HPHS Journal Watch: November/December 2019


Yellow fever and orthotopic liver transplantation: new insights from the autopsy room for an old but re-emerging disease.
Duarte-Neto AN, Cunha MDP, Marcilio I, et al. Histopathology. 2019 Nov;75(5):638-648.

The authors present the pathological findings of 4 autopsies in patients with yellow fever (YF), with emphasis on the pathology of the engrafted liver. YF is a hemorrhagic viral disease caused by an arbovirus of the Flaviviridae family. All patients were men, aged 16–40 years, without vaccination to YF virus (YFV). All the cases depicted typical findings of YF hepatitis in the engrafted liver. Gross examination of the livers showed a similar pattern: increased weight [1692–1944 g (reference range = 1400–1600)] and a congested and tan–yellowish cut surface, without arterial or venous thrombi. Foci of subcapsular ischemic wedge necrosis were found in 3 cases. Microscopy showed typical YF midzonal hepatitis with hepatocytes exhibiting acidophilic degeneration, the so‐called Councilman–Rocha–Lima bodies, macro‐ and microvesicular steatosis and intracellular cholestasis. Kupffer cells were hyperplastic and hypertrophic, some of them with cytophagocytosis. Sinusoids were dilated and congested, with foci of hemorrhage, especially around the centrilobular vein. None of the cases had arteritis, biliary duct damage or interstitial collagen deposition. The main extrahepatic findings were cerebral edema, pulmonary hemorrhage, pneumonia, acute tubular necrosis and ischemic/reperfusion pancreatitis. All four cases had YF virus RNA detected by RT–PCR in the liver and in other organs. Infection of the engrafted liver and other organs by YFV, possibly combined with major ischemic systemic lesions, may have led to their death.

Hepatic sclerosing cavernous haemangioma can mimic the nodular elastosis stage of segmental atrophy.
Findeis-Hosey JJ, Zhou Z, Gonzalez RS. Histopathology. 2019 Dec;75(6):876-881.

Segmental atrophy (SA) of the liver is a recently described pseudotumor that can show a broad spectrum of histological changes. Sclerosing cavernous hemangioma (SCH) can show marked histological overlap with SA. The aim of this study was to examine and compare the clinical and histological features of SA and SCH. The authors identified 20 SCHs and 12 SAs, excluding hemangiomas with treatment effect. Several clinical and morphologic characteristics were examined, and elastin and CD34 staining was performed on cases with available tissue. SA was always asymptomatic, whereas SCH caused symptoms in 56% of patients (P = 0.026); SCH also tended to be larger (mean size: SCH, 47 mm; SA, 16 mm; P = 0.027). Thick‐walled blood vessels were more common in SA than in SCH (92% versus 45%, P = 0.011), as was ductular reaction (50% versus 5%, P = 0.0057). The two lesions had similar rates of border irregularity, residual entrapped hepatocytes, matrix edema, and at least mild elastic fibrosis as seen on special staining, although staining was typically dense and diffuse in SA. CD34 immunostaining demonstrated at least scattered vessels in all cases of SA and SCH. SCH can mimic SA, although it is generally larger and more often symptomatic. Elastin staining provides a useful adjunct to standard H&E histological examination in resolving this differential diagnosis.

Liver Transplantation

Checkpoint Inhibitor–Induced Rejection of a Liver Allograft: A Combination of Acute T Cell–Mediated and Antibody‐Mediated Rejection
Lee BT, Horwich BH, Chopra S, Ahearn A, Han HH. Liver Transpl. 2019 Dec;25(12):1845-1848.

Checkpoint inhibitor therapy has been a novel approach in a new wave of cancer treatments. Medications, such as pembrolizumab or nivolumab, have recently been approved for the treatment of several different types of malignancies. However, their safety in the treatment of cancers in liver transplant recipients is unfamiliar. The authors report a single case of a liver transplant recipient with skin cancer who received nivolumab and developed severe acute T cell–mediated rejection (TCMR) concomitantly with histologic features suspicious for antibody‐mediated rejection (AMR), ultimately resulting in chronic ductopenic rejection and graft loss. Although checkpoint inhibitor therapy has started a revolution of new approaches and strategies in treating these types of malignancies, its use in organ transplant recipients remains uncertain due to the severe consequence of allograft loss. It is unclear which patients are likely to tolerate therapy versus develop severe rejection with subsequent risk of death or re-transplantation. Larger cohort studies are necessary to determine the feasibility of checkpoint inhibitor therapy in the setting of organ transplantation recipients.


The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials
Sanyal AJ, Harrison SA, Ratziu V, et al. Hepatology 2019;70(6): 1913-1927.

