Monday, July 30, 2018

HPHS Journal Watch: May/June 2018

Clinical Gastroenterology and Hepatology

Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple
Steatosis: A Systematic Review and Meta-analysis.

Verhaegh P, Bavalia R, Winkens B, et al. Clin Gastroenterol Hepatol. 2018;16(6):837-861.

This systematic review and meta-analysis studied whether noninvasive tests can differentiate nonalcoholic steatohepatis (NASH) from simple steatosis (SS). There were 122 studies evaluating 219 different blood markers and 22 other tests. Alanine aminotransferase had a pooled sensitivity of 63.5% and specificity of 74.4% to diagnose NASH. Ferritin had pooled sensitivity of 79.1%, specificity of 71.9%, and adinopectin had pooled sensitivity of 72.0% and specificity of 75.7%. The cleaved CK18-M30 as an assay had a pooled sensitivity of 68.4% and specificity of 74.2%. Of –omics approaches, the GlycoNASH test data had a pooled sensitivity of 67.1% and specificity of 63.8%. Scoring systems that combined blood markers, such as NASHTest (combining 10 markers with age, gender, weight, height, and SteatoTest positivity) showed specificity of 95.3% but sensitivity of 22.9% in differentially NASH from borderline NASH and SS. In summary, none of the pooled markers showed both sensitivity and specificity over 80%. More standardized study designs are needed as the majority of the studies contained only limited numbers of patients with significant fibrosis or did not provide the stages of fibrosis.

Acetaminophen-induced Acute Liver Failure Is More Common and More Severe in Women.
Rubin JB, Hameed B, Gottfried M, et al; Acute Liver Failure Study Group. Clin Gastroenterol Hepatol. 2018;16(6):936-946.

Acetaminophen overdose is the leading cause of acute liver failure (ALF) and acute liver injury (ALI), accounting for approximately 50% of all ALF cases. Previous data regarding drug-induced liver injury have shown that women are noted to be at increased risk for progressing to ALF and require subsequent transplant. From a national registry of 32 academic medical centers, 1162 patients with acetaminophen induced ALI (22%) or ALF (78%) were identified. Their presentation, clinical course, and overall survival between genders were studied. Sixty-eight percent (170) of acetaminophen induced ALI and 76% (864) of ALF patients were women. About half of patients with ALF had unintentional acetaminophen overdose and 40% were suicide attempts. More women than men co-ingested acetaminophen with sedating agents such as opioids or benzodiazepines (70% vs. 52%). On presentation, men had higher ALT, bilirubin, albumin, and MELD scores than women, but otherwise, weight-adjusted ALT was similar.  More women had severe clinical courses, including severe hepatic encephalopathy (68% women vs. 58% men), and need for critical care needs. However, transplant-free survival were similar between male and females.

Excellent Outcomes of Liver Transplantation Following Down-Staging of Hepatocellular Carcinoma to Within Milan Criteria: A Multicenter Study.
Mehta N, Guy J, Frenette CT, Dodge JL, et al. Clin Gastroenterol Hepatol. 2018;16(6):955-964.

This was a multi-center study using a standardized down-staging protocol (within Milan criteria) to assess outcomes of liver transplantation in such patients. The type of local regional therapy (LRT) was not standardized. Most received TACE alone or in combination with radio-frequency ablation.16% of patients were not down-staged to within Milan criteria. A factor predicting inability to achieve tumor down-staging was pre-treatment AFP≥1000. The number, size of tumors, MELD score, number of LRT sessions were not significant predictors of inability to be down-staged. Successful down-staging to Milan criteria was achieved in 83.4% (median 2.7 months). Majority were down-staged after a single LRT. Of those who were down-staged, 17% (28 of 156) had subsequent tumor progression and were dropped out of the waitlist. 58% of patients received liver transplant. Following transplant, the explanted liver showed tumor staging within Milan criteria in 45.9% of cases (T1/T2); 19.3% of cases turned out to be understaged by imaging and beyond Milan criteria (T3/T4). Median post-LT follow up was 4.3 years with a survival of 95% at 1 year and 80% at 5 years. HCC recurrence developed in 10% of patients at a median of 19.1 months from transplant. Predictors of recurrence included an AFP >500 and vascular invasion. Down-staging resulted in excellent overall 5-year post-LT survival of 80% and recurrence free probability of 87%. Only 7% had micro- or macro-vascular invasion. Treatment failure predictors included a pretreatment AFP of >1000 and Child’s B/C cirrhosis, suggesting that these patients should not be subjected to the risks of LRT.

Journal of Hepatology

Development of the liver: Insights into organ and tissue morphogenesis
Ober EA, Lemaigre FP.  J Hepatol 2018; 68 (5):1049-1062.

Employing the burgeoning modality of three dimensional imaging and distinct model organisms, this study illustrates the growing understanding of morphogenetic processes in the adult liver.  Stages from endodermal budding giving rise to an asymmetric liver, mechanisms leading to liver and lobe development, morphogenesis of the intra and extrahepatic bile ducts, its reaction to injury, and vascular development are discussed. 

Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors
De Martin E, Michot JM, Papouin B, et al. J Hepatol 2018; 68 (6): 1181-1190.   

The goal of this large scale and well organized study was to accurately evaluate the incidence of  hepatic immune related adverse events (IRAEs) in patients with metastatic cancer treated with anti-cancer anti-PD-1, anti-PDL1, and anti-CTLA-4 immunotherapy.  Using data gathered in 1,425 patients from August 2015 to August 2017 by the REISAMIC pharmacovigilance register, individuals who developed grade ≥3 hepatitis were identified according to the Common Toxicity Criteria for Adverse Events (CTCAE).  The severity of liver injury was classified according to the Drug-Induced Liver Injury Network (DILIN) 5-point scale.  Acute hepatitis due to cancer immunotherapy was reported in only 3.5% of treated patients.  Two distinct types of immune mediated hepatitis were described:  granulomatous hepatitis with fibrin depositis associated with anti-CTLA-4 mABs; and lobular, non-granulomatous hepatitis associated with anti-PD-1/anti-PDL1 mABs.  The authors concluded that liver biopsies have a key role in detailing the severity of injury and in providing guidance in treatment choices.

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. 
Wardell CP, Fujita M, Yamada T, et al. J Hepatol 2018; 68 (5): 959-969.

Biliary tract carcinomas (BTCs) are a heterogenous group frequently exhibiting poor response to treatment.  This study is a large-scale genome sequencing analyses of somatic and germline driver events and genomic landscape mapping to enhance comprehension of carcinogenesis, better classify, and improve treatment strategies of BTCs.  412 BTC samples were analyzed by whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing using subtypes of intrahepatic cholangiocarcinomas (ICCs), distal cholangiocarcinomas (DCCs), peri-hilar type cholangiocarcinomas (PHCs), and gallbladder or cystic duct cancers (GBCs/CDCs). 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some negatively affecting prognosis, were identified. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients.  Learn more and read about BTCs and their distinct genetic features including somatic events and germline predispositions.

Modern Pathology

Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury.
Zen Y, Yeh MM. Mod Pathol 2018; 31: 965–973.

