Saturday, February 17, 2018

HPHS Companion Meeting at USCAP 2018, Vancouver BC

Major Challenges in Liver Pathology
Sunday, March 18, 2018, 8:30 AM - 12:00 PM
Location: To be announced 
Session Credits:
3 CME and 3 SAMs
Moderator:
Michael Torbenson, MD, Mayo Clinic, Rochester, MN
Course Description:
This year's companion meeting focuses on difficult areas of surgical pathology of the liver. Six particularly important and challenging areas have been chosen. These topics will be addressed by speakers with both diagnostic and research expertise in these areas: (1) the best diagnostic approach to cystic biliary lesions, as classifying the lesions correctly has important clinical consequences; (2) how to approach IgG4 disease of the liver, which can mimic many other diseases; (3) Wilson's disease and the challenges posed by the various clinical presentations and the variable histological findings; (4) an update on cholangiocarcinomas, with a focus on key diagnostic and terminology points; (5) soft tissue tumors of the liver--an always challenging area that you will be able to manage more comfortably after this talk; (6) and the pathologists' role in diagnosing antibody mediated rejection of the liver--a critical role that brings into play clinical, laboratory, histological, and immunostain findings.
Learning Objectives:
Upon completion of this educational activity, the learner will be able to:
  • Integrate clinical information and laboratory testing into the interpretation of allograft liver biopsies for antibody mediated rejection.
  • Understand the appropriate approach for liver biopsies in the setting of Wilson’s disease.
  • Effectively use immunohistochemical stains when evaluating soft tissue tumors of the liver.

8:30 AMSoft Tissue Tumors of the Liver: Hard Diagnoses Made Easy - Sometimes
Elizabeth Montgomery, MD, Johns Hopkins University, Baltimore, MD
9:00 AMIgG4 Disease of the Liver: Challenging Mimicker of Other Diseases
Lizhi Zhang, MD, Mayo Clinic, Rochester, MN
9:30 AMWilson's Disease: One Disease, Many Faces
Maha Guindi, FRCP, Cedars-Sinai Medical Center, Los Angeles, CA
10:00 AMBreak
10:30 AMCystic Biliary Lesions of the Liver: Not all Cysts are the Same
Susan Abraham, MD, MD Anderson Cancer Center, Houston, TX
11:00 AMCholangiocarcinoma: Update on Diagnosis and Terminology
Stephen Lagana, Columbia University, New York, NY
11:30 AMAntibody Mediated Rejection in Liver Allografts: Key Role of Pathology Christopher Bellamy, Royal Infirmary of Edinburgh, Edinburgh, UK

HPHS Reception at USCAP Annual Meeting, Vancouver BC

Greetings Everyone - The Hans popper Hepatopathology Society (HPHS) Reception at the USCAP Annual Meeting will be at the date and time below. The HPHS reception promises to be terrific as always. We look forward to the pleasure of your company.

Cheakamus Room on Saturday, March 17, 2018 from 6:00-8:00 PM at the Fairmont Waterfront.

Address:
Fairmont Waterfront
900 Canada Place Way
Vancouver, British Columbia
Canada   V6C 3L5

Thursday, February 1, 2018

Interesting Case: Jan 2018

CLINICAL HISTORY:
A 70- year-old man presented with right upper quadrant pain for 6 months, fatigue, and weight loss of 50 pounds over the past 2 years. Liver function tests were abnormal. AFP was 25,000 ug/mL. The patient did not have known liver disease, or history of malignancy.

IMAGING FINDINGS (COMPUTED TOMOGRAPHY):
There was a heterogenous mass in the right hepatic lobe measuring 23.3 x 12.3 x 13.8 cm. The background liver demonstrated a nodular contour concerning for underlying cirrhosis. The intrahepatic portion of the right portal vein was not visualized. There was a low density extending to the left portal vein concerning for involvement/invasion of the portal vein.

LIVER BIOPSY:


Figure 1: H&E (10X)


Figure 2: H&E (100X)

Figure 3: H&E (100X)

Figure 4: H&E (100X)


Figures 5 & 6: Immunohistochemical stains and mucicarmine stain demonstrate variable immunoprofile in different areas of the tumor. 

LIVER BIOPSY FINDINGS:
The tumor demonstrates heterogeneous growth pattern.
One area shows a poorly differentiated carcinoma characterized by solid nests of tumor cells with frequent central necrosis. In some areas, small acinar/glandular structures bud off the larger nests. Immunohistochemical stains show that this component is positive for HepPar-1 (patchy), AFP (patchy), CK20 (diffuse and strong) and CDX2 (diffuse and weak) and is negative for CK7.
Another area shows conventional hepatocellular carcinoma (HCC) with trabecular/pseudoacinar growth pattern and patchy clearing of the tumor cell cytoplasm. Immunohistochemical stain for CK20 shows occasional positive tumor cells at the periphery of the HCC nests while immunohistochemical stain for CK7 stains native bile ducts and and shows weak cytoplasmic staining of occasional tumor cells at the periphery. This component is negative for HepPar-1, AFP and CDX2.
Immunohistochemical stain for Ki67 shows that the proliferation index is higher in the poorly differentiated carcinoma component.
In both components mucicarmine is negative for mucin, while immunohistochemical stain for glypican-3 shows focal equivocal staining. Immunohistochemical stain for CD10 does not show canalicular pattern staining and synaptophysin, CA19-9, MART1, NapsinA, PSA, and S-100 are negative in both components.


DIAGNOSIS:
HEPATOCELLULAR CARCINOMA, POORLY DIFFERENTIATED.


