Journal Watch September – October 2015

Modern Pathology, Sept-Oct 2015

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases
Schlitter AM, Jang KT, Klöppel G, et al. Mod Pathol. 2015 Sep;28(9):1249-64.

Intraductal tubulopapillary neoplasm of the bile ducts is the biliary counterpart of pancreatic intraductal tubulopapillary neoplasm. In this report, 20 cases were studied focusing on the clinicopathologic features and molecular profiles. The tumors were predominantly intrahepatic (70%) with mean size of 6.9 cm. The neoplasms were immunoreactive for MUC1 (80%) and MUC6 (30%). 80% of the lesions were associated with invasive carcinoma. The overall survival was favorable: 1 year 100%, and 5 years 90%. Molecular studies showed low prevalence of alterations of common oncogenic signaling pathways in this tumor.

American Journal of Pathology, Sept-Oct 2015

Hepatic Progenitor Cells in Action: Liver Regeneration or Fibrosis?
Kaur S, Siddiqui H and Bhat MH. Am J Pathol. 2015 Sept;185:2342-2350.

This is a nice review of the current knowledge regarding hepatic progenitor cells and their role in both hepatic fibrosis and hepatic regeneration during liver injury.

Human Pathology, Sept-Oct 2015

Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.
Liau JY, et al. Hum Pathol. 2015;46(9):1360-6.

Alternative lengthening of telomeres (ALT) can enable endless cancer cell replication. ALT has been associated with inactivation of α-thalassemia/mental retardation syndrome X-linked (ATRX) and death domain-associated (DAXX) protein. This study focused on ATRX/DAXX expression and ALT status in malignant vascular tumors. Loss of ATRX expression was observed in 21% (16/77) of the primary angiosarcomas and 9% (1/11) of epithelioid hemangioendotheliomas. DAXX expression was intact in all but 2 ATRX-deficient angiosarcomas. Telomere-specific FISH was ALT-positive in 28% (17/61) of the primary angiosarcomas and was highly associated with loss of ATRX expression, as 26/28 ALT-positive angiosarcomas were ATRX deficient. Primary liver angiosarcomas were ATRX deficient (8/13) and/or ALT positive (8/12), while none of the secondary angiosarcomas showed these findings. The only ATRX-deficient epithelioid hemangioendothelioma was positive for ALT. The study concludes that ALT and loss of ATRX expression are frequently observed in hepatic angiosarcomas.

Advance in Anatomic Pathology, Sept-Oct 2015

Update on the Liver Imaging Reporting and Data System: What the Pathologist Needs to Know
Tang A. et al . Advance in Anatomic Pathology. 2015, 22(5): 314-322.

Hepatocellular carcinoma (HCC) is frequently diagnosed noninvasively with imaging methods. In 2008, the American College of Radiology supported the development of the Liver Imaging Reporting and Data System (LI-RADS) for standardized terminology and reporting for the diagnosis of HCC. This article reviews the basic concepts of LI-RADS, emphasizing aspects that are most relevant to pathologists, including the categories, diagnostic algorithm, major features, and ancillary features for the diagnosis of HCC. Importantly, LI-RADS is designed to diagnose progressed HCC with high specificity and modest sensitivity, but not designed to detect early HCC and so have limited sensitivity for such lesions. Another relevant point to pathologists is that imaging detection of small (<1 cm) nodules is restricted. For these reasons LI-RADS require lesions to be 1 cm or greater for the noninvasive diagnosis of HCC.

