HPHS Journal Watch: September/October 2020


Prognostic effects of histology‐based tumour microenvironment scores in resected distal bile duct cancer

Hwang HW, Kim JY, Lee SE, et al. Histopathology 2020 Sep;77(3):402-412.


Histology-based tumour microenvironment (TME) scores are useful in predicting the prognosis of gastrointestinal cancer. However, their prognostic roles in distal bile duct cancer (DBDC) have not been previously studied. The authors evaluate the prognostic significance of the TME scores using the Klintrup-Mäkinen (KM) grade, tumour stroma percentage (TSP) and the Glasgow microenvironment score (GMS) in 81 resected DBDCs. A high KM grade was found in 19 patients (24%) and a high TSP was found in 47 patients (58%). A high TSP was significantly correlated with a low KM grade (P < 0.001). The distribution of the GMS, which was developed by combining the KM grade and TSP, was as follows: 0 (n = 19, 24%), 1 (n = 19, 24%) and 2 (n = 43, 52%). A low KM grade, high TSP and high GMS were significantly associated with short overall survival (OS) (P < 0.001) and relapse-free survival (RFS) (P < 0.001). Furthermore, multivariate analysis showed that a low KM grade [hazard ratio (HR) = 3.826; confidence interval (CI) = 1.650-8.869; P = 0.014], high TSP (HR = 2.193; CI = 1.173-4.100, P = 0.002) and high GMS (HR = 7.148; CI = 2.811-18.173) were independent prognostic factors for short RFS; a low KM grade (HR = 4.324; CI = 1.594-11.733) and high GMS (HR = 6.332; CI = 2.743-14.594) were independent prognostic factors for short OS. The authors conclude that histology-based TME scores, including the KM grade, TSP and GMS, are useful for predicting the survival of patients with resected DBDC.

American Journal of Surgical Pathology

Steatohepatitic Variant of Hepatocellular Carcinoma Is Associated With Both Alcoholic Steatohepatitis and Nonalcoholic Steatohepatitis: A Study of 2 Cohorts With Molecular Insights

Qin J, Higashi T, Nakagawa S, et al. Am J Surg Pathol 2020; 44:1406–1412.


This study found that the steatohepatitic variant of hepatocellular carcinoma (SH-HCC) is related to both nonalcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) through comparison of two cohorts—one from Mount Sinai and one from Japan. The Mount Sinai cohort found similar rates of SH-HCC in patients with NASH (71%) as those with ASH (74%). The rate of SH-HCC remained similar within the ASH group when patients with risk factors for NASH were removed. In Japan, similar rates of SH-HCC were also seen in the NASH (26%) and ASH (36%) groups. The Japan cohort also investigated the molecular subclassification of the tumors and saw no difference in subtype between the NASH and ASH groups. Overall, their study suggests that SH-HCC is related to steatohepatitis itself rather than the underlying etiology.

Journal of Hepatology

Chronic hepatitis D and hepatocellular carcinoma: A systematic review and meta-analysis of observational studies

Alfaiate D, Clement S, Gomes D, et al. Journal of Hepatology 2020 Sep;73(3):533-539.


Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis, but its role in hepatocarcinogenesis remains contested.  This article describes a systemic review and meta-analysis of epidemiologic studies to assess whether CHD is associated with an increased risk of HCC.  Ninety-three studies (68 case-control studies including 22,862 patients and 25 cohort studies including 75,427 patients) were included from searches of PubMed, Embase and Web of Science, as well as study references and conference proceedings.  The study found a significantly higher risk of HCC in patients with CHD.  While extended studies are needed to eliminate a potential bias due to antiviral treatments, the findings advocate for improved screening of hepatitis D virus infection in patients with chronic hepatitis B, and stresses the over-arching need for novel and effective antiviral therapies.

Danger signals in liver injury and restoration of homeostasis

Han H, Desert R, Das S, et al. Journal of Hepatology 2020 Oct;73(4):933-951.


This review article illustrates a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury.   Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules promotes inflammation in the context of liver disease.  The role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer, are discussed.