DISCUSSION:
Nuclear CDX2 staining in a carcinoma usually indicates that the tumor originated from the gastrointestinal (GI) tract [1]. When combined with CK20 positivity, colonic origin is suspeted. Immunoreactivity for CDX2 and CK20 is rare in conventional HCC. In our case, the conventional HCC component was negative for CDX2 and CK20. (Figure 2, Figure 6 left column). On the other hand, the poorly differentiated carcinoma component exhibited a weak but diffuse CDX2 expression and strong CK20 positivity (Figure 4, Figure 6 right column).
In a recent study, Shah et al, for the first time, demonstrated that a small subset (9 of 172 cases; 5%) of HCCs can be CDX2 positive. Interestingly, more than half of this small subset (5 of 9; 56%) was poorly differentiated. Moreover, 5 of 16 (31%) poorly differentiated HCC showed nuclear CDX2 expression whereas 4 of 156 (3%) moderately differentiated HCC were CDX2 positive. In their study, arginase 1 was also positive in all 9 CDX2 positive tumors, glypican 3 was positive in 5 of 5 tumors, and CK20 was negative in 6 of 6 cases, when performed.  [2]
CK20 positivity in HCC is rare, but has also been reported. Mourra et al. reported a case of moderately differentiated HCC with diffuse and strong CK20 positivity in the setting of concurrent rectal adenocarcinoma. The HCC was positive for glypican-3 and HepPar-1 while the rectal adenocarcinoma was negative for both. The authors reviewed the literature and reported that the incidence of CK20 reactivity in HCCs is variable, ranging from 0% to 14% without any correlation with histologic grade of HCC. [3]
In order to determine an optimal panel of immunomarkers to diagnose HCC, Nguyen et al employed 5 immunostains - HepPar-1, polyclonal CEA (pCEA), glypican-3, arginase 1 and bile salt export pump transporter (BSEP) - on 79 HCCs, and concluded that arginase 1 is the most sensitive immunomarker in detecting HCC at all levels of differentiation, when the "positivity" was defined as >50% of tumor cells being stained. The combination of arginase 1 and glypican-3 had the highest sensitivity (100%) for diagnosing poorly differentiated HCC. [4]
Our case highlights that co-expression of CDX2 and CK20 does occur in poorly differentiated HCC. While scattered acinar/glandular structure in the periphery of the poorly differentiated component raises the possibility of mixed HCC-cholangiocarcinoma (Figure 3), this is not favored given its negativity for mucicarmine and CK7.
The diagnosis of HCC in our case was relatively straightforward given the clinical presentation including the absence of other gastrointestinal tract tumor. However, this is an unusual and educational case from a pathologic standpoint. The co-expression of CDX2 and CK20 in HCC would pose a diagnostic challenge especially when the biopsy material is limited or if there was compounding clinical history, such as concurrent colon cancer.

Learning point: This case demonstrates aberrant expression of CK20 and CDX2 in poorly differentiated HCC. Marked central necrosis in conjunction with the immunoprofile raised the possibility of metastatic carcinoma from the gastrointestinal tract. However, adjacent conventional HCC-like area (Figure2), patchy HepPar-1 positivity and clinical presentation (single mass in a background of cirrhosis with very high AFP) support that the poorly differentiated component with aberrant immunoprofile also represents HCC. Co-expression of CK20 and CDX2 may be seen in HCC, thus this immunoprofile does not exclude a diagnosis of HCC, especially in a poorly differentiated tumor. The addition of arginase1 may be helpful in similar cases since this appears to be the most sensitive immunomarker for HCC of all differentiation, and a combined use of arginase 1 and glypican-3 showed the highest sensitivity for poorly differentiated hepatocellular carcinoma. [4]

REFERENCES:
1) Werling RW, Yaziji H, Bacchi CE, Gown AM. CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas. Am J Surg Pathol 2003;27:303-310.
2) Shah SS, Wu TT, Torbenson MS, Chandan VS. Aberrant CDX2 expression in Hepatocellular Carcinomas: An Important Diagnostic Pitfall. Hum Pathol. 2017;64: 13-18. doi: 10.1016/j.humpath.2016.12.029.
3) Mourra N, Azizi L. CK20 positivity in hepatocellular carcinoma: a potential diagnostic pitfall in liver biopsy. Appl Immunohistochem Mol Morphol. 2013;21(1):94-95. doi: 10.1097/PAI.0b013e31824c4c4a.
4) Nguyen T, Phillips D, Jain D, et al. Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma. Arch Pathol Lab Med. 2015;139(8):1028-34. doi: 10.5858/arpa.2014-0479-OA.

Case submitted by
Tony El-Jabbour, MD; Resident, Pathology and Laboratory Medicine, Albany Medical College, Albany, NY.
Hwajeong Lee, MD; Associate Professor, Pathology and Laboratory Medicine, Albany Medical College, Albany, NY.


Monday, January 29, 2018

Nominations Open for HPHS Trainee Award (Deadline Feb 16th, 2018)

Dear Hans Popper Society members and all others interested in liver pathology,

Please don’t forget to submit your accepted USCAP liver pathology abstract(s) to the 2018 HPHS Trainee Abstract Award competition if a resident or fellow is listed as the first author.  Many thanks from all of us for all of your efforts in mentoring and nurturing the next generation of liver pathologists. 

You can send the abstract directly to Cindy Guy at cynthia.guy@duke.edu .  Please submit the abstract by Friday February 16th.

Best,
Michael Torbenson, HPHS President
Cindy Guy, HPHS Education Committee Chair

Tuesday, January 23, 2018

HPHS JOURNAL WATCH: November - December 2017

Histopathology

Hepatocellular Malignant Neoplasm, NOS: A Clinicopathological Study of 11 Cases from a Single Institution 
Zhou S, Venkatramani R, Gupta S, et al. Histopathology. 2017;71(5):813-822.

A new provisional entity called hepatocellular malignant neoplasm, not otherwise specified (HEMNOS) has been suggested for a subset of pediatric hepatocellular tumors which have histological features typical of neither hepatoblastoma (HB) nor hepatocellular carcinoma (HCC). Eleven HEMNOS were analyzed retrospectively after a median follow up of over 6 years. The clinical, histopathological and immunohistochemical profiles were detailed. The authors conclude that HEMNOS is a subtype of HB with focal HCC-like histology. The HEMNOS fit a high risk clinical profile but may have favorable outcomes following chemotherapy and complete tumor resection.


Liver transplantation

The 28-Year Incidence of De Novo Malignancies after Liver Transplantation: A Single-Center Analysis of Risk Factors and Mortality in 1616 Patients 
Rademacher S, Seehofer D, Eurich D, et al. Liver Transpl. 2017;23(11):1404-1414.

One of the leading causes of late mortality following liver transplantation is de novo malignancy. The authors followed more than 1600 patients prospectively for a study period of 28 years. De novo malignancies were sub-grouped into 3 categories: hematologic, skin and non-skin solid organ tumors (SOT). In multivariate analysis, increased recipient age and a history of smoking were significantly associated with development of SOT. The development of SOT was also significantly associated with cyclosporine-A treatment compared to tacrolimus treatment.

Bile Duct Regeneration and Immune Response by Passenger Lymphocytes Signals Biliary Recovery versus Complications after Liver Transplantation 
Junger HH, Schlitt HJ, Geissler EK, et al. Liver Transpl. 2017;23(11):1422-1432.

