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.

Regards, 

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.
References
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.

Histopathology

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.

Hepatology

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

Tuesday, March 28, 2017

Journal Watch: January - February 2017

Clinical Gastroenterology and Hepatology


De Boer YS, Kosinski AS et al. Clin Gastroenterol Hepatol. 2017;15:103-112.

Drugs best known to cause liver injury with autoimmune features include nitrofurantoin, minocycline, hydralazine, and methyldopa. This study analyzed 88 cases of DILI attributed to these four drugs from the Drug-Induced Liver Injury Network prospective study from 2004 through 2014. At the onset of DILI, serum IgG levels were elevated in 39% of cases. 72% of the cases tested positive for ANA, 60% for SMA, but none for SLA.  Autoimmune phenotype (autoimmune score ≥ 2) was observed in 82%, 73%, 55% and 43% of cases attributed to nitrofurantoin, minocycline, hydralazine, and methyldopa respectively. On follow-up, a decrease in ANA or SMA positive rate and autoimmune scores was observed. Genetic study revealed that idiopathic AIH risk alleles HLA-DRB1*03:01 and HLA-DRB1*04:01 do not represent risk factors for nitrofurantoin-, minocycline-, methyldopa-, and hydralazine-induced liver injury and the associated autoimmune phenotype.

Khalaf N, Ying J et al. Clin Gastroenterol Hepatol. 2017;15:273-281.

Studying the natural history of untreated HCC is critical for understanding the prognosis and prognostic factors of HCC and the contribution of surveillance to lead time bias. 518 patients without any HCC treatment was identified from a national cohort of 1500 veterans with verified HCC. The mean age at time of HCC diagnosis was 65.7 years. Most patients had HCV (60.6%) or alcohol abuse (79.3%). The median overall survival time was 3.6 months. In multivariate analyses, BCLC stage, MELD score and alpha-fetoprotein levels were prognostic factors and predictive of survival.  Pre-diagnostic HCC surveillance was associated with detection of HCC at an earlier stage and slightly longer survival compared to patients without surveillance (5.2 months vs. 3.4 months).

Hepatology


Veeral A, Perito E, et al., for the NASH Clinical Research Network. Hepatology 2017; 65(1): 65-74.

The NASH Clinical Research Network investigated thirty-two plasma biomarkers for NASH disease activity and severity in 648 participants. Biomarkers associated with significant fibrosis in multivariable analysis included higher levels of interleukin-8, monocyte chemoattractant protein-1, resistin, soluble interleukin-1 receptor I, soluble interleukin-2 receptor alpha, and tumor necrosis factor alpha.

Sumazin P, et al. Hepatology 2017; 65(1): 104-120.

The authors performed molecular profiling on 88 pretreated hepatoblastomas. Their analysis risk-stratified the tumors into three molecular subtypes, characterized by differential activation of hepatic progenitor cell markers and metabolic pathways. The authors suggest that immunohistochemical stains targeting these biomarkers have the potential to improve risk stratification and guide treatment decisions for patients at diagnosis.
  
Dahlqvist G, et al. Hepatology 2017; 65(1): 152-163.

The authors performed a prospective study across a nation-wide French network for the prevalence of anti-mitochondrial antibodies (AMA). Clinical data from 720 AMA-positive patients identified over one year were collected. 229 patients (32%) were considered “nonestablished diagnosis of PBC.” This group was further studied with a mean follow-up duration of 4.0 years. In this group, those patients who had normal alkaline phosphatase and no evidence of cirrhosis had a 5-year incidence rate of 16% for PBC. Limitations of the study include the fact that only a minority of patients (19%) had a biopsy. And, only the reports were available with no central review of the biopsy. The authors report that some of these pathology reports included “mild portal inflammation” or “features compatible with autoimmune hepatitis,” suggesting the possibility that more scrupulous evaluation of the biopsy material may have been worthwhile. This study is in contrast to a prior older UK study (1996, Metcalf et al.) which followed 29 asymptomatic AMA-positive patients for a median time of 17.8 years, and in which the majority of patients developed PBC. The authors suggest this discrepancy may be from inherent discrepancies between the populations studied and methods used (single-center retrospective selection vs. prospective nation-wide screening).

Kaminsky P, Preiss J, Sasatomi E, Gerber D. Hepatology 2017; 65(1): 380-383.

