HPHS Journal Watch May and June 2024

American Journal of Surgical Pathology

An Immunohistochemical Analysis of Osteopontin and S100 Calcium-binding Protein P is Useful for Subclassifying Large- and Small-duct Type Intrahepatic Cholangiocarcinoma

Yoshizawa T, Uehara T, Iwaya M, et al Am J Surg Pathol. 2024;48(6):751-760.

https://pubmed.ncbi.nlm.nih.gov/38584480

Intrahepatic cholangiocarcinoma (iCCA) can be subclassified into two distinct histological type, including large duct-type (LD-type) and small duct-type (SD-type). The authors investigate expression of S100 calcium-binding protein P (S100P) and osteopontin (OPN) in a 74 cases of iCCA. Immunoreactivity for S100P was a highlight sensitive and specific marker for LD-type iCCA, while osteopontin expression was restricted to the SD-type of iCCA. The LD-type of iCCA had a higher rate of lymph node metastasis and significantly worse overall survival and recurrence free survival compared to the SD-type. The authors propose subclassification criteria for iCCA based on immunohistochemical staining for S100P and osteopontin.

Archives Pathol Lab Med

How Molecular Discoveries Have Changed Liver Tumor Pathology: A Brief Review

Taheri N, Graham RP. How Molecular Discoveries Have Changed Liver Tumor Pathology: A Brief Review. Arch Pathol Lab Med. 2024;148(5):e96-e102.

https://pubmed.ncbi.nlm.nih.gov/37639429

In this brief review, the authors explore how recent molecular discoveries in the diagnosis of lvier tumors have led to advances in clinical practice. They begin with a historical review of fibrolamellar carcinoma (FLC), culminating in the discovery of the DNAJB1::PRKACA fusion and, more recently, the existence of rare syndromic cases driven by loss of PRKAR1A. Next, the histologic features of epithelioid hemangioendothelioma (EHE) are discussed, along with the discovery of the WWTR1::CAMTA1 fusion present in this tumor type but absent in other vascular neoplasms. They also discuss the more recent discovery of the YAP1::TFE3 fusion and unique histologic and prognostic features of EHEs lacking a CAMTA1 fusion. Finally, they end with a brief discussion of cholangiocarcinoma, focusing on intrahepatic cholangiocarcinoma and the druggable targets for this tumor type discovered in the last decade.

Clinical Gastroenterology and Hepatology

Prevalence of Steatotic Liver Disease (MASLD, MetALD, and ALD) in the United States: NHANES 2017–2020

Kalligeros M, Vassilopoulos A, Vassilopoulos S, Victor DW, Mylonakis E, Noureddin M. Clin Gastroenterol Hepatol. 2024;22(6):1330-1332.e4.

https://pubmed.ncbi.nlm.nih.gov/37949334

In this research letter, the authors utilize the National Health and Nutrition Examination Survey (NHANES) data set from 2017-2020 to assess the population prevalence of the new classifications of steatotic liver disease (SLD). The new classification system provides criteria for diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD); alcoholic liver disease (ALD); and MetALD for patients who meet both MASLD and ALD criteria. Among US adults, the age-adjusted prevalence of SLD is 37.87%; the prevalence of MASLD is 32.45%; the prevalence of MetALD was 2.56%; and the prevalence of ALD is 1.17%. In multivariate logistic regression, male gender, diabetes, and increased ethnicity-adjusted waist circumference showed an association with clinically significant fibrosis (based on liver stiffness). MetALD was not associated with higher risk of significant fibrosis compared to MASLD, which may point to the need for a re-evaluation of thresholds for defining excessive alcohol consumption. The authors indicate that the improved classification system will help MetALD patients be appropriately evaluated for pharmacologic interventions.