The aim of the study was to evaluate NASH fibrosis progression (or prevention) in patients with bridging fibrosis treated with simtuzumab. The authors analyzed data on longitudinal changes in liver histology, hepatic venous pressure gradient (HVPG), and serum markers of fibrosis in 475 patients with NASH with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in two phase 2b, placebo-controlled trials of simtuzumab. The study was terminated at 96 weeks due to lack of efficacy, so data from treatment groups were combined. Liver biopsies and HVPG measurements (only for patients with F4 fibrosis) were collected at screening, 48 and 96 weeks. Patients were assessed for Ishak fibrosis stage, hepatic collagen content and alpha-smooth muscle actin (by morphometry), NAFLD Activity Score (NAS), and serum markers of fibrosis (ELF, FibroSure, FIB-4, APRI). Progression to cirrhosis occurred in 22% (48/217) of F3 patients, and liver-related clinical events occurred in 19% (50/258) of patients with cirrhosis. Factors significantly associated with progression to cirrhosis included higher baseline values of and greater increases in hepatic collagen content, level of alpha-smooth muscle actin, and Enhanced Liver Fibrosis score. Similar factors, plus lack of fibrosis stage improvement (hazard ratio, 9.30; 95% confidence interval, 1.28-67.37), higher HVPG at baseline, and greater increase in HVPG over time, were associated with an increased risk of liver-related clinical events in patients with cirrhosis. Disease progression was not associated with the NAS at baseline or changes in NAS during treatment after adjustment for fibrosis stage. That said, patients with severe ballooning at baseline were more likely to progress to cirrhosis.

In conclusion, in patients with advanced fibrosis due to NASH (determined by histology and/or serum markers), the primary determinant of clinical disease progression is fibrosis and its change over time.

The 20% Rule of NASH Progression: The Natural History of Advanced Fibrosis and Cirrhosis Caused by NASH.
Loomba R, Adams LA. Hepatology 2019; 70(6): 1885-1888.

This is an editorial article on the risk of progressive fibrosis in NASH patients and key clinical predictors.

American Journal of Surgical Pathology

Sinusoidal-type Angiosarcoma of the Liver: Imaging Features and Potential Diagnostic Utility of p53 Immunostaining.
Zen Y, Sofue K. Am J Surg Pathol. 2019 Dec;43(12):1728-1731.

This letter to the editor describes two additional cases of hepatic angiosarcoma with an intrasinusoidal, non-mass forming growth pattern. The authors provide additional details on clinical and histopathologic characteristics to raise further awareness on this challenging entity.


Increased Risk for Hepatocellular Carcinoma Persists Up to 10 Years After HCV Eradication in Patients With Baseline Cirrhosis or High FIB-4 Scores.
Ioannou GN, Beste LA, Green PK, et al. Gastroenterology. 2019 Nov;157(5):1264-1278.

It is unclear if hepatocellular carcinoma (HCC) risk decreases after hepatitis C virus (HCV) eradication. The authors of this retrospective study of over 48,000 patients in the Veterans Health Administration analyzed changes in HCC annual incidence over time following HCV eradication and searched for markers of HCC risk. Patients with cirrhosis before a SVR to treatment for HCV infection continue to have a high risk for HCC (>2%/year) for many years, even if their Fibrosis-4 (FIB-4) score decreases. Patients without cirrhosis before treatment and FIB-4 scores > 3.25 also have a high risk of HCC. The authors concluded that patients with cirrhosis before a SVR to HCV treatment and patients without cirrhosis before treatment and FIB-4 score > 3.25 should undergo HCC surveillance.

Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma
Singal AG, Rich NE, Mehta N, et al. Gastroenterology. 2019 Nov; 157(5): 1253-1263.

There is controversy regarding the benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). The authors performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs and patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy. Of 797 patients with HCV-related HCC, 383 (48.1%) received DAA therapy and 414 (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow-up, compared with 103 deaths during 526.6 person-years of follow-up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% confidence interval [CI], 0.16–0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio, 0.54; 95% CI, 0.33–0.90). This association differed by sustained virologic response to DAA therapy; risk of death was reduced in patients with sustained virologic response to DAA therapy (hazard ratio, 0.29; 95% CI, 0.18–0.47), but not in patients without a sustained virologic response (hazard ratio, 1.13; 95% CI, 0.55–2.33). In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

Modern pathology

Genomic profiling of well-differentiated hepatocellular neoplasms with diffuse glutamine synthetase staining reveals similar genetics across the adenoma to carcinoma spectrum.
Joseph NM, Umetsu SE, Shafizadeh N, et al.  Mod Pathol. 2019 Nov;32(11):1627-1636.