The authors aimed to characterize the impact of bile duct (BD) epithelial regenerative responses and immune cell infiltration on biliary complications following BD damage from cold storage during organ harvest for liver transplantation. A 2 mm long circular portion of the common BD was obtained during back-table organ preparation for the 41 patients in this study. The authors devised a BD damage score to quantify bile duct injury. The authors used fluorescence in situ hybridization to quantitate bacterial infiltration, and used double immunofluorescence to measure cytokine production. Immunohistochemistry for E-cadherin, cytokeratin19, CD56, CD14, CD4, and CD8 were also used. Patients with damaged BDs but who subsequently had no biliary complications (compared to subjects with BD damage and subsequent biliary complications) had increased mRNA levels of adherens junctions, increased expression of E-cadherin and cytokeratin19 by immunohistochemistry, and enhanced numbers of CD4+ and CD8+ immune cells. The authors conclude that such molecular immunological BD analyses could help to predict patients who are at increased risk of biliary complications following liver transplantation.

Treating Hepatitis C Virus with Direct-Acting Antivirals: Fear Not the Perceived Threat of Hepatocellular Carcinoma 
Mehta N and Yao FY. Liver Transpl. 2017;23(12):1596-1600.

Direct-acting antivirals (DAAs) for hepatitis C virus infection achieve sustained virologic response in >90% of patients. SVR reduces liver-related and overall mortality compared to no treatment or lack of SVR. Some studies, however, have suggested an increased risk of HCC with DAA therapy. This review examines published data involving DAA therapy and risk of HCC in 3 scenarios: DAAs and de novo HCC, DAAs and recurrent HCC following resection or local-regional therapy, and DAA and HCC outcome before and after LT.


American Journal of Surgical Pathology

Cholangitis Lenta: A Clinicopathologic Study of 28 Cases 
Torous V, De La Cruz AL, Naini BV, et al. Am J Surg Pathol. 2017;41(12):1607-1617.

The authors compiled the largest cohort (28 cases) of cholangitis lenta to date to study associated clinical parameters and outcomes. Essentially all patients had acute onset of illness or had undergone abdominal surgery; almost 90% with cholangitis lenta had received liver transplants and the majority were within the 60 day post-op period. The most common clinical findings were elevated liver function tests, leukocytosis, fever, and fatigue. 85% of patients had positive cultures and met the clinical criteria for sepsis. Over half of patients died during hospitalization after initial liver biopsy. In summary, this study lends further support that patients diagnosed with cholangitis lenta require clinical work-up for underlying infectious etiologies and need prompt medical attention given the high mortality. Not a single case was associated with bile duct obstruction in this study.

C-Reactive Protein (CRP) is a Promising Diagnostic Immunohistochemical Marker for Intrahepatic Cholangiocarcinoma and is Associated With Better Prognosis 
Yeh YC, Lei HJ, Chen MH, et al. Am J Surg Pathol. 2017;41(12):1630-1641.

Using bioinformatics to extract data from The Cancer Genome Atlas and Gene Expression Omnibus, these authors identified CRP as a potential marker for intrahepatic cholangiocarcinoma (iCCA) with high specificity. CRP's immunohistochemical performance was tested in 103 iCCAs, 384 other adenocarcinomas, and 34 liver metastases. The sensitivities were 75% and 93% in tissue microarrays and specificities were 91% and 88% in whole tissue sections for CRP in the identification of iCCA, which were similar or better than N-cadherin tested on the same tissue sample set. Patients with tumors that showed CRP expression had a better overall survival and longer recurrence-free time after surgery. In summary, CRP appears to hold promise as a marker that can be used to differentiate iCCA from other adenocarcinomas and may identify patients with a better prognosis.

Radiologically Undetected Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation An Immunohistochemical Correlation With LI-RADS Score 
Xiong W, Cheeney G, Kim S, et al. Am J Surg Pathol. 2017 Nov;41(11):1466-1472.

This retrospective study compared the Liver Imaging Reporting and Data System (LIRADS) score from multiphase dynamic contrast-enhanced CT studies and histologic features in hepatocellular carcinoma (HCC) from cases that were radiologically undetected (14 patients, 25 tumors) prior to transplant vs. those that were radiologically detected (36 patients, 45 tumors). Histologic features assessed included: size, mitoses per 10 HPFs, number of unpaired arteries per 10 HPFs, distribution of unpaired arteries, tumor necrosis, tumor bile production, Mallory-Denk bodies within the tumor, vascular invasion, amount of fat content within the tumor, and microvessel density within the tumor (extent of sinusoidal capillarization assessed by CD34 immunostain). Undetected HCCs were significantly smaller (88% <2 cm), composed of higher proportion of well differentiated tumors (40%), and showed a lower microvessel density. The differences in other histologic features evaluated did not achieve statistical significance. Of the 25 initially undetected HCCs, 10 could be retrospectively identified on imaging (7 LI-RADS score 3, 3 LI-RADS score 4). In summary, HCCs that escape radiologic detection tend to have 3 characteristics: small size, well differentiated histology, and low microvessel density.


Journal of Hepatology 

Molecular Classification of Hepatocellular Adenoma in Clinical Practice 
Nault JC , Paradis V, Cherqui D, et al. J Hepatol. 2017; 67 (5):1074-1083.

Six molecular subtypes of hepatocellular adenoma has been described: HNF1A inactivated HCA (HHCA), 40-50%, β-catenin mutated (CTNNB1) in exon 3 HCA (bex3HCA, 10-15%), β-catenin mutated in exon 7/8 HCA (bex7,8 HCA, 5-10%), inflammatory HCA (IHCA, 35-45%), sonic hedgehog HCA (shHCA, 5%), and unclassified HCA (UHCA, 7%). Molecular subtypes are linked with specific risk factors, clinical behavior, histologic features and imaging characteristics.  bex3HCAs are at high risk of molecular transformation, and shHCAs at risk of bleeding. The impact of molecular classification on clinical care and therapeutic stratification are also discussed. 

Fibrosis Stage but Not Nash Predicts Mortality and Time to Development of Severe Liver Disease In Biopsy-Proven NAFLD 
Hagström H, Nasr P, Ekstedt M, et al. J Hepatol. 2017; 67 (5): 1265-1273.