Gastroenterology

Impact of Longitudinal Alcohol Use Patterns on Long-Term Risk of Cirrhosis Among US Veterans With Steatotic Liver Disease

Wong RJ, Yang Z, Cheung R, Singal AK, Do A, Ahmed A, Yeoh A. Gastroenterology 2024;166:1156-1165.

https://pubmed.ncbi.nlm.nih.gov/38428619

In this retrospective study, the authors aimed to evaluate the impact of longitudinal alcohol use on the risk of cirrhosis among US veterans with steatotic liver disease (SLD). Among the 1,156,189 veterans with SLD, the overall incidence of cirrhosis was 0.53 per 100 person-years in the no alcohol group (54.2%), 0.42 per 100 person-years in the low-risk alcohol group (34.6%), and 0.76 per 100 person-years in the high-risk alcohol use group (11.2%). The study also evaluated the dynamic influence of changes in alcohol use over time on the long-term risk of cirrhosis. Notably, patients with baseline high-risk alcohol use who reported decreasing their alcohol use during follow-up experienced a 39% reduction in the long-term risk of cirrhosis. These results support existing data on the harmful effects of high-risk alcohol use in patients with SLD.

Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease

Schönauer R, Sierks D, Boerrigter M, et al. Gastroenterology. 2024;166(5):902-914.

https://pubmed.ncbi.nlm.nih.gov/38101549

Autosomal dominant polycystic liver disease (ADPLD) is a rare, predominantly female disorder caused by variants in the PRKCSH and SEC63 genes, manifesting with diverse clinical presentations. To mitigate the challenges in predicting early-stage disease progression, a consortium of European and US centers assembled the largest cohort of ADPLD patients, focusing on genotype-phenotype correlations, liver volumes, and hospitalization rates. The study introduced innovative clinical endpoints, including normalized, age-adjusted total liver volume and polycystic liver disease–related hospitalization, for refined prognostic risk stratification. Findings indicated greater disease severity in female patients and those with PRKCSH variants. The integration of imaging and genetic scoring offers a robust framework for assessing patient risk of developing symptomatic disease, with the highest hospitalization risk associated with female sex, PRKCSH variants, and rapid liver volume progression (>6.6% per year).

Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts

Trivedi PJ, Hirschfield GM, Adams DH, Vierling JM. Gastroenterology 2024;166:995-1019

https://pubmed.ncbi.nlm.nih.gov/38342195

This review article delves into the etiopathogenic concepts of autoimmune liver disorders, specifically primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis. Key highlights include the association between mucosal immune activation and gut inflammation with autoimmune liver conditions, as well as genetic and epigenetic factors influencing disease risk and the mediators of liver fibrosis. The authors also address challenging clinical concepts, such as overlap syndromes and disease recurrence following liver transplantation.

Gut

Serum biomarker signature is predictive of the risk of hepatocellular cancer in patients with cirrhosis

El-Serag H, Kanwal F, Ning J, et al. Gut. Published online February 16, 2024.

https://pubmed.ncbi.nlm.nih.gov/38365278

In this longitudinal study, data from 2266 patients with cirrhosis (of whom 126 developed HCC during follow-up of 39.9 months) was analyzed to examine the association of several circulating serum biomarkers that were previously linked with the risk of developing HCC. A total of 39 biomarkers were evaluated to develop an internally validated robust metabolic 9- biomarker signature (insulin growth factor-1, interleukin-10, transforming growth factor β1, adipsin, fetuin-A, interleukin-1 β, macrophage stimulating protein α chain, serum amyloid A and TNF-α.) that was predictive of HCC risk among patients with cirrhosis. These biomarkers were predictive of short as well as intermediate-term HCC risk both independent of as well as in addition to our previously developed base HCC prediction model with demographic, lifestyle and clinical variables. This study is a major step in developing an adaptive multidimensional risk model that contains variables from several domains reflecting distinct aspects of the pathogenetic processes that drive or promote oncogenesis in cirrhosis

Hepatology Communications

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction–associated steatohepatitis

Younossi ZM, Mangla KK, Berentzen TL, et al. Hepatol Commun. 2024;8(6):e0423. Published 2024 May 10.

https://pubmed.ncbi.nlm.nih.gov/38727678

The authors use a single center cohort of 702 MASLD patients to track the association between baseline histology (fibrosis, lobular inflammation, ballooning, and steatosis) with risk of long-term clinical outcomes and mortality due to liver, cardiovascular, or cancer events (median follow up of 4.7 years). In this population, cirrhosis risk was reduced when the baseline biopsy showed less fibrosis, less lobular inflammation, and less hepatocyte ballooning. Additionally, lower fibrosis stage was associated with lower risks of other liver disease and trended with lower risks for cardiovascular-related outcomes. The authors conclude that the severity of fibrosis is associated with the risk of liver-related events and cardiovascular-related events, but weight loss surgery lowered the risk of cardiovascular events and overall mortality.

