hepatocellular-cholangiocarcinomas (CHC) have a prognosis similar to
intrahepatic CC (ICC); staging and treatment generally follow ICC algorithms.
The authors performed capture-based next-generation sequencing of 20 CHC and 10
ICC arising in cirrhosis. Intra-tumor heterogeneity was assessed by separately
sequencing the HCC and CC components. CHC showed molecular profiles similar to
HCC, even in the CC component. CHC harbored recurrent alterations in TERT
(80%), TP53 (80%), cell cycle genes (40%; CCND1, CCNE1, CDKN2A), receptor
tyrosine kinase/Ras/PI3-kinase pathway genes (55%; MET, ERBB2, KRAS, PTEN),
chromatin regulators (20%; ARID1A, ARID2) and Wnt pathway genes (20%; CTNNB1,
AXIN, APC). No CHC had alterations in IDH1, IDH2, FGFR2 or BAP1 (genes
typically mutated in ICC). TERT promoter mutations were consistently identified
in both HCC and CC components, supporting TERT alteration as an early event in
CHC evolution. TP53 mutations were present in both components in slightly over
half the TP53-altered cases. Amplifications of CCND1, MET, ERRB2 and Wnt
pathway alterations, were often exclusive to one component, suggesting that
these are late events in CHC evolution. ICC in cirrhosis revealed alterations
similar to ICC in non-cirrhotic liver, including in IDH1 or IDH2 (30%), CDKN2A
(40%), FGFR2 (20%), PBRM1 (20%), ARID1A (10%) and BAP1 (10%). The data
demonstrated that CHC genetics are distinct from ICC (even in cirrhosis) and
similar to HCC, which may have diagnostic and treatment implications.
Integrative Analysis Defines Distinct Prognostic Subgroups of
performed an integrative analysis on 52 intrahepatic cholangiocarcinomas
(iCCAs) using genetic and epigenetic data with a specific focus on DNA
methylation components. Recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2
(28%) gene mutations, recurrent arm-length copy number alterations (CNAs), and
deletion of 3p21 or amplification of 12q15 were found. Integrative clustering
of genetic and epigenetic data identified four iCCA subgroups with prognostic
relevance further designated as IDH, high (H) (IDH and H showed frequent
deletions in chromosome arms 3p and 6q), medium (M, intermediate genetic and
epigenetic marks), and low (L, few methylation events and lack of CNAs)
alteration groups. The prognosis of the H and M groups was significantly worse
than that of the L group with decreased survival (L group 3-year survival rate
was 91%, compared to 65%, 50%, and 36% for the IDH, H, and M groups). The
authors concluded that using an integrative genomic and epigenomic analysis
approach, four iCCA subgroups (IDH, H, M and L) with widespread genomic and
epigenomic differences with prognostic significance were identified. The data
presented also suggested differences in the cell-of-origin of the iCCA
subtypes, bile duct–type iCCA resembled pancreatic adenocarcinoma, whereas cholangiolar-type
iCCA showed similar patterns to a subgroup of hepatocellular carcinoma.
The Spectrum of Hepatic Involvement in Patients With Telomere Disease.
mutations in genes that encode for components of the telomere repair complex
cause accelerated telomere shortening. Hepatic involvement has been recognized
as a cause of morbidity. The authors reported the prevalence and
characteristics of liver involvement in a cohort of patients evaluated serially
at the National Institutes of Health. One hundred twenty-one patients with
known or suspected telomere disease were screened; 40 patients with liver
involvement were included with a median follow-up of 2.4 years. Forty patients
(40%) with a median age of 42 years showed liver involvement. Liver enzyme
profile revealed a cholestatic pattern; 8 (21%) had drug-related enzyme
elevations. The most common imaging finding was increased hepatic echogenicity
on ultrasound in 39% of patients, followed by hepatomegaly in 26%. Biopsies
were available in 6 patients and demonstrated: nodular regenerative hyperplasia,
steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic
steatosis. The authors concluded that hepatic involvement is common in patients
with telomerase disease and can present in diverse ways, including elevated
liver enzymes as well as histopathologic and imaging abnormalities.
American Journal of Surgical Pathology
of the Liver: Clinicopathologic Features and Morphologic Patterns.
S, Torbenson MS. Am J Surg Pathol. 2019 May;43(5):581-590.
rarely involves the liver and can be challenging to diagnose by clinical and
radiologic means. Published morphologic descriptions on the histology of
hepatic angiosarcomas are limited, so the authors evaluated 21 primary hepatic
angiosarcomas to further characterize morphologic patterns. Four main growth
patterns were identified and their relative frequencies are as follows: (1) 43%
vasoformative mass forming, (2) 33% epithelioid/spindled mass forming, (3) 10%
sinusoidal non-mass forming, and (4) 10% peliotic non-mass forming. This
comprehensive analysis provides further knowledge on the spectrum of
morphologic appearances of hepatic angiosarcoma. Such awareness can help
pathologists recognize subtle clues on biopsies and also avoid mistaking
epithelioid/spindled patterns as a poorly differentiated carcinoma or
The New Look of Yttrium-90.