American Journal of Clinical Pathology

Steatohepatitis-Like Changes in Hepatocellular Adenoma: A Clinical and Pathological Study

Liu Y, Zen Y, Yeh M. Am J Clin Pathol. 2020 Sep 8;154(4):525-532.


This article addresses the frequency of steatohepatitic morphology in hepatocellular adenoma (HCA) and its correlation with risk factors for underlying nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). A series of 41 liver resection specimens diagnosed with HCA.  Its background nonneoplastic liver, and clinical records for risk factors of NAFLD/NASH were also reviewed.  Six steatohepatitic HCAs (SH-HCAs) were identified, with an overall prevalence of six (14.6%) of 41; three were HNF1-inactivated, three were inflammatory, and none were beta-catenin mutated. Five of the six patients with SH-HCA had at least one known risk factor for NAFLD/NASH, including obesity (n = 4; 66.7%), diabetes (n = 5; 83.3%), hypertension (n = 3; 50%), and dyslipidemia (n = 1; 16.7%). Compared with the patients without SH-HCA, the patients with SH-HCA had a higher frequency of type 2 diabetes, obesity, and hypertension. Of the six SH-HCAs, background nonneoplastic liver showed significant steatosis in three (50%) cases and steatohepatitic changes in one (16.7%) case.  In summary, this study showed 15% of HCAs demonstrated steatohepatitic changes, and all SH-HCAs lacked beta-catenin mutated subtype.

Journal of Pathology

Synthesis of diagnostic quality cancer pathology images by generative adversarial networks

Levine AB, Peng J, Farnell D, et al. J Pathol 2020, 252: 2: 178-188.


This study investigates the utility of deep neural networks to synthesize medical images that could be used in deep-learning algorithms. The authors evaluated the efficacy of generative adversarial networks to synthesize high-resolution pathology images of major histological types of cancer (including hepatocellular carcinoma) from The Cancer Genome Atlas. Their results show that the real and synthetic images are classified by histotype with comparable accuracies and the synthetic images are visually indistinguishable from real images. Furthermore, training of computer-aided diagnostic systems can benefit from synthetic images where labeled datasets are limited (e.g. rare cancers).


Endoscopic Ultrasound/Fine Needle Aspiration Is Effective for Lymph Node Staging in Patients With Cholangiocarcinoma

Malikowski T, Levy M, Gleeson FC, et al. Hepatol 2020, 72:3: 940-948


Positive regional lymph nodes (MRLNs) precludes curative oncological resection or liver transplantation for cholangiocarcinoma (CCA). The aim of this study is to evaluate the staging impact of EUS for CCA. The cohort included 157 patients; 24 (15%), 124 (79%), and 9 (6%) with intrahepatic, perihilar, and distal CCA, respectively. EUS was able to identify regional lymph nodes (RLNs) in a higher percentage of patients compared to cross-sectional imaging (86% vs. 47%; P < 0.001). FNA was performed in 133 (98.5%) patients with RLNs (median of three passes per node). EUS-FNA identified MRLN in 27 of 31 (87.1%) patients ultimately found to have MRLNs. For iCCA, EUS detected a higher percentage of RLN compared to cross-sectional imaging (83% vs. 50%; P = 0.048), with MRLNs identified in 4 (17%) patients. Among the entire cohort, identification of at least one MRLN by EUS was associated with lower median survival (353 vs. 1,050 days; P < 0.001) and increased risk of death (hazard ratio = 4.1; P < 0.001). EUS-FNA was effective in identifying MRLN in patients with CCA, and should be routinely incorporated into staging of CCA given the impact of MRLN on prognosis and management decisions.

Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities

Goeppert B, Folseraas T, Roessler S, et al. Hepatol 2020, 72 (4): 1253-1266.


Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and represents the leading cause of death in this population. The study aims to identify clinically relevant genomic and pathological features. A total of 186 patients with PSC-BTC were analyzed and tumor DNA sequencing was performed along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. The authors detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma: TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), etc. On histologic grounds, a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%) were identified.


An Unusual Cause of Fever in a Man With a Liver Mass

Wang Y, Pan Y, Zhou Z. Gastroenterology 2020 Sep;159(3):842-844.


The authors report a case of primary hepatic squamous cell carcinoma.