Identifying NAFLD patients with increased risk of mortality and liver-specific morbidity remains a challenge although NASH has been suggested as a potential risk factor. This is the largest study investigating long -term outcome in a total of 646 biopsy proven NAFLD patients with up to 40 years follow up.  Mortality, severe liver disease and decompensated liver disease are significantly higher in NAFLD cases than controls. Using NASLD with fibrosis stage 0 as controls, and adjusting for age, sex and T2DM, a significantly increase in mortality and severe liver disease was seen in patients with fibrosis stage 3 and 4.  There was a strong collinearity between high stages of fibrosis and presence of NASH. The presence of NASH did not increase the risk of mortality and liver-specific morbidity. The study also showed that the minimal time (lower end of the 95% confidence interval for the 10th percentile of time) to develop severe liver disease was 22-26 years in fibrosis stage 0-1, 9.3 years in stage 2, 2.3 years in stage 3 and 0.9 years to stage 4. 


Hepatology

Argininosuccinate Synthase 1 (ASS1): A Marker of Unclassified Hepatocellular Adenoma and High Bleeding Risk 
Henriet E, Abou Hammoud A, Dupuy JW, et al. Hepatology 2017; 66(6): 2016-2028.

The authors, using mass spectrometry and proteomics, report the up-regulation of the arginine synthesis pathway in unclassified hepatocellular adenomas (UHCA). Arginosuccinate synthase (ASS1) immunohistochemistry was positive in all 17 UHCA, of which 11 presented with bleeding manifestations. ASS1 was also positive in 45% of inflammatory HCA (IHCA), but was negative in all focal nodular hyperplasias (FNH), beta-catenin activated adenomas (b-HCA), beta-catenin activated inflammatory adenomas (b-IHCA), and 10 of 11 HNF1A adenomas (H-HCA). ASS1 positivity was significantly associated with hemorrhage both in UHCA and IHCA. The authors suggest adenomas that are unclassified by H&E and immunohistochemical features, and are ASS1-positive, represent a new HCA subgroup. The authors also suggest the clinical use of ASS1 immunohistochemistry to assess bleeding risk and to help guide decisions regarding resection.

Autoimmune-Like Chronic Hepatitis Induced by Olmesartan 
Barge S, Ziol M, Nault JC. Hepatology 2017; 66(6): 2086-2088.

Most cases of drug-induced AIH (DIAIH) – a condition clinically, serologically, and histologically identical to AIH, but precipitated by a drug, and which responds to drug-withdrawal – are caused by either nitrofurantoin or minocycline. In this paper, the authors report a case of an autoimmune-like chronic hepatitis caused by olmesartan. A 61 year-old man, after 27 months of olmesartan use, presented with elevated ALT/AST, positive ANA, and elevated IgG. Liver biopsy showed interface hepatitis with septal and bridging fibrosis.  A prominent plasma cell population was not appreciated. Three months after olmesartan withdrawal (and no steroid treatment), LFTs normalized, ANA was negative, and IgG levels were normal. Eight months later, a second liver biopsy was performed, which showed fibrosis regression with thin residual fibrous septa. Portal tracts showed a few lymphocytes without interface activity. The authors correlate this autoimmune-like chronic hepatitis case with the previously described condition of olmesartan-associated enteropathy.

Glutamine Synthetase Staining and CTTNB1 Mutation in Hepatocellular Adenomas
Kakar S, Ferrell LD. Hepatology 2017; 66(6): 2092-2093.

This is a letter to the editor asking the authors of a recent study by Rebouissou et al., which correlated b-catenin activation levels and patterns of glutamine synthetase (GS) staining, to clarify several issues regarding categorization of GS staining patterns. The authors of that study reply.


Human Pathology

A subset of well-differentiated hepatocellular carcinomas are Arginase-1 negative. 
Clark I, Shah SS, Moreira R, et al. Hum Pathol. 2017;69:90-95.

Arginase-1 is the most sensitive and specific hepatocellular marker.  In this study, the authors examined needle biopsies in 68 well-differentiated HCC. Arginase-1 was negative in 7 (10%) cases. These findings are clinically significant as most of the previous studies have reported nearly 100% sensitivity for arginase-1 in well-differentiated HCC.


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 Arkansas for Medical Sciences
Maria Westerhoff, MD; University of Michigan 

Monday, January 8, 2018

Congratulations to Drs. Michael Torbenson, Roger Moreira and Lizhi Zhang on the publication of their text "Surgical Pathology of the Liver"! It's a beautifully illustrated text and a useful resource for those in private and academic practices.



Congratulations to Drs. Alastair Burt,  Linda Ferrell and Stefan Hubscher on the publication of the 7th Edition of MacSween's Pathology of the Liver! This well-known resource will be a much used reference.



Hans Popper Hepatopathology Society members are in bold.

Thursday, November 30, 2017

HPHS JOURNAL WATCH: September - October 2017

American Journal of Surgical Pathology

The Almost-Normal Liver Biopsy: Presentation, Clinical Associations, and Outcome.
Czeczok TW, Van Arnam JS, Wood LD, et al. Am J Surg Pathol. 2017 Sep;41(9):1247-1253. 

Liver biopsy continues to serve an essential role in evaluating patients with abnormal liver enzymes and/or ascites.  However, a subset of these biopsies can appear almost normal on microscopic exam.  The investigators in this study sought to determine how frequently such almost-normal liver biopsies occur, and the clinical diagnoses associated with these biopsies, including follow-up data.  The frequency of almost-normal liver biopsies was 0.6% and 3.7% at two institutions; 97 patients and 97 total biopsies were included for study, with a median follow-up of 4.3 years (range 0-10 years).  This study determined that in 72% of patients, the most likely cause of abnormal clinical findings could be placed into one of eight categories: systemic autoimmune inflammatory conditions (18%), vascular/ischemic events (13%), metabolic syndrome (11%), drug reactions (8%), inflammatory conditions of the GI tract (7%), chronic liver disease (7%), biliary outflow impairment (3%), or miscellaneous (3%; Turner syndrome or familial Mediterranean fever).  The remaining 28% had no identifiable clinical association even after workup and on follow-up.  The results of this study can help clinicians and pathologists alike in shedding light on potential diagnostic considerations in patients with abnormal liver enzymes and/or ascites, but with nearly normal findings on liver biopsy.


Archives of Pathology and Laboratory Medicine

Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas
Wang HL, Kim CJ, Koo J, et al. Arch Pathol Lab Med. 2017 Sep;141(9):1155-1180.

This review discusses established and more recent immunohistochemical markers commonly used in daily practice and their diagnostic utility in GI and hepato-pancreato-biliary pathology.


Gastroenterology

Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on 
Molecular Features. 
Sia D, Jiao Y, Martinez-Quetglas I,et al. Gastroenterology. 2017;153(3):812-826.

