HPHS Journal Watch: March/April 2022

American Journal of Clinical Pathology

Development of a Scoring System to Differentiate Amiodarone-Induced Liver Injury From Alcoholic Steatohepatitis

González IA, Fuller LD, Zhang X, et al. Am J Clin Pathol. 2022 Mar 3;157(3):434-442.


Amiodarone-induced liver injury (AILI) and alcoholic steatohepatitis (ASH) can have significant histopathologic overlap. This multi-institutional study provides a scoring system using histologic features that may be helpful in differentiating between AILI and ASH. The scoring system was developed using 17 AILI and 17 ASH cases and validated on a test cohort of 14 AILI cases, with 13 of 14 cases correctly assigned to AILI (sensitivity 92.9% sensitivity, 91.7% specificity, 92.3% accuracy). Histologic features more commonly seen in ASH compared to AILI (and assigned higher point values) included: presence of cholestasis, higher percentage of macrovesicular steatosis, hepatocyte ballooning degeneration, neutrophilic lobular inflammation, satellitosis, Mallory-Denk bodies (non-zone 1), pericellular fibrosis. Although hepatocyte ballooning degeneration was more common in ASH, “balloon-like” hepatocytes were more common in AILI. While pericellular fibrosis is seen in both AILI and ASH, a zone 1 predominance was noted in AILI (versus panacinar or zone 3 distribution in ASH).

American Journal of Surgical Pathology

Hepatic Secondary Syphilis Can Cause a Variety of Histologic Patterns and May Be Negative for Treponeme Immunohistochemistry

Malvar G, Cardona D, Pezhouh MK, et al. Am J Surg Pathol. 2022 April; 46(4):567-575.


A diagnosis of hepatic syphilis is very rare in tissue biopsies. To better understand the histologic patterns of this disease, the authors collected 14 cases from 10 centers across the United States with accompanying clinical data. The majority of patients were men (93%), and six (43%) were known to be HIV-positive. All patients showed elevated AST/ALT and/or alkaline phosphatase. The histologic findings from the 14 liver biopsies were categorized, with most falling into the “biliary pattern” group (36%) or “acute hepatitis pattern” group (29%). One (7%) patient had plasma-cell rich portal cell infiltrate with interface hepatitis, reminiscent of autoimmune hepatitis, two (14%) patients had inflammatory pseudotumors, and the remaining 2 (14%) patients had no particular pattern of injury. The authors conclude that hepatic syphilis has protean manifestations both clinically and histologically and that this infectious disorder should be included in the differential diagnosis with a wide variety of presentations, especially now that cases are on the rise.

Clinical Gastroenterology and Hepatology

Hepatic Sinusoidal Obstruction Syndrome Post-Liver Transplantation: A Rare Complication of Tacrolimus

Li C, Ma H, Sun C. Clin Gastroenterol Hepatol. 2022 Mar;20(3):e347.


In this Images of the Month submission, a case of hepatic sinusoidal obstruction syndrome (SOS) as a post-transplant complication of tacrolimus is presented with a histologic image.


Inhibition of p53 Sulfoconjugation Prevents Oxidative Hepatotoxicity and Acute Liver Failure

Xu P, Xi Y, Wang P, et al. Gastroenterology. 2022 Apr;162(4):1226-1241.


It is known that acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF), and the mechanism of liver injury is via oxidative stress, whereas sulfation of APAP contributes to its detoxification. The PAPS synthase 2 (PAPSS2) is the primary enzyme to synthesize the universal sulfonate donor 3′-phosphoadenosine 5′-phosphosulfate (PAPS). In this study, the authors aimed to determine whether and how PAPSS2 plays a role in APAP-induced ALF. Gene expression was analyzed in APAP-induced ALF in patients and mice. Liver-specific Papss2-knockout mice using Alb-Cre (Papss2ΔHC) or AAV8-TBG-Cre (Papss2iΔHC) were created and subjected to APAP-induced ALF. The authors found that the hepatic expression of PAPSS2 was decreased in APAP-induced ALF in patients and mice. However, Papss2ΔHC mice were protected from APAP-induced hepatotoxicity despite having a decreased APAP sulfation, which was accompanied by increased hepatic antioxidative capacity through the activation of the p53-p2-Nrf2 axis. Treatment with a sulfation inhibitor also ameliorated APAP-induced hepatotoxicity. Gene knockdown experiments showed that the hepatoprotective effect of Papss2ΔHC was Nrf2, p53, and p21 dependent, and p53 was shown to be a novel substrate of sulfation. The authors identified a previously unrecognized p53-mediated role of PAPSS2 in controlling oxidation, and therefore inhibition of p53 sulfation may be explored to clinically manage APAP overdose.


Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies

Mantovani A, Petracca G, Beatrice G, et al. Gut 2022;71:778–788.


There are major extrahepatic diseases of NAFLD in addition to severe liver-related complications (cirrhosis, liver failure, or hepatocellular carcinoma (HCC)) and have considerable effects on healthcare expenditure. An increased prevalence and incidence of colorectal cancer and adenomas was observed in asymptomatic individuals of NAFLD undergoing screening colonoscopy. NAFLD was significantly associated with a nearly 1.5 to two-fold increased risk of developing GI cancers (esophagus, stomach, pancreas, or colorectal cancers). Furthermore, NAFLD was associated with an approximately 1.2 to 1.5-fold increased risk of developing lung, breast, gynecological, or urinary system cancers. All risks were independent of age, sex, smoking, obesity, diabetes, or other potential confounders. The overall heterogeneity for most of the primary pooled analyses was relatively low. This large meta-analysis suggests that NAFLD is associated with a moderately increased long-term risk of developing extrahepatic cancers over a median of nearly 6 years. Further research is required to decipher the complex link between NAFLD and cancer development.


Banff consensus recommendations for steatosis assessment in donor livers

Neil DA, Minervini M, Smith, ML, et al. Hepatology. 2022 Apr;75(4):1014-1025.


A panel of 59 pathologists from 16 countries completed a questionnaire regarding steatosis in donor liver biopsies and subsequently assessed steatosis severity in 18 whole-slide images of donor liver biopsies. Survey results revealed a wide variation in definitions and approaches. Findings were discussed at a workshop held at the 15th Banff Conference on Allograft Pathology, September 2019. The authors propose guidelines for assessing steatosis in these biopsies


Centrizonal hepatocyte dropout in allograft liver biopsies: a clinicopathological study

Bosch DE, Swanson PE, Yeh MM. Histopathology. 2022 Mar;80(4):708-719.


Centrizonal dropout, defined as absent hepatocytes in a perivenular distribution, is a relatively common histological finding in liver biopsies. In allograft liver, centrizonal hepatocyte dropout was associated most frequently with cellular rejection, asymptomatic/protocol biopsies, immediate post-transplantation biopsies, biliary obstruction, and viral hepatitis. Other co-existing histopathological features, radiographic findings, and laboratory values may inform the differential diagnosis. In the context of cellular rejection, centrizonal dropout was associated with shorter transplant-free survival than that of histological severity-matched controls. In time zero allograft biopsies, time to ALT normalization was prolonged in allografts with centrizonal dropout, indicating a greater degree of reversible ischemia/reperfusion injury. In conclusion, centrizonal hepatocyte dropout has low clinicopathological diagnostic specificity. However, it correlates with adverse clinical outcomes in allograft cellular rejection and time zero biopsies.

Lymphoepithelioma-like neoplasm of the biliary tract with ‘probable low malignant potential’

Khandakar B, Liu J, Thung S, et al. Histopathology. 2022 Mar;80(4):720-728.


The authors reported three cases of intrahepatic EBV-associated lymphoepithelioma-like cholangiocarcinoma (LEL-CCA). All three tumors showed bland-appearing interconnecting glands or cords of cells with a low proliferation index. All three patients were alive with no evidence of disease 24-62 months after surgery. The authors proposed that these tumors may represent a variant of lymphoepithelioma-like neoplasm of the biliary tract with probable low malignant potential.

Is nestin a diagnostic marker for combined hepatocellular-cholangiocarcinoma?

Sasaki M, Sato Y, Nakanuma Y. Histopathology. 2022 Apr;80(5):859-868.


This article reported the percentage of nestin expression in combined hepatocellular-cholangiocarcinoma (66.7%), small duct-type intrahepatic cholangiocarcinoma (40.9%), large duct-type intrahepatic cholangiocarcinoma (5%) and hepatocellular carcinoma (2.9%). Nestin-positive combined hepatocellular-cholangiocarcinoma and small duct-type intrahepatic cholangiocarcinoma showed a more frequent presence of cholangiolocellular carcinoma components.

Human Pathology

Liver allograft findings of donation after cardiac death versus brain death in recipients with hepatitis C related cirrhosis: a matched histologic comparison

Byrnes K, Vachharajani N, Doyle MM, Nalbantoglu I. Hum Pathol. 2022 Apr;122:25-31.


