Wednesday, September 6, 2017

In Memoriam Lina Popper

Lina Popper passed away on August 15, 2017 in her Manhattan home at age 100. She was the wife of the eminent physician Dr. Hans Popper, the pathologist who is credited with originating modern liver research and who was a founder and the first academic dean of Mount Sinai Hospital's Medical School, now the Icahn School of Medicine at Mount Sinai. Long revered in the medical community, Lina traveled with her husband to medical meetings all over the world and was a constant and respected presence in the research community long after his 1988 death. She was born in Vienna, Austria to Paul Billig and Rosa Dym Billig on July 4, 1917. She fled the Nazis in 1938 for Chicago. There she met and married Hans, a fellow Viennese immigrant. She was President of the local PTA every year their children were in school in Chicago. They moved in 1957 to New York City, where she lived the rest of her life. She was an early volunteer at the Transplant Living Center at Mount Sinai. Her love of the arts made her a strong supporter and patron of New York's cultural offerings, including opera, classical music, art, education, environmental issues, and Jewish activities. Her day was never complete until she had attended a cultural event with a friend, and she finished The New York Times crossword puzzles every day in pen well into her 90's. Her loving family survives: sons Frank, a Rutgers University and Princeton University professor of city planning, and Charles, a psychiatrist at McLean Hospital and Harvard University Medical School; daughter-in-law and partner Deborah Popper and Leland Perry; grandchildren Joanna and Nicholas, married to Amy Haley; and great- grandchildren Hazel and Celia. The family would appreciate donations to the Visiting Doctors Program at Mount Sinai, a valuable service that provided medical care for Lina at home in the final years.

Wednesday, August 16, 2017

GI/Liver Pathology Fellowship

University of California, Davis School of Medicine (Sacramento, CA)

The University of California, Davis, Department of Pathology and Laboratory Medicine is seeking candidates for its non-ACGME-certified Surgical Pathology Fellowship for the 2018-19 and 2019-2020 academic years.  Sub-specialty emphasis in either GI or GYN pathology is available (limited to one each per year).

UC Davis offers a one-year Surgical Pathology fellowship program which is designed to prepare the fellow as a diagnostic expert in the interpretation of surgical pathology specimens. Expertise will include; intra-operative consultations (frozen section interpretation), gross examination, biopsy diagnosis/interpretation and appropriate work-up of cancer resections. The fellow in Surgical Pathology will develop an analytical approach to diagnoses, which include the appropriate use of ancillary techniques  (electron microscopy, immunohistochemistry and molecular pathology). Training in this program will encompass consultation to health care staff, residents, pathologists and clinicians including tumor boards and other conferences. Participation in a research project, or in a LEAN/ CQI project is expected. The fellow will also participate in departmental teaching activities for residents and medical students. At completion, the successful fellow should be able to demonstrate the knowledge, poise, maturity and communication skills to effectively function at the level of junior staff/faculty.

The Program Director will select from resident applicants who have preferably had four or more years of training with two years anatomic pathology and two years clinical pathology experience.  Completed applications consist of the following and must be free of gaps of time, whether professional or personal: CV/Resume/CAP standardized form; personal statement, three letters of recommendation (one must be from your Residency Program Director), please address to John Bishop, M.D., Director, Surgical Pathology Fellowship; and your letter of interest or intent. Applicants must be licensed in California in the spring prior to their start date.  Please submit application materials to Residency & Fellowship Program Coordinator, Anna Gutierrez at

For additional information, please visit our website at  

John W. Bishop, M.D.
HSC Professor of Pathology and Vice Chair for Clinical Services
UCDMC Pathology
4400 V St, Suite 1116
Sacramento, CA 95817


Wednesday, July 26, 2017


Human Pathology

Shah SS, et al. Hum Pathol. 2017;64:13-18.

This study shows that 5.2% (9/172) resected HCCs were positive for CDX-2, while all 6 resected fibrolamellar carcinomas (FLCs) were negative. CDX2 expression was seen in 5/16 poorly differentiated, and 2.5% (4/156) in well and moderately differentiated HCC. These results show that CDX2 expression does not exclude a diagnosis of HCC.

Chen J, et al. Hum Pathol. 2017;64:118-127.

This study compares the characteristics of 23 cholangiolocellular carcinoma (referred to as combined hepatocellular-cholangiocarcinoma, cholangiolocellular subtype) and 79 conventional intrahepatic cholangiocarcinoma (ICC). Cholangiolocellular carcinoma showed less invasive growth, less involvement of liver capsule and absence of mucous production compared to ICC. Mutations of isocitrate dehydrogenase 1 (IDH1) or IDH2 were higher (35%) in cholangiolocellular carcinoma than in mass-forming ICC (4%) or non-mass forming ICC. The 5-year postresection survival was significantly better in cholangiolocellular carcinoma (52%) compared to mass forming ICC (40%) and non-mass forming ICC (0).


