Spontaneous hepatic hemorrhage secondary to prolonged use of oral contraceptives.

Oral contraceptive pills (OCP) are the most commonly used form of contraception throughout the United States of America. The prolonged usage of oral contraceptives leads to a variety of complications, ranging from subclinical modifications of liver function tests to the development of benign and malignant tumors of the liver. Spontaneous hepatic hemorrhage secondary to oral contraceptive use was only reported once in the early 1980s. We report a case of spontaneous hepatic hemorrhage secondary to prolonged ingestion of combined OCPs followed by multiple pulmonary emboli without underlying thrombophilia.

Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis.

Over the years, a variety of abnormal immune reactions to minocycline have been reported including arthritis, systemic lupus erythematosus, and hepatitis. The current report describes the detailed clinical and pathologic features of 3 patients who presented with chronic/autoimmune hepatitis alone while on minocycline at our hospital over a 2-year period. Minocycline use in these patients was temporally related to onset of severe hepatitis. Adolescents with such a reaction to minocycline have been included in previous reports but have not been well described as a distinct entity. We have compared our cases with similar cases previously reported with a review of the literature and a discussion of the implications for prescribing physicians.

Clinical, pathologic, and molecular features of early-onset colorectal carcinoma.

The incidence of colorectal carcinoma has increased among patients <40 years of age for unclear reasons. In this study, we describe the clinical, pathologic, and molecular features of colorectal carcinomas that developed in young patients. We compiled a study group of 24 patients <40 years of age with colorectal carcinoma, and 45 patients > or =40 years of age served as controls. Cases were evaluated for clinical risk factors of malignancy and pathologic features predictive of outcome. The tumors were immunohistochemically stained for O6-methylguanine methyltransferase, MLH-1, MSH-2, MSH-6, beta-catenin, chemokine (C-X-C motif) receptor 4, epidermal growth factor receptor, TP53, p16, survivin, and alpha-methylacyl-CoA racemase; assessed for microsatellite instability and mutations in beta-catenin, APC, EGFR, PIK3CA, KRAS, and BRAF; evaluated for micro-RNA expression (miR-21, miR-20a, miR-183, miR-192, miR-145, miR-106a, miR-181b, and miR-203); and examined for evidence of human papillomavirus infection. One study patient each had ulcerative colitis and hereditary nonpolyposis colorectal cancer. Ninety-two percent of tumors from young patients occurred in the distal colon (P=0.006), particularly the rectum (58%, P=0.02), and 75% were stage III or IV. Tumors from young patients showed more frequent lymphovascular (81%, P=0.03) and/or venous (48%, P=0.003) invasion, an infiltrative growth pattern (81%, P=0.03), and alpha-methylacyl-CoA racemase expression (83%, P=0.02) compared with controls. Carcinomas in this group showed significantly increased expression of miR-21, miR-20a, miR-145, miR-181b, and miR-203 (P< or =0.005 for all comparisons with controls). These results indicate that early-onset carcinomas commonly show pathologic features associated with aggressive behavior. Posttranslational regulation of mRNA and subsequent protein expression may be particularly important to the development of colorectal carcinomas in young patients.

S100 protein expression distinguishes metanephric adenomas from other renal neoplasms.

Metanephric adenoma is a benign renal neoplasm with morphologic features similar to those of malignant renal neoplasms, such as papillary renal cell carcinoma (RCC) and Wilms' tumor. Different methods have been used to distinguish between metanephric adenoma and papillary RCC and Wilms' tumor. However, some techniques are not always available, such as certain immunohistochemical stains, cytogenetics, molecular genetics, and electron microscopy. In the current study, we compared the expression of S100 protein in 15 cases of metanephric adenoma, 10 cases of Wilms' tumor, and 13 cases of papillary RCC. Our results revealed strong expression of S100 proteins in all cases of metanephric adenoma, weak expression in two cases of Wilms' tumor, and no expression in any of the cases of papillary RCC. These findings indicate that S100 could be a useful and accessible tool for the diagnosis of metanephric adenoma.

Sp1, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma.

Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths in the United States. Sp1 is a sequence-specific DNA binding protein that is important in the transcription of a number of regulatory genes involved in cancer cell growth, differentiation, and metastasis. In this study, we investigated Sp1 expression in pancreatic ductal adenocarcinoma and its association with clinical outcome. We studied 42 patients with primary pancreatic adenocarcinoma. The expression of Sp1 in pancreatic adenocarcinoma was evaluated by immunohistochemical staining. All 42 patients had clinical follow-up information and were evaluated for survival. Sp1 protein was aberrantly overexpressed in a subset of primary pancreatic adenocarcinoma. These tumors all developed metastasis, whereas none of the primary tumors without lymph node metastasis showed Sp1 overexpression. Statistically, Sp1 overexpression was associated with higher stage, higher grade, and lymph node metastasis (P < 0.001, P = 0.036, and P < 0.0001, respectively). Additionally, patients of this subset had a much shorter overall survival than patients without Sp1 overexpression, as evidenced by Kaplan-Meier plots and the log-rank test (P = 0.002). The 5-year overall survival rate was 19% in patients with Sp1 overexpression, compared with 55% in patients without Sp1 overexpression. The median survival was only 13 months for patients with Sp1 overexpression, compared with 65 months for patients without Sp1 overexpression. In conclusion, Sp1 is a new biomarker that identifies a subset of pancreatic ductal adenocarcinoma with aggressive clinical behavior. It can be used at initial diagnosis of pancreatic adenocarcinoma to identify patients with an increased probability of cancer metastasis and much shortened overall survival.

Evaluation of site-specific and seasonal variation in colonic mucosal eosinophils.

Several systemic disorders and gastrointestinal diseases may be associated with increased colonic mucosal eosinophils, which may vary in number throughout the normal colon. Some investigators have proposed that colonic eosinophilia reflects allergen exposure, although this hypothesis has never been validated, and values quantifying the number of mucosal eosinophils that can be regarded as a normal finding are lacking. The aims of this study were to determine the number of intramucosal eosinophils normally present throughout the colon and evaluate the relationship between colonic eosinophilia and seasonal allergen exposure. Eosinophils in the crypt epithelium and lamina propria were evaluated in 198 mucosal biopsy specimens obtained from the ascending (n = 98) and descending (n = 100) colon of patients with normal colonoscopic examinations. The cases were stratified into 12 groups, reflecting the months during which the samples were obtained, and the mean number of mucosal eosinophils was determined for each group. Daily air pollen counts were recorded, and the mean determined for each month. Fifty-five percent of mucosal biopsy specimens from the ascending colon contained eosinophils in the crypt epithelium, compared with only 5% of biopsy specimens from the descending colon (P < .001). Lamina propria eosinophils were, on average, 3 times more numerous in the ascending compared with the descending colon (P < .001). Mucosal eosinophils were slightly more numerous in samples obtained in April and May, corresponding to periods of highest pollen counts, but this relationship was not significant (P > .05). We conclude that intramucosal eosinophils are commonly present in the proximal colon but show only mild fluctuations with ambient allergen exposure.

Cell blocks of breast FNAs frequently allow diagnosis of invasion or histological classification of proliferative changes.

Two major limitations of breast fine needle aspiration (FNA) compared with core needle biopsies (CNB) are the inability to determine whether a cancer is invasive and to classify proliferative lesions. We studied 40 consecutive "rapid cell blocks" from breast FNAs with surgical pathology follow-up to test whether cell blocks can overcome these limitations. Of 25 carcinomas, invasion could be identified in the cell block sections in 11 (44%). One cystosarcoma phyllodes was suspected based on the cell block sections. Cell blocks from 12 of 14 benign breast FNAs showed sufficient cells to assign a histologic diagnosis of no hyperplasia (1 case, confirmed on follow-up) and usual hyperplasia (11 cases; confirmed in eight of 11 on follow-up). Specific histologic diagnoses included intraductal papilloma (2 cases), and in situ lobular neoplasia (2 cases). Cell blocks complement smears and monolayers and appear to overcome major limitations of breast FNA.

Normal variation in intraepithelial lymphocytes of the terminal ileum.