This study determined gene expression pattern of inflammatory cells in HCC from 956 patients and correlated this with immune infiltrates and immune regulatory molecules determined by immunohistochemistry, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Markers of inflammatory response were observed in 25% of HCCs with high expression of CD274 (PDL-1); these tumors had fewer chromosomal abnormalities. This category was labeled as ‘Immune class’ and had 2 subtypes: adaptive T-cell response group and exhausted immune response group. The latter was associated with expression of genes regulated by TGF-β1. There was no difference in numbers of mutations in the ‘Immune class’ compared to other HCCs. The authors speculate that agents that block regulatory pathways in T cells such as inhibitors of PDL-1 and TGF-β1 may be effective for ‘Immune class’ HCCs.

Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. 
Kanwal F, Kramer J, Asch SM, et al. Gastroenterology. 2017;153(4):996-1005.

This is a retrospective study of 22,500 hepatitis C virus patients treated with DAA in 2015 (SVR 19,518; no SVR 2982). There were 271 new cases of HCC, of which 183 occurred in the setting of SVR. The risk of HCC was significantly lower with SVR (adjusted hazard ratio, 0.28, 95% CI=0.22-0.36), with highest incidence in cirrhosis cases after SVR compared to those without cirrhosis (adjusted hazard ratio, 4.73. 95% CI, 3.34-6.68).  Majority of HCC were stage 1 and less than 5 cm. The authors conclude that SVR reduces risk of HCC, and that DAA therapy does not increase risk of HCC. The risk of HCC remains high in cirrhosis cases, and ongoing surveillance is required. 

Risk for Hepatocellular Carcinoma After Hepatitis C Virus Antiviral Therapy With Direct-Acting Antivirals: Case Closed? (Editorial)
Maan R, Feld JJ. Gastroenterology. 2017 Oct;153(4):890-892.

The accompanying editorial is a nice discussion of the controversy about increased risk of HCC in hepatitis C patients treated with DAA agents. Contrary to early reports, data from 3 prospective French cohorts did not find an increase in HCC recurrence in patients with SVR and this studies supports these findings. There have been reports that HCC arising after DAA therapy are more aggressive, multifocal and clinically advanced. This study does not support these conclusions. 


Human Pathology

Histopathological evidence of neoplastic progression of von Meyenburg complex to intrahepatic cholangiocarcinoma.
Bhalla A, Mann SA, Chen S, et al. Hum Pathol. 2017;67:217-224.

The preneoplastic potential of Von Meyenburg complex (VMC) for intrahepatic cholangiocarcinoma (ICC) has been reported but remains controversial. This is a retrospective study of 86 resected cases of ICC. A morphologic association between VMC and ICC was observed in 35% of cases: VMC with low-grade biliary dysplasia in 24 cases and high-grade biliary dysplasia in 13 cases. The evolution was also supported by Ki67 and p53 immunostains. ICC associated with VMC had favorable histologic features such as small size, well to moderately differentiation, anastomosing glandular architecture, ductal carcinoma in situ–like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, complete pushing border and low stage (T1). 


Gut

Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease in patients with severe obesity.
Bedossa P, Tordjman J, Aron-Wisnewsky J, et al. Gut 2017;66:1688-1696. 

The authors analyzed 798 consecutive liver biopsies from patients undergoing morbid obesity surgery.  Histologic features were correlated with clinical, biological, anthropometrical, and body composition characteristics.  Patients who had normal liver biopsies tended to be significantly younger and had a different distribution of fat compared to those with steatosis and NASH (more peripheral and less truncal fat).  The presence of truncal fat correlated with severity of histologic disease.  Adipocyte size also correlated with liver disease, but only in females. The difference in fat distribution was not related to duration of obesity as this was similar across age groups (younger individual tended to have an earlier age of onset of obesity).  The authors conclude that young obese individual tend to store fat in subcutaneous tissues.  It is the shift of fat to visceral adipose tissue that correlates with liver damage.


Clinical Gastroenterology and Hepatology

Features and Treatment of Dapsone-Induced Hepatitis, Based on Analysis of 44 Cases and Literature Review
Devarbhavi H, Raj S, Joseph T, et al. Clin Gastroenterol Hepatol 2017;15:1805–1807.

Dapsone-induced hepatitis accounted for 5.2% of drug induced liver injury cases (44 cases among 850) in this study. The average length of treatment prior to onset of liver injury was approximately 34 days. Almost all of the patients also had skin rashes, fever, lymphadenopathy and eosinophilia. More than half also had jaundice. The liver injury pattern was mixed hepatitic/cholestatic in almost half of the cases, followed by hepatitic in 34%, and cholestatic in 16%. Acute liver failure occurred in 16%. 14% of patients died. In a literature review, liver was found to be the most common organ besides the skin to be affected by dapsone hypersensitivity syndrome. Latency period between treatment and dapsone induced hepatitis had a range of 7-150 days, with an average of 32 days. Hence, dapsone induced hepatitis occurs within the first month of therapy with a mixed hepatitic/cholestatic pattern of injury. Steroid treatment leads to lower mortality. 

Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity
Fracanzani AL, Petta S, Lombardi R, et al. Clin Gastroenterol Hepatol 2017;15:1604–1611.

Patients with BMI <25 who have non-alcoholic fatty liver disease are categorized as having “Lean NAFLD”. This study evaluated 143 “Lean NAFLD” Caucasian patients, including histology using classification from Kleiner, Brunt, et al. (Hepatology 2005;41:1313–1321). This group tended to be younger than NAFLD patients with BMI greater than 25. Having a waist circumference >102 cm for males or >88 cm for females was associated with a higher likelihood of having fibrosis score ≥2, among other factors, including diabetes and hypertension. 17% of the lean NAFLD group had severe liver disease, defined as having NASH and fibrosis score 2 or higher. Having GG PNPLA3 polymorphism was the only independent variable associated with NASH and significant fibrosis. A significantly higher prevalence of carriers of the TM6SF2 E167K variant was also found in the lean NAFLD patients. This variant is reported to be associated with decreased secretion of very-low-density lipoproteins, lower circulating lipids, more severe steatosis, inflammation, and NASH.


Hepatology

Uncommon Extrahepatic Metastases From Hepatocellular Carcinoma

Florimonte L, Iavarone M, Castellani M, et al. Hepatology 2017; 66(3): 986-988.

The authors report a case of a 56 year-old man with HBV-cirrhosis and multifocal HCC who underwent transplantation after downstaging of disease with radiofrequency ablation. Explant histology demonstrated residual disease with vascular invasion and six Edmondson grade 2 satellite nodules. Fifteen months post-transplant, the patient developed biopsy-proven metastases in the right ventricle and gluteus muscle, picked up by PET/CT scan. The authors suggest the utility of PET scan to pick-up distant metastasis in patients with high-risk features such as theirs: vascular invasion and multiple satellite nodules.