Goeppert B, Roessler S, Becker N, et al. Histopathology. 2017 Jun;70(7):1064-1071.

Expression patterns of deleted in malignant brain tumors 1 (DMBT1) was analyzed in 157 biliary tract cancer patients, including intrahepatic and extrahepatic cholangiocarcinoma, adenocarcinomas of the gallbladder, and BilIN 3. DMBT1 expression was high in BiLN3 compared to normal biliary epithelium and BTC (both p<0.0001). However, BTCs showed no significantly different expression levels compared to non-neoplastic biliary tissue (p=0.315). Absent DMBT1 expression in non-neoplastic biliary tissue in BTC patients was associated with poor survival. The authors conclude that DMBT1 expression is elevated in BilIN 3, but expression levels of DMBT1 in BTC declines to levels comparable to non-neoplastic biliary epithelium. Absent DMBT1 expression in non-neoplastic biliary tissues of BTC patients correlates with poor patient survival (p=0.027), and the aggregate findings suggest a tumor-suppressor role for DMBT1.

Liver Transplantation

Tan A, Florman SS, and Schiano TD. Liver Transpl. 2017 May;23(5):663-678.

This is a nice review article delineating several genetic disorders (including inherited cholestatic disorders, urea cycle disorders and hereditary hemochromatosis) which can potentially be transmitted following liver transplantation.

Haga H. Yan IK, Borrelli DA et al. Liver Transpl. 2017 Jun;23(6):791-803.
Hepatic ischemia/reperfusion injury (IRI) is associated with significant liver dysfunction and complications following liver surgery and transplantation. These authors studied the effects of systemically administered extracellular vesicles from mesenchymal stem cells (MSC-EV) in an experimental mouse model of hepatic IRI. Compared to controls, intravenous administration of MSC-EVs dramatically reduced the extent of tissue necrosis, decreased caspase-3-positive and apoptotic cells, reduced serum aminotransferase levels, and reduced RNA expression of several inflammatory cytokines such as IL6. MSC-EV increased cell viability and suppressed oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. The authors conclude that administration of extracellular vesicles from bone marrow derived MSCs may improve IRI by reducing hepatic injury through tempering the inflammatory response.

Journal of Hepatology

Moeini A, Sia D et al. J Hepatol. 2017; 952-961.

Molecular characterization of mixed HCC-CCA was studied including histologic features, whole genome expression profile, single-nucleotide polymorphism array and whole exome sequencing. In classic type, clonality analysis revealed HCC-like and iCC-like components were derived from same clone. Exome sequencing revealed an average of 63 non-synonymous mutations per tumor, among which TP53 was the most frequently mutated gene. Stem cell subclass tumors were characterized by SALL4 positivity, showed enrichment of progenitor like signatures (CK19, EpCAM), activation of MYC and IGF oncogenic pathways, and associate with poor prognosis. In contrast, cholangiolocellular carcinoma (CLC) showed NCAM positivity, chromosomal stability and enrichment of TGF-β and immune related signaling. The data suggest that CLC stands alone as an independent biliary-derived entity, not sharing any molecular traits of HCC.

Vesterhus M, Holm A, et al. J Hepatol. 2017; 1214-1222.

Biomarkers to predict prognosis of primary sclerosing cholangitis are lacking. Using a bead-based array targeting 63 proteins related to inflammation and fibrosis, the authors studied bile samples from 55 PSC patients and 20 controls, and identified 13 proteins that showed significant difference between PSC and control, and 18 proteins that showed significant difference between mild and advanced PSC. Further studies identified ICAM-1, MMP7, S100A4 and S100 A12 as the group of markers that collectively best distinguished PSC from controls, and Calprotectin alone as the protein best capturing the difference between mild and advanced PSC. In addition, serum analyses were performed in two independent cohorts. IL-8 was identified as the best predictor of transplant-free survival in PSC, and correlated with the ELF score and Mayo score.

Schaberg KB, Kambham N, Sibley RK, et al. Am J Surg Pathol. 2017 Jun;41(6):810-819.

