HPHS Journal Watch: May/June 2019

Journal of Pathology

Genomic profiling of combined hepatocellular-cholangiocarcinoma reveals similar genetics to hepatocellular carcinoma.
Joseph NM, Tsokos CG, Umetsu SE, et al. J Pathol. 2019 Jun;248(2):164-178.

Combined hepatocellular-cholangiocarcinomas (CHC) have a prognosis similar to intrahepatic CC (ICC); staging and treatment generally follow ICC algorithms. The authors performed capture-based next-generation sequencing of 20 CHC and 10 ICC arising in cirrhosis. Intra-tumor heterogeneity was assessed by separately sequencing the HCC and CC components. CHC showed molecular profiles similar to HCC, even in the CC component. CHC harbored recurrent alterations in TERT (80%), TP53 (80%), cell cycle genes (40%; CCND1, CCNE1, CDKN2A), receptor tyrosine kinase/Ras/PI3-kinase pathway genes (55%; MET, ERBB2, KRAS, PTEN), chromatin regulators (20%; ARID1A, ARID2) and Wnt pathway genes (20%; CTNNB1, AXIN, APC). No CHC had alterations in IDH1, IDH2, FGFR2 or BAP1 (genes typically mutated in ICC). TERT promoter mutations were consistently identified in both HCC and CC components, supporting TERT alteration as an early event in CHC evolution. TP53 mutations were present in both components in slightly over half the TP53-altered cases. Amplifications of CCND1, MET, ERRB2 and Wnt pathway alterations, were often exclusive to one component, suggesting that these are late events in CHC evolution. ICC in cirrhosis revealed alterations similar to ICC in non-cirrhotic liver, including in IDH1 or IDH2 (30%), CDKN2A (40%), FGFR2 (20%), PBRM1 (20%), ARID1A (10%) and BAP1 (10%). The data demonstrated that CHC genetics are distinct from ICC (even in cirrhosis) and similar to HCC, which may have diagnostic and treatment implications.


Integrative Analysis Defines Distinct Prognostic Subgroups of Intrahepatic Cholangiocarcinoma.

Goeppert B, Toth R, Singer S, et al. Hepatology. 2019 May;69(5):2091-2106.

The authors performed an integrative analysis on 52 intrahepatic cholangiocarcinomas (iCCAs) using genetic and epigenetic data with a specific focus on DNA methylation components. Recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2 (28%) gene mutations, recurrent arm-length copy number alterations (CNAs), and deletion of 3p21 or amplification of 12q15 were found. Integrative clustering of genetic and epigenetic data identified four iCCA subgroups with prognostic relevance further designated as IDH, high (H) (IDH and H showed frequent deletions in chromosome arms 3p and 6q), medium (M, intermediate genetic and epigenetic marks), and low (L, few methylation events and lack of CNAs) alteration groups. The prognosis of the H and M groups was significantly worse than that of the L group with decreased survival (L group 3-year survival rate was 91%, compared to 65%, 50%, and 36% for the IDH, H, and M groups). The authors concluded that using an integrative genomic and epigenomic analysis approach, four iCCA subgroups (IDH, H, M and L) with widespread genomic and epigenomic differences with prognostic significance were identified. The data presented also suggested differences in the cell-of-origin of the iCCA subtypes, bile duct–type iCCA resembled pancreatic adenocarcinoma, whereas cholangiolar-type iCCA showed similar patterns to a subgroup of hepatocellular carcinoma.

The Spectrum of Hepatic Involvement in Patients With Telomere Disease.
Kapuria D, Ben-Yakov G, Ortolano R, et al. Hepatology. 2019 Jun;69(6):2579-2585.

