HPHS JOURNAL WATCH: November – December 2017


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. 


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 

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