The authors reviewed adverse effects of immune checkpoint inhibitors in liver and compared clinicopathologic features between checkpoint inhibitor-induced liver injury and acute autoimmune hepatitis or idiosyncratic drug-induced liver injury. They have seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2). They also performed IHC for B and T cell markers and found large numbers of CD3+ and CD8+ lymphocytes in immune checkpoint inhibitor treated livers. CD20+ B cells and CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in autoimmune hepatitis or drug-induced liver injury. They conclude that liver injury caused by cancer immunotherapy shares some features with autoimmune hepatitis; however, there are obvious differences between the two conditions.

Journal of Gastroenterology and Hepatology

Individual and combined effects of hepatitis B surface antigen level and viral load on liver cancer risk
Yang Y, Gao J, Tan YT, et al. J Gastroenterol Hepatol 2018 ;33(5):1131-1137. 

Hepatitis B surface antigen (HBsAg) and viral load are both hallmarks of hepatitis B virus (HBV) infection. The authors carried out a nested case–control study including 211 liver cancer cases and 221 controls who were seropositive for HBsAg within two populationbased cohorts. They found that elevated levels of HBVDNA and HBsAg are associated with increased risks of liver cancer. Compared with subjects with HBVDNA < 2000 IU/ml, the adjusted ORs increased from 2.11 (95%CI: 0.99–4.50) to 10.47 (95%CI: 5.06–21.68) for those with HBVDNA level at 2000–19 999 to ≥ 20 000 IU/ml. Compared with subjects at a low level of HBsAg (0.05–99 IU/ml), the adjusted ORs increased from 1.82 (95%CI: 0.90–3.68) to 2.21 (95%CI: 1.10–4.43) for those with HBsAg level at 100–999 to ≥ 1000 IU/ml.


Histological assessment of the liver explant in transplanted hepatitis C virus patients achieving sustained virological response with direct-acting antiviral agents. 
Putra J., Schiano TD., Fiel MI. Histopathol 2018;72(6):990-996.

Direct-acting antiviral agents (DAAs) have transformed the management of patients with chronic hepatitis C virus, and treatments are now associated with sustained virological response (SVR) rates of > 95 %.  With the success of DAAs, histologic examination for hepatitis C has, at least anecdotally, become less commonplace.  This study evaluated the histologic findings of both inflammation and fibrosis, of HCV patients who achieved SVR after receiving DAA treatment and compared them to the histologic findings of a control group of HCV patients who did not achieve SVR and did not receive DAA treatment.  The authors report a lack of demonstrable association between histologic findings and SVR status and persistent inflammation in HCV patients with SVR despite receiving DAAs.

Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study. 
Sasami M, Kuo FY, Huang CC, et al. Histopathol 2018;72(7):1164-1171.

Cellular senescence plays a role in the pathogenesis of various non-neoplastic diseases, including primary biliary cholangitis and other adult cholangiopathies.  This study investigated the role of cellular senescence, through established senescence markers p16, p21, and NCAM, in patients with biliary atresia, the most common form of pediatric obliterative cholangiopathy.  The study examined expression of these markers in bile ducts and bile ductules at early (Kasai procedure) and late (transplant) stages of biliary atresia and compared them to a normal control group.  Study findings indicate that increased expression of senescence regulators may be involved in the progression of biliary atresia in a manner similar to that observed in adult cholangiopathies.

American Journal of Pathology

Understanding Liver Regeneration: From Mechanisms to Regenerative Medicine.
Gilgenkrantz H, Collin de l’Hortet A. Am J Pathol 2018; 188(6): 1316-1327.

This review article summarizes the published data in the past five years in liver regeneration, discussing the mechanisms leading to regeneration disruption in chronic liver diseases.

Human Pathology

DJ-1 is a useful biomarker for invasive extrahepatic cholangiocarcinoma. 
Tabata Y., Nakanishi Y., Hatanaka Y., et al.  Hum Pathol. 2018;76:28-36.

Through a liquid -chromatography mass spectrometry-based proteomics approach, the authors previously reported that DJ-1 protein is up-regulated in cholangiocarcinoma compared with non-neoplastic bile duct epithelium.  Building on those findings, the authors evaluated expression of DJ-1 in patients with invasive extrahepatic cholangiocarcinoma (EHCC) by evaluating immunohistochemical (IHC) staining for anti–DJ-1 antibody and the impact of IHC staining score on postoperative survival.  Additionally, serum levels of DJ-1 in invasive EHCC patients with and without metastasis were compared.  Although limited by the number of patients studied, DJ-1 protein in IHC staining and serum examinations may offer a biomarker for prognosis in patients with invasive EHCC.

Low-level clonal FGFR2 amplification defines a unique molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population.
Pu XH., Ye Q., Yang J., et al. Hum Pathol. 2018; 76:100-109.

Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several tumor types, including intrahepatic cholangiocarcinoma (ICC).  Multiple clinical trials are under way for repurposing the drugs that target the FGF signaling pathway as an innovative ICC treatment.  In Western countries, the   frequency of FGFR2 fusions in ICC ranges from a reported 7%-45%.  This study assess the incidence of FGFR2 aberrations, including translocations and amplification, in Chinese patients.  122 ICCs were evaluated for translocations and amplifications of FGFR2 by fluorescence in situ hybridization as well as protein expression by immunohistochemistry.  The relationship between genetic aberrations and protein expression were then compared to clinicopathologic characteristics and prognostic outcomes.  Molecular aberrations were identified in 23/122 (19%) of tumors.  Low-level amplification of FGFR2 was twice as common as FGFR2 translocation; and these tumors were generally of lower stage and associated with better overall survival.

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
Cynthia Guy MD; Duke University
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

Friday, July 13, 2018

Interesting Case: July 2018

Case contributed by:
 Iván González, M.D., resident, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
Deyali Chatterjee, M.D., Assistant Professor, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO

Clinical History
A 71-year-old man with a history of orthotopic liver transplant in 2013 secondary to idiopathic hepatic artery dissection (without previous episodes of acute cellular rejection) presented five years later with transaminitis and hyperbilirubinemia (AST 596 U/L, ALT 743 U/L, alkaline phosphatase 203 U/L), preceded by a viral-like illness. An extensive infectious work-up was negative, other than a CMV viremia of 6447 IU/mL by PCR, for which he was treated with valganciclovir. Liver biopsy showed a mixed portal infiltrate, bile duct injury without ductular reaction, lobular neutrophilic microabscesses, and zone 3 injury with dropout and hemorrhage. He was treated with prednisone without improvement. Over the next 5 months, he developed worsening liver failure (AST 107 U/L, ALT 201 U/L, alkaline phosphatase 88 U/L, total bilirubin 36.6 mg/dl, direct bilirubin 35 mg/dl) and renal failure, and underwent a second liver transplant (explant images shown here).

Imaging Findings
Computed tomography demonstrated an aneurysmal dilatation of the celiac artery with marked short segment narrowing of the origin of the common hepatic artery.  ERCP did not reveal any biliary strictures.