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

Innes H, Buch S, Hutchinson S, et al. Gastroenterology 2020 Oct;159(4):1276-1289.


Little is known about genetic factors that affect development of alcohol-related cirrhosis. In this genome-wide association study (GWAS) of nearly 36,000 participants from the United Kingdom Biobank (UKB), the authors identified and validated (in 5 European cohorts) single nucleotide polymorphisms that affect risk of alcohol related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk whereas the minor C allele in HNRNPUL1:rs15052 increases risk. Further studies are needed to determine how variants in these genes might contribute to development of cirrhosis in patients with alcohol use disorders.

Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis

Lassailly G, Caiazzo R, Ntandja-Wandji LC, et al. Gastroenterology 2020 Oct;159(4):1290-1301.


This prospective study of 180 severely obese patients aimed to evaluate the long-term effects of bariatric surgery for patients with nonalcoholic steatohepatitis (NASH). Patients underwent bariatric surgery at a single center in France and were followed for 5 years. Liver samples were obtained from 125 of 169 patients (76%) having reached 1 year and 64 of 94 patients (68%) having reached 5 years after surgery. NASH resolved in liver biopsies from 84% of patients 5 years later. The reduction of fibrosis began during the first year and continued through 5 years. Although this is a single cohort of patients, data demonstrate bariatric surgery is an effective treatment for NASH in severely obese patients.

Journal of Gastroenterology and Hepatology

Effect of weight loss induced by laparoscopic sleeve gastrectomy on liver histology and serum adipokine levels

Salman AA, Sultan AAEA, Abdallah A, et al. J Gastroenterol Hepatol. 2020 Oct;35(10):1769-1773.


This study prospectively examined the impact of laparoscopic sleeve gastrectomy (LSG) on liver histopathology, and blood levels of adiponectin, leptin, resistin, and pre‐B cell enhancing factor/Nampt/visfatin. The postoperative biopsies showed a significant reduction in steatosis (P < 0.001), liver fibrosis (P < 0.001), lobular inflammation (P < 0.001), and hepatocyte ballooning (P < 0.001) compared to the pre‐surgery biopsies.

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan

Kitagataya T, Suda G, Nagashima K, et al. J Gastroenterol Hepatol. 2020 Oct;35(10):1782-1788.


Grade ≥ 3 immune-related adverse events (irAE) hepatitis was observed in 4.0% of the patients who were treated with immune checkpoint inhibitors. Female sex was significantly associated with the incidence of grade ≥ 3 irAE hepatitis.

Clinical Gastroenterology and Hepatology

A Model to Identify Heavy Drinkers at High Risk for Liver Disease Progression

Delacôte C, Bauvin P, Louvet A, et al. Clin Gastroenterol Hepatol. 2020 Sep;18(10):2315-2323.


Alcohol-related hepatic injury is a common cause of chronic liver disease. The authors used patients’ drinking history and amount, stage of liver disease, and demographic features to determine risk of disease progression.  They used data from surgical pathology reports for their validation cohort.  They developed a Markov model that integrates data on level and duration of alcohol use to identify patients at high risk of liver disease progression.  They also found that women with F3-F4 fibrosis had a higher a risk of complications when compared to men with similar fibrosis stages.

Diagnostic Accuracy of Noninvasive Tests to Detect Advanced Hepatic Fibrosis in Patients With Hepatitis C and End-Stage Renal Disease

Schmoyer CJ, Kumar D, Gupta G, Sterling RK. Clin Gastroenterol Hepatol. 2020 Sep;18(10):2332-2339.


Patients with hepatitis C virus (HCV) infection and end-stage renal disease (ESRD) often need an assessment of liver fibrosis prior to kidney transplantation. The authors evaluated the accuracy of non-invasive tests to identify advanced hepatic fibrosis in patients with HCV and ESRD. They determined that FIB-4 scores, King’s scores, and the APRI were able to successfully identify those with advanced fibrosis with AUROC values ranging from 0.68–0.71. They then showed that the accuracy of the non-invasive testing increased modestly in patients that had increased ALT when compared to those with a normal ALT.  Overall, the non-invasive testing was best when used for patients with definite cirrhosis.

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
Lindsey Westbrook MD; University of Colorado

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