CA, Pezhouh MK, Lam-Himlin D, Pittman ME, VandenBussche C, Voltaggio L. Am J
Surg Pathol. 2019 May;43(5):688-694.
two constructs used in delivery of selective internal radiation
therapy/transarterial radioembolization (SIRT/TARE) for the treatment of
unresectable liver tumors. This study is the first known published case series
characterizing morphologic features of 90Y-TS.
Histologically processed, nonradiated microspheres were compared to 90Y-TS from
15 hepatectomy specimens, showing 20-30 mm
diameter colorless microspheres with identical features: occasional internal
bulls’-eye structures with the condenser out and internal crosses under
polarized light microscopy. It is important to be familiar with the appearance
of 90Y-TS, as
it is different from 90Y-SS and its colorless nature can make
it easy to be mistaken for air bubble artifact. Recognition of 90Y-TS can
help pathologists detect nearby malignancy or determine the cause of
of a Congestive Hepatic Fibrosis Scoring System.
DE, Koro K, Richards E, Hoch BL, Jalikis F, Koch LK, Swanson PE, Truong CD,
Liou I, Yu L, Bhattacharya R, Yeh MM. Am J Surg Pathol. 2019 Jun;43(6):766-772.
biopsy is one approach for evaluating the extent of fibrosis in congestive
hepatopathy (CH), which can impact a patient’s candidacy for heart transplant.
This study was conducted on 38 liver biopsies from patients with clinically
established heart failure and histologic features of CHto provide more data on the use of a scoring
system for staging fibrosis in CH (CHF score) that was originally proposed by
the same principal investigator in 2014. Three rounds of scoring were
conducting by seven GI/liver subspecialist pathologists; the same set of 38
liver biopsies was evaluated in each round. Glutamine synthetase
immunohistochemistry (GS IHC) was also performed on 32 of the cases and
provided in the third round to determine if loss of centrizonal staining in
cases with higher fibrosis scores (as reported in previous studies) could also
be confirmed. The investigators found that interobserver variability in CHF
score was improved after a multiheaded microscope training session and
provision of GS IHC along with Masson trichrome stains (weighted concordance
coefficient S* = 0.66). Higher average CHF scores were associated with higher
right atrial pressures, severity of right atrial dilation, presence of right
ventricular dilation, elevated ALT, lower platelet counts, longer prothrombin
times, and higher MELD scores. In summary, this study demonstrates the
reproducibility of the CHF score and supports its clinical relevance by showing
its association with known clinical and laboratory parameters of CH.
Clinical Gastroenterology and Hepatology
Liver Masses Found After Evaluation for Asymptomatic Alkaline Phosphatase
Berry S, Nissen N, Sundaram V. Clin
Gastroenterol Hepatol. 2019 Jun;17(7):e71-e72.
The authors report a case of a 41-year-old woman with Gilbert’s
syndrome who had increased alkaline phosphatase levels for 3 years ranging from
170 to 195 U/L, but was asymptomatic. She had previously taken oral
contraceptives. Imaging showed hepatomegaly without fatty infiltration, two
arterially enhancing lesions, and one with minimal enhancement.There were numerous isointense hypoenhancing lesions in the right lobe, the largest measuring
6.3 cm. Biopsy showed dilated sinusoids, inflammation, and abnormal portal
tracts consistent with inflammatory hepatic adenomatosis, defined as 10 or more
to the Liver Imaging Reporting and Data System for Hepatocellular Carcinoma
The differential diagnosis of an increase in
alanine aminotransferase (ALT) level and/or aspartate aminotransferase (AST)
level of ≥1000 IU/L often is stated to include 3 main etiologies: ischemic
hepatitis, acute viral hepatitis (typically hepatitis A and hepatitis B), and
drug-induced (more specifically, acetaminophen/paracetamol) liver injury
(DILI). This study was conducted to confirm these causes were correct.They determined that these three etiologies accounted
for approximately 51.8% of acute liver injury.Pancreaticobiliary complications were also common.Their main conclusion was that the
differential for acute liver injury should be expanded beyond ischemic, viral,
and drug (Tylenol)-related causes.
Journal of Gastroenterology and Hepatology
Association between HLA‐DQA1/DRB1 polymorphism and development of hepatocellular carcinoma
during entecavir treatment
Kozuka R, Enomoto M, Sato-Matsubara M,
et al. J Gastroenterol Hepatol. 2019
paper examines the association between single-nucleotide
and development of hepatocellular carcinoma (HCC) during entecavir (ETV) treatment in
nucleos(t)ide analog-naïve patients with chronic hepatitis B virus infection.