The explant showed submassive hepatocellular necrosis with marked cholestasis, and markedly dystrophic changes in bile duct epithelium in the portal tracts, but there was no ductopenia. Ductular reaction was conspicuously absent. The portal tracts showed mild chronic inflammatory infiltrate, associated with mild focal endothelialitis, and reduced number of small arterial branches. Medium-sized bile ducts showed periductal fibrosis along with dystrophic epithelial changes. Large bile ducts showed foci of intraepithelial lymphocytes, and focal reactive changes. There was central perivenulitis, with foci of lobular microabscesses. There was no foam cell arterial lesion, fibro-muscular intimal thickening, or inflammatory infiltration of muscular arteries. Trichrome stain highlighted fine perisinusoidal fibrosis, extending to portal tracts, but there is no bridging fibrosis. Reticulin showed a largely preserved architecture. A cytomegalovirus immunostain was negative.

Histologic features of chronic rejection and ischemia.

We present an intriguing and unusual presentation of chronic rejection (CR).This challenging case was reviewed by several prominent pathologists within and outside our institution.

CR is an immune-mediated irreversible injury to the bile ducts, arteries and veins, that usually has an insidious onset and is often preceded by prior episodes of acute cellular rejection (ACR), that get progressively resistant to treatment. Nowadays less common with improved immunosuppression, another clinical setting includes a more acute presentation, with rapid progression of graft failure within a few weeks after transplantation. There can also be a late CR with insidious onset and indolent clinical course, without preceding ACR. The clinical course observed in our case, an accelerated clinical course although presenting late after transplantation (> 5 years), is therefore very unusual.

The histologic diagnostic features for CR include presence of dystrophic bile duct epithelium, bile duct loss, and foam cell obliterative arteriopathy. Some cases of late CR have also been reported to show chronic hepatitis-like changes.  As has been described with acute presentations of chronic rejection, this case showed prominent inflammatory infiltrate, including endothelialitis and perivenulitis, which initially raised the histologic concern for acute rejection. The patient however remained unresponsive in spite of marked immunosuppressive therapy, and over time in the course of a few months, the inflammation reduced (reflected by the decrease in liver enzymes) whereas the bile duct dystrophy became more conspicuous, characteristically with no ductular reaction. With these clinical and histologic features, this was deemed as an unusual course of CR.
With the abnormal imaging and operative finding of the small caliber of proximal hepatic artery, and due to histologic overlap with CR, a component of ischemic cholangiopathy could not be entirely excluded. 

Although rare, acute presentation of chronic rejection can occur at any time interval after transplantation. Although cases of chronic rejection presenting acutely can show histologic overlap with acute cellular rejection especially early in the clinical course, dystrophic biliary epithelial changes, absence of ductular reaction, and unresponsiveness to immune suppressive therapy should indicate development of chronic rejection. Ductopenia or foam cell arteriopathy may not be seen in these cases which have an accelerated clinical course.

1-     Burt A, Ferrell L, Hubscher S. MacSween’s Pathology of the Liver. 7th edition. Churchill Livingston Elsevier; 2018. Chapter 14, Transplantation Pathology. 
2-     Demetris A, Adams D, Bellamy C, et al. Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel. Hepatology 2000; 31(3): 792-799.
3-     Blakomer K, Jain A, Ruppert K, et al. Chronic liver allograft rejection in a population treated primarily with tacrolimus as baseline immunosuppression: long-term follow-up and evaluation of features for histopathologic staging. Transplantation 2000; 69(11): 2330-2336.
4-     Mourad M, Algarni A, Liossis C, Bramhall S. Aetiology and risk factors of ischaemic cholangiopathy after liver transplantation. World J Gastroenterol 2014; 20(20): 6159-6169.

Saturday, May 26, 2018

HPHS Journal Watch: March/April 2018

American Journal of Surgical Pathology
MDM2 is an independent oncogene and also a negative regulator of p53. A recent whole-exome sequencing study identified MDM2 amplification in 5% of cholangiocarcinomas. The investigators sought to determine the frequency of MDM2-amplified intrahepatic cholangiocarciomas (iCCAs) and evaluate their clinicopathologic features. The study cohort consisted of surgical resections from Korean and Japanese patients. Tissue microarrays (TMAs) were constructed and tested for MDM2 amplification by in situ hybridization. Tumors that showed MDM2 amplification on TMA had whole tissue sections made and were re-tested to assess for heterogeneity in MDM2 amplification. In addition, all MDM2-amplified and 25 MDM2-nonamplified iCCAs were sequenced for KRAS and IDH1/2 mutations. All cases were tested for SMAD4 expression by immunohistochemistry.
MDM2-amplification was found only in iCCAs with large-duct type morphology and comprised 6% of cases; amplification was diffuse in 77% of iCCAs. KRAS and IDH1 mutations were only detected in MDM2-nonamplified iCCAs. Loss of SMAD4 expression was more frequent in MDM2-amplified iCCAs. Patients with MDM2-amplified iCCAs had a worse survival than those without MDM2-amplification (median survival 16 vs. 28 mo., median follow-up 39 mo.); however, when comparing only patients with large-duct type morphology iCCAs, MDM2-amplified and MDM2-nonamplified patients showed no statistically significant difference in survival. In summary, this study identified that MDM2-amplification is present in a subset of iCCAs and MDM2 inhibitor therapy may play a role in the future.

Liver Transplantation
This review summaries the use of radiation therapy for hepatocellular carcinoma, makes comparisons with other local ablative therapies, and addresses potential novel strategies for optimizing future utility.
Currently, normothermic machine perfusion (NMP) of donor livers using packed red blood cells and fresh frozen plasma is being used in clinical trials, and some suggest it will revolutionize organ transplantation. This paper discusses using NMP with a new synthetic solution created from a polymerized bovine hemoglobin-based oxygen carrier and a gelatin-based colloid suspension as an alternative to using scare and expensive human blood products. Included is a brief discussion, with photomicrographs, of NMP-related histopathologic ischemia-reperfusion injury changes.

This is a nice and fairly comprehensive review of the interplay between the gut microbiota and the liver in health and disease. 

Clinical Gastroenterology and Hepatology
Classically, in adults, the histologic findings of NASH include zone 3 steatosis, inflammation, and ballooned hepatocytes. In children, on the other hand, fatty liver disease may have fewer ballooned hepatocytes, more portal based inflammation, and can have zone 1 steatosis. The purpose of this study was to determine clinically relevant associations between zone 1 vs. zone 3 steatosis in children. Liver biopsies of 776 pediatric patients were scored for degree and location of steatosis, inflammation (lobular & portal), ballooned hepatocytes, and fibrosis.
19% had zone 1 steatosis, 31% had zone 3, and the remaining were panacinar (42%) or azonal (8%). Compared with children with zone 3 steatosis, those with zone 1 steatosis were younger, more likely to be Hispanic, have higher fasting triglyceride levels, male, and have higher AST. Children with zone 3 steatosis had higher waist circumference and blood pressure.
Biopsies with zone 3 steatosis had more ballooned hepatocytes than those with zone 1, higher NAFLD activity score, and NASH. Those with zone 1 steatosis had more portal inflammation and more fibrosis, with 2.34 times the odds of having advanced fibrosis compared to zone 3 steatosis patients.
In conclusion, zone 1 vs. zone 3 steatosis in pediatric NAFLD have informative risk differences in fibrosis and steatohepatitis, with zone 1 patients being more likely to be younger, Hispanic, and male; importantly they are more likely to have fibrosis.