Loss-of-function mutations in genes that encode for components of the telomere repair complex cause accelerated telomere shortening. Hepatic involvement has been recognized as a cause of morbidity. The authors reported the prevalence and characteristics of liver involvement in a cohort of patients evaluated serially at the National Institutes of Health. One hundred twenty-one patients with known or suspected telomere disease were screened; 40 patients with liver involvement were included with a median follow-up of 2.4 years. Forty patients (40%) with a median age of 42 years showed liver involvement. Liver enzyme profile revealed a cholestatic pattern; 8 (21%) had drug-related enzyme elevations. The most common imaging finding was increased hepatic echogenicity on ultrasound in 39% of patients, followed by hepatomegaly in 26%. Biopsies were available in 6 patients and demonstrated: nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic steatosis. The authors concluded that hepatic involvement is common in patients with telomerase disease and can present in diverse ways, including elevated liver enzymes as well as histopathologic and imaging abnormalities.

American Journal of Surgical Pathology

Angiosarcoma of the Liver: Clinicopathologic Features and Morphologic Patterns.

Yasir S, Torbenson MS. Am J Surg Pathol. 2019 May;43(5):581-590.

Angiosarcoma rarely involves the liver and can be challenging to diagnose by clinical and radiologic means. Published morphologic descriptions on the histology of hepatic angiosarcomas are limited, so the authors evaluated 21 primary hepatic angiosarcomas to further characterize morphologic patterns. Four main growth patterns were identified and their relative frequencies are as follows: (1) 43% vasoformative mass forming, (2) 33% epithelioid/spindled mass forming, (3) 10% sinusoidal non-mass forming, and (4) 10% peliotic non-mass forming. This comprehensive analysis provides further knowledge on the spectrum of morphologic appearances of hepatic angiosarcoma. Such awareness can help pathologists recognize subtle clues on biopsies and also avoid mistaking epithelioid/spindled patterns as a poorly differentiated carcinoma or undifferentiated sarcoma.

90Y-TheraSpheres: The New Look of Yttrium-90.
Arnold CA, Pezhouh MK, Lam-Himlin D, Pittman ME, VandenBussche C, Voltaggio L. Am J Surg Pathol. 2019 May;43(5):688-694.

90Y-TheraSpheres (90Y-TS) and 90Y-SIRSpheres (90Y-SS) are two constructs used in delivery of selective internal radiation therapy/transarterial radioembolization (SIRT/TARE) for the treatment of unresectable liver tumors. This study is the first known published case series characterizing morphologic features of 90Y-TS. Histologically processed, nonradiated microspheres were compared to 90Y-TS from 15 hepatectomy specimens, showing 20-30 mm diameter colorless microspheres with identical features: occasional internal bulls’-eye structures with the condenser out and internal crosses under polarized light microscopy. It is important to be familiar with the appearance of 90Y-TS, as it is different from 90Y-SS and its colorless nature can make it easy to be mistaken for air bubble artifact. Recognition of 90Y-TS can help pathologists detect nearby malignancy or determine the cause of radiation-related injury.

Validation of a Congestive Hepatic Fibrosis Scoring System.
Bosch DE, Koro K, Richards E, Hoch BL, Jalikis F, Koch LK, Swanson PE, Truong CD, Liou I, Yu L, Bhattacharya R, Yeh MM. Am J Surg Pathol. 2019 Jun;43(6):766-772.

Liver biopsy is one approach for evaluating the extent of fibrosis in congestive hepatopathy (CH), which can impact a patient’s candidacy for heart transplant. This study was conducted on 38 liver biopsies from patients with clinically established heart failure and histologic features of CH  to provide more data on the use of a scoring system for staging fibrosis in CH (CHF score) that was originally proposed by the same principal investigator in 2014. Three rounds of scoring were conducting by seven GI/liver subspecialist pathologists; the same set of 38 liver biopsies was evaluated in each round. Glutamine synthetase immunohistochemistry (GS IHC) was also performed on 32 of the cases and provided in the third round to determine if loss of centrizonal staining in cases with higher fibrosis scores (as reported in previous studies) could also be confirmed. The investigators found that interobserver variability in CHF score was improved after a multiheaded microscope training session and provision of GS IHC along with Masson trichrome stains (weighted concordance coefficient S* = 0.66). Higher average CHF scores were associated with higher right atrial pressures, severity of right atrial dilation, presence of right ventricular dilation, elevated ALT, lower platelet counts, longer prothrombin times, and higher MELD scores. In summary, this study demonstrates the reproducibility of the CHF score and supports its clinical relevance by showing its association with known clinical and laboratory parameters of CH.