The number of intraepithelial lymphocytes (IELs) is often increased in the terminal ileum of patients with immune-mediated inflammatory diseases of the colon. However, data regarding their number in normal ileal mucosa of asymptomatic patients are lacking. We aimed to establish the acceptable range of IELs in biopsy specimens of normal ileal mucosa. Ileal mucosal biopsy specimens obtained during colonoscopy of 61 asymptomatic patients without endoscopic or pathologic evidence of colitis were immunostained for CD3 to assess the number of IELs present in each specimen. CD3+ lymphocytes were counted in 3 well-oriented villi and results expressed as the average for each biopsy specimen. The study group included 25 males and 36 females, ranging in age from 10 to 84 years (mean, 44.4 years). The mean +/- SD number of ileal CD3+ cells per 100 enterocytes for the group was 3.8 +/- 2 (median, 3; range, 0-9). In addition, there was a significant inverse relationship between the number of villus IELs and increasing age. Occasional IELs (approximately 4/100 villus enterocytes) are normally present in ileal biopsy specimens from asymptomatic patients without colitis. One should avoid overinterpreting the importance of occasional IELs in ileal biopsy specimens from asymptomatic patients.

Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C.

BACKGROUND & AIMS: Iron overload may cause or contribute to hepatic injury and fibrosis. Mutations in the HFE gene may influence development or progression of chronic liver disease by increasing iron stores or modulating immune responses. The aim of this work was to assess the influence of HFE mutations and serum and hepatic measures of iron status on baseline features and response to lead-in therapy in subjects with advanced chronic hepatitis C enrolled in the Hepatitis C Anti-viral Long-term Treatment to prevent Cirrhosis (HALT-C) Trial. METHODS: Entry criteria included an Ishak fibrosis score >2 and lack of iron overload (Scheuer iron grade <3+) according to local study pathologists. All baseline biopsy specimens were rescored by consensus of study pathologists, and detailed assessment of stainable iron was performed. Hepatic iron concentrations were measured on portions of 144 liver biopsy specimens. A total of 1051 out of 1145 subjects agreed to HFE mutational testing (C282Y, H63D, S65C). RESULTS: Thirty-five percent carried at least one HFE gene mutation. There were no significant differences in the prevalence of HFE gene mutations among subjects with fibrosis (35.5%) versus cirrhosis (32.9%). Thirty-three percent of subjects had end-of-treatment and 16% sustained virologic responses. Presence of HFE mutations, in particular the H63D variation, was associated with increased end-of-treatment (40% vs 29%, P = .0078) and sustained virologic responses (20% with HFE mutation vs 14% sustained virologic response without HFE mutation; P = .009). CONCLUSIONS: Although HFE mutations (especially the most frequent H63D mutation) are associated with increased iron loading, they are also associated with increased sustained virologic responses in US patients with advanced chronic hepatitis C.

Duodenal intraepithelial lymphocytes in inflammatory disorders of the esophagus and stomach.

BACKGROUND & AIMS: Duodenal cluster designation 3 positive (CD3+) intraepithelial T lymphocytes (IELs) are increased in gluten-sensitive enteropathy (GSE) and, because of the dispersed nature of the gut immune system, might also be increased in mucosa distant from the duodenum. Conversely, little is known about their frequency in the duodenum during inflammatory conditions of the stomach and esophagus. This study assessed whether CD3+ IELs are increased in duodenal biopsies in patients with esophagitis or gastritis relative to normal control subjects. METHODS: Cases (n=46) with concurrent mucosal biopsies of the duodenum, stomach, and esophagus were divided into 4 groups: I, no inflammation in any site; II, active esophagitis only; III, chronic active gastritis only, with Helicobacter pylori bacteria; IV, chronic gastritis only, without H pylori bacteria. Immunostains against CD3 were performed by using standard techniques, the number of CD3+ cells/100 enterocytes in 3 well-oriented villi was recorded, and the results for the groups were compared statistically. RESULTS: The average number of CD3+ IELs/100 enterocytes for each group was I, 6.7; II, 11.8; III, 7.2; and IV, 9.1. The differences among the groups were not statistically significant. There was no correlation between the number of duodenal IELs and severity of inflammation, patient age or sex, or symptoms. CONCLUSIONS: Duodenal mucosal biopsies from patients with esophagitis and/or gastritis may have a slightly increased number of CD3+ IELs relative to normal control subjects. This finding may reflect an underlying mechanism of diffuse inflammation in the gastrointestinal tract.