The authors report a case of a 50-year-old woman presenting with concurrent erythema multiforme and autoimmune hepatitis. Despite the presence of several confounding factors, the authors do a convincing job of establishing the diagnosis. There is a brief discussion regarding the challenge of distinguishing lupus-related hepatitis from autoimmune hepatitis, and the clinical significance of doing so.

The authors report an unusual case of hepatocellular carcinoma (HCC) presenting as a lateral eyebrow skin metastasis in an 83-year-old man who was subsequently found to have alcoholic cirrhosis. There is a brief discussion on the limited literature on HCC cutaneous metastases.

American Journal of Pathology
This study evaluated the differences in progenitor cell niche activation between primary sclerosing cholangitis (PSC) (n=20), primary biliary cholangitis (PBC) (n=20), and healthy livers (n=5). Ductular reaction, progenitor cell phenotype, and signaling pathways were investigated by IHC and immunofluorescence. Ductular reaction was found to be more expansive and more proliferative in PBC than PSC. Ductular reaction correlated with fibrosis and clinical prognostic risk scores both in PSC and PBC. The ductular phenotype was predominantly biliary in PBC, as compared to signs of hepatocyte commitment in PSC.

Small-RNA sequencing was used to profile miRNA expression in cirrhotic nodules (CNs), dysplastic nodules, early HCCs, and small progressed HCCs in 17 patients having chronic liver disease of various etiologies. An miRNA expression signature of 62 miRNAs distinguishing small progressed HCCs from matched CNs was identified. The authors suggest that identification of miRNAs discriminating CNs from neoplastic nodules may have relevant translational implications in early HCC diagnosis.

Modern Pathology
These authors shed much needed light on the difficult subject of diagnosing liver graft versus host disease by creating a three-tiered scoring system and histopathological algorithm. Their results show a high sensitivity, specificity and accuracy when compared to controls, including drug-induced liver injury cases. This is an exciting and “must read” paper.  

The aim of this study was to identify the relationship of xanthogranulomatous cholecystitis (XGC) with IgG4-related cholecystitis.  The histological features of 57 XGC cases were compared with those of 104 conventional chronic cholecystitis (CC) cases.  XGC cases showed increased gallbladder wall thickening and histiocytic infiltration as compared with CC cases.  XGC cases also more commonly showed dense lymphoplasmacytic infiltration, storiform fibrosis, and extensive IgG4+ plasma cell infiltration.  XGC demonstrated an increased mean number of IgG4+ plasma cells (35/hpf) as compared with CC (5/hpf) [p <0.001].  The XGC cases were further classified based on a cut-off of 50 IgG4+ plasma cells because this threshold was proposed for IgG4-related disease in the liver, pancreas, and bile duct.  IgG4-high XGC cases (n=16) had a mean number of 78 IgG4+ plasma cells compared to IgG4-low XGC cases (n =41) that had a mean number of 11 IgG4+ plasma cells.  Nine IgG4-high XGC cases (16%) had denser lymphoplasmacytic infiltration, fibrosis, and a higher IgG4/IgG ratio, suggesting that a subset of XGC cases share histological features with IgG4-related cholecystitis.  XGC cases with histological features suggestive of IgG4-related cholecystitis were also found to show clinical features such as extracholecystic involvement and mass-forming inflammation.  Of the nine IgG4-high XGC cases that had histologic features suggestive of an IgG4-related disease, only one case also had IgG4-related disease at another site.  The study findings suggest that XGC and IgG4-related cholecystitis have overlapping histologic features but are at best weakly associated with other typical organ manifestations of IgG4-related disease.

This is a prospective, biopsy-controlled, study conducted to compare 10 liver fibrosis markers in 289 patients [Enhanced Liver Fibrosis test (ELF), FibroTest, transient elastography, 2-D shear-wave elastography, and 6 indirect marker tests] in detection of advanced liver fibrosis (defined as Kleiner stage > F3).  The liver biopsy fibrosis stage was used as the reference standard.  The aim of the study was 1) to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease in primary and secondary health centers using a literature-established cutoff value of 10.5 as seen in the setting of NAFLD; and 2) to assess the diagnostic accuracy for significant fibrosis or cirrhosis and to determine whether combinations of fibrosis markers increases diagnostic yield.  The prevalence of advanced fibrosis by liver biopsy was 23% (66/289); 6% (8/128) in primary care and 36% (58/161) in secondary care. Both ELF and FibroTest identified advanced fibrosis with comparable high accuracy (AUROC of 0.92 and 0.90, respectively) in both primary and secondary care settings. ELF >10.5 correctly diagnosed advanced fibrosis in 79% of patients and absence of advanced fibrosis in 91%.  In the primary care setting, for an ELF score < 10.5, the negative predictive value to rule out advanced fibrosis was 98%, but the positive predictive value to affirm a diagnosis of advanced fibrosis was lower at 60%.  ELF better identified patients with advanced liver fibrosis than indirect markers.  However, combining ELF and FibroTest did not increase diagnostic yield of detecting advanced liver fibrosis and did not differ from transient elastography. The study suggests that ELF and FibroTest identified advanced liver fibrosis in alcoholic patients from primary and secondary care with high diagnostic accuracy (AUROC values of 0.90 or higher using biopsy as reference).

Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis) and pancreas (autoimmune pancreatitis). The sera of patients with IAC/AIP was compared control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies for reactivity against human H69 cholangiocyte lysates on immunoblot. The choice of PSC sera as one of the controls is interesting as it is recognized that in a subset of patients there is an overlap with IgG4-RD. Annexin A11 was identified as the main target antigen. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD and not in controls.  Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes. This suggests that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.

Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Cynthia Guy MD; Duke University
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 

Tuesday, May 8, 2018

President's Message April 2018

Dear Friends and Fellow Hepatophiles:

It is an honor to serve as President of the Hans Popper society following the footsteps of illustrious mentors and colleagues who have shepherded the society over the years. Thanks to Mike Torbenson for the outstanding leadership in the last two years.
It has been an eventful last couple of years for the Society. The reception that started off as a one-time tribute to Dr. Popper has now become a regular annual event, facilitating the members to interface with each other and grow as a society. Kudos to Isabel Fiel for the flawless organization of the receptions. Apart from the wonderful reception, the excellent companion society meeting contributed to the Society’s success during the recent USCAP meeting.

Another new endeavor this year was a membership survey on the use of special stains in liver biopsies. The results were presented at the reception and are available on the website. More practice-based surveys are planned for this year with the hope that the information will help members to be cognizant of the spectrum of practice in our field, enabling discussions and improvement in our respective practices.

The executive committee has also proposed a plan to publish guidelines/best practices articles on behalf of the society. The proposed guidelines for this endeavor have been posted on the website. Please review and provide your feedback in the comment region.

In keeping with the social media movement, the Society now has a Twitter handle. Thanks to Dora Lam-Himlin, our website committee chair, for enabling our entry into the digital age.

There are a lot of interesting posts on Twitter regarding events related to liver pathology and we currently have more than 200 followers. If you are at a national or international liver meeting, you can share new advances and ‘pearls’ with fellow members by posting on Twitter. Join the Twiterrati and become active hepatotweeps.
The academic presence of the Society will widen beyond the USCAP meeting with a joint session by Hans Popper Society and European Digestive Diseases working group at the 2018 European Society of Pathology meeting. We hope that this collaboration will continue in the future and our Society will have a regular presence at international meetings.