They conclude that patients with AA genotype in
the HLA-DQA1/DRB1 gene or cirrhosis should be carefully followed up
as a population potentially at higher risk of HCC during ETV treatment.
and pathological features of combined hepatocellular–cholangiocarcinoma
compared with other liver cancers
Combined hepatocellular-cholangiocarcinoma (CHC)
is a primary liver cancer containing both hepatocellular carcinoma
(HCC) and intrahepatic cholangiocarcinoma (ICC) elements. This paper tries to
clarify the clinicopathological features.
The clinical features of CHC, including sex, hepatitis B virus
infection, and α-fetoprotein were similar to HCC, while its prognosis
and pathological features, including vascular invasion and lymph node
metastasis, were similar to ICC. Carcinoembryonic antigen levels and tumor size
were independent prognostic factors in patients with CHC.
Journal of Hepatology
EASL Clinical Practice Guidelines: Drug-induced liver injury
Visit the June edition of
JOH for the latest clinical practice guidelines by the European
Association for the Study of Liver for drug-induced liver injury (DILI)
focusing on idiosyncratic DILI. Some highlights include lists
of drugs associated with intrinsic versus idiosyncratic DILI, known herbal
and dietary supplements involved in hepatotoxicity, drugs associated with
hepatic adverse reactions, assessments for exclusion of underlying diseases in
DILI diagnosis, management of immune-mediated liver injury induced by
immune checkpoint inhibitors, and histological features indicative of poor
prognosis. Since liver biopsy is not required for diagnosis if the
suspected drug is a known hepatotoxic compound, liver biopsy is recommended
to provide information supporting the diagnosis of DILI or an alternative,
to rule out autoimmune hepatitis, when resolution fails following drug
withdrawal, and to provide prognostic
information. Click on the link above for the latest on
Identification of key challenges in
liver pathology: data from a multicenter study of extramural consults
Torbenson MS, Arnold CA, Graham RP, et
al. Hum Pathol. 2019 May; 87: 75-82.
for challenging pathology cases is an important part of patient care. This
study identified challenges in liver pathology by analyzing data from 541
cases.Cases were submitted for
questions on medical (61%) and tumor pathology (39%). This analysis of consult
patterns identifies challenging areas in medical and tumor liver pathology,
which benefit from consult services and can be focused on by continuing medical
of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement
in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver
Eddowes PJ, Sasso M, Allison M, et al.
Gastroenterology. 2019 May; 156(6): 1717-1730.
The authors estimated the accuracy of
FibroScan vibration-controlled transient elastography controlled attenuation
parameter (CAP) and liver stiffness measurement (LSMs) in assessing steatosis
and fibrosis in patients with suspected nonalcoholic liver disease (NAFLD).
Data from 450 consecutive adults who underwent liver biopsy analysis for
suspected NAFLD at 7 centers in the United Kingdom from March 2014 through
January 2017 were collected.Biopsies
were scored by 2 blinded expert pathologists according to nonalcoholic
steatohepatitis clinical research network criteria. Diagnostic accuracy was
estimated using the area under the receiver operating characteristic curves
(AUROCs) for the categories of steatosis and fibrosis. In a prospective
analysis of patients with NAFLD, we found CAP and LSM by FibroScan to assess
liver steatosis and fibrosis, respectively, with AUROC values ranging from 0.70
Impact of tumour budding grade in
310 patients who underwent surgical resection for extrahepatic
Ogino M, Nakanishi Y, Mitsuhashi T, Hatanaka Y, Amano T,
Marukawa K, Nitta T, Ueno T, Ono M, Kuwabara S, Yamada T, Hirano S.Histopathology. 2019 May;74(6):861-872.
This study evaluated the prognostic impact of tumour budding
grade and its association with clinicopathological andepithelial–mesenchymal transition (EMT)‐related features
in perihilar cholangiocarcinoma (PHCC) or distal cholangiocarcinoma (DCC). It
included 195 PHCC and 115 DCC patients (n=310). In both PHCC and DCC patients,
high tumour budding grade was associated with poor histological
differentiation, higher pT factor, presence of lymphatic, venous, perineural
invasion and regional lymph node metastasis. In PHCC patients, residual
invasive tumour in the resected margin was also associated with high tumour
budding grade. For both PHCC and DCC patients, high tumour budding grade was an
independent adverse prognostic factor in multivariate analysis (P < 0001 and
P = 0.046, respectively). Immunohistochemical examination revealed that the
number of tumour buds increased in patients with tumors showing a mesenchymal
profile (negative for E‐cadherin and positive for vimentin). The authors
concluded that higher tumour budding grade is associated with invasive
clinicopathological features, adverse postoperative prognosis and EMT status in
Molecular profiling of the biphasic
components of hepatic carcinosarcoma by the use of targeted next-generation
Zhang X, Bai Q, Xu Y, Wang W, Chen L, Han J, Zhu H, Zhang Z, Hou
Y, Zhou J, Zhou Y, Ji Y. Histopathology. 2019 May;74(6):944-958.