Regression of Hepatocellular Adenomas and Systemic Inflammatory Syndrome After Cessation of Estrogen Therapy
Sinclair M, Schelleman A, Sandhu D, et al. Hepatology 2017; 66(3): 989-991.

The authors report a case of a 43 year-old woman on OCPs who presented with generalized abdominal discomfort, debilitating fatigue, malaise, intermittent night sweats, and arthralgias. She was found to have an elevated ESR at 100 mm/hour, and an elevated C-reactive protein at 45 mg/L. MRI demonstrated multiple arterially enhancing liver lesions most consistent with hepatic adenomas, the largest of which was 8.5 cm. Biopsy was not performed. A diagnosis of adenoma-driven systemic inflammation was considered. OCP was discontinued. There was a steady decline in inflammatory makers and decrease in size of the liver lesions. Four years after OCP cessation, systemic symptoms had resolved, inflammatory markers had normalized, and the largest adenoma had shrunk to 4.2 cm. Although no biopsy was done, the authors suggest that the case represents another rare example of a systemic inflammatory syndrome associated with inflammatory-type hepatic adenoma (IHA), a syndrome believed to be associated with the interleukin-6 (IL-6) pathway activating mutations characteristic of such tumors.


Journal of Hepatology

Visualization of hepatitis E virus RNA and proteins in the human liver
Lenggenhager D, Gouttenoire J, Malehmir , et al. J Hepatol. 2017 (67); 471-479.

A panel of 12 commercially available antibodies against HEV open reading frame (ORF) 1-3 proteins were evaluated for immunohistochemistry (IHC) and two probes for in situ hybridization (ISH) in human FFPE tissues and HuH7 cells. ORF2 protein was detectable in both HEV protein expression cells and liver tissues of patients with hepatitis E. IHC for ORF2 revealed a patchy cytoplasmic, canalicular, and nuclear staining in liver specimens. Positive ORF2 IHC for HEV ORF2 protein in individual hepatocytes correlated with the detection of HEV RNA by ISH. The sensitivity and specificity of ORF2 IHC is comparable with HEV PCR.  ORF2 protein can be visualized in the liver of patients with hepatitis E. ORF2 IHC may be used to detect HEV in FFPE samples.

Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. 
Calderaro J, Couchy G, Imbeaud S, et al. J Hepatol. 2017 (67); 727-738. 

The correlation of phenotype with molecular features was investigated in 343 surgically resected HCC samples by pathological review, immunohistochemistry, gene expression profiling and sequencing. CTNNB1 mutations (40%) define a specific cholestatic well-differentiated subtype of HCC associated with Wnt/β-catenin activation. TP53 mutated HCC (21%) are poorly differentiated, highly proliferative and macrotrabecular-massive, and exhibited PI3K/AKT pathway activation. The scirrhous HCC subtype was characterized by TSC1/TSC2 mutation, lack of CTNNB1 mutations, and CK19 expression. The steatohepatitic subtype showed frequent IL-6/JAK/STAT activation without CTNNB1, TERT and TP53 pathway alterations.  A novel macrotrabecular-massive subtype of HCC (MTM-HCC) was identified during the pathological review characterized by a predominant (>50%) macrotrabecular growth pattern, more frequent in HBV infected patients, high AFP serum levels, histological features of aggressiveness (satellite nodules, macrovascular and microvascular invasion), and frequent TP53 mutations and FGF19 amplifications. Finally, integration of clinical, genetic, and pathological features showed phenotypically distinct tumour subclasses closely related to G1-G6 subgroups. 


Histopathology 

Detection of Viral Hepatitis E in Clinical Liver Biopsies
Prost S, Crossan CL, Dalton HR, et al. Histopathology 2017 Oct;71:580-590.

Using in-situ hybridization and qPCR the authors examined 36 FFPE liver biopsies from 29 patients infected with viral hepatitis E. A brief review of hepatitis E virus (HEV) clinicopathologic findings is provided. The authors conclude that qPCR is more effective than in-situ RNA testing.

Mucinous Cystic Neoplasms of the Liver and Pancreas: Relationship between KRAS Driver Mutations and Disease Progression
Fujikura K, Akita M, Abe-Suzuki S, et al. Histopathology 2017 Oct;71:591-600.

Twenty five cases of mucinous cystic neoplasm (MCN) were sequenced for KRAS, GNAS, RNF43 and PIK3CA, including 17 MCN of the pancreas (MCN-P) and 8 MCN of the liver (MCN-L).  The molecular findings were correlated with the clinicopathologic features and immunohistochemistry findings. KRAS mutations were rare in MCNs with low grade dysplasia (5%), but were often detected in higher grade tumors (80%). The authors conclude that KRAS mutations appear to be major oncogenic drivers in both MCN-P and MCN-L. Within an individual case, an identical KRAS mutation was detected within the low grade and high grade dysplastic areas. The authors postulate that KRAS mutations within low grade dysplasia may lead to tumor progression, and preoperative testing could potentially contribute to patient management.


Liver Transplantation 

Dropout Rate from the Liver Transplant Waiting List Because of Hepatocellular Carcinoma Progression in Hepatitis C Virus-Infected Patients Treated with Direct-Acting Antivirals
Zanetto A, Shalaby S, Vitale A, et al. Liver Transplantation. 2017 Sept;23:1103-1112.

As background information: Interferon-based therapies for HCV reduced the risk of HCC recurrence in patients who achieved a sustained virologic response (SVR).  Direct-acting antiviral (DAA)-based therapy has markedly increased the number of HCV patients who can achieve SVR, improves hepatocellular function and decreases the need for liver transplantation, however, questions remain whether DAAs are effective in the tertiary prevention of HCV-related HCC following definitive therapy of the tumor. 
This paper compared 23 patients with HCV-related HCC treated with DAAs and 23 HCV-HCC controls listed for liver transplantation, with a median follow up of 10 and 7 months, respectively. Although the cohorts were small and the follow up time short, the authors concluded that viral eradication using DAAs does not seem to be associated with an increased risk of dropout due to neoplastic progression in HCV-HCC patients awaiting LT.
http://www.ncbi.nlm.nih.gov/pubmed/28544587  

Determination of Hepatocellular Carcinoma Grade by Needle Biopsy is Unreliable for Liver Transplantation Candidate Selection
Court CM, Harlander-Locke MP, Markovic D, et al. Liver Transplantation. 2017 Sept;23:1123-1132.