The authors report a case of a biliary adenofibroma with malignant features and review the literature on this rare tumor. The malignant features they report include “low papillary epithelial overgrowth with increased mitotic activity,” and “small islands of tumors cells infiltrating the fibrous stroma.”
  

Histopathology


Interesting series with review articles covering wide range of pathology most of which are of interest to the most pathologists. With topics that include a review of progress and evolution of pathology as a specialty in the last 50 years and digital pathology, this volume will be of interest in general. It also includes an article on drug-induced liver injury by David Kleiner, the abstract of which is presented below:

Kleiner DE. Histopathology. 2017;70(1):81-93

Drug-induced liver injury (DILI) presents unique challenges to the pathologist. It is not only an uncommon reason for liver biopsy, but the pathology of DILI is spread across the entire spectrum of hepatic injury patterns. It is important for the pathologist to suspect DILI when the histological changes are unusual or out of synchronicity with the patient's history. A systematic evaluation approach will yield the most information. It begins with the characterization of the general pattern of injury which, for most cases, will be found in a handful of necroinflammatory and cholestatic patterns. A careful assessment of the severity of injury across the various anatomic compartments will provide information on the probable natural history of the injury. Correlation of liver injury with the patient's medication history and clinical findings will help to narrow the differential diagnosis, particularly when it is recognized that most drugs have a limited range of histological findings and vary in their propensity to cause injury. This review provides an overview of the assessment of the liver biopsy and its use to confirm or exclude particular drugs as contributing to the patient's liver injury.

Sasaki M, Sato Y, Nakanuma Y. Histopathology. 2017;70(3):423-434.

These authors investigated the expression profile of several genes in 53 patients with combined HCC and cholangiocarcinoma (cHC-CC) and found that some (e.g. TERT promoter gene) could have etiologic significance while others could potentially segregate these tumors into histogenetic and/or biological groups.
Abstract
AIMS: Combined hepatocellular carcinoma and cholangiocarcinoma (cHC-CC), which generally has a poor prognosis, comprises hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and diverse components with intermediate features between HCC and CC. Histological subtypes with stem cell (SC) features (the SC subtype) have different clinicopathological significance in cHC-CC. The mutational status may reflect the clinicopathological subgroup of cHC-CC together with the histological subtype.
METHODS AND RESULTS: We examined the mutational statuses of KRAS, IDH1 or IDH2 (IDH1/2), ARID1A, the TERT promoter, and TP53, and their relationships with clinicopathological features in 53 patients with cHC-CC. Background liver diseases were hepatitis B (n = 9), hepatitis C (n = 22), alcoholic liver disease (n = 5), non-alcoholic fatty liver disease (NAFLD) (n = 8), and unknown (n = 9). Mutations in KRAS, IDH1/2, ARID1A, the TERT promoter and TP53 were detected in four (7.5%), six (11.8%) seven (13.2%), 16 (31.3%), and 24 patients (45.3%), respectively. KRAS mutations correlated with higher histological diversity scores and a higher M-factor (P < 0.05). ARID1A mutations correlated with alcoholic liver disease, smaller tumour size, a lower grade of coexistent HCC, and α-fetoprotein (AFP) positivity, and were associated with cholangiolocellular carcinoma subtype predominance (P < 0.05). TERT promoter mutations correlated with hepatitis B, an intermediate subtype-predominant histology, higher clinical stage, and a higher N-factor (P < 0.05), and were associated with gender (female-predominant) and previous therapy. TP53 mutations correlated with AFP positivity (P < 0.05).
CONCLUSIONS: The results of the mutational analysis revealed that cHC-CC has diverse types of mutations, and also that mutations in the TERT promoter and ARID1A may reflect aetiological impact, different histological subtypes, histogenesis, and tumour aggressiveness. These results suggest the potential efficacy of molecular-based subclassification of cHC-CC.