Adenovirus can lead to severe infection, including hepatitis, in immunocompromised patients.  The authors searched the archives from a single institution to compile the largest series to date (12 cases including biopsies as well as autopsies) of adenovirus hepatitis and review the histopathologic and clinical features.  All patients were immunocompromised and adenovirus hepatitis was fatal in all 4 adult patients and 5 of the 8 pediatric patients.  All patients presented with fever and had a hepatitic-dominant elevation in liver enzymes (mean AST 5879 U/L, mean ALT 1894 U/L, mean Alk Phos 453 U/L, mean total bilirubin 3.8 mg/dL).  Coagulative necrosis was seen in all cases, but the extent varied from focal to massive.  Necrosis was usually nonzonal, but half of cases showed an apparent accentuation of necrosis in periportal regions on biopsies.  Over half of cases were paucy inflammatory, but when inflammation was present, it tended to be focal, lymphohistiocytic and periportal.  All cases showed characteristic viral cytopathic effect (smudgy, glassy, predominantly basophilic intranuclear inclusions), most often in hepatocytes surrounding areas of necrosis.  Rarely, portal tract granulomas and viral inclusions were seen in biliary epithelium.  The minority of patients who survived their infection showed limited necrosis on initial biopsy and comparatively mild elevations in liver enzymes; these findings may be predictive of patients who are more likely to survive.  In conclusion, the authors remind us that adenovirus hepatitis is a serious and often fatal infection in immunocompromised hosts, more often seen in pediatric patients. 


Sun Y, Theise ND, You H, Jia J, et al. Hepatology 2017; 65(5): 1438-1450.

This study evaluated the utility of applying some of the histologic features of fibrosis regression, coined by Ian Wanless and colleagues as the hepatic repair complex (HRC). The authors examined 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir-based therapy for 78 weeks. Fibrosis was categorized into one of three groups:

1.       Predominantly progressive: defined as more than 50% fibroseptal stroma showing wide/broad, loosely aggregated collagen fibers, often a mix of light and dark staining fibers on trichrome, which are moderately to markedly cellular containing, variably, inflammatory cells, macrophages, and ductular reactions.

2.       Predominantly regressive: defined as more than 50% fibroseptal stroma showing features of hepatic repair complex, namely thin, densely compacted stroma, largely darkly staining on trichrome, which are largely acellular.

3.       Indeterminate: defined as an uncertain mix/balance between progressive and regressive scarring.

Progressive, indeterminate, and regressive scarring was observed in 58%, 29%, and 13% of patients before treatment versus 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 53% has fibrosis improvement of at least one Ishak stage and 45% had improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. The authors propose a “Beijing Classification” for liver biopsy assessment, which includes both the degree of fibrosis and the presence of progressive, indeterminate, or regressive features, in order to reflect the directionality of the fibrosis. In the same Hepatology issue, there is an editorial (pg. 1432-1434) on the study by Dr. David Kleiner.

Modern Pathology

Balitzer D, et al. Modern Pathology 2017; May (30): 773-783

Simplified criteria for diagnosis of autoimmune hepatitis are based on autoantibodies, serum immunoglobulin G, histologic features, and negative viral serology. A score of 6 points is necessary for the designation of probable autoimmune hepatitis and 7 points or more for definite autoimmune hepatitis. The presence of three histologic features (interface hepatitis, emperipolesis, and rosettes) is required for categorizing a case as typical (2 points). In the absence of all three features, a chronic hepatitis picture is considered compatible (1 point). This study used the modified histologic criteria (interface/lobular activity, number of plasma cells, and presence of biliary features) and compared the validity for the diagnosis of autoimmune hepatitis. Clinical data and liver biopsies were reviewed for 88 cases of autoimmune hepatitis, 20 primary biliary cholangitis, and 13 non-autoimmune acute hepatitis. Interface/lobular activity, number of plasma cells, copper/CK7 stains, and presence of biliary features were assessed. Using the modified histologic features, histologic score of 2 increased from 8 to 77%, and the total simplified score of >6 increased from 69 to 86%. There was no increase in total simplified score for primary biliary cholangitis or non-autoimmune acute hepatitis. Rosettes and emperipolesis are difficult to interpret, and lack sensitivity and sensitivity for autoimmune hepatitis diagnosis. The current histologic criteria used in the current simplified score lead to underscoring of autoimmune hepatitis cases. The modified histologic criteria increased the histologic score and led to a probable/definite diagnosis of autoimmune hepatitis in 17% of cases that would have otherwise been classified as non- autoimmune hepatitis by simplified score.

Tsai JH, et al. Modern Pathology 2017; June (30): 834-842
Non-alcoholic steatohepatitis is a slowly progressive disease, although patients may rarely present in acute liver failure. This study characterizes clinicopathologic features of 6 patients who had aggressive non-alcoholic steatohepatitis following rapid weight loss (4) or malnutrition (2) and developed severe hepatic dysfunction. Four patients either died or received an urgent liver transplant. Pathologic findings were characterized by advanced alcoholic steatohepatitis-like features, including severe centrizonal pericellular fibrosis, central scar with perivenular sclerosis/veno-occlusion with superimposed hepatocellular dropout, prominent hepatocyte ballooning, and numerous Mallory–Denk bodies, although any of them had a history of excess alcohol consumption. The mechanism of liver injury in aggressive steatohepatitis is unclear, but rapid fat mobilization may be a potential cause of oxidative stress in the liver injury.

