Clinical Gastroenterology and Hepatology
De Boer YS, Kosinski
AS et al. Clin Gastroenterol Hepatol. 2017;15:103-112.
Drugs best known to
cause liver injury with autoimmune features include nitrofurantoin,
minocycline, hydralazine, and methyldopa. This study analyzed 88 cases of DILI
attributed to these four drugs from the Drug-Induced Liver Injury Network
prospective study from 2004 through 2014. At the onset of DILI, serum IgG
levels were elevated in 39% of cases. 72% of the cases tested positive for ANA,
60% for SMA, but none for SLA. Autoimmune phenotype (autoimmune
score ≥ 2) was observed in 82%, 73%, 55% and 43% of cases attributed to
nitrofurantoin, minocycline, hydralazine, and methyldopa respectively. On
follow-up, a decrease in ANA or SMA positive rate and autoimmune scores was
observed. Genetic study revealed that idiopathic AIH risk alleles HLA-DRB1*03:01 and HLA-DRB1*04:01 do
not represent risk factors for nitrofurantoin-, minocycline-, methyldopa-, and
hydralazine-induced liver injury and the associated autoimmune phenotype.
Khalaf N, Ying J et
al. Clin Gastroenterol Hepatol. 2017;15:273-281.
Studying the natural
history of untreated HCC is critical for understanding the prognosis and
prognostic factors of HCC and the contribution of surveillance to lead time
bias. 518 patients without any HCC treatment was identified from a national
cohort of 1500 veterans with verified HCC. The mean age at time of HCC diagnosis
was 65.7 years. Most patients had HCV (60.6%) or alcohol abuse (79.3%). The
median overall survival time was 3.6 months. In multivariate analyses, BCLC
stage, MELD score and alpha-fetoprotein levels were prognostic factors and
predictive of survival. Pre-diagnostic HCC surveillance was
associated with detection of HCC at an earlier stage and slightly longer
survival compared to patients without surveillance (5.2 months vs. 3.4 months).
Hepatology
Veeral A, Perito E, et
al., for the NASH Clinical Research Network. Hepatology 2017; 65(1): 65-74.
The NASH Clinical Research
Network investigated thirty-two plasma biomarkers for NASH disease activity and
severity in 648 participants. Biomarkers associated with significant fibrosis
in multivariable analysis included higher levels of interleukin-8, monocyte
chemoattractant protein-1, resistin, soluble interleukin-1 receptor I, soluble
interleukin-2 receptor alpha, and tumor necrosis factor alpha.
Sumazin P, et al.
Hepatology 2017; 65(1): 104-120.
The authors performed
molecular profiling on 88 pretreated hepatoblastomas. Their analysis
risk-stratified the tumors into three molecular subtypes, characterized by
differential activation of hepatic progenitor cell markers and metabolic
pathways. The authors suggest that immunohistochemical stains targeting these
biomarkers have the potential to improve risk stratification and guide
treatment decisions for patients at diagnosis.
Dahlqvist G, et al.
Hepatology 2017; 65(1): 152-163.
The authors performed a
prospective study across a nation-wide French network for the prevalence of
anti-mitochondrial antibodies (AMA). Clinical data from 720 AMA-positive
patients identified over one year were collected. 229 patients (32%) were
considered “nonestablished diagnosis of PBC.” This group was further studied
with a mean follow-up duration of 4.0 years. In this group, those patients who
had normal alkaline phosphatase and no evidence of cirrhosis had a 5-year
incidence rate of 16% for PBC. Limitations of the study include the fact that
only a minority of patients (19%) had a biopsy. And, only the reports were
available with no central review of the biopsy. The authors report that some of
these pathology reports included “mild portal inflammation” or “features
compatible with autoimmune hepatitis,” suggesting the possibility that more
scrupulous evaluation of the biopsy material may have been worthwhile. This
study is in contrast to a prior older UK study (1996, Metcalf et al.) which
followed 29 asymptomatic AMA-positive patients for a median time of 17.8 years,
and in which the majority of patients developed PBC. The authors suggest this
discrepancy may be from inherent discrepancies between the populations studied
and methods used (single-center retrospective selection vs. prospective
nation-wide screening).
Kaminsky P, Preiss J, Sasatomi
E, Gerber D. Hepatology 2017; 65(1): 380-383.
The authors report a
case of a biliary adenofibroma with malignant features and review the
literature on this rare tumor. The malignant features they report include “low
papillary epithelial overgrowth with increased mitotic activity,” and “small
islands of tumors cells infiltrating the fibrous stroma.”