Neoadjuvant and adjuvant systemic therapy in HCC: Current status and the future

Singal AG, Yarchoan M, Yopp A, Sapisochin G, Pinato DJ, Pillai A. Hepatol Commun. 2024;8(6):e0430.

https://pubmed.ncbi.nlm.nih.gov/38829199

In this review, the authors discuss the current and future state of neoadjuvant and adjuvant therapy in treatment of hepatocellular carcinoma (HCC). Although prior attempts as using tyrosine kinase inhibitors have failed to improve survival in a durable manner, more recent clinical trials have suggested that immunotherapy in HCC shows significant improvements in recurrence-free survival in up to 30% of patients with advanced disease. Pathological response has historically been a primary end point in these studies, but there continues to be discussion on whether pathological response is a valid surrogate for other clinically relevant outcomes. Currently, there are a number of clinical trials evaluating the efficacy of immune checkpoint inhibitors even in earlier stages of HCC or as a bridge therapy to liver transplantation.

Histopathology

Heterogeneity of small duct- and large duct-type intrahepatic cholangiocarcinoma

Kinzler MN, Schulze F, Jeroch J, et al.  Histopathology. 2024 May;84(6):1061-1067.

https://pubmed.ncbi.nlm.nih.gov/38409827

The histological subtype of intrahepatic cholangiocarcinoma (iCCA) is associated with different mutational characteristics that impact clinical management. So far, data are lacking on the presence of small duct iCCA (SD-iCCA) and large duct iCCA (LD-iCCA) in a single patient. This study determined the presence and degree of intratumorally heterogeneity of SD- and LD-iCCA features in different tumor regions. Of 129 patients with surgically resected iCCA, features of either SD- or LD-iCCA were present in 67.4% (n = 87) and 24.8% of the patients (n = 32), respectively; 7.8% (n = 10) had histomorphological features of both SD- and LD-iCCA, seven patients (5.4%) of which had sufficient formalin-fixed, paraffin-embedded tissue for further analysis. Heterogeneity of both subtypes could be confirmed with immunohistochemistry. In five of seven (71.4%) patients, molecular profiling revealed intratumorally differences in genetic alterations between the SD- and LD-iCCA region. In one patient, a BRAF mutation (p.V600E) was found in the SD-iCCA but not in the LD-iCCA region of the tumor. In conclusion, a marked portion of patients with iCCA exhibits both SD- and LD-iCCA in different tumor regions. In case of the presence of histopathological heterogeneity, mutational profiling should be considered to avoid missing therapeutically relevant genetic alterations.

Human Pathology

Oncocytic type has distinct immunohistochemical and recurrence-free survival than other histologic types of the intraductal papillary neoplasm of the bile duct

Chun J, Sung YN, An S, Hong SM. Hum Pathol 2024;148:72-80.

https://pubmed.ncbi.nlm.nih.gov/38782100

Intraductal papillary neoplasm of the bile duct (IPNB) is grouped into four histologic types. The authors compared the pathologic, immunohistochemical, and clinical characteristics of oncocytic IPNB (N=13) to other types: gastric (N=15), pancreatobiliary (N=39), and intestinal (N=60). The authors note that oncocytic IPNBs were more frequently identified in females (61.5%), were larger (5.3 ± 2.2 cm), more commonly demonstrated a mixed histologic type (61.5%), and had a higher recurrence-free survival rate compared to those with other types. Moreover, the oncocytic type more frequently showed combined HepPar-1 and CD117 expression. Due to these distinct clinicopathologic features, the authors suggest that the oncocytic type is an independent entity, similar to intraductal oncocytic papillary neoplasm of the pancreas, and should not be considered a histologic type of IPNB.

Journal of Pathology

Obliteration of portal venules contributes to portal hypertension in biliary cirrhosis.

