HPHS Journal Watch: July/August 2018

Advances in Anatomic Pathology

An Update on the Clinicopathologic Features and Pathologic Diagnosis of Hepatitis E in Liver Specimens.
Lenggenhager D,  Weber A. Adv Anat Pathol 2018;25:273–281.
This review paper highlights how to diagnose hepatitis E (HEV) on liver specimens. Once thought to be a self-limiting waterborne infection restricted to developing countries where it had its worst impact on pregnant women, it has become clear for nearly a decade that HEV is more common in industrialized countries than previously known. The seroprevalence is 30% in France and up to 21% in the US. Molecular detection of HEV RNA in the blood is over a short viremic period of about 3 weeks. In stool samples, the virus is detectable for an additional 2 weeks. Molecular detection is more robust than antibody-based serological testing. Acute HEV infection can be in the typical acute hepatitis pattern. The cholestatic pattern can show swollen hepatocytes, rosette formation and bilirubinostasis. Immunocompromised patients may get chronic HEV infection with rapid progression to cirrhosis. Chronic HEV can look similar to those of chronic viral HBV or HCV. Ancillary tools are necessary to help make the diagnosis given the nonspecific and overlapping morphologic histologic features. PCR targeting the ORF2 and 3 gene region of the virus can be done on formalin-fixed paraffin embedded tissues. In situ RNA testing is specific but less sensitive than PCR. Immunohistochemistry using ORF2 antibody can be useful particularly in immunocompromised patients.

Clinical Gastroenterology and Hepatology

Nonalcoholic Fatty Liver Disease Associates With Increased Overall Mortality and Death From Cancer, Cardiovascular Disease, and Liver Disease in Women but Not Men.
Hwang YC, Ahn HY, Park SW, Park CY. Clin Gastroenterol Hepatol 2018;16:1131–1137.
Using a large health study database of 318,224 people from Korea, followed for a median of 5.7 years, the causes of mortality were identified in subjects with NAFLD. The prevalence of NAFLD determined by ultrasound was 26%. The cumulative mortality rate was 0.51%, with cancer being the highest cause of death. In men, having NAFLD at baseline was not associated with overall cardiovascular or liver associated death. Women with NAFLD at baseline had higher cancer related and liver related mortality. Having liver fibrosis had an additional risk of death compared to NAFLD alone in women as well. In men, neither obesity nor NAFLD alone was associated with cancer-related mortality. Cardiovascular-related mortality was increased in men who had either obesity or NAFLD alone. In women, having either obesity or NAFLD alone was associated with increased overall and cancer related mortality, although the combination of the 2 conditions did not confer additional predictive power for mortality. In women, cardiovascular and liver related mortality was increased when they had both obesity and NAFLD. The study concludes that the impact of NAFLD appears stronger in women than in men, with NAFLD associating more closely with obesity metabolic syndrome and inflammation in women than in men, which may explain the higher mortality rate.
High Prevalence of Liver Fibrosis Among European Adults With Unknown Liver Disease: A Population-Based Study.
Caballería L, Pera G, Arteaga I, et al. Clin Gastroenterol Hepatol 2018;16:1138–1145.
This population-based, cross-sectional study investigated the prevalence of liver fibrosis as evaluated by transient elastography using Fibroscan with M probe. Three thousand fourteen participants were randomly chosen from a total of 162,950 subjects between 18-75 years. Those with a history of liver disease were excluded. In 92 subjects, a liver biopsy was performed and assessed by 2 liver pathologists blinded to the liver stiffness measurement. Risk factors associated with increased liver stiffness included male gender, abdominal obesity, type 2 diabetes, serum glucose level, triglyceride levels, and increased AST or ALT levels. Comparing biopsy to liver stiffness measurement, patients with F0 to F1 had measurement of 8.4, whereas those with F4 had a measurement of 30.8kPa. Per the table listed in the article, 53% of those with F0 had liver stiffness measurement of greater than 8.0kPa. The authors state that using a cutoff of >6.8kPa, 32% of the the patients had significant liver fibrosis, but using a cutoff of >9.0 kPa, 65% of the patients had significant liver fibrosis (defined by F1-F4). This gave a sensitivity of 93%, specificity of 78%, and predictive accuracy of 83%. They propose a screening algorithm that starts with a detailed medical history identifying risk factors for liver fibrosis, followed by calculating fatty liver index, and then screening with transient elastography for only those with risk factors and a fatty liver index >60. They suggest that transient elastography can be useful for screening for liver fibrosis in the community.