The demand for liver transplants exceeds organ availability, and 5-10% of patients listed will die while waiting for transplant in the US. In this setting, there is a need to expand the graft pool. Liver allografts of donation after cardiac death (DCD) have been considered suboptimal due to (1) the risk of primary nonfunction, (2) hepatic artery thrombosis, and (3) ischemic cholangiopathy; one study has also shown worse patient outcomes associated with DCD liver allografts and more biliary complications. However, other studies have shown equivalent survival in those with DCD liver allografts as compared to donation after brain death (DBD) donor liver transplants. The authors of this matched cohort study evaluated the histologic features of 60 DCD liver allograft biopsies from 20 DCD patients and compared them to 71 DBD allograft biopsies from 20 DBD patients, and also evaluated clinical outcomes in each cohort. In both groups, the indication for liver transplantation was chronic HCV. The study showed that in time 0 biopsies, more DCD cases had zone 3 (43.8 vs 29%) and bridging necrosis (19 vs 0%); pericholangitis (30.4% vs 18.8%) and acute cholestasis (21.7% vs 12.5%) were more common in DCD, but none of these findings reached statistical significance. Postoperative biliary complications were more common in DCD (19% vs 0%). The authors found that overall, both groups had similar bile duct injury, portal inflammation, and fibrosis.  However, despite more prevalent biliary alterations in the 0–6 month time period in DCD biopsies, the three-year and 10-year graft survival and patient outcomes were similar in both cohorts. The findings suggest that carefully selected DCD liver allografts are a viable option for transplantation.

Hepatocellular neoplasms with loss of liver fatty acid binding protein: Clinicopathologic features and molecular profiling

Joseph NM, Blank A, Shain AH, et al. Hum Pathol. 2022 Apr;122:60-71.


The authors of this study explore the morphologic and genomic implications of LFABP loss in 68 hepatocellular neoplasms: HNF1A-inactivated hepatocellular adenoma (H-HCA) (n=33), atypical hepatocellular neoplasms (AHN) (n=10), well-differentiated hepatocellular carcinoma (WD-HCC) (n=7), and moderately or poorly differentiated (MD/PD) HCC (n=18). Capture based sequencing was performed in 13 cases (8 AHN, 5 WD-HCC).  The 7 LFABP-negative WD-HCC resembled H-HCA, and it was atypical features including small cell change and multifocal reticulin loss that facilitated classification as WD-HCC; these tumors also occurred in the absence of advanced fibrosis and were more frequent in women, suggesting the WD-HCC arose from H-HCA. Minimal or no fat, prominent pseudoacini, myxoid change, and lipofuscin pigmentation were all found to be high risk features in LFABP-negative tumors – and the authors recommend labeling tumors with these features as AHN rather than H-HCA to facilitate appropriate patient follow-up. Focal nodular hyperplasia-like changes and focal SAA staining occurred in a small proportion of H-HCA cases (important to note to avoid diagnostic error in small biopsy material). LFABP loss also occurred in MD/PD HCC with conventional morphologic features, male predominance, and in the background of cirrhosis. Biallelic HNF1A alterations were seen in all 13 (100%) sequenced cases. Interestingly, alterations of Wnt signaling pathway genes (CTNNB1, APC, AXIN1) were not observed in this series, despite the observation of diffuse glutamine synthetase (GS) staining in 13% of cases. In summary, variant features such as lack of fat, peliosis, myxoid change, pseudoacini and abundant lipofuscin are more common in AHN and/or WD-HCC. LFABP-negative MD/PD HCC have different clinicopathologic features compared to WD-HCC.

Journal of Hepatology

Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder.

Fromme M, Schneider CV, Trautwein C, et al. J Hepatol. 2022 Apr;76(4):946-958.


This review provides a comprehensive update on the clinical aspects of alpha-1 antitrypsin deficiency which may be helpful to pathologists.

Modern Pathology

Molecular features of primary hepatic undifferentiated carcinoma

Tsai JH, Jeng YM, Lee CH, Liau JY. Mod Pathol. 2022 May;35(5):680-687.


The authors examined 14 primary hepatic undifferentiated carcinomas, rare liver tumors lacking evidence of hepatocellular or cholangiocytic differentiation. Immunohistochemistry, FISH, and targeted NGS were performed on a 14-gene panel. The most common mutations found in their cohort were TERT promoter (57%) and TP53 (57%), mirroring the genetic alterations most frequently seen in hepatocellular carcinoma. Of note, no changes typical of intrahepatic cholangiocarcinoma were identified (e.g. IDH1/IDH2, FGFR2 fusions, aberrant BAP1 expression). Evidence of SWI/SNF deficiency was noted in 43% of cases, and PD-L1 immunohistochemistry showed expression in 79% of tumors within this cohort, suggesting possible therapeutic targets in these aggressive tumors.

Prepared by:
Lindsey Westbrook, MD (Editor); University of Colorado
Dana Balitzer, MD; 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
Meredith Pittman, MD; Maimonides Medical Center
Daniel Roberts, MD; Cleveland Clinic
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Xuefeng Zhang, MD; Cleveland Clinic

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