This study evaluated the clinicopathological and
immunohistochemical (IHC) and molecular features of hepatic carcinosarcoma
(HCS). This study included 13 cases of HCS. Molecular alterations were analyzed
in separately microdissected carcinomatous and sarcomatous components in 8
cases by using targeted next‐generation sequencing with a panel of 329
cancer‐related genes. The most common gene alterations found in both components
were TP53 (75%, 6/8) and NF1/2 (38%, 3/8) mutations and VEGFA amplification
(25%, 2/8), which may be strongly associated with HCS tumorigenesis.
Amplifications involving MET (38%, n = 3/8) and PDGFRA (25%, n = 2/8) were
present only in the sarcomatous components, whereas mutation affecting ERBB4
(25%, n = 2/8) and amplifications of CCND1 and FGF3/4/19 (38%, n = 3/8) were
present only in the carcinomatous components, indicating their involvement in
the clonal evolution of HCS. The authors conclude that HCS could have been of monoclonal
origin, and that the diverse clonal evolution might be driven by special
molecular alterations in each tumour component. This study also identified
multiple therapeutic targets in HCS, which may be valuable for the personalized
treatment of HCS.
Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis Strnad P, Buch S, Hamesch K, et al. Gut. 2019 Jun; 68(6): 1099-1107. https://www.ncbi.nlm.nih.gov/pubmed/30068662 It is
well established that homozygous alpha1-antitrypsin (AAT) deficiency increases
the risk for developing cirrhosis; the significance of heterozygous carriage is
less clear. In this study the impact of the two most relevant AAT variants
(‘Pi*Z’ and ‘Pi*S’) on subjects with non-alcoholic fatty liver disease (NAFLD)
or alcoholic liver disease (ALD) were studied. These variants are present in up
to 10% of Caucasians. The Pi*Z variant presented in 14% of patients with
cirrhotic NAFLD and 6% of cirrhotic ALD but only in 2% of their corresponding
groups without liver fibrosis. In
contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and
only borderline with ALD cirrhosis. The authors conclude that the Pi*Z variant
is the hitherto strongest single nucleotide polymorphism-based risk factor for
cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a
weak risk in alcohol misusers and should be considered in genetic counselling
of affected individuals. Histopathologists have a significant role in
identifying these cases.
American Journal of Gastroenterology
Spectrum of Liver Disease in Hepatitis B Virus (HBV) Patients Co-infected with Human Immunodeficiency Virus (HIV): Results of the HBV-HIV Cohort Study. Sterling RK, Wahed AS, King WC, et al. Am J Gastroenterol. 2019 May; 114(5): 746-757. https://www.ncbi.nlm.nih.gov/pubmed/30410040 The histologic spectrum of liver disease in HBV/HIV coinfection is poorly defined. In this prospective study, liver biopsies in 114 patients coinfected with HBV and HIV were assessed by a central pathology committee chaired by Dr. David Kleiner. Liver biopsies showed significant periportal, lobular, and portal inflammation in 14%, 31%, and 22% respectively. 37% of biopsies had significant fibrosis (Ishak stage ≥2); 24% had advanced fibrosis (Ishak stage ≥3). Higher ALT and lower platelet count, but not HBV DNA, were independently associated with advanced fibrosis.
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
This study evaluated a number of genes for mutations and defects in protein expression in 77 primary liver tumors with a cholangiolocellular carcinoma (CLC) component. Tumors were further subdivided for analysis based on their proportion of a CLC component. The degree of ductal plate malformation (DPM) growth pattern in each tumor was also scored to determine any association with genetic alterations. The investigators found that loss of ARID1A expression was present in 20.8% of tumors with a CLC component and was seen more frequently in tumors with a higher proportion of a CLC component; 68.8% of this subset showed an extensive DPM-pattern. These findings suggest differences in CLC and provide data to support the possibility of molecular-morphologic classification of primary liver tumors in the future. More detailed information on additional genetic mutations and associations with morphologic findings are available in the manuscript.
Intrasinusoidal Spread of
Hepatic Epithelioid Hemangioendothelioma: Implications for the Diagnosis in
Agostini-Vulaj D, Pehlivanoglu B, Weiss SW, et al. Am J Surg Pathol.
The authors examined 18 cases of hepatic epithelioid hemangioendothelioma (EHE) and found that 17 showed tumor cells within sinusoids that appeared histologically separate, but within 1 to 8 mm, from the main mass. These intrasinusoidal tumor cells did not have the classic epithelioid or dendritic cell appearance of EHE, but rather showed hyperchromatic, cerebriform-like nuclei with multinucleation that in some cases mimicked megakaryocytes in over one-third of cases. Pathologists should be mindful of this phenomenon, as needle biopsies may only sample the periphery of mass lesions. Recognition of these intrasinusoidal tumor cells in limited samples can prevent misdiagnosis as non-lesional hepatic parenchyma. Immunohistochemical stains for CAMTA1, ERG, and sometimes CAM5.2 can assist in highlighting tumor cells.