Abstract
AIMS: Both homozygous and heterozygous α1 -antitrypsin (AAT) deficiency patients are at risk of developing hepatocellular carcinoma (HCC), but also of developing cholangiocarcinoma and combined HCC and cholangiocarcinoma. The aim of our study is to report a series of bile duct adenomas (BDAs) and intrahepatic cholangiocarcinoma (ICCs) in adult AAT deficiency patients, observed in our institution over a 5-year period. Our observational study includes a detailed investigation of their immunohistochemical profile and BRAF V600Emutation status.
METHODS AND RESULTS: Eleven biliary lesions from five AAT deficiency patients (six BDAs from three cirrhotic patients with other concurrent liver diseases; three BDAs and two ICCs from two non-cirrhotic patients) were identified between 2010 and 2015 during routine histological investigation. Most BDAs expressed CD56, EpCAM, CD133, and CA19-9, similarly to hepatic progenitor cells (HPCs), and carried the BRAF V600Emutation (87.5%). One ICC showed a similar immunohistochemical profile but no evidence of the BRAF V600Emutation.
CONCLUSIONS: Most of the biliary proliferations in AAT deficiency patients have an appearance of BDA with an HPC-related immunohistochemical profile. Their frequent BRAF V600E mutations support their neoplastic nature, but not necessarily their progression to ICC. We believe that this may depend on the patient genotype, or require a different pathway or a second mutational hit for malignant transformation. We postulate that BDA represents a heterogeneous group of biliary lesions, and that those associated with AAT deficiency may constitute a group of their own.

Lequoy M, Desbois-Mouthon C, Wendum D, Gupta V, Blachon JL, Scatton O, Dumont S, Bonnemaire M, Schmidlin F, Rosmorduc O, Fartoux L. Histopathology. 2017;70(3):492-498

This paper investigated various somatostatin receptor expressions by RT-PCR and immunohistochemistry in 53 patients with hepatocellular carcinoma. Among other findings, SSTR2 was found to be overexpressed in 32% of these tumors and its expression immunohistochemically (in 38% of tumors) correlated with other markers of poor differentiation, including CK19.
Abstract
AIMS: To investigate the status of somatostatin receptors (SSTRs) in resected hepatocellular carcinoma (HCC).
METHODS AND RESULTS: Transcript and protein levels of SSTR2, SSTR3 and SSTR5 were investigated, with real-time polymerase chain reaction (PCR) and manual and automated immunohistochemistry (IHC), in 53 resected HCCs and paired non-tumour tissues. SSTR1, SSTR4, SSTR5TMD4 and SSTR5TMD5 were analysed with real-time PCR. SSTR3 and SSTR5 transcripts were expressed in ~25% of HCCs, but not in adjacent non-tumour tissues. SSTR1 and SSTR2 transcripts were overexpressed in 42% and 32% of HCCs, respectively. SSTR4, SSTR5TMD4 and SSTR5TMD5 were not detected. Membrane staining for SSTR2 was detected in 38% of HCCs, whereas SSTR5 protein was detectable in only 11% of HCCs. SSTR3 protein was detected in the majority of HCCs and adjacent non-tumour liver tissues, but membrane staining was <20% of that in HCCs. The results obtained with the two IHC methods were highly correlated (P < 0.0001). Statistical analyses also showed a positive correlation between SSTR2 membrane staining and cytokeratin 19 expression (P = 0.04), serum α-fetoprotein level (P = 0.002), and poor differentiation (P = 0.05).
CONCLUSIONS: Membrane SSTR2 is detected reliably in HCCs by IHC, and is a potential therapeutic target, as it is coexpressed with markers of poor prognosis.

Journal of Gastroenterology and Hepatology


Lee YK et al. Journal of Gastroenterology and Hepatology Feb. 2017, 32(2): 487-98.

This study evaluated clinical outcomes of patients with hepatocellular carcinoma who underwent transarterial chemoembolization (TACE) using drug-eluting beads (DEB).
This study retrospectively compared the clinical outcomes of 250 patients who had hepatocellular carcinoma and underwent transarterial chemoembolization (TACE) using drug-eluting beads (DEB) (n = 106) versus those with conventional TACE (cTACE) (n = 144). The most common etiology was hepatitis B virus infection. The median index tumor size was 2.8 cm, and 150 (60.0%) patients had Barcelona Clinic Liver Cancer stage B. Median TTP in the cTACE group was longer than in the DEB-TACE group (13.3 vs10.8 months; P = 0.023). However, DEB-TACE and cTACE groups showed no significant differences for mean OS (46.6 vs 44.9 months; P = 0.660) and disease control rate at 1 month (78.3% vs 86.8%; P = 0.076). The OS, TTP, and disease control rate were also not different between two groups, even when subgrouped by index tumor size. The complication rates within 1 month were higher in the cTACE group (6.6% vs 14.6%; P = 0.048). Drug-eluting beads TACE appears to be a safe intra-arterial therapy, although it is not superior to cTACE in terms of efficacy.