Cholangitis: a histologic classification based on patterns of injury in liver biopsies.

Inflammatory disorders of the biliary tract present difficult diagnostic problems in liver needle biopsies. The aim of this study was to perform a detailed histologic analysis of liver biopsies from patients with biliary tract disorders, classify them by pattern of inflammation, and determine the accuracy of the histologic classification by clinical follow-up. Percutaneous liver needle biopsies from the surgical pathology files of UmassMemorial Healthcare (UMMHC) from 2000 to 2003 with a diagnosis suggesting a biliary tract process (n = 32) and four biopsies from cases with systemic non-biliary tract disorders were analyzed for multiple histologic features and classified as one of five patterns: acute cholangitis/pericholangitis (ACP), lymphocytic cholangitis (LC), granulomatous (G), ductopenia (D), or non-specific (NS). When compared to the "gold standard" diagnosis based on all clinical data, the concordance between the histologic classification and the clinical diagnosis was: 50% for ACP and bile duct obstruction; 77% for LC and immune-mediated cholangitis NOS; 100% for G and G cholangitis; 100% for D and idiopathic adulthood D; and 50% for NS and non-biliary tract disorders. Our findings suggest that classifying biopsies by pattern of injury is helpful in guiding the subsequent clinical work-up. ACP pattern correlates with bile duct obstruction, infection, and ischemia. LC correlates with serologic studies supporting immune-mediated processes. G pattern suggests further work-up for PBC, drug, tuberculosis, or sarcoidosis. D pattern establishes the clinical diagnosis. NS pattern includes cases of primary sclerosing cholangitis, which cannot be diagnosed by biopsy alone.

Expression of CD3 antigens in renal tubule epithelium and renal oncocytomas.

CD3 antigen, formerly thought to be specific for T lymphocytes, has been identified in Purkinje cells of the cerebellum and gastric parietal cells in several species, including humans. The antibodies commonly used to recognize CD3 are directed against the epsilon-subunit of the T cell receptor. This subunit has a role in signal transduction in T lymphocytes and possibly other types of cells. We immunostained sections for CD3 from normal kidneys of several species, including humans, and from different primary human renal cortical neoplasms to determine if CD3 antigen is expressed in normal and in neoplastic tubular epithelium. CD3 expression was strong in normal proximal and distal tubular epithelium in most species and in renal oncocytomas, weak in chromophobe carcinoma, and negative in clear cell carcinomas, in papillary renal cell carcinoma, and in a transitional cell carcinoma. These findings suggest that this marker may be useful in the diagnostic workup and classification of renal cortical neoplasms.

A dietary enzyme: alpha-methylacyl-CoA racemase/P504S is overexpressed in colon carcinoma.

Epidemiological studies have shown that consumption of red meat increases the risk of developing colon cancer. An enzyme, alpha-methylacyl CoA racemase (AMACR), also known as P504S, plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids from red meat and dairy products. High expression of AMACR was recently found in prostate cancer. In this study, we investigated expression of AMACR in 242 cases of colonic tumors including 176 colorectal carcinomas, 38 colon adenomas and 28 hyperplastic (non-neoplastic) polyps by immunohistochemical analysis. The mRNA levels of AMACR expression in normal and colon cancer tissues were assessed by real-time PCR. Significant up-regulation of AMACR mRNA was found in colon carcinomas compared to normal tissue. There was very low or no expression of AMACR protein in normal colon, but AMACR was highly expressed in 76 and 75% of well and moderately differentiated colon carcinomas, respectively, and in 79% of adenomas. In contrast, only 4% of hyperplastic polyps expressed AMACR. Since this enzyme is involved in the metabolism of branched-chain fatty acids from beef, milk and dairy products, our results provide important molecular information regarding a possible link between diet and development of colon cancer. AMACR may also serve as a molecular marker for colon cancers and its precursor lesions.

Expression of alpha-methylacyl-CoA racemase (P504s) in various malignant neoplasms and normal tissues: astudy of 761 cases.