Gastroenterology and Hepatology

Bonacini M, Shetler K, Yu I, Osorio RC, Osorio RW. Clin Gastroenterol Hepatol. 2017; May;15(5):776-779.
This brief report of acute liver failure due to toxic mushroom exposure aimed to evaluate mortality due to mushroom poisoning and factors associated with survival without liver transplantation. Twenty-seven patients presented within 24 hours after ingesting toxic mushrooms. Amanita phalloides was the cause in 41% and Amanita ocreata was the cause in 11%. All patients had elevated liver transaminases, with a median alanine aminotransferase of 2185 IU/L. Of these patients, 3 died, 1 received liver transplant, and the remaining survived without transplant. Overall, the probability of poor outcome (transplant or death) due to Amanita hepatotoxicity was 17% in those who have a peak total bilirubin >2 mg/dL (signifying hepatocellular jaundice). Patients who have bilirubin >2 mg/dL or AST >4000 IU/L at presentation or follow up need to be evaluated for transplant.

Tanaka A, Tazuma S, Okazaki K, Nakazawa T, Inui K, Chiba T, Takikawa H. Clin Gastroenterol Hepatol. 2017; Jun;15(6):920-926.

IgG-4 related sclerosing cholangitis is clinically distinct from primary sclerosing cholangitis and found often in association with autoimmune pancreatitis. This article showcases the largest case series of IgG-4 related sclerosing cholangitis (527 patients) and describes the clinical features in detail. The majority of patients were male (83%) and the median age at presentation was 66 years. The presenting symptoms included jaundice (35%), pruritus (13%), abdominal pain (11%), and cholangitis (10%). Eighty-four percent had elevated IgG4 levels. Even though 28% were asymptomatic (28%), 95% of these patients had evidence of other IgG4-related organ involvement. Sixty-three patients had pathologic samples, but the findings were not described in this paper. Diagnoses were based on Japanese criteria. There was an excellent response to prednisolone in 90% of patients. Death from hepatobiliary disease was rare in a 5–10 year period, none of the patients required liver transplant was not required in any of the patients, and cholangiocarcinoma was seen in less than 1%. Based upon this large data set, it appears that IgG-4 related sclerosing cholangitis is a generally benign condition with excellent response to treatment with corticosteroids, and overall good prognosis over a 10-year period. It is noted, however, that there is the possibility that IgG4-sclerosing cholangitis might be able to progress to cryptogenic cirrhosis, in which any diagnostic evidence such as elevated IgG-4 levels or typical radiographic findings are no longer present.

Mukewar S, Sharma A, Lackore KA, Enders FT, Torbenson MS, Kamath PS, Roberts
LR, Kudva YC. Clin Gastroenterol Hepatol. 2017; Jun;15(6):927-933.

This is the largest study of glycogenic hepatopathy in diabetes type 1 patients. It is also a case control study comparing type 1 diabetic patients with and without glycogenic hepatopathy. The purpose was to determine whether type 1 diabetics with glycogenic hepatopathy have more frequent diabetic ketoacidosis (DKA) episodes and evidence of poor glycemic control. The study shows that over half of the patients with glycogenic hepatopathy more frequently had recurrent DKA and elevated HbA 1c levels compared with type 1 diabetics with normal liver enzymes.  Glycogenic hepatopathy did not lead to adverse long-term outcomes and the liver enzymes eventually normalized in most patients on follow-up.

Prepared by:
Daniela Allende, MD (Editor), Cleveland Clinic
Wenqing Cao, MD; New York University
Cynthia Guy, MD; Duke University
Sanjay Kakar, MD; University of California, San Francisco
Jingmei Lin, MD, PhD; Indiana University
Rish Pai, MD, PhD; Mayo Clinic Arizona
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Eric Yee, MD; University of Oklahoma
Maria Westerhoff, MD; University of Washington

Thursday, June 15, 2017

President's Message June 2017

Dear Members of the Hans Popper Hepatopathology Society,

In this president’s message, I want to bring up an important item for your consideration, one regarding the logo used by our society.  It has been brought to the attention of the Executive Committee that the Society’s logo perhaps should be reconsidered, for the reasons briefly outlined below.  

Such an important decision is best made after full consideration and feedback by the membership, so we are asking for your feedback on this question.  The HPHS website will soon post a poll and comment section for your feedback.  Please make any suggestions/comments by August 1, 2017, so that the Executive Committee can proceed accordingly.  

Also please note that the name of the society is not being reconsidered, only the logo.

Current logo

Reasons to consider redesigning the logo
First, the depiction of tobacco use by a medical society could appear to be out of touch with current understandings of the dangers of tobacco.   
Second, logos for medical societies in general tend to depict key aspects of the specialty (as opposed to an important founding member).