Archives of Pathology and Laboratory Medicine


Gonzalez RS, Gilger MA, Huh WJ, Washington MK. Arch Pathol Lab Med 2017; 141 (1):98-103.

Cardiac hepatopathy (CH) and Budd-Chiari syndrome (BCS) are 2 conditions in the category of venous outflow obstruction that have different pathophysiology and typical clinical/radiologic presentations, but share the histologic findings of sinusoidal dilation and centrilobular necrosis.  In situations where clinical findings are indeterminate for etiology or nonspecific (e.g. elevated liver enzymes), it would be helpful if there were histologic findings that could distinguish between CH and BCS.  The authors retrospectively reviewed 26 CH and 23 BCS cases for the presence of certain histologic parameters to determine if any correlated more closely with one disease versus the other.  Pericellular/sinusoidal fibrosis, fibrosis around central veins, and glycogenated nuclei were significantly more common in CH while centrilobular hepatocyte dropout/necrosis was significantly more common in BCS.  Histologic features common to both CH and BCS included sinusoidal dilation, portal tract fibrosis, chronic inflammation, and bile ductular reaction; while this constellation of findings can be seen in other processes, they should not exclude a diagnosis of CH or BCS.

American Journal of Surgical Pathology


Everett J, Srivastava A, Misdraji J. Am J Surg Pathol. 2017;41(1):134-137.

Fibrin ring granulomas are a distinctive histologic finding that have been described in a number of infections including Q fever, Hepatitis A, Hepatitis C, R. typhi, CMV, EBV, toxoplasmosis, and visceral leishmaniasis as well as some noninfectious conditions.  The authors herein report on 2 cases of combination ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1)-induced hepatitis that showed fibrin ring granulomas in liver biopsies.  Immune checkpoint inhibitors are increasingly being used in cancer therapy, and this case series presents 2 patients who developed transaminase elevations (predominantly hepatitic pattern, ALT up to 643 IU/L) after initiation of combination ipilimumab/nivolumab therapy.  Resolution of symptoms was seen after termination of checkpoint inhibitor therapy and initiation of immunosuppressive treatment.  Likely other causes of transaminase elevations in these patients were excluded and one patient had recurrence of transaminase elevation upon restarting nivolumab.  The main histologic findings this series were hepatocyte necrosis and histiocytic aggregates, focally forming fibrin ring granulomas, colocalizing with steatosis.  Steatosis was predominantly seen in zone 3 in one patient and zone 1 in the other patient.  While the microscopic findings in ipilimumab-induced hepatitis have been previously reported, this case series raises the possibility that fibrin ring granulomas may be also be seen with checkpoint inhibitor therapy, or perhaps even be specific for combination ipilimumab/nivolumab therapy.

Zhelnin K, Xue Y, Quigley B, Reid MD, Choi H, Memis B, Adsay V, Krasinskas AM. Am J Surg Pathol. 2017;41(1):116-120.

A recent proposal by Dr. Albores-Saavedra and colleagues calls for categorizing pancreatic and hepatic cystic lesions with ovarian-type stroma into two entities based on whether the epithelial component is considered mucinous or nonmucinous rather than grouping all such lesions into the term “mucinous cystic neoplasm” (MCN) as defined by the 2010 WHO.  In this study, the authors reviewed 104 pancreatic and 32 hepatic cases from two institutions to characterize the epithelium present in MCNs and explore the significance of percent nonmucinous versus mucinous epithelium in any given case.  81% of cases had a mixture of nonmucinous and mucinous epithelium (having ≥ 5% of each phenotype).  47% of cases had abundant (> 50%) nonmucinous epithelium.  None of the 58 cases having > 50% nonmucinous epithelium contained high-grade dysplasia or invasive carcinoma.  In contrast, 31% of the 71 cases having ≤ 50% nonmucinous epithelium contained high-grade dysplasia or invasive adenocarcinoma.  Given these findings, nonmucinous epithelium may be the precursor, whereas mucinous change may be the key feature in MCN transformation to malignancy.  As such, the authors suggest that perhaps MCNs with predominantly mucinous epithelium are at higher risk and thus should be sampled more thoroughly to exclude malignancy.  With regards to terminology, since a mixture of nonmucinous and mucinous epithelium are frequently found in MCNs, there does not appear to be sufficient evidence at this time to justify separating these lesions into two entities based on epithelial phenotype. 