Clinical Gastroenterology and Hepatology

Unusual Liver Masses Found After Evaluation for Asymptomatic Alkaline Phosphatase Elevation

Berry S, Nissen N, Sundaram V. Clin Gastroenterol Hepatol. 2019 Jun;17(7):e71-e72.

The authors report a case of a 41-year-old woman with Gilbert’s syndrome who had increased alkaline phosphatase levels for 3 years ranging from 170 to 195 U/L, but was asymptomatic. She had previously taken oral contraceptives. Imaging showed hepatomegaly without fatty infiltration, two arterially enhancing lesions, and one with minimal enhancement.  There were numerous isointense hypoenhancing lesions in the right lobe, the largest measuring 6.3 cm. Biopsy showed dilated sinusoids, inflammation, and abnormal portal tracts consistent with inflammatory hepatic adenomatosis, defined as 10 or more hepatic adenomas.

Introduction to the Liver Imaging Reporting and Data System for Hepatocellular Carcinoma
Tang A, Singal AG, Mitchell DG, Hecht EM, Fowler KJ, Kulik L, Parikh ND, Kono Y, Sirlin CB. Clin Gastroenterol Hepatol. 2019 Jun;17(7):1228-1238.

This paper highlights the different imaging modalities used to diagnose hepatocellular carcinoma, including the Liver Imaging Reporting and Data System (LI-RADS) criteria.

A Multicenter Study Into Causes of Severe Acute Liver Injury
Breu AC, Patwardhan VR, Nayor J, Ringwala JN, Devore ZG, Ganatra RB, Hathorn KE, Horton L, Iriana S, Tapper EB. Clin Gastroenterol Hepatol. 2019 May;17(6):1201-1203.

The differential diagnosis of an increase in alanine aminotransferase (ALT) level and/or aspartate aminotransferase (AST) level of ≥1000 IU/L often is stated to include 3 main etiologies: ischemic hepatitis, acute viral hepatitis (typically hepatitis A and hepatitis B), and drug-induced (more specifically, acetaminophen/paracetamol) liver injury (DILI). This study was conducted to confirm these causes were correct.  They determined that these three etiologies accounted for approximately 51.8% of acute liver injury.  Pancreaticobiliary complications were also common.  Their main conclusion was that the differential for acute liver injury should be expanded beyond ischemic, viral, and drug (Tylenol)-related causes.

Journal of Gastroenterology and Hepatology

Association between HLA‐DQA1/DRB1 polymorphism and development of hepatocellular carcinoma during entecavir treatment

Kozuka R, Enomoto M, Sato-Matsubara M, et al. J Gastroenterol Hepatol. 2019 May;34(5):937-946.

This paper examines the association between single-nucleotide polymorphisms (SNPs) and development of hepatocellular carcinoma (HCC) during entecavir (ETV) treatment in nucleos(t)ide analog-naïve patients with chronic hepatitis B virus infection. They conclude that patients with AA genotype in the HLA-DQA1/DRB1 gene or cirrhosis should be carefully followed up as a population potentially at higher risk of HCC during ETV treatment.

Clinical and pathological features of combined hepatocellular–cholangiocarcinoma compared with other liver cancers
Wakizaka K, Yokoo H, Kamiyama T, et al. J Gastroenterol Hepatol. 2019 Jun;34(6):1074-1080.

Combined hepatocellular-cholangiocarcinoma (CHC) is a primary liver cancer containing both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) elements. This paper tries to clarify the clinicopathological features. The clinical features of CHC, including sex, hepatitis B virus infection, and α-fetoprotein were similar to HCC, while its prognosis and pathological features, including vascular invasion and lymph node metastasis, were similar to ICC. Carcinoembryonic antigen levels and tumor size were independent prognostic factors in patients with CHC.