American Journal of Clinical Pathology, Sept-Oct 2015

The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis
Tana MM et al. Am J Clin Pathol  2015;144:601-606

The significance of autoantibodies (AMA, ANA) in PBC disease stage and prognosis is unclear.  In this article, the authors tested serial serum samples from patients with PBC for autoantibodies, and correlated the levels of autoantibodies with clinical, laboratory, and histologic outcomes.  145 serum samples from 27 PBC patients were studied. The medium follow up time was 20 years. In the initial serum samples, the positivity for autoantibodies was:  AMA (93%), ANA (100%), SSA-52 (48%), sp100 (22%), gp210 (22%), centromere (19%), SS-A (15%), chromatin (4%), SS-B (4%), RNA polymerase III (0%), SLA (0%), Scl-70 (0%), respectively. Most antibody levels did not change significantly over time except for sp100 (a specific type of ANA). Furthermore, there was a significant inverse relationship between change in sp100 autoantibody level and fibrosis score on serial liver biopsy specimens. The data suggests that changing sp100 level despite treatment might indicate disease progression.

Histopathology, Sept-Oct 2015

Hypoxia after transarterial chemoembolization may trigger a progenitor cell phenotype in hepatocellular carcinoma.
Lai JP, Conley A, Knudsen BS, Guindi M. Histopathology. 2015 Oct;67(4):442-50.

This study tested the expression of three markers in recurrent lesions of hepatocellular carcinoma (HCC) treated by TACE (Transcatheter Arterial Chemoembolization). The three markers are carbonic anhydrase IX (CAIX) [marker of hypoxia] as well as the cholangiocytic/progenitor markers cytokeratin (CK19) and epithelial cell adhesion molecule (EpCAM) [as markers of aggressive HCC biology]. The authors operated on the hypothesis that these markers were expressed in post-TACE hypoxic areas, and by implication contributed to a selection of aggressive clone that recurred. Out of 40 recurrent tumors, 19 expressed CAIX (versus 2/17 in untreated controls). They found that only recurrent tumors expressing CAIX co-expressed CK19 (6 of 19 tumors) and EpCAM (7/19), although EpCAM and CK19 were only co-expressed in 3 of 7 tumors that expressed EpCAM. This finding concluded that TACE paradoxically selected for aggressive tumor phenotype by causing hypoxia, which in turn “may trigger the expression of proteins that are normally associated with cholangiocytic/progenitor cell.

Journal of Gastroenterology and Hepatology, Sept-Oct 2015

Clinical outcomes of cryptogenic compared with non-cryptogenic cirrhosis: A retrospective cohort study
Mohammed OK. et al. Journal of Gastroenterology and Hepatology, 2015, 30(9):1423-8.

The consequences of cryptogenic versus non-cryptogenic cirrhosis were compared in a large, single academic center over 5-year duration. The study included 301 patients with cirrhosis (94 cryptogenic and 207 non-cryptogenic). Compared with non-cryptogenic cirrhosis, patients with cryptogenic cirrhosis were older (mean age 66.4 vs 60.7 years), had more females (43.6% vs 26.6%), had less disease severity (Child–Pugh C 8.5% vs 15.9%), and had a higher prevalence of the metabolic syndrome (83% vs 51.2%). Cryptogenic cirrhosis is associated with a longer duration of hospitalization compared with non-cryptogenic cirrhosis at an early stage of the disease. This difference is due to a greater burden of non-liver-related complications in the former. Kaplan–Meier survival analysis showed no significant differences in survival between both types of cirrhosis for all grades of severity.

Hepatology, Sept-Oct 2015

The Significance of Nonobstuctive Sinusoidal Dilation of the Liver: Impaired Portal Perfusion or Inflammatory Reaction Syndrome.
Marzano C, Cazals-Hatem D, Rautou PE et al. Hepatology. 2015 Sept;62:956-963.

This very nice review highlights conditions associated with nonobstructive sinusoidal dilation and discusses the pathogenic roles played by interleukin-6, Notch1 and VEGF.

Hepatic Lipid Droplet Biology: Getting to the Root of Fatty Liver.
Mashek DG, Khan SA, Sathyanarayan A et al. . Hepatology. 2015 Sept;62:964-967.

This review highlights recent advances in our knowledge of lipid droplet biology and associated liver disease.