Taxy JB, Gibson WE, Kaufman MW. Am J Surg Pathol. 2017;41(1):94-100.

The major species E. granulosus and E. multilocularis are common worldwide but are unusual in the United States.  Imaging and laboratory studies such as ELISA and electrophoresis can aid in diagnosis of infection, but these tests may not be ordered, as echinococcal infection is sometimes unsuspected, especially in nonendemic areas.  The authors reviewed 7 historical cases of echinococcosis that were encountered in the Chicago area and remind us of the findings.  Microscopic diagnosis of echinococcus rests on identification of scolices and hooklets, whether on wet mount or histologic sections.  In the absence of these worm parts, cyst walls with an acellular hyaline lining that may be surrounded by calcifications and chronic inflammation are highly suggestive, especially in the appropriate clinical context.  Given the ease and frequency of modern day international travel, pathologists should remember echinococcosis as a diagnostic possibility when encountered with a cystic lesion, whether intra- or extrahepatic.  Prompt diagnosis can be important, particularly in the setting of an intraoperative consultation in a clinically unsuspected case, as this may facilitate treatment and prevent anaphylaxis from intraperitoneal spillage of cyst contents.

Deniz K, Moreira RK, Yeh MM, Ferrell LD. Am J Surg Pathol. 2017;41(2):277-281.

Distinguishing benign hepatocellular lesions from hepatocellular carcinoma can be a difficult diagnostic challenge for pathologists.  Steatohepatitis-like changes (SLC) in focal nodular hyperplasia (FNH) may have similar features with the steatohepatitic variant of hepatocellular carcinoma (HCC).  The authors reviewed FNH resections from 3 institutions to determine the frequency of SLC in FNH and their concurrence with other findings that are typically thought to be associated with HCC, mainly hepatocellular rosettes and/or widened hepatic cell plates (> 3 cells in thickness).  SLC were defined as the presence of ballooned hepatocytes and/or Mallory-Denk bodies.  Of the 33 FNH cases, 54% showed SLC, 70% showed hepatocellular rosettes (almost half of these cases also showed SLC), and 42% showed widened hepatic cell plates (over one-third also showed SLC) but all 3 features tended to be focal in extent.  The fibrosis pattern in steatotic FNH was different than the steatohepatitic variant of HCC: thick fibrous bands with radiating smaller septa and thick-walled vessels are seen in the former, and a “chicken-wire,” pericellular pattern is seen in the latter.  In conclusion, pathologists need to be aware that SLC, hepatocellular rosettes and widened hepatic plates can be seen in FNH and caution needs to be exercised in limited biopsy material as to not over-diagnose these lesions as the steatohepatitic variant of HCC.

Gastroenterology


Elmasry S, et al. Gastroenterology. 2017 Feb;152(3):550-553.

Detection of HCV in liver or peripheral blood in the setting of negative serum HCV RNA is referred to as occult hepatitis C. This is a prospective study comprising 134 hepatitis C cases, who underwent DAA treatment and developed recurrent HCV infection after liver transplantation. Transaminases were abnormal in >10% of the patients who achieved SVR12 (n=14). Of the 9 of these 14 cases, 5 (55%) had occult HCV based on detection by reverse transcription quantitative PCR. The authors conclude that occult HCV infection is present in a subset of patients with abnormal liver enzymes after achieving SVR.

Koutsoudakis G, et al. Gastroenterology. 2017 Feb;152(3):472-474.
This is an editorial that accompanies the previous article.

Gut


Garnelo, M., Tan A, Her Z., et al. Gut 2017;66(2):342-351.

The interaction between tumor cells and the immune system has been the subject of extensive research in the past few years.  In this study, Garnelo et al examine the role of tumor infiltrating lymphocytes in the progression of hepatocellular carcinoma.  Using immunohistochemistry, immunofluorescence, PCR, and flow cytometry from human hepatocellular carcinoma they demonstrate that the presence of tumor infiltrating T-cells and B-cells correlates with improved outcomes.  They demonstrate that the density of tumor infiltrating B-cells correlates with T-cell and NK cell activation and decreased tumor cell viability.


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