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