Hepatic elastin content is predictive of adverse outcome in advanced fibrotic liver disease.
Kendall TJ, Dolman GE, Duff CM, et al. Histopathol 2018;73(1):90-100.
Elastin is an extracellular matrix (ECM) protein conferring elastic recoil to tissues. The aim of this study was to determine if elastin content in needle core native liver biopsies was predictive of clinical outcome in patients with chronic hepatitis C virus-related chronic liver disease. The authors evaluated elastin contents in liver biopsies by image analysis and correlated it with outcome in patients with advanced (Ishak stage ≥5) chronic hepatitis C virus-related chronic liver disease. Elastin content (but not absolute scar content or Ishak stage) was predictive for future clinical outcomes. In a cohort of patients without sustained virological response, the median hepatic elastin content was 3.4%, and 17 patients (57%) progressed to a liver-related clinical outcome; 11 of the 15 patients (73%) with a hepatic elastin content of >3.4% progressed to a clinical outcome, as compared with only six of 15 (40%) with an elastin content of <3.4%. The difference in time to outcome was significant. This study describes a simple and reproducible method for elastin quantification in liver biopsies that provides potentially valuable prognostic information to inform clinical management.
Hepatic angiomyolipoma: mutation analysis and immunohistochemical pitfalls in diagnosis.
Yan Z, Grenert JP, Joseph NM, et al. Histopathol 2018;73(1):101-108.
Hepatic angiomyolipoma (AML) often shows epithelioid morphology with inconspicuous fat and can mimic hepatocellular adenoma (HCA) or carcinoma (HCC). This study examines the expression of commonly used markers for HCA or HCC in hepatic AML and highlights pitfalls in diagnosis. 16 resected cases of AML were stained with reticulin, LFABP, glutamine synthetase (GS), beta catenin, CD68 and CD117.  Sanger sequencing of exon 3 of CTNNB1 and next-generation sequencing (NGS) was also performed. High-risk histological features were often present in tumors with benign outcome: marked atypia (19%), mitoses (20%) and necrosis (33%). GS staining (≥10% of tumor) was seen in epithelioid components in 13 (87%) cases, and was diffuse (>50% of tumor) in six (40%) cases. LFABP staining or nuclear beta catenin staining was not seen in any case. Sanger sequencing and NGS did not reveal CTNNB1 mutation in any tested case. NGS demonstrated TSC2 mutations in all five cases tested. The authors conclude that absence of LFABP and presence of fat can be mistaken for HNF1a-inactivated HCA. Diffuse GS staining can be mistaken for b-catenin-activated HCA or HCC. Diffuse GS expression is not related to CTNNB1 mutation. All tested cases showed TSC2 mutation, supporting this as the driving genetic event for hepatic AML.
Hepatic granulomas: a 17-year single tertiary centre experience.
Gaspar R, Andrade P, Silva M, et al. Histopathol 2018;73(2):240-246.
The reported incidence of granulomas in liver biopsies ranges from 1 to 15%. The authors assess the clinical relevance, presenting features and underlying aetiology in a non-transplant, tertiary referral center. During the 17-year study period (January 1998–December 2014), 9374 biopsies were performed and granulomas were found in 297. Of these, 57 were excluded. Overall, the most common etiology was tuberculosis (35.8%), followed by primary biliary cholangitis (PBC) – 15.0%. In 30 patients (12.5%) granulomas were idiopathic. From 1998 to June 2006 there were 147 granulomas in 5304 biopsies (2.8%), a frequency that did not change significantly compared to the period from July 2006 to December 2014 (93 granulomas in 4070 biopsies, 2.3%, P > 0.05). However, for the majority of cases (61.9%) there was a shift in granuloma etiology during the former time-period that infectious diseases were responsible, whereas in the latter, autoimmune liver diseases (43%) were the main etiology. The authors conclude that hepatic granulomas can result from various infectious and non-infectious diseases. During recent years, an epidemiological shift regarding granuloma etiology was observed, from systemic infectious diseases to non-infectious, mainly immune-mediated primary liver disorders.