What would a new logo look like?
If the decision is made to redesign the logo, then the society would sponsor a friendly design competition/suggestion, where potential designs would be submitted by members.  Hopefully there would be enough interest (and artistic talent in the membership) so that the top 3-5 designs/suggestions could then be posted to the web for a vote. 

What would happen if the vote is for no change in the current logo?
Nothing—the current logo would continue to be used.


Mike Torbenson
President, Hans Popper Hepatopathology Society

Interesting Case June 2017

Clinical History
The patient is a 32-year old woman G3P2 who suffered a miscarriage after her first child.

Imaging Findings 
MRI reveals an ill-defined, heterogeneously T2 hyperintense, right lobe liver segment 7/8 lesion, without washout. The mass measures 4.0 x 3.4cm and has been stable since 2014. The background liver is within normal limits.

Liver Biopsy Findings
February and June 2015 needle core biopsies were performed. Provided for review are two parts of core needle biopsies obtained from 2015.  The first core needle biopsy from February of 2015, site unspecified consists of three portal tracts without significant fibrous expansion.  No steatosis or significant histopathologic findings are seen.  The second specimen labeled mid lesion #2 shows quite different histopathologic findings of striking sinusoidal dilation and corresponding hepatocyte atrophy (see Figure 1).

There is one vascular structure with fibrin within the lumen.  No significant macrovesicular steatosis or inflammation is seen in either of the two liver biopsies.  There are focal areas of hemorrhage and other areas with hepatocyte dropout. Another liver biopsy was obtained from the patient four months later in June of 2015. Again, striking zone 3 hepatocellular atrophy and sinusoidal dilatation was seen (Figure 2.) Fibrin was identified in several of the portal venules (Figure 3).

Figure 1. February 2015 biopsy 20X.
Figure 2. June 2015 biopsy 100X
Figure 3. June 2015 biopsy 200X

As a mass lesion has been demonstrated on radiologic evaluation, a panel of immunohistochemical stains were performed to further evaluate the possibility of a hepatic adenoma. CRP is interpreted as negative. No loss of LAFB was seen. Heat shock protein 70 (HSP70) is negative and no nuclear staining is seen using Beta-Catenin.  CD34 highlights the vessels within the portal tracts and fails to stain in the area with the dilated sinusoids. Glutamine Synthetase shows the typical zone 3 pattern of staining.

Diagnosis and Discussion
Striking zones 2 and 3 sinusoidal dilation with corresponding hepatocyte atrophy
Focal hemorrhage and hepatocyte dropout.
See comment

Prior to discussing this challenging case, please note that this patient’s liver biopsies were reviewed by several prominent hepatopathologists and their respective diagnoses were not necessarily in concert. Upon careful review, maintenance of the portal tracts are seen, but the spacing of the portal tracts is irregular. The histopathology varies between the two specimen parts from the biopsies from February of 2015, with one being relatively unremarkable hepatic parenchyma and the other demonstrating hepatocellular atrophy and sinusoidal dilatation.  There are areas with hepatocyte dropout.  The hepatic biopsy from June of 2015 shows similar histopathologic findings with sinusoidal dilation. 

The panel of immunohistochemical stains were quite helpful in the evaluation for hepatic adenoma.  CRP (Figure 4) is interpreted as negative and therefore, the diagnosis of telangiectatic adenoma is not supported. LAFBP retained staining and therefore, type 1 hepatic adenoma is not supported.  In addition, the absence of macrovesicular steatosis does not support this diagnosis.  Heat shock protein 70 (Figure 6) is negative and no nuclear staining is seen using Beta-Catenin. CD34 (Figure 7) highlights the vessels within the portal tracts and fails to stain in the area with the dilated sinusoids. Glutamine Synthetase (Figure 8) shows the typical zone 3 pattern of staining, and therefore, the diagnosis of focal nodular hyperplasia is not supported. 

Figure 4. C-reactive protein (CRP) immunostain.
Figure 5. LAFBP immunostain.
Figure 6. HSP immunostain.
Figure 7. CD34 immunostain.
Figure 8. Glutamine synthetase immunostain.

Given the histopathologic findings and immunophenotypic staining pattern, the diagnosis of adenoma or focal nodular hyperplasia is not supported. There is the possibility that these parenchymal changes are that of tissue adjacent to a mass lesion. Therefore, sampling cannot be completely excluded. 

The differential diagnoses of histopathologic findings of striking sinusoidal dilation with corresponding hepatic atrophy can be seen in hypercoagulable states, mass lesion, vascular injury, infectious etiologies, or adverse drug reaction.  A hypercoagulable workup was suggested for this patient. Other causes of hypercoagulability include oral contraceptive use and hematologic malignancies.  Congestive heart failure and constrictive pericarditis can result in this histopathologic picture, but given the young age of this patient and per findings in the electronic medical record, the likelihood of these etiologies were less likely.  