Histopathology
Interesting series with
review articles covering wide range of pathology most of which are of interest
to the most pathologists. With topics that include a review of progress and
evolution of pathology as a specialty in the last 50 years and digital
pathology, this volume will be of interest in general. It also includes an
article on drug-induced liver injury by David Kleiner, the abstract of which is
presented below:
Kleiner DE.
Histopathology. 2017;70(1):81-93
Drug-induced liver
injury (DILI) presents unique challenges to the pathologist. It is not only an
uncommon reason for liver biopsy, but the pathology of DILI is spread across
the entire spectrum of hepatic injury patterns. It is important for the
pathologist to suspect DILI when the histological changes are unusual or out of
synchronicity with the patient's history. A systematic evaluation approach will
yield the most information. It begins with the characterization of the general
pattern of injury which, for most cases, will be found in a handful of
necroinflammatory and cholestatic patterns. A careful assessment of the
severity of injury across the various anatomic compartments will provide
information on the probable natural history of the injury. Correlation of liver
injury with the patient's medication history and clinical findings will help to
narrow the differential diagnosis, particularly when it is recognized that most
drugs have a limited range of histological findings and vary in their
propensity to cause injury. This review provides an overview of the assessment
of the liver biopsy and its use to confirm or exclude particular drugs as
contributing to the patient's liver injury.
Sasaki M, Sato Y,
Nakanuma Y. Histopathology. 2017;70(3):423-434.
These authors
investigated the expression profile of several genes in 53 patients with
combined HCC and cholangiocarcinoma (cHC-CC) and found that some (e.g. TERT
promoter gene) could have etiologic significance while others could potentially
segregate these tumors into histogenetic and/or biological groups.
Abstract
AIMS: Combined
hepatocellular carcinoma and cholangiocarcinoma (cHC-CC), which generally has a
poor prognosis, comprises hepatocellular carcinoma (HCC), cholangiocarcinoma
(CC), and diverse components with intermediate features between HCC and CC.
Histological subtypes with stem cell (SC) features (the SC subtype) have
different clinicopathological significance in cHC-CC. The mutational status may
reflect the clinicopathological subgroup of cHC-CC together with the
histological subtype.
METHODS AND RESULTS: We
examined the mutational statuses of KRAS, IDH1 or IDH2 (IDH1/2), ARID1A, the
TERT promoter, and TP53, and their relationships with clinicopathological
features in 53 patients with cHC-CC. Background liver diseases were hepatitis B
(n = 9), hepatitis C (n = 22), alcoholic liver disease (n = 5), non-alcoholic
fatty liver disease (NAFLD) (n = 8), and unknown (n = 9). Mutations in KRAS,
IDH1/2, ARID1A, the TERT promoter and TP53 were detected in four (7.5%), six
(11.8%) seven (13.2%), 16 (31.3%), and 24 patients (45.3%), respectively. KRAS
mutations correlated with higher histological diversity scores and a higher
M-factor (P < 0.05). ARID1A mutations correlated with alcoholic liver
disease, smaller tumour size, a lower grade of coexistent HCC, and
α-fetoprotein (AFP) positivity, and were associated with cholangiolocellular
carcinoma subtype predominance (P < 0.05). TERT promoter mutations
correlated with hepatitis B, an intermediate subtype-predominant histology,
higher clinical stage, and a higher N-factor (P < 0.05), and were associated
with gender (female-predominant) and previous therapy. TP53 mutations correlated
with AFP positivity (P < 0.05).
CONCLUSIONS: The results
of the mutational analysis revealed that cHC-CC has diverse types of mutations,
and also that mutations in the TERT promoter and ARID1A may reflect
aetiological impact, different histological subtypes, histogenesis, and tumour
aggressiveness. These results suggest the potential efficacy of molecular-based
subclassification of cHC-CC.
Abstract
AIMS: Both homozygous
and heterozygous α1 -antitrypsin (AAT) deficiency patients are at risk of
developing hepatocellular carcinoma (HCC), but also of developing
cholangiocarcinoma and combined HCC and cholangiocarcinoma. The aim of our
study is to report a series of bile duct adenomas (BDAs) and intrahepatic
cholangiocarcinoma (ICCs) in adult AAT deficiency patients, observed in our
institution over a 5-year period. Our observational study includes a detailed
investigation of their immunohistochemical profile and BRAF V600Emutation
status.
METHODS AND RESULTS:
Eleven biliary lesions from five AAT deficiency patients (six BDAs from three
cirrhotic patients with other concurrent liver diseases; three BDAs and two
ICCs from two non-cirrhotic patients) were identified between 2010 and 2015
during routine histological investigation. Most BDAs expressed CD56, EpCAM,
CD133, and CA19-9, similarly to hepatic progenitor cells (HPCs), and carried
the BRAF V600Emutation (87.5%). One ICC showed a similar immunohistochemical
profile but no evidence of the BRAF V600Emutation.