This study examined 27 well-differentiated hepatocellular neoplasms with diffuse glutamine synthetase staining, including 7 atypical hepatocellular neoplasms with no cytoarchitectural atypia, 6 atypical hepatocellular neoplasms with focal cytoarchitectural atypia, and 14 well-differentiated hepatocellular carcinomas. Alterations in WNT pathway genes (CTNNB1APCAXIN1) were seen in 81% of cases (10/13 atypical hepatocellular neoplasms and 12/14 of hepatocellular carcinomas). Molecular basis of diffuse glutamine synthetase staining was unclear in the remaining 19% of cases. Additional non-WNT pathway mutations (TP53, TSC1, DNMT3A, CREBBP) or copy number alterations were present in 56% of atypical hepatocellular neoplasms, with no significant difference in cases with or without focal cytoarchitectural atypia, supporting that all cases with β-catenin activation should be classified as atypical irrespective of atypia. Atypical hepatocellular neoplasm and hepatocellular carcinoma show similar genomic profiles, but TERT promoter mutations were restricted to hepatocellular carcinoma (21%). Copy number alterations were more common in hepatocellular carcinoma (64 vs 31%).

A comparability study of immunohistochemical assays for PD-L1 expression in hepatocellular carcinoma.
Shi L, Zhang SJ, Chen J, et al. Mod Pathol. 2019 Nov;32(11):1646-1656.

This study aimed to compare the analytical performance of different PD-L1 antibodies (22C3, 28–8, SP142, and SP263) and evaluate the reliability of pathologists (X5) in PD-L1 scoring. Consecutive sections hepatocellular carcinoma cases from 55 patients were stained with four standardized PD-L1 Abs(22C3, 28–8, SP142, and SP263). They also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of genes associated with tumor immune microenvironment by the NanoString platform. 22C3, 28–8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent. Pathologists were less reliable in scoring combined positive score than tumor proportion score. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28–8 and SP263 assays.

Histologic pattern is better correlated with clinical outcomes than biochemical classification in patients with drug-induced liver injury. Tian QJ, Zhao XY, Wang Y, et al. Mod Pathol. 2019, Dec;32(12):1795-1805.

The correlation between the histologic patterns and long-term clinical outcomes in drug-induced liver injury (DILI) has not been well established. In the 133 cases used in this study, histologic injury pattern (compared with biochemical classification) had better predictive ability for abnormal biochemistry at 6 months (Areas under Receiver Operating Characteristic Curves 0.92 versus 0.60, P< 0.001) and 1 year (Areas under Receiver Operating Characteristic Curves 0.94 versus 0.69, P< 0.001). Interlobular bile duct loss in >25% portal areas was independently associated with abnormal biochemistry at 6 months, 1 year, and 2 years. The authors conclude histologic injury pattern is better correlated with clinical outcome at 6 months and 1 year than biochemical classification.

Journal of Gastroenterology and Hepatology

Symptomatic hepatic splenosis.
Guedes TP, Fernandes B, Pedroto I. J Gastroenterol Hepatol. 2019 Dec;34(12):2061.https://www.ncbi.nlm.nih.gov/pubmed/31317571
A case report of hepatic splenosis.

Clinical Gastroenterology and Hepatology

AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review.
Bowlus CL, Lim JK, Lindor KD. Clin Gastroenterol Hepatol. 2019 Nov;17(12):2416-2422.

The most important points from this article for pathologists include the following (directly quoted from the article):

  • “Best practice advice 3:  Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC.”
  • “Best practice advice 4: Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture.”
  • “Best practice advice 5: Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma.”

Journal of Hepatology

Natural history of liver adenomatosis: A long-term observational study.
Barbier L, Nault JC, Dujardin F, et al. J Hepatol. 2019 Dec;71(6); 1184-1192.

Liver adenomatosis (LA) is a rare condition categorized by the existence of 10 hepatocellular adenomas (HCAs) at the minimum.  The natural history remains uncertain. The goal of this study was to review the natural history and complications of LA.  40 patients with LAs were analyzed.  Highlights of the study include the following: LA is a rare heterogenous disease; if all HCAs are steatotic, a germline HNF1A mutation should be searched for.  There are risks for malignant transformation (3%) and tumor bleeding (15%).  In familial steatotic liver adenomatosis, bleeding risk exists even in small adenomas.


Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas.
Zhang Q, Lou Y, Yang J, et al. Gut. 2019 Nov; 68:2019-2031.

The classification of hepatocellular carcinoma is a rapidly evolving field (as demonstrated in the most recent WHO Classification of Tumours. Digestive System Tumours. Fifth Edition).  This paper proposes another approach to classifying these tumours: dividing them into immunocompetent, immunodeficient, and immunosuppressive types, based on immunohistochemically assessed expression of CD45 and Foxp3. The authors state that this is a clinically practical classification which may be useful in the management and monitoring of HCC patients.

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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