Major Learning Points
  1. A mass lesion in the liver does not always represent a neoplasm. The possibility of vascular flow abnormality need be entertained.
  2. Pause before making a diagnosis of hepatic adenoma in the presence of portal triads. 
  3. Performance of a battery of immunohistochemical stains is immensely helpful in diagnosing or excluding hepatic adenoma and focal nodular hyperplasia.
Odze and Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 3rd Edition, Robert Odze and John Goldblum, Philadelphia, PA, © 2015 by Saunders, an imprint of Elsevier IncSaunders.
MacSween’s Pathology of the Liver, SIXTH EDITION, Alastair D. Burt, Bernard C. Portmann and Linda D. Ferrell. New York, © 2012, Elsevier Limited.

This case was submitted by:
Erin Rubin, MD, FCAP, James Park Dewar, MD, Professorship of Pathology, Department of Pathology, University of Oklahoma School of Medicine, Oklahoma City, OK

Thursday, June 1, 2017

HPHS Journal Watch: March-April 2017

American Journal of Gastroenterology

Kabbany, M, et al. Am J Gastroenterol 2017;112:581-587.

The authors analyzed data from the National Health and Nutrition Examination Survey data to estimate the prevalence of NASH cirrhosis and NAFLD-associated advanced fibrosis during two time periods: 1999-2002 and 2002-2012.  Compared to the 1999-2002 cohort, the rate of obesity, diabetes, and insulin resistance were all increased in the 2002-2012 group.  The prevalence of NASH-cirrhosis was estimated using the AST to platelet ratio (ratio > 2 was used as the cutoff for cirrhosis) with at least one of the following: obesity, diabetes, insulin resistance and metabolic syndrome.  An estimated 0.178% of American adults had NASH-related cirrhosis in the 2002-2012 group compared to 0.072% in the 1999-2002 group.  The estimated prevalence of advanced fibrosis (defined using cutoffs for AST to platelet ratio, fibrosis-4 index, and NAFLD fibrosis score) increased from 0.85 to 1.75%.  From these results, an estimated 4,104,871 individuals in 2010 had NAFLD-associated advanced fibrosis.

Journal of Hepatology

Lackner C, et al. J Hepatol. 2017; 610-618.

Few data exist on predictors of long-term prognosis in patients with alcoholic liver disease (ALD). This retrospective study investigated 192 consecutive patients with biopsy proven ALD. Five year liver-related mortality was 13% in early/compensated ALD (n=60) and 43% in decompensated ALD (n=132).  In early/compensated ALD, severe fibrosis stage (F3-4) was associated with significantly lower 10-year survival rate compared to F0-2. Multivariate analysis revealed fibrosis stage as the only prognostic indicator of long-term survival in patients with early/decompensated ALD. In contrast, in decompensated ALD patients, a combination of histological (pericellular fibrosis), clinical (sex) and biochemical (bilirubin and INR) parameters were predict variables predictive of liver related death. Alcohol abstinence was associated with improved survival in both early/compensated and decompensated ALD.

Caruso S, Calderaro J, et al. J Hepatol. 2017; 734-742.

DICER1 germline mutations are known to predispose individuals to the development of malignant tumors, mainly pleuropulmonary blastoma and ovarian Sertoli-Leydig cell tumor.  In this paper, the authors first investigated two patients of a single family who developed multiple well-differentiated hepatocellular tumors over the years. Germline DICER1 mutation was identified in the family and the tumors showed well differentiated morphology with activated Wnt-β-catenin pathway. They then screened 243 sporadic liver tumors and identified 6 (2.5%) tumors with somatic DICER1 mutations. Further studies revealed that In HCCs, DICER1 mutations were significantly associated with CTNNB1 mutations. miRNA profiling identified a specific expression profile in DICER1-mutated tumors with a decreased expression of mature miRNAs.  The data suggest the role of DICER1 mutation in liver carcinogenesis.

Liver Transplantation

Fernandez-Sevilla E, et al. Liver Transplant 2017;23(4):440-447.

Recurrence of HCC following liver transplant (LT) is considered by many to be an essentially terminal condition and the role of surgery in this setting is uncertain. The authors of this paper aimed to identify prognostic factors of survival after post-LT HCC recurrence and to evaluate the impact of surgery. In multivariate analysis, the independent unfavorable factors of post-LT recurrence survival were AFP of >100 ng/mL, intrahepatic recurrence location, and multifocal recurrence. The use of surgery for patient management was identified as an independent favorable factor. The authors conclude that surgical resection of recurrent HCC post-LT is associated with improved patient survival and should therefore be considered when feasible.