This retrospective analysis included 965 patients undergoing liver transplantation for HCC over a >25 year period. Of those, 234 (24%) patients underwent preoperative needle biopsy (PNB) at a median of 280 days prior to transplantation. Grade of HCC in PNB had poor concordance to the final explant pathology HCC grade (κ = 0.22; p = 0.003), and low sensitivity (29%) and positive predictive value (35%) for identifying poorly differentiated tumors. Vascular invasion was predicted by explant pathologic grade (p < 0.001) but not PNB grade (p = 0.5). The final conclusions of this manuscript were that incorporation of PNB of HCC to guide transplant candidate selection appears unjustified.


Liver Transplantation (October edition).

This Supplemental Issue focused on Maximizing the Allograft Function. There are 3 sections: (1) Impact of Donors, (2) Allograft in the Peri-operative Period, and (3) Post Transplant Allograft Struggles. Although none of the papers are specifically focused on histopathology, each manuscript has high general knowledge value and is recommended reading for liver pathologists who sign out transplant cases.


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 Arkansas for Medical Sciences
Maria Westerhoff, MD; University of Michigan 

Saturday, September 23, 2017

President's Message September 2017


Dear Friends and Colleagues:

In this president’s message we will consider one of the major functions of the office of the President—organizing the Hans Popper Hepatopathology companion meeting.

The President proposes topics and speakers to the Executive Committee, who provide feedback and additional suggestions before the agenda is finalized.  The topics are usually organized around a central theme.  For 2018, the theme will be Major challenges in liver pathology, with topics selected because they pose ongoing challenges, even to those with a lot of experience in diagnostic liver pathology.  Speakers are chosen because they have demonstrable expertise by way of experience and publications.  In many cases, there are multiple excellent speaker candidates, so other factors might be considered, such as geographic variation and if/when an individual spoke at the last Hans Popper companion meeting.  With the new SOPs, we try to hear a wider range of expert voices, selecting whenever possible speakers who have not given talks at the companion within the last three years.  Is there a topic you would be interested in?  Feel free to propose a topic or speaker by sending an email to the president.

Many of the speakers attend the annual Hans Popper Reception, which takes place on Saturday night before the companion meeting, and this is a great place to meet them informally. They are fun and interesting people!  If you get the chance, please take the opportunity to thank the speakers.  They do not receive honorarium or travel expenses with the new SOPs, but agree to speak because of their interest, expertise, and passion for liver pathology.

In the table below are the topics and speakers for the 2018 meeting.  I believe it will be an excellent session and hope you can attend.  


Please don’t forget to mark your calendars for the Hans Popper Reception in Vancouver (Saturday night)—location will be announced later.

Finally, at the reception we raffle off a handful of liver pathology books.  If you would like to donate a book, please send me an email (and the book) and I will get it to the reception.  It can be a book you wrote, or even one that you like a lot and think it would be a good addition to the raffle.

Regards,

Michael Torbenson, MD
President, Hans Popper Society

HPHS JOURNAL WATCH: July - August 2017

Gastroenterology

De Marco L, Pellicano R. Gastroenterology. 2017 Jul;153(1):327.

This communication is in response to an article published by Elmasry et al (Gastroenterology 2017)regarding elevated ALT levels in patients with occult hepatitis C virus (HCV) infection (OCI) who had achieved sustained virologic response (SVR), after therapy with direct-acting antiviral (DAA). The authors point out 3 forms of OCI: (1) Undetectable HCV-RNA in serum and normal transaminases, but positive HCV-RNA in peripheral blood mononuclear cells or liver, (2) HCV-RNA undetectable in serum and persistent elevation of transaminases. In the study by Elmasry et al, 9 cases with SVR and elevated ALT had OCI, which led to the suggestion that these patients should receive additional antiviral therapy. IN this communication, the authors emphasize that evaluation for OCI and possibly additional treatment should also be considered for patients who have been treated for HCV prior to liver transplantation, and this can potentially reduce recurrent hepatitis C in the allograft liver. These reports to not mention liver histology, but the increasing recognition of OCI is interesting as persistent inflammation in the liver has been reported in many studies after SVR for hepatitis C. The correlation of histology with OCI is not fully understood as inflammatory changes are seen more often than detection of HCV-RNA in liver.

American Journal of Gastroenterology

Bugianese, E, et al. Am J Gastroenterol 2017;112:1277-1286.

The authors analyzed 288 consecutive Caucasian Italian overweight/obese children to determine any associations between clinical parameters and histologic features.  12.2% of this cohort was small for gestational age and this was associated with severe steatosis, portal inflammation, and NAS score ≥5.  Lobular inflammation and ballooning were similar between groups.  Children who were large for gestational age were more likely to have type 1 NAFLD (steatosis, ballooning, and/or perisinusoidal fibrosis without portal inflammation or periportal fibrosis) compared to children who were small for gestational age or appropriate for gestational age.

Journal of Hepatology

Urban TJ, Nicoletti P, et al. J Hepatol. 2017 (67); 137-144.

Minocycline drug-induced liver injury (DILI) can present with prominent autoimmune features. To determine the genetic characters of minocycline DILI, the authors studied 25 Caucasian patients with genome-wide genotyping and compared to unexposed population controls. HLA-B35:02 was identified as a potential genetic risk factor for minocycline DILI: 16% carrier rate in DILI compared to 0.6% in population control. This data was confirmed with sequence based genotyping. In addition, HLA docking study suggested that minocycline had the potential to bind HLA-B*35:02 antigen binding cleft. HLA-B35:02 may be useful diagnostic maker of minocycline DILI.

Patouraux S, Rousseau D, et al. J Hepatol. 2017 (67); 328-338.

The roles of CD44 in hepatic inflammation and fibrosis were studied in a mouse model of steatohepatitis and human tissues. Compared to wild type mice on methionine- and choline deficient diet (MCDD), CD44-/- mice showed significantly less liver inflammatory infiltrates (macrophages and neutrophils), CCL2/CCR2 expression, hepatocyte injury and fibrosis.  CD44 silencing strongly enhanced M2 macrophage polarization and decreased the expression of pro-inflammatory cytokines such as IL-6 and TNFα. Neutralization of CD44 corrected hepatic inflammation and liver injury induced by MCDD. In obesity patients, hepatic CD44 expression was upregulated and strongly correlated with macrophage recruitment and markers of inflammation including TNFα, IL1β, MCP1 and CCR2. Correction of NASH with Bariatric surgery was associated with less hepatic CD44 positive cells. Serum levels of CD44 increased with the severity of steatosis and NAFLD. The study suggests CD44 is a key player in NASH and a potential therapeutic target.