Nonalcoholic Steatohepatitis Is the
Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant
Z, Stepanova M, Ong JP, et al. Clin Gastroenterol Hepatol. 2019
The authors used the Scientific Registry of Transplant Recipients (2002–2016) to estimate the trends in prevalence of HCC in liver transplant candidates with the most common types of chronic liver disease: alcoholic liver disease (ALD), chronic hepatitis B (CHB), chronic hepatitis C (CHC), and NASH. The proportions of HCC accounted for by CHC and ALD remained stable (both trend P > .10), the proportion of CHB decreased 3.1-fold (P < .0001), while the proportion of NASH in HCC increased 7.7-fold (from 2.1% to 16.2%; P < .0001). Over the study period, CHC was still the most common etiology for HCC (65%).
Cost Effectiveness of Transplanting
HCV-Infected Livers Into Uninfected Recipients With Preemptive Antiviral
Transplanting hepatitis C virus (HCV)-infected livers into HCV uninfected recipients is a controversial topic that is still not supported by current Guidelines. Direct-acting antivirals (DAAs) can be used to treat donor-derived HCV infection. The cost of DAA therapy may be a limitation. The authors evaluated the cost effectiveness of transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy. Using a Markov-based mathematical model, they found that transplanting HCV-positive livers into HCV-negative patients with planned DAA therapy after transplantation was a cost-effective strategy that could improve health outcomes. It is important for pathologists who review liver transplant biopsies to be aware that under these circumstances, histopathologic features of HCV may still need to be evaluated.
Gastroenterology and Hepatology
histopathological features of immunoglobulin G4‐associated autoimmune hepatitis
Aydemir Y, Akcoren Z, Demir H, et al. J Gastroenterol Hepatol. 2019
They reviewed frequency and the characteristics of immunoglobulin G4 (IgG4)‐associated autoimmune hepatitis in 40 pediatric patients with autoimmune hepatitis who had liver biopsies. IgG4‐associated autoimmune hepatitis was defined as presence of more than 10 IgG4‐positive plasma cells/high‐power field. They found a positive correlation between IgG4‐positive plasma cell count and degree of portal (r: 0.406, P: 0.009) and lobular inflammation (r: 0.37, P: 0.019), grade of interface hepatitis (r: 0.33, P: 0.03), and fibrosis (r: 0.318, P: 0.046). Time required for normalization of liver transaminases and serum IgG level was significantly shorter in IgG4‐associated autoimmune hepatitis.
Journal of Hepatology
assessment of the liver graft: Is it relevant?
Nahon P, Soubrane O. J Hepatol. 2019 Mar;70(3):346-347.
This editorial addresses the nuances in assessing the severity of fat involvement of liver grafts in transplantation, which in severe cases represents the main cause of donor livers being declined. It also emphasizes the yet unmet need for a fast, quantitative and reliable method to serve as an alternative to the current gold standard procedure of histological semi-quantitative evaluation performed on frozen biopsy section at the time of transplantation. Magnetic resonance spectroscopy, fibroscan devices, and user friendly non-invasive pocket spectrometer that can be administered by the harvesting surgeon to assess donor liver fat are being developed.
This case series describes in detail the histopathological features of portal cavernoma cholangiopathy (PCC, formerly portal biliopathy), a type of biliary injury that occurs in association with a portal vein thrombus or cavernoma. Cases are noted to clinically mimic cholangiocarcinoma, cirrhosis, and may present as a hilar mass. Microscopic features are reminiscent of hepatoportal sclerosis and/or bile duct obstruction, and show obliterated or miniaturized portal veins, with ductular reaction, reactive epithelia atypia, and mixed inflammatory cell infiltrate and neutrophils.
Not All Cellular Rejections
Are the Same: Differences in Early and Late Hepatic Allograft Rejection
Jadlowiec CC, Morgan PE, Nehra AK, et al. Liver Transpl. 2019
T cell–mediated rejection (TCMR) is common after liver transplantation
(LT), and it is often thought to have a minimum impact on outcomes. The authors
investigated the role of the timing of TCMR on patient and allograft survival
and examined the risk factors for early and late TCMR. They reviewed protocol
liver biopsies for 787 consecutive LT recipients with an 8.6‐year follow‐up.