The society is engaged in several member-centric activities such as Journal Watch, Case of the Month and quarterly newsletters. If you are interested to contribute to these activities, join one of the committees, or would like to share ideas or feedback, please contact the committee chairs or any of the executive committee members. Your involvement is key to the success of the Society and I look forward to working with all of you in the coming year.


Sanjay Kakar, MD
President, Hans Popper Society

Friday, May 4, 2018

Interesting Case: April 2018

Case submitted by
Kalpesh Patel M.D. 1, Cassandra Gandle M.D. 2, Sadhna Dhingra M.D. 3
1. Department of Gastroenterology, Baylor College of Medicine, Houston TX
2. Department of Internal Medicine, Baylor College of Medicine, Houston TX
3. Department of Pathology and Immunology, Baylor College of Medicine, Houston TX

A 55 year-old Hispanic woman with rheumatoid arthritis, chronic back pain, disc prolapse and multiple surgeries on chronic opiate use, presents with chronic abdominal pain and rectal bleeding. Her gastric emptying studies were normal. Rectal bleeding was mild and secondary to hemorrhoids. Laboratory studies showed normal liver function tests, including normal transaminases and normal alkaline phosphatase. Urinalysis on multiple occasions over the past 3 years showed trace proteinuria. She underwent an esophagogastroduodenoscopy to rule out chronic pancreatitis.

Endoscopic findings for esophagus, stomach and duodenum were normal. There were no endoscopic changes in common bile duct and pancreas. Endosonographic imaging showed diffuse abnormal echotexture in the left lobe of the liver. This was characterized by a hyperechoic appearance. EUS-FNA (fine needle biopsy) of the liver was performed.

The liver biopsy showed multifocal amorphous globular eosinophilic deposits in a perivenular (zone 3) and portal/periportal distribution. These deposits were congophilic (congo red stain) and showed apple green birefringence on polarizing microscopy. The deposits also displayed fluorescence on fluorescent microscopy using Texas Red filter. The background liver parenchyma was unremarkable. No steatosis, lobular or portal inflammation was seen. No portal fibrosis was seen. The tissue was sent to Mayo Clinic Laboratories for mass spectroscopic analysis for accurate identification of amyloid. However, the amyloid deposition was minimal and insufficient for the mass spectroscopy to be performed. The diagnosis was based on the morphology and pattern of distribution.


Liver is a frequent site of amyloid deposition in systemic amyloidosis. The most common type of amyloid deposition is AL (light chain-associated) amyloid or SAA (serum amyloid A) amyloid. We report a case of incidental hepatic ALECT2 in a hispanic female with clinical history significant for rheumatoid arthritis (RA). RA is a chronic inflammatory disease, which is usually associated with acute phase reactant serum amyloid A deposition in organs. Our patient had normal liver function tests and underwent an EUS-guided liver biopsy for abnormal echotexture while being evaluated for abdominal pain. The diagnosis of ALECT2 was made based on the morphology and pattern of distribution of amyloid deposition in the liver. Pure globular hepatic amyloid is specific for LECT2 amyloid. 1 Immunostain for LECT 2 using mouse monoclonal IgG antibody is highly specific and sensitive.

Leucocyte cell-derived chemotaxin 2 (LECT 2) is a relatively recently described amyloid protein first recognized in the international classification of amyloidosis in 2010. 2 It’s deposition was first described in the kidneys in 2008. 3 Although, abnormal amyloid bodies were noted in liver by Livni et al 4 as early as 1977, hepatic “globular’ amyloid deposition was first described in 1981. 5 The clinical significance of these deposits was unknown at the time of first description, and it was considered not to be distinctive from other systemic amyloidosis. 5, 6 In 2007, Makhlouf and Goodman, 7 reported globular hepatic amyloid in 9.6% of cases with hepatic amyloidosis, and hypothesized that this may represent an early form of liver involvement in generalized amyloidosis. Subsequently, the first case of hepatic ALECT2 was reported in 2014. 8 Chandan et al (2015) 1 reported that globular hepatic amyloid is highly sensitive and specific for ALECT2.
ALECT2 is associated with a distinctive clinical and pathological profile. It occurs in Hispanic patients with a median age range of 60.5 years and has female predilection. It has also been reported in other ethnic groups such as Punjabis (ethnic group in India and Pakistan), Arabs, Israelis, Native Americans and First Nation People from British Columbia. 9 The most common site of deposition is kidney and liver, but rare cases have been reported in spleen, small bowel, pancreas, gallbladder, parathyroid, prostate and lung. 10, 11 In contrast to AL amyloidosis or SAA amyloidosis, the presence of hepatic ALECT 2 is incidental, and not associated with abnormal liver function tests. 12 The pathogenesis of ALECT2 is unknown. The LECT2 protein is secreted by hepatocytes by the activation of LECT 2 gene present on chromosome 5q31.1. It is hypothesized that constitutive activation of gene or activation secondary to hepatocellular damage leads to secretion of LECT 2.

ALECT2 (globular amyloid) is a recently described distinctive subtype of amyloid. This is seen in predominantly in Hispanic population with a male to female ratio of 0.6:1. It is an incidental finding in the liver biopsies. The amyloid deposition can be minimal/minute in some cases, and in this situation the demonstration of apple green birefringence of congophilic material by polarizing microscopy can be quite challenging. In this situation, congo red fluorescence using Texas Red filter increases the diagnostic yield. 13 Based on the current literature, at the time of reporting of this case, hepatic ALECT2 is not associated with clinically significant liver disease. However, in kidneys it is associated with slowly progressive chronic renal disease without systemic disease. Therefore, a nephrology consultation may be a consideration when this is first detected in liver biopsies. Knowledge and identification of this specific amyloid is important to avoid unnecessary administration of toxic therapeutic drugs for AL or AA amyloid.

