. These systems are complex and wrought with specific pathologic challenges brought on by new treatment modalities. Such interventions as endoscopic mucosal resection, photodynamic therapy, and chemotherapy/radiation combinations present the pathologist with new histologic challenges that have a direct impact on patient care. In this article, we discuss staging issues pertinent to early cancers, histologic sequelae of various treatments, and how these factors affect the pathologist's role in evaluating esophageal carcinoma.

Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma.

Pyloric gland adenoma (PGA) is a rare neoplasm demonstrating gastric epithelial differentiation. In this series, we studied 41 PGAs from 36 patients. We compared them to 28 gastric foveolar type gastric adenomas (GTAs) from 25 patients. PGAs occurred in an older population with a mean age of 73 compared with 48 in GTAs (P<0.001). There was a significant female predominance, particularly for gastric PGAs. Morphologically, PGAs were characterized by closely packed pyloric gland-type tubules with a monolayer of cuboidal to low columnar epithelial cells containing round nuclei and pale to eosinophilic cytoplasm with a ground glass appearance. The cells lacked an apical mucin cap, a feature distinct from GTAs. An immunohistochemical panel of mucin core peptides (MUCs) and CDX2 was performed on a subset of the lesions. All PGAs expressed MUC6 with coexpression of MUC5AC, whereas GTAs expressed predominantly MUC5AC without MUC6. Both lesions lacked CDX2 and MUC2 except in areas of intestinal metaplasia (IM) found in some PGAs. Histologic features consistent with conventional dysplasia were found in 26 (63.4%) PGAs. Using a 2-tier grading system, 5 (12.2%) cases demonstrated low-grade dysplasia whereas 21 (51.2%) cases showed high-grade dysplasia including 5 (12.2%) cases with an associated intramucosal or more deeply invasive adenocarcinoma. This was significantly different from GTAs; all cases showed only low-grade dysplasia (P<0.001). In addition, 60% of gastric PGAs were associated with IM in the surrounding mucosa and 40% of lesions arose in a background of autoimmune gastritis, whereas these 2 conditions were only associated with 1 case (3%) of GTA. In summary, PGA is a distinct entity. Despite its bland histologic appearance, it is much more likely to be accompanied by background IM and autoimmune gastritis and can evolve into invasive adenocarcinoma displaying pyloric gland differentiation.