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.


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). 


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.


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. 


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.

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 

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