American Journal of Pathology
  
Labgaa I, Stueck A, Ward S. American Journal of Pathology 2017; 187(7): 1438-1444.

This is an excellent review and summary of the literature on both lymphoepithelioma-like hepatocellular carcinoma and lymphoepithelioma-like cholangiocarcinoma.

American Journal of Surgical Pathology

Yang Z, Klimstra DS, Hruban RH, Tang LH. Am J Surg Pathol. 2017 Jul;41(7):915-922.

The treatment of neuroendocrine tumors (NETs) can differ depending on the primary site of the tumor.  Therefore, identifying the site of origin for metastatic NETs can be important.  In patients with distant metastases, the liver is the most common site to be involved.  The authors compiled 85 cases of metastatic well-differentiated NETs to the liver and assessed the effectiveness of a panel of immunostains (TTF1, CDX2, ISL1, NKX2.2, PDX1) in predicting the site of origin.  Tissue from microarrays (42 cases) and whole sections (43 cases) were used in this study that included NETs from the pancreas (35%), small bowel (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown origin (12%); the sites of origin were determined based on previous or concurrent pathologic specimens in 74% and the remainder were based on radiologic findings or clinical history.  The use of a 3-marker panel composed of TTF1, CDX2, and ISL1 gave a sensitivity of 63-89%, specificity of 94-100%, positive predictive value of 89-100%, and a negative predictive value of 84-96% in differentiating among sites of origin when grouped as small bowel, lung, and pancreas/rectum.  In examining the 12% of tumors of unknown origin, over half of the cases showed staining for at least one of these 3 markers and was suggestive of small bowel or pancreas/rectum as the primary site.  In conclusion, the authors propose using this 3-marker panel along with any clinical findings for predicting the site of origin of well-differentiated NETs to the liver.  NKX2.2 and PDX1 did not add any additional information regarding site of origin when used in conjunction with the proposed 3-marker panel. 

Clinical Gastroenterology and Hepatology

Freeman AJ, Ng VL, Harpavat S, et al. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1133-1135.

The authors evaluate the utility of gamma glutamyltransferase (GGT) as a potential marker of disease progression for patients affected by biliary atresia who survive without liver transplant. Thrombocytopenia is a recognized surrogate marker for disease progression and portal hypertension. The authors find that a GGT level ≥100 U/L at 2 years of age correlated with progressive decline in platelet counts at 4, 5, and 6 years of age. In comparison, having a GGT level < 100 U/L predicted a low risk of developing subsequent thrombocytopenia. The potential ramifications of this finding is that GGT levels obtained at age 2 may predict the development of thrombocytopenia, a feature of portal hypertension. If these findings are validated with further long term studies, such patients may need additional monitoring or closer follow up in consideration of therapeutic intervention.

Jacobson IM, Washington MK, Buti M, et al. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1087-1094.e2.

Some chronic hepatitis B patients continue to have abnormal levels of alanine aminotransferase (ALT) despite antiviral therapy. This study of chronic hepatitis B patients treated with tenofovir showed 18% to continue to have increased ALT level at year 5, despite long term tenofovir disoproxil fumarate treatment. Grade 1 steatosis (34% to <66%), pretreatment HBeAg seropositivity, and younger age were the main factors associated with increased ALT at year 5. Compared to patients who achieve normalized ALT levels (n=384), those with persistently elevated ALT (n=18) were less likely to achieve virologic suppression and less likely to have cirrhosis regression at year 5 (80% vs 47%). In addition, in the group with persistently elevated ALT, HBeAg+ patients with steatosis on baseline biopsy had a higher frequency of progressing in steatosis over 5 years. The correlation between ALT abnormality and steatosis was not related to PNPLA3 genotype status.

Whitcomb E, Choi W, Jerome K, et al. Clin Gastroenterol Hepatol. 2017 Aug;15(8):1279-1285.

Hepatitis C infection is now curable, as defined by the absence of detectable serum HCV RNA after treatment completion. This study evaluated liver biopsies from patients who received liver transplant for chronic hepatitis C. Even after sustained virologic response (SVR) to antiviral therapy, ~70% of liver biopsies showed histologic features of active HCV infection, posing a potential pitfall of misdiagnosis to pathologists unaware of treatment status. PCR results, however, were negative for HCV in the liver tissue after sustained virological response, despite the histologic findings of hepatitis C infection. Of interest, approximately 30% of the patients had an increase in fibrosis stage in subsequent biopsy. This study characterizes the persistent histologic features of HCV in post-SVR allograft liver biopsies, although PCR is negative for hepatitis C virus in the tissue. Pathologists should avoid incorrect diagnosis of recurrent or persistent HCV in these patients who have completed therapy successfully. Nevertheless, the progression of fibrosis in a subset of these patients raises the question of what may be causing increase in disease stage, whether it be low but undetectable levels of persistent virus or other mechanisms such as idiopathic post-transplant hepatitis.

Histopathology

Kim YJ, Rhee H, Yoo JE, et al. Histopathology. 2017 Aug;71(2):217-226.

The authors use immunohistochemistry including keratins and markers of stemness (K19, K7, EpCAM, and NCAM), inflammation and inflammatory signaling (CD163, CD68, and pSTAT3), proliferation (Ki-67), and fibroblast activation protein (FAP) to mark cancer-associated fibroblasts (CAFs) on 17 scirrhous HCCs and 6 fibrolamellar carcinomas to evaluate differences in the supporting stroma/tumor microenvironment.

Liver Transplantation

Bajaj JS, Fagan A, Sikaroodi M et al. Liver Transpl. 2017 Jul;23(7):907-914.

The effects of liver transplantation on the gut microbial composition were evaluated and correlated with cognitive function and health-related quality of life measures in patients with cirrhosis.

Perito ER, Vase T, Ramachandran R et al. Liver Transpl. 2017 Jul;23(7):957-967.

The prevalence, persistence and association of post-transplant steatosis and chronic liver damage were evaluated in children in this single center study with long-term follow up.

Kasahara M, Sakamoto S, Sasaki K et al. Liver Transpl. 2017 Aug;23(8):1051-1057.

In this study, the authors report their experience with 12 children <3 months of age who underwent liver transplantation at a single center. The overall cumulative 10-year patient and graft survival rates were both excellent at 90.9%.


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 Arkansas for Medical Sciences
Maria Westerhoff, MD; University of Michigan