Journal Watch May-June 2015

American Journal of Surgical Pathology, June 2015

Hyaline Droplets in Kupffer Cells: A Novel Diagnostic Clue for Autoimmune Hepatitis.  
Tucker SM, et al.  Am J Surg Pathol. 2015 Jun;39(6):772-8.

The authors of this study compare autoimmune hepatitis liver biopsies from 30 children to those with hepatitis B and hepatitis C in order to identify any characteristic histologic features of pediatric autoimmune hepatitis.  In half of the pediatric autoimmune hepatitis cases, hyaline droplets were identified in Kupffer cells.  Hyaline droplets were associated with markedly elevated serum IgG levels, and immunohistochemical analysis demonstrated that the globules were positive for IgG, occasionally for IgA, and rarely for IgD.  None of the biopsies from pediatric patients with hepatitis C contained hyaline droplets.  Only one patient with hepatitis B contained hyaline droplets.  The hyaline droplets were readily identified on a PAS/D stain.  The well circumscribed globular and waxy appearance of the hyaline droplets separates it from other material often seen within Kupffer cells.  The authors suggest that hyaline droplets within Kupffer cells can be helpful in the diagnosis of autoimmune hepatitis.  

Am J Pathology, June 2015

Profiles of Cancer Stem Cells Subpopulations in Cholangiocarcinomas. 
Cardinale V et al. Am J Pathol 2015 Jun;185(6):1724-1739

Cancer stem cells (CSCs) from human cholangiocarcinoma (CCA) subtypes (mucin-secreting intrahepatic and perihilar versus a peripheral mixed subtype) where characterized for immunohistochemical markers and tumorogenic potential (subcutaneous injection versus injection into normal and cirrhotic murine livers). The authors found that human CCAs were rich in CSCs and that CSC subpopulations generate different types of cancers depending on the microenvironment.

Histopathology, Apr-Aug 2015

Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma.
Qu, P, et al.  Histopathology. 2015 Apr;66(5):706-14.

Abnormal nuclear expression of Pygopus-2 in human primary hepatocellular carcinoma correlates with a poor prognosis.

Zhang, S, et al.  Histopathology. 2015 Aug;67(2):176-84.

Low expression of B-cell associated 31 protein in human primary hepatocellular carcinoma correlates with a poor prognosis

Tan, N., et al.  Histopathology. 2015 May 15.

Three papers published recently in Histopathology found three separate markers that correlated with various adverse outcome indices of hepatocellular carcinoma. These are loss of CD155, an immune modulator (Histopathology. 2015 Apr;66(5):706-14); abnormal nuclear expression of Pygopus-2, a co-activator of the Wnt/b-catenin transcriptional and an enhancer of b-catenin function (Histopathology. 2015 Aug;67(2):176-84.); and low expression of BAP31, a B-cell receptor associated protein which when depleted with EpCAM, decreased cyclins D1 and E expression causing suppression PI3K/Akt signaling (Histopathology. 2015 May 15. Epub ahead of print]). The three studies found these three markers to be independently predictive of tumor biology and/or outcome.  Concerning CD155, Qu P. et al found that loss of CD155 expression by immunohistochemistry was associated significantly with “higher serum alpha-fetoprotein level (P = 0.016) and a higher incidence of portal vein tumour thrombus (P = 0.050)”. Also patients with retained expression of CD155 had “better overall survival after surgery than those with negative CD155 expression (P = 0.005)”.
Concerning Pygopus-2, Zhang S et al. reported that abnormal nuclear Pygopus-2 “… expression in HCC patients was associated with age (P = 0.025), tumour size (P = 0.005), intra- or extra-hepatic metastasis (P = 0.029), vascular invasion (P = 0.026) and tumour differentiation (P = 0.004)”, while patients with normal expression had better short term (1-year) and long term survival. A third marker, the B-cell receptor associated protein BAP31, operates at the level of endoplasmic reticulum (ER). The authors based their premises on recent report that ER stress was related to the hepatocellular carcinogenesis and development. Since BAP31 with EpCAM depletion had been reported to reduce cyclins D1 and E causing growth advantage the authors decided to investigate the role of BAP31. Using relative intensity of expression (rather than a positive-negative algorithm), the authors found that “decreased” expression of BAP31 correlated with poor overall survival.
It is difficult to say at these early stages how much a role, if any these prognostic markers will play in clinical management of hepatocellular carcinoma, but just like CK19 before them, they require continuing monitoring as confirmatory (or refuting) evidence unfolds.

Modern Pathology, June 2015 

DNAJB1-PRKACA is specific for fibrolamellar carcinoma 
Graham RP, et al. Mod Pathol. 2015 Jun;28(6):822-9.