CONCLUSIONS: Most of the
biliary proliferations in AAT deficiency patients have an appearance of BDA
with an HPC-related immunohistochemical profile. Their frequent BRAF V600E
mutations support their neoplastic nature, but not necessarily their progression
to ICC. We believe that this may depend on the patient genotype, or require a
different pathway or a second mutational hit for malignant transformation. We
postulate that BDA represents a heterogeneous group of biliary lesions, and
that those associated with AAT deficiency may constitute a group of their own.
Lequoy M,
Desbois-Mouthon C, Wendum D, Gupta V, Blachon JL, Scatton O, Dumont S,
Bonnemaire M, Schmidlin F, Rosmorduc O, Fartoux L. Histopathology.
2017;70(3):492-498
This paper investigated
various somatostatin receptor expressions by RT-PCR and immunohistochemistry in
53 patients with hepatocellular carcinoma. Among other findings, SSTR2 was
found to be overexpressed in 32% of these tumors and its expression
immunohistochemically (in 38% of tumors) correlated with other markers of poor
differentiation, including CK19.
Abstract
AIMS: To investigate the
status of somatostatin receptors (SSTRs) in resected hepatocellular carcinoma
(HCC).
METHODS AND RESULTS:
Transcript and protein levels of SSTR2, SSTR3 and SSTR5 were investigated, with
real-time polymerase chain reaction (PCR) and manual and automated
immunohistochemistry (IHC), in 53 resected HCCs and paired non-tumour tissues.
SSTR1, SSTR4, SSTR5TMD4 and SSTR5TMD5 were analysed with real-time PCR. SSTR3
and SSTR5 transcripts were expressed in ~25% of HCCs, but not in adjacent
non-tumour tissues. SSTR1 and SSTR2 transcripts were overexpressed in 42% and
32% of HCCs, respectively. SSTR4, SSTR5TMD4 and SSTR5TMD5 were not detected.
Membrane staining for SSTR2 was detected in 38% of HCCs, whereas SSTR5 protein
was detectable in only 11% of HCCs. SSTR3 protein was detected in the majority
of HCCs and adjacent non-tumour liver tissues, but membrane staining was
<20% of that in HCCs. The results obtained with the two IHC methods were highly
correlated (P < 0.0001). Statistical analyses also showed a positive
correlation between SSTR2 membrane staining and cytokeratin 19 expression (P =
0.04), serum α-fetoprotein level (P = 0.002), and poor differentiation (P =
0.05).
CONCLUSIONS: Membrane SSTR2
is detected reliably in HCCs by IHC, and is a potential therapeutic target, as
it is coexpressed with markers of poor prognosis.
Journal of Gastroenterology and Hepatology
Lee YK et al. Journal of
Gastroenterology and Hepatology Feb. 2017, 32(2): 487-98.
This study evaluated
clinical outcomes of patients with hepatocellular carcinoma who underwent
transarterial chemoembolization (TACE) using drug-eluting beads (DEB).
This study
retrospectively compared the clinical outcomes of 250 patients who had
hepatocellular carcinoma and underwent transarterial chemoembolization (TACE)
using drug-eluting beads (DEB) (n = 106) versus those with conventional TACE
(cTACE) (n = 144). The most common etiology was hepatitis B virus infection.
The median index tumor size was 2.8 cm, and 150 (60.0%) patients had Barcelona
Clinic Liver Cancer stage B. Median TTP in the cTACE group was longer than in
the DEB-TACE group (13.3 vs10.8 months; P = 0.023). However, DEB-TACE and cTACE
groups showed no significant differences for mean OS (46.6 vs 44.9 months; P =
0.660) and disease control rate at 1 month (78.3% vs 86.8%; P = 0.076). The OS,
TTP, and disease control rate were also not different between two groups, even
when subgrouped by index tumor size. The complication rates within 1 month were
higher in the cTACE group (6.6% vs 14.6%; P = 0.048). Drug-eluting beads TACE
appears to be a safe intra-arterial therapy, although it is not superior to
cTACE in terms of efficacy.
Archives of Pathology and Laboratory Medicine
Gonzalez RS, Gilger MA,
Huh WJ, Washington MK. Arch Pathol Lab Med 2017; 141 (1):98-103.