The incidence of early TCMR (≤6 weeks after LT) was 33.5% with nonalcoholic
steatohepatitis patients having the lowest incidence. Younger recipient age (P
< 0.01), number of human leukocyte antigen mismatches (P < 0.01), and use
of deceased donor allografts (P = 0.01) were associated with increased risk of
early TCMR, which had no impact on allograft (hazard ratio [HR], 1.02; 95% CI,
0.79‐1.32; P = 0.89) or overall survival (HR, 1.03; 95% CI, 0.78‐1.34; P =
0.86). Late TCMR (>6 weeks after LT) was less common (17.7%) and was
associated with different risk factors. The majority of late TCMR (56.2%)
episodes had no antecedent early TCMR, although moderate‐to‐severe early TCMR
(HR, 2.85; 95% CI, 1.55‐5.23; P < 0.01) and steroid resistance (HR, 3.62;
95% CI, 1.87‐6.99; P < 0.01) were associated with late TCMR. Late TCMR
increased risk of mortality (HR, 1.89; 95% CI, 1.35‐2.65; P = 0.001) and graft
loss (HR, 1.71; 95% CI, 1.23‐2.37; P = 0.001). In summary, the majority of
early TCMR episodes after LT are mild and do not appear to adversely impact
long term patient or allograft survival, provided that they are treated
adequately. By contrast, late TCMR may carry deleterious effects with
associated long term risk of graft loss and decreased survival. The authors
suggest that it is important to describe TCMR after LT in the context of its
timing and histologic grade. Early moderate‐to‐severe or steroid‐resistant
rejection may play a role in late TCMR as multiple or inadequately treated TCMR
episodes are risk factors for chronic rejection. Patients with
moderate‐to‐severe early TCMR are at an increased risk for late TCMR and
warrant closer clinical follow‐up. The occurrence of late TCMR carries
deleterious effects with increased long term risk of graft loss and decreased
A phenotypical map of
disseminated hepatocellular carcinoma suggests clonal constraints in metastatic
Martins-Filho SN, Alves VAF, Wakamatsu, et al. Histopathology. 2019
Access to tissue in patients with hepatocellular carcinoma (HCC) is limited
compared to other malignancies. This has precluded a thorough characterization
of molecular drivers of HCC dissemination, particularly in relation to distant
metastases. The authors evaluate 88 patients with HCC who underwent autopsy,
including multiregional sampling of primary and metastatic sites totalling 230
nodules that were analyzed. The study included morphological assessment,
immunohistochemistry and mutation status of the TERT promoter, which is the
most frequently mutated gene in HCC. Immunohistochemistry (IHC) was performed
for markers of hepatocyte differentiation (HepPar1 and arginase), WNT pathway
(β‐catenin and glutamine synthetase), HCC progenitor cell features (K19, CD44
and EpCAM), markers of EMT (vimentin and claudin‐1) and cell proliferation
(Ki67). Results for β‐catenin and glutamine synthetase IHC were combined as a
proxy for WNT signaling pathway activation. Most of the patients were male (62
of 88, 70%), with background liver cirrhosis (79 of 88, 90%) due to hepatitis C
virus (HCV) infection (47 of 88, 53%). The results of this study confirm a
strong predilection of HCC for lung dissemination, including subclinical
micrometastases (unrecognized during imaging and macroscopic examinations) in
30% of patients with disseminated disease. Size of dominant tumour nodule;
multinodularity; macrovascular invasion; high histological, nuclear and
architectural grades; and cellular crowding were associated with the presence
of extrahepatic metastasis. Among the immunohistochemistry markers tested,
metastatic nodules had significantly higher CK19 and EpCAM expression than
primary liver tumors. Morphological and immunohistochemical features showed
that metastatic HCC could be traced back to the primary tumour, sometimes to a
specific hepatic nodule. Their study also illustrates how autopsies can go
beyond their primary objective of defining the cause of death and help address
Accuracy of the Liver Imaging Reporting and Data System
in Computed Tomography and Magnetic Resonance Image Analysis of Hepatocellular
Carcinoma or Overall Malignancy-A Systematic Review
van der Pol CB, Lim CS, Sirlin CB et al. Gastroenterology. 2019
The Liver Imaging Reporting and Data System (LI-RADS) categorizes
observations from imaging analyses of high-risk patients based on the level of
suspicion for hepatocellular carcinoma (HCC) and overall malignancy. However,
the actual percentage of HCC and overall malignancy within each LI-RADS
category is not known. The authors performed a systematic review to determine
the percentage of observations in each LI-RADS category for computed tomography
and magnetic resonance imaging that are HCCs or malignancies. The authors
searched the MEDLINE, Embase, Cochrane CENTRAL, and Scopus databases from 2014
through 2018 for studies that reported the percentage of observations in each
LI-RADS v2014 and v2017 category that were confirmed as HCCs or other
malignancies based on pathology, follow-up imaging analyses, or response to
treatment (reference standard). Of 454 studies identified, 17 (all
retrospective studies) were included in the final analysis, consisting of 2760
patients, 3556 observations, and 2482 HCCs. The pooled percentage of patients
with HCC were 94% for patients who, on CT/MRI, had a lesion classified LR-5,
74% for LR-4, 38% for LR-3, 13% for LR-2, and 36% for LR-M. No malignancies
were reported in the LR-1 category. Several potential variables associated with
accuracy such as modality (CT vs. MRI) and lesion size could not be evaluated
because of either lack of eligible studies or individual participant data.