The Severity of Steatosis Influences Liver Stiffness Measurement in Patients with Nonalcoholic Fatty Liver Disease.
Petta S, Maida M, Macaluso FS, et al. Hepatology. 2015 Oct;62:1101-1110.

In many chronic liver diseases (CLDs), the risk of liver-related and overall mortality, as well as therapeutic decision-making, is linked to the fibrosis stage.  Methods for noninvasive and rapidly performed point-of-care testing are being sought, especially for highly prevalent CLDs such as NAFLD. Vibration-controlled transient elastography (VCTE) by Fibroscan, which uses liver stiffness measurement (LSM) as a surrogate of liver fibrosis, has been validated in viral hepatitis. The authors of this paper assessed the impact of liver steatosis severity on LSM values and transient elastography accuracy in a 253 patient cohort of biopsy proven NAFLD. They report that among patients with low amounts of fibrosis (F0-F1 and F0-F2), median LSM values were significantly higher in subjects with severe steatosis (>66% on liver biopsy) and that about one-third of the subjects with BMI >30 kg/m2 had an unreliable LSM. They conclude that in patients with severe steatosis, LSM might overestimate liver fibrosis.

Salivary Microbiota Reflects Changes in Gut Microbiota in Cirrhosis with Hepatic Encephalopathy.
Bajaj JS, Betrapally NS, Hylemon PB et al. Hepatology 2015 Oct;62:1260-2171.

It has become well established that patients with cirrhosis have enteric dysbiosis and that an altered gut microbiome is associated with systemic inflammation and cirrhosis decompensation. The aim of this study was to evaluate the oral microbiome in cirrhosis and compare it with the stool microbiome. Ninety-day liver-related hospitalizations were also noted. The cohort consisted of 102 patients (43 with previous hepatic encephalopathy [HE]) and 32 age-matched controls. Thirty-eight patients were hospitalized within 90 days and these patients salivary dysbiosis was significantly worse and predicted this outcome independent of cirrhosis severity. Salivary inflammation was studied in an additional 86 age-matched subjects (43 controls and 43 patients with cirrhosis. Significantly higher inflammatory markers (interleukin-6 and interleukin-1β, secretory IgA and lower lysozyme and histatins 1 and 5 were found in the cirrhotic patients. The authors conclude that dysbiosis is present in both stool and saliva in cirrhosis patients and cirrhotic patients have impaired salivary defenses and worse inflammation. Salivary dysbiosis was greater in patients with cirrhosis who developed 90-day hospitalizations. These findings may reflect a global mucosal-immune interface dysfunction in cirrhosis.

Gut, Sept-Oct 2015

Impact of common risk factors of fibrosis progression in chronic hepatitis C.
Rueger S, Bochud P-Y, Dufour J-F. et al.  Gut.  2015;64:1605-1615

The authors follow 1461 Swiss patients with chronic HCV hepatitis who had at least 1 biopsy and an estimated date of infection.  The factors that were associated with accelerated fibrosis (defined as ≥0.13 Metavir fibrosis units per year) were identified.  Older age at infection, male sex, genotype 3, and route of infection (intravenous drug use) were associated with accelerated progression.  Age at infection was the strongest contributor to accelerated fibrosis followed by route of infection.  This was confirmed in other cohorts and by a meta-analysis.  Diabetes, BMI, and HIV infection were not associated with accelerated fibrosis progression.  Three single nucleotide polymorphisms were also associated with fibrosis progression.  Although the important factors that favor fibrosis progression are not modifiable the knowledge of these factors may help prioritize treatment of HCV infection.

Gastroenterology, Sept-Oct 2015

Liver Stem Cells: Experimental Findings and Implications for Human Liver Disease.
Michalopoulos GK, Khan Z. Gastroenterology. 2015;149(4):876-82.