Liver transplantation

Morphological characterization of chronic antibody-mediated rejection in ABO-identical or ABO-compatible pediatric liver graft recipients.
Dao M, Habès D, Taupin JL, et al. Liver Transpl 2018;24(7):897-907.

This study aims to define the morphological profile associated with the presence of donor‐specific antibodies (DSAs) and/or C4d immunostaining in ABO‐identical or compatible pediatric liver grafts. The authors study a cohort of 53 cases with a 10‐year protocol biopsy aims to define the morphological changes associated with the presence of DSA and/or C4d immunostaining in liver grafts, in order to refine the diagnosis criteria of cAMR. All biopsies demonstrated fibrotic changes with a mean liver allograft fibrosis score (LAFSc) of 5.1 ± 2.2. A total of 31 (58%) biopsies exhibited C4d positivity. DSAs were detected in 20 (45%) patients. LAFSc, perivenular fibrosis and portal inflammation were significantly higher in the double‐DSA and C4d‐positive group versus the double‐negative group. The authors defined a histological scoring system from these results, which was integrated with the 2016 Banff definition and allowed reclassifying patients for the diagnosis of chronic active antibody‐mediated rejection (cAMR; 11/53 versus 13/53). Their study confirmed that perivenular fibrosis and portal inflammation in late pediatric liver graft biopsies are features of cAMR.

American Journal of Surgical Pathology

A Point-based Histologic Scoring System for Hepatocellular Carcinoma Can Stratify Risk of Posttransplant Tumor Recurrence.
Roberts DE, Kakar S, Mehta N, et al. Am J Surg Pathol 2018;42(7):855-865.
Eligibility for liver transplant in patients with HCC relies on tumor size and number that is based on radiographic assessment. However, the pre-operative radiographic impression and pathologic assessment of explanted livers for HCC has been shown to be discordant in up to 30% of cases. The goal of this study was to determine whether certain histologic features were associated with tumor recurrence after transplant. Evaluation of 109 explanted livers showed that scirrhous and solid growth patterns, nuclear pleomorphism, nuclear-to-cytoplasmic ratio, and cytoplasmic amphophilia were found to be high-risk histologic features. Assigning points based on these parameters, the total score was called the Recurrence Risk Assessment Score (RRAS). The authors then validated the RRAS performance in a separate cohort of 81 explants in predicting tumor recurrence. When compared against conventional tumor grade by WHO histologic criteria, the RRAS was superior in predicting HCC recurrence. This study provides further support that histologic evaluation may provide another useful, if not better, method of predicting HCC recurrence as compared to radiographic studies alone.

Archives of Pathology and Laboratory Medicine

Factors Impacting the Performance Characteristics of Bile Duct Brushings: A Clinico-Cytopathologic Analysis of 253 Patients.
Hacihasanoglu E, Memis B, Pehlivanoglu B, et al. Arch Pathol Lab Med 2018;142(7):863-870.
The goal of this study was to determine the performance of bile duct brushings (BDBs) in detecting malignancies over a span of 15 years at a major academic medical center. 253 cases with at least 18 months of histopathologic or clinical follow-up were reviewed. Overall, the authors found BDBs to have a sensitivity of 35%, specificity of 100%, positive predictive value of 100%, negative predictive value of 58%, and accuracy of 66% in detecting malignancy. In addition, a number of detailed analyses and statistics were generated, including various grouping of diagnostic categories (from benign, atypical, suspicious, and malignant), comparison of conventional smears to ThinPrep, accounting for stent effects, categorizing the type of carcinoma, and evaluating test performance over time. In brief, the finding that sensitivity nearly doubled and accuracy increased while specificity and positive predictive value only minimally decreased when atypical, suspicious, and malignant categories were combined suggests that further refinement in atypical and suspicious categories may be helpful. Also, in cases where patients had a history of stenting, the statistics generated suggest that cases were only diagnosed as malignant when cytologic features were unequivocal.