Alpha-methylacyl CoA racemase (AMACR), also known as P504S, plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids. It has recently been shown that AMACR is highly expressed in prostate cancer and that it may be an important diagnostic marker for prostate carcinoma. However, little is known about expression of AMACR in normal tissues and other malignant tumors. In this study, we investigated expression of AMACR in 539 malignant tumors and 222 normal human tissues of various types by immunohistochemical analysis. mRNA levels of AMACR in normal organs and in selected tumors were assessed by real time PCR. In normal tissue, high expression of AMACR mRNA was identified in liver, kidney and salivary gland, while AMACR protein was detected in liver (hepatocytes), kidney (tubular epithelial cells), lung (only bronchial epithelial cells), and gallbladder (only mucosal epithelial cells). High expression of AMACR mRNA was found in prostate, liver, and kidney cancers but rarely in stomach and bladder cancers. A high percent of adenocarcinomas arising from these organs express AMACR, including 17 of 21 (81%) of hepatocellular carcinomas and 18 of 24 (75%) of renal cell carcinomas. In addition, carcinomas arising from tissues normally not expressing AMACR were also positive for the antigen, including 17 of 18 (94%) prostate carcinomas, 9 of 29 (31%) of urothelial carcinomas, and 4 of 15 (27%) of gastric adenocarcinomas. Two hundred and fifty cases of adenocarcinomas from lung, breast, pancreas, bile duct, adrenal gland, salivary gland, ovary, thyroid and endometrium were negative or rarely positive for AMACR. Neuroendocrine carcinomas rarely expressed AMACR. Melanomas, squamous cell carcinomas, basal cell carcinomas, soft tissue tumors (including epithelioid sarcomas and synovial sarcoma), thymomas, and germ cell tumors were negative for AMACR. Our data provide important baseline information for using AMACR in clinical practice and also are valuable in furthering understanding of the pathogenic role of AMACR in malignant neoplasms.

Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C.

BACKGROUND/AIMS: Recent evidence implicates iron as a comorbid factor for development of non-hemochromatotic liver diseases. Mutations or polymorphisms in the HFE gene or the TfR1 gene may influence the accumulation of iron in the liver or other tissues or may influence chronic viral hepatitis apart from effects on iron homeostasis. The aim of this study was to assess the role of hepatic iron, HFE and TfR1 variations on development and progression of chronic hepatitis C infection. METHODS: We studied 119 consecutive patients with chronic hepatitis C, correlating clinical, laboratory, histopathological, and genetic data. Frequencies of genetic variations were compared with local and national controls. RESULTS: HFE mutations were more common in patients than controls (48% vs. 38%, P=0.04), and advanced degrees of fibrosis developed at younger ages in subjects with the C282Y mutation (38.6 vs. 46.5 years, P=0.03). Patients carrying C282Y had higher mean hepatic iron concentrations (P=0.02), hepatic iron indices (P<=0.0001), and hepatic fibrosis scores (P=0.01). Hepatic fibrosis was correlated with hepatic iron concentration (P=0.03). TfR1 polymorphisms bore no detectable relation to disease severity or response to therapy. CONCLUSIONS: Hepatic iron and HFE mutations are comorbid factors that increase development and progression of chronic hepatitis C.

Benefits of chronic plasmapheresis and intravenous heme-albumin in erythropoietic protoporphyria after orthotopic liver transplantation.

Erythropoietic protoporphyria (EPP) is characterized by a deficiency of ferrochelatase the final enzyme of the heme biosynthetic pathway. Patients with EPP may overproduce protoporphyrin IX, chiefly in developing erythrocytes. In some, protoporphyrin accumulates and causes toxicity, particularly to the skin and liver. Orthotopic liver transplantation (OLT) treats the severe liver disease that sometimes occurs in EPP; however, it does not correct the underlying metabolic disorder. We recently reported a patient with EPP who was improved with plasmapheresis and i.v. heme-albumin before OLT. Subsequently he developed histological and biochemical evidence of recurrent hepatotoxicity from protoporphyrin in the graft liver. We now report successful treatment of the patient with additional plasmapheresis and heme-albumin with improvement of hepatic histological and biochemical abnormalities. We conclude that plasmapheresis and heme-albumin are of benefit in EPP complicated by hepatotoxicity before and after liver transplantation.