Journal of Hepatology

EASL Clinical Practice Guidelines: Drug-induced liver injury

European Association for the Study of the Liver. Journal of Hepatology 2019 Jun; 70(6): 1222–1261.
It is well established that homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis; the significance of heterozygous carriage is less clear. In this study the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’) on subjects with non-alcoholic fatty liver disease (NAFLD) or alcoholic liver disease (ALD) were studied. These variants are present in up to 10% of Caucasians. The Pi*Z variant presented in 14% of patients with cirrhotic NAFLD and 6% of cirrhotic ALD but only in 2% of their corresponding groups without liver fibrosis.  In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with ALD cirrhosis. The authors conclude that the Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers and should be considered in genetic counselling of affected individuals. Histopathologists have a significant role in identifying these cases.

Visit the June edition of JOH for the latest clinical practice guidelines by the European Association for the Study of Liver for drug-induced liver injury (DILI) focusing on idiosyncratic DILI.  Some highlights include lists of drugs associated with intrinsic versus idiosyncratic DILI, known herbal and dietary supplements involved in hepatotoxicity, drugs associated with hepatic adverse reactions, assessments for exclusion of underlying diseases in DILI diagnosis, management of immune-mediated liver injury induced by immune checkpoint inhibitors, and histological features indicative of poor prognosis.  Since liver biopsy is not required for diagnosis if the suspected drug is a known hepatotoxic compound, liver biopsy is recommended to provide information supporting the diagnosis of DILI or an alternative, to rule out autoimmune hepatitis, when resolution fails following drug withdrawal, and to provide prognostic information.  Click on the link above for the latest on DILI. 

Human Pathology

Identification of key challenges in liver pathology: data from a multicenter study of extramural consults
Torbenson MS, Arnold CA, Graham RP, et al. Hum Pathol. 2019 May; 87: 75-82.

Extramural consultation for challenging pathology cases is an important part of patient care. This study identified challenges in liver pathology by analyzing data from 541 cases.  Cases were submitted for questions on medical (61%) and tumor pathology (39%). This analysis of consult patterns identifies challenging areas in medical and tumor liver pathology, which benefit from consult services and can be focused on by continuing medical educational activities.


Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease
Eddowes PJ, Sasso M, Allison M, et al. Gastroenterology. 2019 May; 156(6): 1717-1730.

The authors estimated the accuracy of FibroScan vibration-controlled transient elastography controlled attenuation parameter (CAP) and liver stiffness measurement (LSMs) in assessing steatosis and fibrosis in patients with suspected nonalcoholic liver disease (NAFLD). Data from 450 consecutive adults who underwent liver biopsy analysis for suspected NAFLD at 7 centers in the United Kingdom from March 2014 through January 2017 were collected.  Biopsies were scored by 2 blinded expert pathologists according to nonalcoholic steatohepatitis clinical research network criteria. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for the categories of steatosis and fibrosis. In a prospective analysis of patients with NAFLD, we found CAP and LSM by FibroScan to assess liver steatosis and fibrosis, respectively, with AUROC values ranging from 0.70 to 0.89. 


Impact of tumour budding grade in 310 patients who underwent surgical resection for extrahepatic cholangiocarcinoma.
Ogino M, Nakanishi Y, Mitsuhashi T, Hatanaka Y, Amano T, Marukawa K, Nitta T, Ueno T, Ono M, Kuwabara S, Yamada T, Hirano S. Histopathology. 2019 May;74(6):861-872.

