HPHS Journal Watch Jan/Feb 2024


The utility of P-I-R classification in predicting the on-treatment histological and clinical outcomes of patients with hepatitis B and advanced liver fibrosis.

Chang X, LvC, Wang B, et al. Hepatology 2024;79:425-437.


Recently, the Beijing Classification was proposed to describe advanced fibrosis of the liver as predominantly progressive, indeterminate, or predominantly regressive (P-I-R). Several studies have validated this system in evaluating liver fibrosis regression in chronic HBV or HCV infection. This study aimed to test whether the P-I-R classification predicts clinical outcomes in a cohort of patients enrolled in a multicenter randomized controlled clinical trial. Patients with treatment naïve chronic HBV were enrolled to receive either entecavir or entecavir plus a traditional Chinese medicine. Liver biopsies were assessed by Ishak Fibrosis, Knodell activity, Laennec classification of cirrhosis, and Beijing classification. Ultimately, 646 patients had both initial and second liver biopsy at week 72. After 72 weeks of treatment (either arm), the proportion of patients who had Ishak 4 or more decreased (74% to 52%). The proportion of cases showing regression on liver biopsy increased from 13% to 64%. The reversal of fibrosis was identified by Ishak in 57% of patients as opposed to 64% by P-I-R classification. Importantly, among patients with stable Ishak scores (n= 218), 42% were predominantly regressive and 38% were predominantly progressive. Clinical outcomes were worse in patients with worse Ishak scores than among better Ishak scores. Among those with Ishak stable scores, HCC developed in 19.5% of P-I-R progressives compared to 6.8% indeterminate and 2.2% regressives. Multivariate analysis demonstrated that P-I-R classification was an independent factor for clinical outcomes. In conclusion, P-I-R classification can stratify patients with stable Ishak scores into those with higher risk of poor clinical outcome. The authors advocate that P-I-R is complementary to Ishak fibrosis score, particularly for assessing regression in clinical trials.

Hepatology Communications

Histological features of chronic hepatitis B patients with normal alanine aminotransferase according to different criteria

Huang R, Liu J, Wang J, et al. Hepatol Commun. 2024 Jan 11;8(1):e0357.


Although different international guidelines use different cutoffs for the upper limit of normal (ULN) for ALT, serum ALT levels are critical in determining whether to initiate antiviral therapy in patients with chronic hepatitis B (CHB). The aim of this study was to evaluate the histological injury in patients with detectable HBV DNA levels and normal ALT levels by different ULNs. Using the Scheuer’s scoring system, liver biopsies were scored with grade of 2 or higher and stage of 2 or higher being considered significant inflammation and significant fibrosis, respectively. The authors found that 48.1%, 48.1%, and 62.3% of patients with detectable serum HBV DNA and ALT < 35/25 U/L for male/female had significant inflammation, significant fibrosis, and significant histological disease. While adopting a more stringent ULN of ALT values may slightly reduce the risk of significant histological disease, significant histological disease was found in over half of CHB patients with detectable HBV but normal ALT levels even when using the lowest ULN. The authors suggest that persistently normal ALT levels were more important for excluding patients with CHB with a high probability of significant histological disease and recommend monitoring with request ALT testing.


Multiregional analysis of combined hepatocellular-cholangiocarcinoma reveals histologic diversity and molecular clonality

Na HY, Kim JH, Kim H, et al. Histopathology. 2024 Jan;84(2):402-408.


The histology and genomic alterations of recurrent/metastatic combined hepatocellular-cholangiocarcinoma (cHCC-CC) are poorly understood. This article included six patients with cHCC-CC (four classic cHCC-CCs and two intermediate cell carcinomas [ICs]) whose recurrent or metastatic tumours were histologically confirmed. The clinicopathological features were evaluated, and next-generation sequencing was performed in 17 multiregional and longitudinal tumour samples. The histology of recurrent/metastatic lesions of classic cHCC-CCs was variable: hepatocellular carcinoma (HCC) was observed in one (25.0%) patient, cHCC-CC in one (25.0%) patient, and cholangiocarcinoma (CC) in two (50.0%) patients. Among 13 samples from four classic cHCC-CC patients, the most frequent pathological variants were TP53 (46.2%), TERT promoter (38.5%), ARID1A mutations (23.1%), and MET amplification (30.8%). In the sequencing analysis of each HCC and CC component, three (75.0%) of the four classic cHCC-CCs shared pathogenic variants. A large proportion of mutations, both pathogenic and those of undetermined significance, were shared by each HCC and CC component. Regarding ICs, the ATM mutation was detected in one patient. In conclusion, the histology of recurrent/metastatic cHCC-CCs was heterogeneous. Genomic profiling of classic cHCC-CCs revealed similar genomic alterations to those of HCC. Considerable overlapping genomic alterations in each HCC and CC component were observed, suggesting a monoclonal origin. Genetic alterations in ICs were different from those in either HCC or CC, suggesting the distinct nature of this tumour.

Differential diagnosis of small hepatocellular nodules in cirrhosis: surrogate histological criteria of TERT promoter mutations

Beaufrère A, Paisley S, Ba I, et al. Histopathology. 2024 Feb;84(3):473-481.