Misumi K, et al. Histopathol 2017 70(5):766-774.

BAP1 and PBRM1 expression loss in intrahepatic cholangiocarcinoma (ICC) by immunohistochemistry was evaluated analyzed for clinicopathological and genetic associations. BAP1 loss and PBRM1 loss are both frequent in ICC. BAP1 loss correlated with small-duct type ICC. By multivariate Cox regression analysis, BAP1 loss was an independent prognostic factor for improved overall and recurrence-free survival.


de Vries E, et al. Hepatology 2017; 65(3): 907-919.

Liver biopsies from primary sclerosing cholangitis (PSC) patients (n=119) from seven European institutions were collected. Medium follow-up time was 142 months. Biopsies were scored by six liver pathologists using Nakanuma, Ishak, and Ludwig scoring systems. All three staging systems were independent predictors of liver transplantation and liver related events. Only the Nakanuma staging system was, in addition, independently associated with PSC-related death, and also showed the strongest predictive value for these adverse outcomes. Of the individual staging components, periportal copper-associated protein deposition by orcein stain was the most valuable histologic predictor. None of the staging systems were of prognostic importance for the development of cholangiocarcinoma. The authors conclude that the Nakanuma staging system, which incorporates bile duct loss and copper deposition as features of chronic biliary disease, may be considered the preferred scoring system for PSC liver biopsies.

Bonkovsky H, U.S Drug Induced Liver Injury Network Investigators. Hepatology 2017; 65(4): 1267-1277.

All cases of drug-induced liver injury enrolled into a prospective database over a 10-year period that had undergone liver biopsies (n=363) were scored for the presence of bile duct loss and assessed for clinical and laboratory features, causes, and outcomes. 26 patients (7%) had bile duct loss, scored as moderate-to-severe in 14 (<50% of portal areas with bile ducts) and mild in 12 (50-75% of portal areas with bile ducts). The most common presentation was cholestatic hepatitis. Cases with duct loss were more likely to develop chronic liver injury (94% vs. 47%), which was usually cholestatic and sometimes severe. The most predictive factor of poor outcome was the degree of bile duct loss on liver biopsy. A high proportion of patients were treated with corticosteroids and ursodiol, with little evidence of effect in individual cases or overall.

American Journal of Surgical Pathology

Lobeck IN et al.  Am J Surg Pathol. 2017 Mar;41(3):354-364.

Cystic biliary atresia (CBA) and early choledochal cysts (CC) have overlap in age presentation and radiologic findings and there is debate about whether they represent a spectrum of disease or distinct entities.  Despite clinical similarities, treatment and prognosis are different – CC is treated with complete cyst excision and a biliary to enteric anastomosis while CBA is treated with cyst wall and/or hilar plate to enteric anastomosis.  The authors compared 10 cases of CBA to a similarly aged cohort of 13 infants as well as older patients who underwent surgery for CC to confirm and/or identify differences in anatomy and histology between the two entities.  This study confirms observations from previous literature as well as novel findings: CBA usually (1) lacks epithelium and inflammatory infiltrates and (2) cyst walls have an inner, dense sclerotic (scar-like) layer associated with myofibroblastic hyperplasia that often delaminates, imparting a grossly identifiable inner cyst wall; CC (1) has mostly intact epithelium and does not show a subepithelial scar-like fibrotic layer and (2) immunohistochemistry for smooth muscle actin and smooth muscle myosin heavy chain highlights smooth muscle bundles that are not seen in CBA.  These differences support the current management approach to treat CBA and CC as two different entities.

Choi WT, et al. Am J Surg Pathol. 2017 Mar;41(3):365-373.

Given the shortage of liver allografts and the increasing prevalence of obesity in the general population, transplantation of steatotic livers is likely to increase.  However, conflicting data regarding outcomes in transplantation of livers with > 30% large droplet steatosis and varying definitions for small droplet steatosis have made it difficult to determine the significance of these findings.  The authors conducted a single institution, retrospective review of 134 donor liver biopsies over a 15-year period to determine if there is an association between large and/or small droplet macrovesicular steatosis (MaS) and poor outcomes.  The authors clearly stated their definitions for what constitutes large and small droplet MaS and devised a scoring system for assessing steatosis in this study; excellent interobserver agreement (κ = 0.682) was achieved for estimation of large and small droplet MaS among 3 pathologists.  With mean and median follow-up times of 68 and 63 months, respectively, moderate (30-60%) large droplet MaS was found not to be a risk factor for acute cellular rejection, but ≥ 30% small droplet MaS was found to be a risk factor for acute cellular rejection (HR = 2.5, p = 0.01) and bile duct loss suggestive of chronic ductopenic rejection (HR = 2.4, p = 0.01).  Despite differences in histologic outcomes, there was no impact on clinical outcomes, as patient survival was similar regardless of subtype and percentage of MaS.  The authors conclude that liver allografts with up to 60% large droplet MaS can be safely transplanted without adverse outcomes and those with ≥ 30% small droplet MaS should prompt notification of the transplant team of the potential increased risk for acute cellular rejection.  This newly designed scoring system can facilitate a standardized method to separately report small and large droplet MaS.