Human Pathology

Bim is an independent prognostic marker in intrahepatic cholangiocarcinoma.
Zhang H, Jenkins SM, Lee CT, et al. Hum Pathol. 2018;78:97-105.
Bim protein is an important cell apoptosis initiator that can be altered in tumorigenesis.  The authors analyzed the correlation of Bim expression by immunohistochemistry with various clinicopathological features and survival in a cohort of 56 patients with intrahepatic cholangiocarcinoma.  Nineteen of 56 (34%) tumors had high Bim expression (>10%).  Patients who had tumors with high Bim expression had significantly longer overall survival than those with low or no staining.  Additionally, high Bim expression correlated with low Ki-67 index and lack of lymph node metastasis at the time of surgery.  The study findings suggests Bim is an independent prognostic marker in intrahepatic cholangiocarcinoma.
Mucinous intrahepatic cholangiocarcinoma: a distinct variant.
Chi Z, Bhalla A, Saeed O, et al. Hum Pathol 2018;78:131-137.
In this retrospective study from a tertiary medical center with a large volume of hepatectomies, mucinous variant of intrahepatic cholangiocarcinomas (n=7) were compared to conventional intrahepatic cholangiocarcinomas (n=79).  This study describes demographic, histopathologic, immunohistochemical, and molecular findings specific to mucinous intrahepatic cholangiocarcinomas.  This variant presents at advanced stage upon diagnosis with shorter survival time compared with conventional type cholangiocarcinomas.
Resection of the largest reported hepatic small vessel neoplasm.
Walcott-Sapp S, Tang E, Kakar S, et al. Hum Pathol 2018;78:159-162.
A case report describing a large hepatic small vessel neoplasm with characteristic morphologic and staining features, which underscores consideration for his entity regardless of lesion size.


Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study. Costentin CE, Layese R, Bourcier V, et al. Gastroenterol 2018;155(2):431-442.
This multi-center study aimed to determine how compliance with hepatocellular carcinoma semi-surveillance guidelines affects survival times of patients with HCV and HBV-associated compensated cirrhosis who developed HCC.  216 patients with detected HCC with biopsy-proven viral cirrhosis were included.  After lead-time adjustment, overall survival time was longer in patients compliant with surveillance guidelines (53.2 months) than noncompliant patients (25.4 months).  This study offers the most robust evidence available of a survival benefit with six-month HCC surveillance and strongly supports the implementation of interventions aiming at improving patients’ compliance.
Incidence of Hepatocellular carcinoma in Patients with HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents.
Calvaruso V. Gastroenterol 2018;155(2):411-421.
Studies have produced conflicting results of the incidence of hepatocellular carcinoma (HCC) in patients with in hepatitis C virus (HCV)-associated cirrhosis treated with direct-acting antivirals (DAAs).  This was a large prospective study of 2, 249 consecutive patients with HCV-associated cirrhosis treated with DAAs were followed.  At 1 year after exposure to DAAs, HCC developed in 2.1% of patients with Child-Pugh class A with an SVR and 6.6% of patients with no SVR; and in 7.8% of patients with Child-Pugh class B with an SVR and 12.4% of patients with Child-Pugh class B.  This study demonstrated that the SVR to DAA treatment decreased the incidence of HCC over a mean follow-up of 14 months.


Macrotrabecular-Massive Hepatocellular Carcinoma: A Distinctive Histological Subtype with Clinical Relevance.
Ziol M, Pote N, Amaddeo G, et al. Hepatology 2018; 68(1): 103-112.
The authors report a series of “macrotrabecular-massive” hepatocellular carcinoma (MTM-HCC), defined as the presence of >50% macrotrabecular architecture (more than six cells thick). They retrospectively reviewed 237 HCC resections and 284 HCC biopsies, and identified MTM-HCC in 12% of the whole cohort. It was associated with poor prognostic factors, including tumor size, AFP level, satellite nodules, and vascular invasion. It was an independent factor of early and overall recurrence. There is an editorial on the paper by Dr. David Kleiner in the same issue.
cHCC-CCA: Consensus Terminology for Primary Liver Carcinomas With Both Hepatocytic and Cholangiocytic Differentiation.
Brunt E, Aishima S, Clavien PA, et al. Hepatol 2018; 68(1): 113-126.
This article is a consensus paper from an international group of pathologists, radiologists, and clinicians and gives recommendations for working terminology surrounding combined hepatocellular-cholangiocarcinoma (cHCC-CCA). They recommend the diagnosis be based on H&E, with immunostains being supportive of the diagnosis. Other recommendations include morphologically typical HCC with positive CK19 or other markers of “stemness” should NOT be called cHCC-CCA, and morphologically typical CCA with only immunohistochemical expression of hepatocytic or stem-cell markers should NOT be called cHCC-CCA. They also recommend “there should no longer be formal diagnostic subtypes based on the identification of stem/progenitor cells, but rather if stem/progenitor cell features are observed, they are noted in a comment as ‘stem/progenitor cell features present.’” The paper is essential reading for anyone who routinely diagnoses primary liver carcinomas.
Polycystic Liver Disease: Hepatic Venous Outflow Obstruction Lesions of the Noncystic Parenchyma Have Major Consequences.
Barbier L, Ronot M, Aussilhou B, et al. Hepatol 2018; 68(2): 652-662.
The authors retrospectively reviewed 125 cases (resection or transplantation) of polycystic liver disease and evaluated for features of hepatic venous outflow obstruction (HVOO), seen in 92% of the cases, and correlated the findings with clinical parameters.