Understanding the accuracy of each LI-RADS category for liver cancer allows
physicians to quantify and communicate risk associated with different findings
on CT/MRI, allowing for more well-informed management decisions. LR 2 and 3
lesions had non-trivial cancer risks.
Hepatic mast cell concentration directly correlates to stage of
fibrosis in NASH
Lombardo J, Broadwater
D, Collins R. et al. Hum Pathol. 2019 Apr;86:129-135.
Recent research has described an association between an
increased concentration of mast cells in the liver and the
severity of hepatic fibrosis in animal models. The role
of mast cells in the liver with regard to fibrosis is not well
understood. The authors retrospectively investigated whether a correlation
exists between stages
of fibrosis and mast cell concentrations. 106 tissue
slides were collected from a large military hospital of known cases of
unremarkable liver, non-alcoholic fatty liver disease (NAFLD), and
each stage of NASH. Tryptase staining was used to highlight and
quantify the mast cell concentration in each diagnostic
category. Mast cells in five 400× fields (1 square mm) in both the
periportal and parenchymal regions of each slide were counted.The study demonstrated an increase
in mast cells in NASH stage 3-4 fibrosis compared
to unremarkable liver (35.48 versus 18.23, respectively, P < .001) and a
direct correlation (r = 0.287) between the number of mast cells and
the stage of fibrosis. Better characterization of the role
of mast cells in the development
of hepatic fibrosis may further develop our understanding of the
pathophysiology of non-NASH NAFLD and NASH.
Steatotic and nonsteatotic scirrhous hepatocellular carcinomas reveal
distinct clinicopathological features
Hatano M, Ojima H,
MasugiY, et al. Hum Pathol. 2019 Apr;86:222-232.
investigated the clinicopathological and molecular characteristics of scirrhous
HCC.120 resected HCC cases were
evaluated, including tumor area containing fibrous stroma and the percentage of
steatotic cells within the tumor.37
cases with fibrous stroma making up > 50% of the largest tumor area
were defined as scirrhous HCC (sHCC); the other 83 cases were categorized as
common HCC (cHCC). Clinicopathologically, sHCC had fewer poorly differentiated
tumors (p=0.037) and a higher percentage of cases with steatosis (p=.025) than
cHCC.sHCC cases were subsequently
divided into two subgroups: those with > 5% steatotic cells
(steatotic sHCC) and those with < 5% steatotic cells (nonsteatotic
sHCC).Steatotic sHCC tended to have a
longer time to recurrence than nonsteatotic sHCC, and both sHCC subgroups
exhibited different clinicopathologic and molecular features from cHCC.
Prevalence and burden of hepatitis
D virus infection in the global population: a systematic review and
Shen DT, Ji D, et al. Gut 2019;68:512-521.
It is well known that Hepatitis D
virus is a defective virus that completes its life cycle only with hepatitis B
virus. However, there is limited data on the global burden of HDV infection. A
systematic review found that 11% of HBsAg carriers (without histories of either
intravenous drug use or high-risk sexual behaviour) were coinfected with
Hepatitis D virus, which is twice previous estimates. A significantly higher
HDV prevalence was noted in intravenous drug users (38%) and high-risk sexual
behaviour (17%). Clearly, coinfection with HDV needs to be actively
considered by histopathologists, as well as other clinicians, in patients with
HBV, especially those in high risk groups.
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
I would like to thank everyone who attended the HPHS reception at the USCAP meeting. We had a vibrant gathering and the room was packed within a few minutes. Hanlin and Ilke welcomed everyone at the door as part of the membership committee and the book raffle was a big hit as always. Thanks to all the authors who generously donated the books; I already have a few for the next year! Thanks also to all the executive members, Mike, Grace and Cindy for organizing the reception as well as to past president Isabel, who has been instrumental in the logistical aspects of the reception.
The companion society meeting was very well attended and I have received a lot of positive feedback about the speakers as well as the topics.
Thanks to all the speakers for an outstanding session: Joe Misdraji (MGH), Bita Naini (UCLA), Andrew Bellizzi (U Iowa), Achim Weber (Zurich), Andrew Clouston (Brisbane) and Christine Sempoux (Lausanne). If you have any suggestions about the topics and speakers for next year’s meeting, please let me know.
A brief summary of the steatohepatitis survey was shared at the Hans Popper reception. The detailed results will be posted soon on the website and a notification will be sent to the members. Thanks again to the membership for their robust participation in the survey.
The committee chairs shared their annual reports in the Business meeting at the USCAP. The society’s activities including the Journal watch, case of the month and resident abstract award are going well, the
finances are sound, and the Twitter presence is growing. Please continue your active participation in the society’s activities.