Arnason T, et al. Am J Surg Pathol. 2017 Apr;41(4):499-505.

Biliary adenofibroma is a rare hepatic neoplasm with only 14 cases reported in the literature to date.  Given the rarity of this entity, the authors compiled 6 cases from multiple institutions and attempted to better characterize this lesion and its behavior with central pathology review, chart review with extended follow-up, and select molecular analysis. Macroscopically, tumors were relatively well circumscribed and had both solid and cystic areas.  Microscopically, tumors were mostly comprised of tubules and cysts lined by bland to mildly atypical cuboidal epithelium within fibrous stroma; however, cases sometimes showed tubules with irregular shapes and branching, simple papillae formation, and areas with nuclear elongation and hyperchromasia, resembling low-grade dysplasia.  The epithelial components were typically immunoreactive for CK AE1/3, CK7, CK19, and CA19-9; Ki-67 showed a proliferation index ≤10% in the epithelial component and <1% in the stroma.  Abdominal pain was a common symptom and lesions were usually solitary.  Two patients who had positive margins on surgical resection later had local recurrence (at 1 and 6 years).  Multiplex PCR SNaPshot assay for common mutations in a battery of cancer genes showed no mutations, but array comparative genomic hybridization showed amplifications of the CyclinD1 and Her2/neu genes in one case.  In conclusion, this study along with previous reports suggests that these tumors, while rare, are likely slowly progressive neoplasms that warrant complete surgical resection when possible.

Archives of Pathology and Laboratory Medicine

Wales C, et al. Arch Pathol Lab Med. 2017 Mar;141(3):323-324.

Currently, commonplace methods for HCV genotyping include probe-based (PCR) assays and Sanger sequencing.  However, probe-based assays can yield ambiguous genotype/subtype results in some patients and Sanger sequencing can only determine the most prevalent genomic variant, a limitation in detecting coinfection.
Next-generation sequencing (NGS) can detect coinfection and offers potential advantages in efficiency.  In this letter to the editor, the authors created cDNA libraries of plasma samples and then used next-generation sequencing (NGS) methods to sequence them and compared accuracy, speed, and costs to Sanger sequencing, the current gold standard.  The authors found 100% concordance of genotypes for NGS vs. Sanger, observed the ability of NGS to detect coninfection, a prep time of 12.1 for NGS vs. 16.25 for Sanger [min/sample], and a cost efficient breakpoint of 52 samples/run when NGS becomes advantageous over Sanger for reagent cost alone.  In conclusion, HCV genotyping by NGS can detect coinfection and has the potential advantages of being more cost effective, faster, and higher throughput.

Xue Y, et al. Arch Pathol Lab Med. 2017 Apr;141(4):517-527.

This review provides updates, recommendations and experiences in gastrointestinal and hepatobiliary pathology practice from experts at Emory University.  Histopathologic effects of select drugs, an overview of new endoscopic technologies including in vivo microscopy and minimally invasive techniques, and a summary and algorithmic approach to molecular testing are discussed.  Practical tips and considerations in the gross assessment of hepatic explant specimens that have received neoadjuvant therapy and controversies in pancreatic parenchymal margin evaluation are also presented. 

Journal of Gastroenterology and Hepatology

Del Bello A et al. J Gastroenterol Hepatol. 2017 Apr;32(4):887-893.

Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. Nine cases of aAMR, including both an initial and followup liver biopsied, were described in this study. Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, that was confirmed by donor-specific antibody tests. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), some (3 patients) with polyclonal antibodies or intravenous immunoglobulins (3 patients). At the last follow up (21 [4-90] months post-aAMR), 7 patients were alive, including 2 patients with normal liver tests. Grafts' survival was 66%. The liver biopsy performed at 11.5 (5-48.5) months post-aAMR showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). In summary, a B-cell-depleting agent seemed to improve aAMR in selected cases, although several patients kept active status of antibody-mediated rejection.

Prepared by:
Editor, Daniela Allende, MD, Cleveland Clinic
Wenqing Cao, MD; New York University
Cynthia Guy, MD; Duke University
Sanjay Kakar, MD; University of California, San Francisco
Jingmei Lin, MD, PhD; Indiana University
Rish Pai, MD, PhD; Mayo Clinic Arizona
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Eric Yee, MD; University of Oklahoma