Modern Pathology

Progression and regression of fibrosis in viral hepatitis in the treatment era: the Beijing classification.
Theise ND, Jia J, Sun Y, et al. Mod Pathol 2018; 31:1191–1200.
New staging system, the Beijing Classification, for assessment of liver biopsies from patients with treated chronic viral (B and C) hepatitis. The Beijing Classification includes extent (stage) of fibrosis, and adds quality of fibrosis to the staging in order to clarify presence of regressive vs progressive fibrosis.
Journal of Gastroenterology and Hepatology
Role of heat shock factor 1 expression in the microenvironment of intrahepatic cholangiocarcinomas.
Kawashita H, Morine Y, Saito Y, et al. J Gastroenterol Hepato 2018;33(7):1407-1412.
Clinical significance and biological effect of Heat shock factor 1 (HSF1) expression in intrahepatic cholangiocarcinoma (IHCC) remain unknown. Specimen from forty‐nine patients with intrahepatic cholangiocarcinoma (IHCC) who underwent hepatic resection was stained with HSF1 immunostain. HSF1 expression was significantly higher in tumors than in normal tissue. The overall survival rate was significantly lower in patients with high than low HSF1. Multivariate analysis showed that high HSF1 expression was a factor independently prognostic of patient survival.

American Journal of Clinical Pathology

Detection of Albumin Expression by RNA In Situ Hybridization Is a Sensitive and Specific Method for Identification of Hepatocellular Carcinomas and Intrahepatic Cholangiocarcinomas. 
Lin F, Shi J, Wang HL, et al.  Am J Clin Pathol, 150: 58–64.
Ever wonder what the data is regarding the detection of albumin expression by ribonucleic acid (RNA) in situ hybridization in HCC, ICCs, and carcinomas from various organs using manual and automated staining?  This original article addresses the utility of RNAscope (Advanced Cell Diagnostics, Hayward, CA) employing 482 cases on tissue microarray sections and on 22 cases of ICCs.  This study concludes that RNAscope for albumin is highly sensitive and specific for identifying HCCs and is highly specific and moderately sensitive for detection of ICCs.  Further, rare non-HCC and non-ICC, can also have aberrant expression of albumin. 

Journal of Hepatology

European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. 
Thursz M, Gual A, Lackner C, et al. J Hepatol. 2018 Jul;69(1):154-181.
The July publication of J. of Hepat contains the current clinical practice guidelines for alcohol-related liver disease.  While many clinical aspects are addressed, the article merits a closer read by pathologists specifically regarding the importance of our role in diagnosis, identification of co-morbidities, and in provision of prognostic pathological features. 
Hepatology Snapshot: Drug-induced chronic liver injury.
Dakhoul L, Ghabril M, Chalasani N.  J Hepatol. 2018 Jul;69(1):248-250.
Visit this extremely helpful, easy to use, and guaranteed to make your signouts more efficient tabular illustration of drug induced liver injury by causative agents detailing distinguishing histopathological findings and helpful clinicopathological features. 
Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; Mayo Clinic, Rochester
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Eric Yee MD; University of Arkansas for Medical Sciences
Maria Westerhoff MD; University of Michigan

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