Nice review of histologic and experimental aspects of liver stem cells. The review emphasizes that the potential of hepatocytes to rescue cholangiocytes is widely accepted, while the possibility of cholangiocytes giving rise to liver progenitor cells and hepatocytes is not supported by experimental studies and remains controversial. Some studies in mice suggest that cholangiocyte to hepatocyte transdifferentiation can occur and depends on inhibition of hepatocyte proliferation The ability of hepatocytes and cholangiocytes to serve as potential stem cells for each other may help prevent more effectively than tissue-specific stem cells.

Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.
Zucman-Rossi J, et al. Gastroenterology. 2015;149(5):1226-1239.

Comprehensive review on the genetics of hepatocellular carcinoma (HCC) including common abnormalities such as TERT promoter mutation (60%), TP53 and CTNNB1 mutations (25-30%), chromosomal aberrations [DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), homozygous deletions in chromosome 9 (CDKN2A)], and less frequently involved genes (AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2),. The potential for specific therapeutic approaches targeting the involved pathways is discussed. Based on genomic profiling data, 2 major molecular clusters (proliferation and nonproliferation) of HCC are described.

Clinical Gastroenterology and Hepatology, Sept-Oct 2015

Association Between Endogenous Sex Hormones and Liver Fat in a Multiethnic Study of Atherosclerosis
Lazo M et al. Clin Gastroenterol Hepatol. 2015;13(9):1686-1693
Metabolic abnormalities are considered the major cause for Nonalcoholic fatty liver disease (NAFLD). In previous studies with small sample size, the association between circulating sex hormones and metabolic abnormalities has been reported. The current study is however the first large cohort study to evaluate the association between circulating sex hormones (testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG)) and fatty liver; included are 2835 postmenopausal women and 2899 men aged 45-84 years.. The data indicated that 1) higher levels of estradiol are associated with fatty liver in both men and women independent of demographic, anthropometric, and cardiometabolic risk factors. 2) Postmenopausal women with high level of bioavailable testosterone are at greater risk for fatty liver than women with low levels. 3) In men, higher levels of SHBG are associated with reduced risk for fatty liver.

Journal of Hepatology, September 2015

Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis.
Lanthier N et al.  Journal of Hepatology 2015; 63: 609-621.

Alcoholic hepatitis (AH) is a distinct manifestation of alcoholic liver disease that is associated with significant morbidity and mortality. Many scoring systems have been developed to assess the disease severity of AH. However, there is no ideal prognostic scoring system for clinical use. In this study, Lanthier et al. investigated the association of liver progenitor cell (LPC), macrophage and gene expression patterns with prognosis of AH. Liver biopsies obtained from AH and abstinent alcoholic cirrhotic patients were studied by immunohistochemistry and microarray gene expression. The related cytokines in serum from AH and control patients were also measured. CD68+ macrophages, CK7+/ki-67- and CK7+/Ki67+ LPCs were increased in AH compared to abstinent cirrhosis. In the follow-up study, patients with significant expansion of liver macrophages and a high number of proliferating hepatocytes as well as proliferating LPCs showed a better outcome. In addition, when compared to controls, an obvious upregulation of genes involved in cell cycle, mitosis and proliferation pathways, as well as a high expression of SPINK1 was found in AH patients. The study suggested that increased proliferating hepatocytes and LPCs, high expression of certain genes, and macrophage expansion in biopsy samples might act as markers for favorable outcome. The data from the gene expression study provided important information to help identifying the potential targets for AH treatment.

Prepared by:
Rish Pai, MD, PhD; Mayo Clinic Arizona
Sanjay Kakar, MD; University of California, San Francisco
Cindy Guy, MD; Duke University
Wenqing Cao, MD; New York University
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto
Charles Lassman, MD; University of California, Los Angeles

Journals Reviewed
American Journal of Surgical Pathology, Modern Pathology, Histopathology, Human Pathology, American Journal of Clinical Pathology, Journal of Pathology, Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, Hepatology, Journal of Hepatology, Liver Transplantation, Gastroenterology, Gut, Clinical Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, American Journal of Gastroenterology, Nature

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