The differential diagnosis of small hepatocellular nodules in cirrhosis between dysplastic nodules and hepatocellular carcinoma (HCC) remains challenging on biopsy. As TERT promoter (pTERT) mutations may indicate the nodules already engaged in the malignant process, this study aimed to identify histological criteria associated with pTERT mutations in small hepatocellular nodules arising in cirrhosis. This study included a bicentric cohort data set of 339 hepatocellular nodules < 2 cm from cirrhotic samples, divided into a test cohort of 299 resected samples and a validation cohort of 40 biopsies. Pathological review, based on the evaluation of 14 histological criteria, classified all nodules. pTERT mutations were identified by droplet digital PCR (ddPCR) in formalin-fixed paraffin-embedded (FFPE) biopsy samples. Among the 339 nodules, ddPCR revealed pTERT mutations in 105 cases (31%), including 90 and 15 cases in the test and validation cohorts, respectively. On multivariate analysis, three histological criteria were associated with pTERT mutations in the test cohort: increased cell density (P = 0.003), stromal invasion (P = 0.036) and plate-thickening anomalies (P < 0.001). With the combination of at least two of these major criteria, the AUC for predicting pTERT mutations was 0.84 in the test cohort (sensitivity: 86%, specificity: 83%) and 0.81 in the validation cohort (sensitivity: 87%, specificity: 76%). These three histological criteria may be used as surrogate markers of pTERT mutations to classify small hepatocellular nodules arising in cirrhosis.

Human Pathology

Enteroblastic cholangiocarcinoma: An uncommon, underrecognized subtype of bile duct cancer.

Chun J, Moore M, Kelly P, et al. Hum Pathol. 2024 Feb;144:46-52.


Enteroblastic carcinoma is most often described in the stomach and is defined histologically by tumor cells with clear cytoplasm and blastic-appearing coarse chromatin arranged in tubules, papillary structures or as solid nests. These rare tumors produce AFP and sometimes contain a component of hepatoid carcinoma. Enteroblastic features have not been well characterized in tumors of the biliary tree. The authors described the morphologic and immunophenotypic features of four cases of enteroblastic cholangiocarcinoma (n=2 intrahepatic and n=2 extrahepatic). All of cases were positive for AFP, glypican 3, and SALL4 (the latter was widely expressed in all cases, at least focally). HepPar-1 was positive in one case, and arginase-1 was negative in all cases. The authors also review the literature and prior case reports of enteroblastic or hepatoid cholangiocarcinoma.

Journal of Hepatology

Inflammatory bowel disease and primary sclerosing cholangitis: One disease or two?.

Van Munster KN, Bergquist A, Ponsioen CY, et al. J Hepatol. 2024 Jan;80(1):155-168.


In this review, the authors provide a summary of the currently available data regarding the epidemiology and pathophysiology of inflammatory bowel disease (IBD) in primary sclerosing cholangitis (PSC) to explore whether PSC and IBD should be considered one or two disease(s).

Artificial intelligence-assisted digital pathology for non-alcoholic steatohepatitis: current status and future directions.

Ratzlu V, Hompesh M, Petitjean M, et al. J Hepatol. 2024 Feb;80(2):335-351.


This review provides an overview of digital pathology (DP)/artificial intelligence (AI) currently in development for evaluation of specimens from patients with nonalcoholic steatohepatitis (NASH), including a comparison of four commercial tools. Regulatory considerations are discussed as well as current status, future prospects in clinical management and drug development, and limitations.

Modern Pathology

Gene Rearrangement and Expression of PRKACA and PRKACB Govern Morphobiology of Pancreatobiliary Oncocytic Neoplasms

Itoh T, Omori Y, Seino M et al. Mod Pathol. 2024 Jan;37(1):100358.


The authors analyzed PRACA/B fusion genes in 80 pancreatobiliary Intraductal oncocytic papillary neoplasms (IOPNs). PRKACA/B fusion genes were detected in 100% (32/32) of tumors with mature IOPN morphology and 46% (13/28) of tumors with partial IOPN morphology. This study identified a strong association between oncocytic morphology and upregulation of PRKACA/B, representing a possible therapeutic target.

Comparative Clinicopathologic and Genomic Analysis of Hepatocellular Neoplasm, Not Otherwise Specified, and Hepatoblastoma.

Zhou S, Sarabia SF, Estrine D et al. Mod Pathol. 2024 Feb;37(2):100385.


The authors aimed to identify the similarities and differences between hepatocellular neoplasm, not otherwise specified (HCN-NOS) and hepatoblastoma (HB). 16 pediatric patients with HCN-NOS and 23 pediatric patients with HB were included in this study. They found no significant differences in AFP levels, and the most frequently mutated gene in both groups was CTNNB1. On the other hand, TERT promoter mutations and clinically significant variants (BRAF, NRAS, and KMT2D) were exclusively present to HCN-NOS. While HCN-NOS exhibits more frequent high-risk genetic alterations compared with HB, patients in both groups exhibit comparable survival when treated aggressively.

Correlation of Vein-Rich Tumor Microenvironment of Intrahepatic Cholangiocarcinoma With Tertiary Lymphoid Structures and Patient Outcome.

Doi N, Ino Y, Fuse M et al. Mod Pathol. 2024 Feb;37(2):100401.


The authors examined 261 cases of intrahepatic cholangiocarcinoma (iCCA) with a specific focus on tertiary lymphoid structures (TSL), which are ectopic lymphoid organs comprised of a morphologic T zone and follicular formation with high endothelial venules. TSL have been associated with antitumor immunity and favorable prognosis in several cancers. The authors found that TLS appeared more frequently in large-duct type iCCA than in small-duct type iCCA, and TLSs were associated with increased survival in large-duct type iCCA only.

Prepared by:
Dana Balitzer, MD (Editor); University of California San Francisco

Soo-Jin Cho, MD, PhD; University of California San Francisco

Ashim Das, MD; Post Graduate Institute of Medical Education and Research, India

Gillian Hale, MD, MPH; University of Utah

Joseph Misdraji, MD; Yale School of Medicine

Meredith Pittman, MD; Maimonides Medical Center

Daniel Roberts, MD; Cleveland Clinic

Lindsey Westbrook, MD; University of Colorado

Xuefeng Zhang, MD; Cleveland Clinic

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