1. Chandan VS, Shah SS, Lam-Himlin DM, Petris GD, Mereuta OM, Dogan A, Torbenson MS, Wu TT. Globular hepatic amyloid is highly sensitive and specific for LECT2 amyloidosis. Am J Surg Pathol. 2015 Apr;39(4):558-64.
2. Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G, Saraiva MJ, Westermark P. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid. 2010 Sep;17(3-4):101-4.
3. Benson MD, James S, Scott K, Liepnieks JJ, Kluve-Beckerman B. Leukocyte chemotactic factor 2: A novel renal amyloid protein. Kidney Int. 2008 Jul;74(2):218-22.
4. Livni N, Behar AJ, Lafair JS. Unusual amyloid bodies in human liver. Ultrastructural and freeze-etching studies. Isr J Med Sci. 1977;13:1163–1170.
5. French SW, Schloss GT, Stillman AE. Unusual amyloid bodies in human liver. Am J Clin Pathol. 1981 Mar;75(3):400-2.
6. Kanel GC, Uchida T, Peters RL. Globular hepatic amyloid--an unusual morphologic presentation. Hepatology. 1981 Nov-Dec;1(6):647-52.
7. Makhlouf HR, Goodman ZD. Globular hepatic amyloid: an early stage in the pathway of amyloid formation: a study of 20 new cases. Am J Surg Pathol. 2007 Oct;31(10):1615-21
8. Damlaj M, Amre R, Wong P, How J. Hepatic ALECT-2 amyloidosis causing portal hypertension and recurrent variceal bleeding: a case report and review of the literature. Am J Clin Pathol. 2014 Feb;141(2):288-91
9. Nasr SH, Dogan A, Larsen CP. Leukocyte Cell-Derived Chemotaxin 2-Associated Amyloidosis: A Recently Recognized Disease with Distinct Clinicopathologic Characteristics. Clin J Am Soc Nephrol. 2015 Nov 6;10(11):2084-93.
10. Said SM, Sethi S, Valeri AM, Chang A, Nast CC, Krahl L, Molloy P, Barry M, Fidler ME, Cornell LD, Leung N, Vrana JA, Theis JD, Dogan A, Nasr SH. Characterization and outcomes of renal leukocyte chemotactic factor 2-associated amyloidosis. Kidney Int. 2014 Aug;86(2):370-7.
11. Khalighi MA, Yue A, Hwang MT, Wallace WD. Leukocyte chemotactic factor 2 (LECT2) amyloidosis presenting as pulmonary-renal syndrome: a case report and review of the literature. Clin Kidney J. 2013 Dec;6(6):618-21.
12. Mereuta OM, Theis JD, Vrana JA, Law ME, Grogg KL, Dasari S, Chandan VS, Wu TT, Jimenez-Zepeda VH, Fonseca R, Dispenzieri A, Kurtin PJ, Dogan A. Leukocyte cell-derived chemotaxin 2 (LECT2)-associated amyloidosis is a frequent cause of hepatic amyloidosis in the United States. Blood. 2014 Mar 6;123(10):1479-82.
13. Clement CG, Truong LD. An evaluation of Congo red fluorescence for the diagnosis of amyloidosis. Hum Pathol. 2014 Aug;45(8):1766-72

Wednesday, April 11, 2018

HPHS Survey Results: Special Stains in Liver Biopsies

The summary of the results of the special stains survey are posted here. Guidelines for future society sponsored manuscripts drafted by the HPHS Executive Committee were posted on the website for member comments in March. 

Please review and provide comments by April 23, 2018.

Thursday, March 29, 2018

HPHS Journal Watch: Jan/Feb 2018

Am J Gastroenterol
The rate of publication of new guidelines is accelerating – the European Association of Liver Disease is about to publish their updated guidelines for alcoholic liver disease (ALD) later this year.  This paper includes guidance on the role of liver biopsies in the management of ALD. One of the key statements is that “Liver biopsy is not routinely recommended for diagnosis of alcoholic fatty liver disease. However, liver biopsy and non-invasive tools of fibrosis may be considered for diagnosis of steatohepatitis and/or liver fibrosis”. This cautiously worded indication is focused in a subsequent one: “In patients with suspected AH, a transjugular liver biopsy is recommended when the clinical diagnosis is confounded by another liver disease etiology or there is uncertainty on alcohol consumption history.”  Having said this, the authors require histology for a definitive diagnosis of alcoholic hepatitis. This paradox is not unique to this paper. Tellingly, they quote a recent paper (J Hepatol 2017 ; 66 : 610 – 8) which showed that one-third of patients with clinically early disease have advanced fibrosis/cirrhosis on histology.
The authors refer to the paper by Altamirano ( Gastroenterology2014; 146 : 1231 – 9 ), one of the most evidence based papers in this field, but do not elevate it to the level of a recommendation. There are a number of nuggets such as the inflammation is more marked in patients with the alcohol withdrawal syndrome than those without it (Alcohol Clin Exp Res 2004 ; 28 : 131 – 6)

Chromosomal instability (CIN) is the most common promoter of hepatocellular carcinoma (HCC) progression. It does so by increasing tumour heterogeneity, drug resistance and immune escape. The DNA damage response protein checkpoint kinase 2 (Chk2) expression was evaluated in an animal model (of diethylnitrosamine-induced HCC) and also in two cohorts of human HCC specimens. In the animal model it was shown that overexpression/phosphorylation and mislocalisation within the mitotic spindle of Chk2 contributes to the induction of lagging chromosomes. The forkhead-associated domain of Chk2 was required for Chk2 mislocalisation to mitotic structures. A cohort and independent validation cohort show a strong cytoplasm to nuclear Chk2 translocation in a subset of patients with HCC.
This study suggests Chk2 is a putative biomarker that can be used to detect DNA damage and chromosomal instability in HCC providing a valuable support, for prognosis, and for identifying patients who are likely to have a response to therapy.

Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation and a  massive infiltration of myeloid cells into the  necrotic areas. This study investigated the impact of Mer tyrosine kinase (MerTK) during ALF and how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. The human work demonstrated a significant expansion of resolution-like MerTK+HLA-DRhigh macrophages in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance.
In this paper, the authors have clearly demonstrated the liver protective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and that it represents a potential immunotherapeutic target to promote resolution responses following acute liver injury. For the histopathologist, the immunohistochemical identification of this subset of macrophages has the potential to identify patients more likely to have an inflammatory response that will resolve.  This may be important in a wide range of liver diseases.

The most recent evidence based official recommendations of the American Association for the Study of Liver Diseases (AASLD) on the surveillance, diagnosis, and treatment of hepatocellular carcinoma (HCC) occurring in the setting of adults with cirrhosis was recently released using for the first time the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. The developers of the guidelines addressed 10 crucial scenarios that health care providers frequently encounters in the management of patients with HCC.  HCC is unique among malignancies as its diagnosis can be obtained noninvasively, particularly in a cirrhotic patient, and treatment can be initiated based on imaging alone, without assenting biopsy. Find out the latest AASLD recommendations addressing the role of biopsy in adults with cirrhosis and an indeterminate hepatic nodule; and other key clinical situations.

Am J Clin Pathol
"Whole Slide Imaging diagnosis is feasible and accurate" concludes French investigators, Villa et al., in a concordance study between glass slide and digital slide diagnosis published in the latest issue of AJCP.  Concordance was reported in 87% of cases, minor discordance in 10%, and major discordance with therapeutic impact in 2.5%.  Causes of major discordance were attributed to technical issues including poor image quality and logistics issues.  Recent works have shown these factors were no longer a problem indicating rapid improvement of the technology.  Clearly, standardization and quality control need to be implemented in order for whole slide imaging diagnosis to be successfully incorporated in the laboratory workflow.

Mod Pathol
The authors address the role of bile ductular reaction as a prognostic factor in NASH progression, based on periportal or centrizonal location. They studied liver biopsies from 90 patients (over 17 years of age) with primary diagnosis of NASH. 47 patients, who received no treatments, had paired liver biopsies, at least 12 months apart. They excluded cases with other superimposed chronic liver diseases such as HCV, alcohol, VOD, cirrhosis and transplant. Centrilobular ductular reaction was identified in 90% of patients and 38% of centrilobular zones. The prevalence of centrilobular ductular reaction increased in correlation with NASH grade and fibrosis stage. The frequency of centrilobular ductular reaction in the initial biopsies was significantly higher in the patients who showed fibrosis progression (P=0.02). They concluded that presence of centrilobular ductular reaction correlates significantly with increasing necroinflammatory activity and fibrosis stage and can predict progression of fibrosis in subsequent biopsies.

Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. They developed a break-apart FISH assay to detect this fusion and examine its diagnostic performance. 104 cases that were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma' were used. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, they also identified two tumors with unusual FISH patterns in the morphologically typical fibrolamellar carcinoma. Both had DNAJB1-PRKACA fusion but one had an additional amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. PRKACA FISH was negative in 88 conventional HCC. They conclude that PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity.

J Gastroenterol Hepatol
The authors screened the effectiveness of hepatic steatosis index (HSI) and fatty liver index (FLI), as well as their link to metabolic syndrome in type 1 diabetes in an observational pilot study. FLI and HSI were calculated for 201 patients with type 1 diabetes. 40 patients with FLI/HSI values corresponding to different risk of liver steatosis were invited for liver MRI. Twelve (30.0%) patients had liver steatosis. For FLI, sensitivity was 90%; specificity, 74%; positive likelihood ratio, 3.46; negative likelihood ratio, 0.14; PPV, 0.64; and NPV, 0.93. For HSI, sensitivity was 86%; specificity, 66%; positive likelihood ratio, 1.95; negative likelihood ratio, 0.21; PPV, 0.50; and NPV, 0.92. HSI correlated with waist circumference and C-reactive protein. FLI ≥ 60 and HSI ≥ 36 were significantly associated with metabolic syndrome and nephropathy. They concluded that FLI, can serve as surrogate markers for liver fat content and metabolic syndrome in type 1 diabetes.

2017 update on the guidelines for the assessment and management of non-alcoholic fatty liver disease (NAFLD) by the Asia–Pacific Working Party on NAFLD.

2017 update on the guidelines for the assessment and management of non-alcoholic fatty liver disease (NAFLD) by the Asia–Pacific Working Party on NAFLD

Liver macrophages are activated in chronic hepatitis B virus (CHB) infection and play a pivotal role in hepatic inflammation and fibrosis. However, their role during antiviral treatment is unclear. The soluble (s) macrophage activation markers, sCD163 and mannose receptor (sMR), are released during liver damage, and their serum levels reflect liver disease severity and portal hypertension. The authors investigated the associations between sCD163 (IHC and serum level) and sMR (ELISA) and histopathological activity (using ISHAK score) and fibrosis in pre and post antiviral treated CHB patients.The had 254 liver biopsies, 71 patientswith pre and post treatment biopsies. They found elevated sCD163 and sMR correlated with histologic inflammatory activity and fibrosis. Both were reduced with antiviral treatment.

This is a review article on the significance of microvascular invasion in surgical specimen and correlation with high post-operative HCC recurrence.

Am J Surg Pathol
The investigators reviewed 36 hepatobiliary mucinous cystic neoplasms (MCNs) with the requirement that ovarian type stroma (OS) be present to better determine its frequency among hepatic cysts, clinicopathologic characteristics, and risk for malignant transformation.  MCNs accounted for 36 of 241 cases (15%).  100% of cases occurred in women, 72% were located in the left lobe, mean size was 11.6 cm, mean age of patients was 51 years old, and median follow-up time was 18.5 months.  Only 2 of the 36 cases (5.5%) harbored high-grade dysplasia/carcinoma in situ (HGD/CIS); both cases of HGD/CIS also had associated foci of invasive carcinoma that measured 7 and 8 mm.  This study also found that the presence of OS and mucinous epithelium can be very focal.  In conclusion, this study adds further data to our understanding of hepatobiliary MCNs and the rarity of malignant transformation in these lesions.

This resident short review summarizes clinical, imaging, and histologic features, differential diagnosis, and treatment options for hepatic epithelioid hemangioendothelioma. 

Am J Pathol
The authors evaluated mucin 13 (MUC13) in hepatocellular carcinoma (HCC). Overexpression of MUC13 was detected in 74 of 168 HCCs (44%), and was significantly associated with tumor size, stage, encapsulation, venous invasion, and poor outcome. MUC13 promoted cellular G1/S phase transition by activating Wnt signaling, promoting nuclear translocation of β-catenin and up-regulation of downstream target genes.

Clin Gastroenterol Hepatol
This is a systemic review and meta-analysis aimed at characterizing racial and ethnic differences in the prevalence of NAFLD. It also looked at the differences in severity and prognosis of NAFLD among different ethnic groups. This article used NAFLD as diagnosed by biochemical, radiological, or histologic criteria per AASLD guidelines and assessed severity as presence of steatohepatitis and advances (stage F3-F4) fibrosis. Thirty-four studies totaling 368,569 patients showed that NAFLD is highest in Hispanics and lowest in Blacks but fibrosis was not significantly different among racial groups. Nearly 1 in 6 Americans have NAFLD and 30% had evidence of NASH with nearly 20% having evidence of advanced fibrosis. Clear differences in prognosis among ethnic groups were not identified. It is unclear why disparities exist, as diabetes and obesity are higher in black vs white, but white subjects have significantly higher risk of NAFLD. Similarly, further studies are needed to characterize the contribution of genetic factors, in particular PNPLA3, TM6SF2, and MBOAT single nucleotide polymorphisms vs. contribution of environmental factors.

The authors performed a competing-risk analysis to evaluate factors associated with survival of patients with HCC and developed a prognostic model based on features of HCC patients before liver transplantation. The training set comprised 1018 patients (western cohort) and a validation set of 341 consecutive patients (eastern cohort) who underwent liver transplantation for HCC.  In the competing-risk regression, the sum of tumor number and size and of log10 level of AFP were significantly associated with HCC-specific death (P < .001). Five-year cumulative incidence of non-HCC-related death was 8.6% in HCV-negative patients and 18.1% in HCV-positive patients. For patients with HCC to have a 70% chance of HCC-specific survival 5 years after transplantation, their level of AFP should be <200 ng/mL and the sum of number and size of tumors (in centimeters) should not exceed 7; if the level of AFP was 200-400 ng/mL, the sum of the number and size of tumors should be </= 5; if their level of AFP was 400-1000 ng/mL, the sum of the number and size of tumors should be </=4. In the validation set, the model identified patients who survived 5 years after liver transplantation with 0.721 accuracy (95% confidence interval, 0.648%-0.793%). The authors proposed that their model, based on patients’ level of AFP and HCC number and size, outperformed the Milan; University of California, San Francisco; Shanghai-Fudan; Up-to-7 criteria (P < .001); and AFP French model (P ¼ .044) to predict which patients will survive for 5 years after liver transplantation. To predict 5-year survival and risk of HCC-related death using an online calculator, please see

Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor-beta (TGF-β) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. The authors performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas. In addition, they screened 301 HCCs reported in the Catalogue of Somatic Mutations in Cancer and 202 from Cancer Genome Atlas for mutations in genome sequences. They found somatic mutations in at least 1 gene whose product is a member of TGF-β signaling pathway in 38% of HCC samples. SPTBN1 was mutated in the largest proportion of samples (12 of 202, 6%). Unsupervised clustering of transcriptome data identified a group of HCCs with activation of the TGF-β signaling pathway (increased transcription of genes in the pathway) and a group of HCCs with inactivation of TGF-β signaling (reduced expression of genes in this pathway). Patients with tumors with inactivation of TGF-β signaling had shorter survival times than patients with tumors with activation of TGF-β signaling (P = .0129). Patterns of TGF-β signaling correlated with activation of the DNA damage response and sirtuin signaling pathways. HepG2, SNU398, and SNU475 cells that expressed the D1089Y mutant or with knockdown of SPTBN1 had increased sensitivity to DNA crosslinking agents and reduced survival compared with cells that expressed normal SPTBN1 (controls). In summary, in genome and transcriptome analyses of HCC samples, they found mutations in genes in the TGF-b signaling pathway in almost 40% of samples. These correlated with changes in expression of genes in the pathways; up-regulation of genes in this pathway would contribute to inflammation and fibrosis, whereas downregulation would indicate loss of TGF-b tumor suppressor activity. Their findings indicate that therapeutic agents for HCCs can be effective, based on genetic features of the TGF-b pathway; agents that block TGF-b should be used only in patients with specific types of HCCs.