Shan S, Zhao X, Wood-Trageser MA, et al. J Pathol 2024;263:178-189.

https://pubmed.ncbi.nlm.nih.gov/38551075

This study examined obliteration of portal venules (OPV) in both routine histology (2-D) and 3-D reconstruction in a group of patients with biliary disease (biliary atresia and PBC) and Hep-B cirrhosis. OPV was also examined in rat models of CCl4 toxicity and bile duct ligation. 63 patients with atresia (42 post Kasai), 18 patients with PBC, and 35 Hep-B cirrhosis were included. OPV in 2-D assessment was found in 79% of portal tracts in BA, 65% in PBC, and 29% in HBV, suggesting that OPB is more severe and frequent in biliary cirrhosis. In atresia, Kasai reversed fibrosis and ductular reaction, but not OPV, suggesting that the vascular changes may be irreversible. In the rat model, 2D-OPV was higher in bile duct ligation than in CCl4 toxicity, as was portal pressure. Given the increased bile duct density in biliary cirrhosis, the authors concluded that the bile duct proliferation in these conditions compresses the terminal branch of the portal vein, and that the mechanical compression of the terminal branch of the portal vein may lead to OPV and portal hypertension. The findings may explain why portal hypertension occurs earlier and more severely in biliary diseases.

Integrated analyses of the genetic and clinicopathological features of cholangiolocarcinoma: cholangiolocarcinoma may be characterized by mismatch-repair deficiency

Makino K, Ishii T, Takeda H, et al. Journal of Pathology 2024;263:32-46.

https://pubmed.ncbi.nlm.nih.gov/38362598

This study compared 8 cases of cholangiolocarcinoma (CLC) to 119 intrahepatic cholangiocarcinomas (iCCA) and 17 cHCC-ICC. Whole-exome sequencing (WES) showed driver mutations in CLC that mirrored those in iCCA, including IDH1 mutations, but not TERT promoter mutations. CLC demonstrated a mutation signature that suggested acquired dMMR, with heterogeneous loss of expression by immunohistochemistry amounting to > 10% of the tumor in almost all CLC (which was defined as negative expression). Several of these showed high CD8+ tumor-infiltrating lymphocytes, a high tumor mutational burden, and a PD-L1 combined positive score > 1. The authors concluded that while CLC has features of iCCA, it also has dMMR features that are not found in iCCA.

Liver Transplantation

Primary sclerosing cholangitis and other risk factors for post-transplant lymphoproliferative disease after liver transplantation in adults

Ruijter BN, Tushuizen ME, van der Helm D, et al. Liver Transpl. 2024 Jun 1;30(6):640-646.

https://pubmed.ncbi.nlm.nih.gov/37698933

The risk factors for post-transplant lymphoproliferative disease (PTLD) are ill-defined. This study aimed to assess the risk factors for PTLD after liver transplantation (LT) in adults. A total of 1281 patients were included, of whom 29 (2.3%) developed PTLD. Independent risk factors for PTLD after LT in adults were no Epstein-Barr virus load monitoring strategy, primary sclerosing cholangitis as an indication for LT, era (historic era linked to more intense long-term immunosuppression), and Epstein-Barr virus-seronegative recipient. No other independent risk factors were identified in this study. Of the 207 patients with primary sclerosing cholangitis as an indication for LT, 13 (6.3%) developed PTLD versus 16 out of 1074 (1.5%) patients with other underlying liver diseases (log-rank p <0.001). The yearly PTLD incidence was higher in the first year than in the later years after LT (2.4%/y vs. 0.6%/y) for primary sclerosing cholangitis, but not for other indications (0.16%/y). In Epstein-Barr virus-seronegative recipients PTLD occurred earlier after LT, while in 97% of seropositive recipients it could occur very late after LT.

Prepared by:

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

Clifton Fulmer, MD, PhD; Cleveland Clinic

Nigar Anjuman Khurram, MD; University of Pittsburgh

Yuanxin Liang, MD, PhD; Yale School of Medicine

Joseph Misdraji, MD; Yale School of Medicine

Juan Putra, MD; Boston Children’s Hospital

Daniel Roberts MD; Cleveland Clinic

Angela R. Shih, MD; Massachusetts General Hospital

Xuefeng Zhang, MD; Cleveland Clini