In this study, RT-PCR and FISH assays to detect the rearrangements of PRKACA locus were performed on a total of 106 primary liver tumors to test the diagnostic specificity for fibrolamerllar hepatocellular carcinoma. RT-PCR was successful in 92% of tested fibrolamellar carcinoma cases (24/26) and the DNAJB1-PRKACA fusion transcript was not detected in other tumor types, including conventional hepatocellular carcinoma, cholangiocarcinoma, hepatic adenoma, and hepatoblastoma. In addition, FISH and RNA in situ hybridization displayed similar results. In summary, detection of DNAJB1-PRKACA fusion is sensitive and specific to support the diagnosis of fibrolamellar carcinoma.

Liver Transplantation, June 2015

Donation after Cardiac Death Liver Transplantation: Graft Quality Evaluation Based on Pretransplant Liver Biopsy.  
Xia W, et al.  Liver Transplantation.  2015 Jun;21(6):838-46.

Donation after cardiac death has been associated with inferior patient and graft survival.  Thus, many DCD livers are discarded due to concerns of inferiority.  In this study the authors assess the ability of liver biopsy to predict graft survival in 127 DCD liver transplants in China.  The biopsies were assessed for macrovesicular steatosis, hepatocyte swelling, hepatocyte vacuolation, hepatocyte necrosis, and sinusoidal neutrophilic infiltrate.  Factors associated with poor graft survival were macrovesicular steatosis greater than 20% [hazard ratio 2.9] and a sinusoidal neutrophilic infiltrate (> 2 sinusoidal neutrophils per high power field in the most affected area) [hazard ratio 6.9].  The donor characteristic that was associated with poor survival was a high total bilirubin.

Gut, May 2015

Pathobiology of Liver Fibrosis: A Translational Success Story.  
Ye YA, et al. Gut. 64(5):830-41.

In this review, Lee and colleagues discuss the recent developments in hepatic fibrosis with a particular focus on reversibility.  They discuss the cellular sources of fibrosis, the mechanism extracellular matrix deposition, and the pathways that lead to a fibrosis regression.  Antifibrotic therapies are also discussed.  This article may be of interest to those more interested in understanding the mechanisms of fibrosis and novel therapies aimed at reducing hepatic fibrosis.

Journal of Hepatology, June 2015

Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease.
Reilly NR et al. Journal of Hepatology 2015; 62: 1405-1411.

The association of celiac disease (CD) and non-alcoholic fatty liver disease (NAFLD) is unclear. This large population-based cohort study of 16,816 CD patients and 130,051 matched reference individuals with 10 years median follow-up reveals that individuals with CD have significantly higher risk of NAFLD compared to general population. Furthermore, their data indicates the risk of NAFLD is highest in children and is highly increased in the first year after the diagnosis of CD. The risk of NAFLD may persist over a long time (15 years).

Gastroenterology, June 2015

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. 
Chalasani N, et al.  Gastroenterology. 2015; 148(7):1340-1352.

This is an initial report from 1257 patients enrolled in a prospective study being done by Drug-Induced Liver Injury Network. DILI resulted in chronic liver disease in 17% of cases. Disease severity and mortality tended to be higher in patients with pre-existing disease.  Antimicrobial agents were the most common etiology for cases with a short latent period (≤7  days), while nitrofurantoin and minocycline were most commonly associated with long latency (>365 days). Cholestatic injury was more common in older individuals (>65 years)

β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis.
Monga SP. Gastroenterology. 2015; 148(7):1294-1310.

β-catenin activation has been implicated in hepatocellular neoplasms including adenoma and carcinoma either through mutations/deletions in β-catenin or involvement of other members of the WNT signaling pathway. β-catenin interacts with a variety of transcription factors including T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α, and can regulate the expression of many target genes. This extensive review discusses the role of β-catenin in metabolic zonation, and hepatocellular tumors.

Hepatology, May 2015

Hepatocyte Buds Derived from Progenitor Cells Repopulate Regions of Parenchymal Extinction in Human Cirrhosis

Stueck AE, Wanless IR. Hepatology 2015 May;61:1696-1707

The authors use immunohistochemistry for EpCAM, K19, CD34, glutamine synthetase and Ki-67 to investigate the origin of cells which repopulate the liver following parenchymal extinction lesions. Semiquantitative analysis of the morphologic sequence of hepatic “bud” maturation is described. The authors conclude that the stem/progenitor pathway is manifested by the bud sequence and that the majority of distal cholangiocytes have stem-like properties and the availability of bile ducts/or venous drainage are limiting facts for regeneration.

Hepatology, June 2015

Adaptive Remodeling of the Biliary Architecture Underlies Liver Homeostasis
Kaneko K, et al. Hepatology 2015 June;61:2056-2066.

The authors developed a novel imaging technique using infusion of ink containing carbon black into mice livers following various types of injury in order to visualize the global and fine-scale architecture of the regenerating biliary tree. They show the emergence and expansion of liver progenitor cells along with the structural transformation of the intrahepatic biliary tree. They conclude that the hepatobiliary system possesses structural flexibility and can remodel dynamically and adapt to various injury conditions.

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

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