Sanjay Kakar, MD
President, Hans Popper Hepatopathology Society
Case contributed by:
Madhavi Rayapudi, MD and Stephen C. Ward, MD, PhD
Department of Pathology, Icahn School of Medicine at Mount Sinai, New
55 year old female with past medical history of IgG lambda multiple myeloma diagnosed 3 years prior. She is status post multiple treatments and is currently in remission. She presents now with intermittent high fevers, dry cough, and elevated liver enzymes - AST 247 (Ref range 15-37IU/L); ALT 280 (Ref range 15-56 IU/L); Alkaline phosphatase 145 (Ref range 48-118 U/L); Bilirubin 0.5 (Ref range 0.2-1.5MG/DL). Liver biopsy was performed.
Liver needle biopsy specimen shows multiple nonnecrotizing granulomas predominantly located within the hepatic parenchyma. Several granulomas contain a lipid droplet, some with a loose ring of fibrin around the fat droplets (best seen on Masson trichrome stain). Mild macrovesicular steatosis without significant ballooning degeneration is also seen.
Granulomatous hepatitis with fibrin ring features secondary to immune checkpoint inhibitor toxicity.
The patient had been treated with venetoclax, ixazomib, dexamethasone, nelfinavir, and thalidomide. Immune checkpoint inhibitor therapy with anti-CTLA-4 agent ipilimumab and anti-PD-1 agent nivolumab was initiated three weeks prior to the biopsy. Following the biopsy the immune checkpoint inhibitor therapy was discontinued and liver enzymes returned to normal.
Immune checkpoint inhibitors have become standard of care in many types of malignancies; however, the underlying mechanism of hepatotoxicity is still not completely understood. In a retrospective study of 187 patients, an overall incidence of all grade hepatotoxicity with CTLA-4 inhibitors (e.g. ipilimumab) was 24%, 37% with PD-1 inhibitors (e.g. nivolumab), and 73% with the combination therapy (1). Immune check point inhibitor mediated hepatitis (ICIIMH) and idiopathic autoimmune hepatitis (iAIH) share some histologic similarities (2,3) but significant differences have also been described. ICIIMH was characterized by lobular hepatitis with abundant infiltration by CD3+ or CD8+ T-lymphocytes, while CD20+ or CD4+ lymphocytes were less likely to be seen in ICIIMH as compared to iAIH (4). Recently a granulomatous hepatitis with fibrin ring features has been described in patients treated with CTLA-4 inhibitors alone or in combination with PD-1 inhibitors. (5, 6). The granulomas consist of collections of epithelioid cells with a central lipid vacuole and a surrounding ring of fibrin. These cases also showed steatotosis with either spotty necrosis or perivenular confluent necrosis as well as central vein endotheliitis. Fibrin ring granulomas are not specific for immune checkpoint inhibitor toxicity. The differential diagnosis for fibrin ring granulomas also includes infection [Q fever (Coxiella burnetii), hepatitis A, visceral leishmaniasis, Epstein-Barr virus, toxoplasmosis, boutonneuse fever (Rickettsia conorii), staphylococcal infection, and salmonella], autoimmune (e.g. systemic lupus erythematosus), other drugs (e.g. allopurinol), Hodgkin disease, giant cell arteritis, metastases, as well as in the metabolic syndrome with hepatic steatosis, and mitochondrial injury (7, 8, 9).
1.Shah N, Puthiamadathil J, Serzan M, et al. Clinical Outcome of immune related hepatitis (IrHep) in patients with advanced melanoma (AM) treated with single agent or combination immune checkpoint inhibitors (ICI) [abstract]. Ann Oncol. 2018 Oct; 29(8):viii433.
2.Kleiner DE, Berman D. Pathologic changes in ipilimumab- related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012; 57:2233–2240.
3.Johncilla M, Misdraji J, Pratt DS, et al. Ipilimumab-associated Hepatitis. Am J Surg Pathol. 2015 Aug 1;39(8):1075–1084
4.Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol 2018; 31:965–973.
5.De Martin E, Michot JM, Papouin B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018 Jun 1; 68(6):1181–1190.
6.Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol. 2017; 41: 134–137.
7.Lewis JH. Chapter 40. Granulomas of the liver. In: Schiff ER, Maddrey WC, Reddy KR, editors Schiff’s disease of the liver. 12th ed. Wiley-Blackwell New Jersey, USA. 2018. p. 1028–1052.
8. Aguilar-Olivos N, Del Carmen Manzano-Robleda M, Gutiérrez-Grobe Y, et al. Granulomatous hepatitis caused by Q fever: a differential diagnosis of fever of unknown origin. Ann Hepatol. 2013 Jan 15; 12 (1):138–141.
9.Joseph J. Jennings, Rohan Mandaliya, Ahmad Nakshabandi & James H. Lewis (2019) Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies, Expert Opinion on Drug Metabolism & Toxicology, 2019 15:3, 231-244, DOI: 10.1080/17425255.2019.1574744