Hum Pathol
The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, the authors determined protein expression of BRCA1 and BRCA2 in 4 digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry on tissue microarrays. A total of 1546 samples of 4 types of cancer tissues, their matched adjacent nontumor tissues, and corresponding benign tissues were studied, respectively. Immunohistochemistry expression patterns of the 2 proteins and their correlation with patients' clinical parameters and overall survival were analyzed. The results showed that low expression of cytoplasmic BRCA1 and BRCA2 was commonly associated with advanced tumor–lymph node–metastasis stage, whereas high expression of nuclear BRCA1 was generally correlated with advanced tumor stages in these cancers. High expression of cytoplasmic BRCA1 and BRCA2 had significantly favorable overall survival in digestive system cancers; in contrast, BRCA1 nuclear expression usually predicted poor outcomes. They conclude that BRCA1 and BRCA2 could be used as clinicopathological biomarkers to evaluate the prognosis of digestive system cancers.

Patients with hepatocellular carcinoma (HCC) frequently have multiple anatomically distinct tumors. In these patients, multifocal HCC could represent intrahepatic metastases (IMs) of a single cancer or multicentric carcinogenesis (MC) with multiple independent neoplasms. To determine the frequency and clinical implications of these 2 possibilities, the authors performed histological and molecular analysis of 70 anatomically distinct HCCs from 24 patients. They assayed mutations in the TERT promoter region by Sanger sequencing and used next-generation sequencing to analyze the entire coding regions of 7 well-characterized HCC driver genes—based on shared or discordant mutations in these genes, we classified the HCCs in each patient as IM, MC, or indeterminate. Mutations in the TERT promoter were the most common alteration in their cohort, present in 71% of tumors analyzed. Mutations in the remaining genes occurred in less than 20% of analyzed tumors. They were able to determine the relatedness in 58% of the patients analyzed: MC occurred in 41% of patients, with 33% with exclusively MC and 8% with both MC and IM. IM occurred exclusively in 17% of patients, whereas the remainder were indeterminate. This study highlights the utility of molecular analyses to determine relatedness in multifocal HCC; however, targeted sequencing can only resolve this distinction in approximately 60% of patients with multifocal HCC.

The histone methyltransferase G9a (EHMT2) is a key enzyme for dimethylation of lysine 9 at histone 3 (H3K9me2), a suppressive epigenetic mark. G9a is over-expressed in tumor cells and contributes to cancer aggressiveness. The authors analyzed G9a expression in 68 BTC specimens and correlated the data with clinicopathological and survival data. They measured G9a expression in a panel of BTC cell lines and evaluated the cytotoxic effect of G9a inhibition in BTC cells using established small-molecule G9a inhibitors. G9a was considerably expressed in about half of BTC cases and was significantly associated with grading and tumor size. There were significant differences of G9a expression between growth type and tumor localization groups. G9a expression diametrically correlated with Vimentin (positive) and E-Cadherin (negative) expression. Importantly, survival analysis revealed G9a as a significant prognostic factor of poor survival in patients with BTC. In BTC cells, G9a and H3K9me2 were detectable in a cell line–dependent manner on mRNA and/or protein level, respectively. Treatment of BTC cells with established small-molecule G9a inhibitors resulted in reduction of cell viability as well as reduced G9a and H3K9me2 protein levels. The present study strongly suggests that G9a contributes to BTC carcinogenesis and may represent a potential prognostic factor as well as a therapeutic target.

Liver Transplantation
A growing body of literature is illuminating the relationship between platelets and tumor growth and metastasis. The authors of this paper stratify living donor liver transplant recipients into two groups, one with a low platelet count (<75 x 109 /L) and one with a platelet count of >75 x 109 /L. The platelet count was incorporated into the Milan criteria. Incorporation of the preoperative platelet count into the Milan criteria significantly improved HCC recurrence predictive power. HCC recurrence risk was higher in the high platelet group on both univariate and multivariate analysis. The authors conclude that the preoperative platelet count is an important host factor affecting HCC recurrence following living donor liver transplantation.

Calcineurin inhibitors (CNIs; cyclosporine and tacrolimus) are common agents used for immunosuppression following orthotopic liver transplantation (OLT). Neurotoxic side effects are well known to occur within the first week following OLT, but the long term effects have not been well documented. These authors studied 85 OLT patients and grouped them into CNI-free, CNI low-dose, and CNI standard-dose categories. 33 healthy patients adjusted for age, gender and education served as controls. Subjects underwent psychometric testing and cerebral MRI approximately 10 years following OLT. Patients receiving CNIs showed significantly worse visuospatial/constructional ability compared with controls. Patients with low-dose CNI therapy had an overall impaired cognitive function compared with controls. Patients treated with CNIs showed significantly more white matter hyperintensities (WMH) than CNI-free patients and controls. The authors conclude that OLT patients on longterm CNI therapy carry a significant risk of cognitive dysfunction, and patients may benefit from a change to CNI-free therapies.

This well-respected author provides an update and overview of the recent NAFLD guidance documents provided from the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) with regards to issues pertaining to liver transplantation.

As the population ages and incidence of obesity rises, the projected rates of deceased donor liver utilization are projected to fall from the current rate of 78% to 44% by 2030. Judicious donor selection will become increasingly critical to avoid discarding potentially adequate grafts. The authors of this manuscript evaluate the safety of and rate of liver utilization with preretrieval (or prerecovery) liver biopsy (PLB) in extended criteria liver donors. Three organ procurement organizations (OPOs) were included and the outcomes measured included complications, preempted liver recovery, and successful liver transplantation. The PLB group had fewer complications. In the liver-only and propensity score-matched multiorgan donor subgroups, the PLB group had fewer complications and the preempted liver recovery rate was significantly higher without a decrease in liver transplantation rate. The authors conclude that in extended criteria liver donors, PLB is safe and decreases the rate of futile liver recovery without decreasing the overall liver transplantation rate. PLB, especially in liver-only donors, is likely to save costs to OPOs and transplant centers as well as improve efficiencies in organ allocation.

This is a nice review article on the usefulness of next generation sequencing in pediatric patients with suspected monogenic diseases.

The authors present and illustrate a great case to remind us that not all “infiltrating” perineural and intraneural glands are malignant.

The liver is the leading site of colorectal carcinoma metastasis. This review summarizes a detailed protocol for specimen handling and for the reporting of important histopathological features in liver resections for metastatic colorectal carcinoma.

Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Robert Goldin MD; Imperial College, London
Cynthia Guy MD; Duke University
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