This study evaluated the prognostic impact of tumour budding grade and its association with clinicopathological and epithelial–mesenchymal transition (EMT)‐related features in perihilar cholangiocarcinoma (PHCC) or distal cholangiocarcinoma (DCC). It included 195 PHCC and 115 DCC patients (n=310). In both PHCC and DCC patients, high tumour budding grade was associated with poor histological differentiation, higher pT factor, presence of lymphatic, venous, perineural invasion and regional lymph node metastasis. In PHCC patients, residual invasive tumour in the resected margin was also associated with high tumour budding grade. For both PHCC and DCC patients, high tumour budding grade was an independent adverse prognostic factor in multivariate analysis (P < 0001 and P = 0.046, respectively). Immunohistochemical examination revealed that the number of tumour buds increased in patients with tumors showing a mesenchymal profile (negative for E‐cadherin and positive for vimentin). The authors concluded that higher tumour budding grade is associated with invasive clinicopathological features, adverse postoperative prognosis and EMT status in extrahepatic cholangiocarcinoma.

Molecular profiling of the biphasic components of hepatic carcinosarcoma by the use of targeted next-generation sequencing.
Zhang X, Bai Q, Xu Y, Wang W, Chen L, Han J, Zhu H, Zhang Z, Hou Y, Zhou J, Zhou Y, Ji Y. Histopathology. 2019 May;74(6):944-958.

This study evaluated the clinicopathological and immunohistochemical (IHC) and molecular features of hepatic carcinosarcoma (HCS). This study included 13 cases of HCS. Molecular alterations were analyzed in separately microdissected carcinomatous and sarcomatous components in 8 cases by using targeted next‐generation sequencing with a panel of 329 cancer‐related genes. The most common gene alterations found in both components were TP53 (75%, 6/8) and NF1/2 (38%, 3/8) mutations and VEGFA amplification (25%, 2/8), which may be strongly associated with HCS tumorigenesis. Amplifications involving MET (38%, n = 3/8) and PDGFRA (25%, n = 2/8) were present only in the sarcomatous components, whereas mutation affecting ERBB4 (25%, n = 2/8) and amplifications of CCND1 and FGF3/4/19 (38%, n = 3/8) were present only in the carcinomatous components, indicating their involvement in the clonal evolution of HCS. The authors conclude that HCS could have been of monoclonal origin, and that the diverse clonal evolution might be driven by special molecular alterations in each tumour component. This study also identified multiple therapeutic targets in HCS, which may be valuable for the personalized treatment of HCS.


Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis
Strnad P, Buch S, Hamesch K, et al. Gut. 2019 Jun; 68(6): 1099-1107.

It is well established that homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis; the significance of heterozygous carriage is less clear. In this study the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’) on subjects with non-alcoholic fatty liver disease (NAFLD) or alcoholic liver disease (ALD) were studied. These variants are present in up to 10% of Caucasians. The Pi*Z variant presented in 14% of patients with cirrhotic NAFLD and 6% of cirrhotic ALD but only in 2% of their corresponding groups without liver fibrosis.  In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with ALD cirrhosis. The authors conclude that the Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers and should be considered in genetic counselling of affected individuals. Histopathologists have a significant role in identifying these cases. 

American Journal of Gastroenterology

Spectrum of Liver Disease in Hepatitis B Virus (HBV) Patients Co-infected with Human Immunodeficiency Virus (HIV): Results of the HBV-HIV Cohort Study.

Sterling RK, Wahed AS, King WC, et al. Am J Gastroenterol. 2019 May; 114(5): 746-757.

The histologic spectrum of liver disease in HBV/HIV coinfection is poorly defined. In this prospective study, liver biopsies in 114 patients coinfected with HBV and HIV were assessed by a central pathology committee chaired by Dr. David Kleiner. Liver biopsies showed significant periportal, lobular, and portal inflammation in 14%, 31%, and 22% respectively. 37% of biopsies had significant fibrosis (Ishak stage ≥2); 24% had advanced fibrosis (Ishak stage ≥3). Higher ALT and lower platelet count, but not HBV DNA, were independently associated with advanced fibrosis.

Prepared by:
Nafis Shafizadeh MD (Editor); Southern California Permanente Medical Group
Daniela Allende MD; Cleveland Clinic
Vishal Chandan MBBS; University of California Irvine
Robert Goldin MD; Imperial College, London
Bella Goyal MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Heather Stevenson-Lerner MD PhD; University of Texas
Eric Yee MD; University of Arkansas

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