Cardiac hepatopathy (CH)
and Budd-Chiari syndrome (BCS) are 2 conditions in the category of venous
outflow obstruction that have different pathophysiology and typical
clinical/radiologic presentations, but share the histologic findings of
sinusoidal dilation and centrilobular necrosis. In situations where
clinical findings are indeterminate for etiology or nonspecific (e.g. elevated
liver enzymes), it would be helpful if there were histologic findings that
could distinguish between CH and BCS. The authors retrospectively
reviewed 26 CH and 23 BCS cases for the presence of certain histologic
parameters to determine if any correlated more closely with one disease versus
the other. Pericellular/sinusoidal fibrosis, fibrosis around central
veins, and glycogenated nuclei were significantly more common in CH while
centrilobular hepatocyte dropout/necrosis was significantly more common in
BCS. Histologic features common to both CH and BCS included
sinusoidal dilation, portal tract fibrosis, chronic inflammation, and bile
ductular reaction; while this constellation of findings can be seen in other
processes, they should not exclude a diagnosis of CH or BCS.
American Journal of Surgical Pathology
Everett J, Srivastava A,
Misdraji J. Am J Surg Pathol. 2017;41(1):134-137.
Fibrin ring granulomas
are a distinctive histologic finding that have been described in a number of
infections including Q fever, Hepatitis A, Hepatitis C, R. typhi, CMV, EBV,
toxoplasmosis, and visceral leishmaniasis as well as some noninfectious
conditions. The authors herein report on 2 cases of combination
ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1)-induced hepatitis that
showed fibrin ring granulomas in liver biopsies. Immune checkpoint
inhibitors are increasingly being used in cancer therapy, and this case series
presents 2 patients who developed transaminase elevations (predominantly
hepatitic pattern, ALT up to 643 IU/L) after initiation of combination
ipilimumab/nivolumab therapy. Resolution of symptoms was seen after
termination of checkpoint inhibitor therapy and initiation of immunosuppressive
treatment. Likely other causes of transaminase elevations in these
patients were excluded and one patient had recurrence of transaminase elevation
upon restarting nivolumab. The main histologic findings this series
were hepatocyte necrosis and histiocytic aggregates, focally forming fibrin
ring granulomas, colocalizing with steatosis. Steatosis was
predominantly seen in zone 3 in one patient and zone 1 in the other
patient. While the microscopic findings in ipilimumab-induced hepatitis
have been previously reported, this case series raises the possibility that
fibrin ring granulomas may be also be seen with checkpoint inhibitor therapy,
or perhaps even be specific for combination ipilimumab/nivolumab therapy.
Zhelnin K, Xue Y,
Quigley B, Reid MD, Choi H, Memis B, Adsay V, Krasinskas AM. Am J Surg Pathol.
2017;41(1):116-120.
A recent proposal by Dr.
Albores-Saavedra and colleagues calls for categorizing pancreatic and hepatic
cystic lesions with ovarian-type stroma into two entities based on whether the
epithelial component is considered mucinous or nonmucinous rather than grouping
all such lesions into the term “mucinous cystic neoplasm” (MCN) as defined by
the 2010 WHO. In this study, the authors reviewed 104 pancreatic and
32 hepatic cases from two institutions to characterize the epithelium present
in MCNs and explore the significance of percent nonmucinous versus mucinous
epithelium in any given case. 81% of cases had a mixture of
nonmucinous and mucinous epithelium (having ≥ 5% of each phenotype). 47%
of cases had abundant (> 50%) nonmucinous epithelium. None of the
58 cases having > 50% nonmucinous epithelium contained high-grade dysplasia
or invasive carcinoma. In contrast, 31% of the 71 cases having ≤ 50%
nonmucinous epithelium contained high-grade dysplasia or invasive
adenocarcinoma. Given these findings, nonmucinous epithelium may be
the precursor, whereas mucinous change may be the key feature in MCN
transformation to malignancy. As such, the authors suggest that
perhaps MCNs with predominantly mucinous epithelium are at higher risk and thus
should be sampled more thoroughly to exclude malignancy. With
regards to terminology, since a mixture of nonmucinous and mucinous epithelium
are frequently found in MCNs, there does not appear to be sufficient evidence
at this time to justify separating these lesions into two entities based on
epithelial phenotype.
Taxy JB, Gibson WE,
Kaufman MW. Am J Surg Pathol. 2017;41(1):94-100.
The major species E.
granulosus and E. multilocularis are common worldwide but are unusual in the
United States. Imaging and laboratory studies such as ELISA and
electrophoresis can aid in diagnosis of infection, but these tests may not be
ordered, as echinococcal infection is sometimes unsuspected, especially in
nonendemic areas. The authors reviewed 7 historical cases of
echinococcosis that were encountered in the Chicago area and remind us of the
findings. Microscopic diagnosis of echinococcus rests on
identification of scolices and hooklets, whether on wet mount or histologic
sections. In the absence of these worm parts, cyst walls with an
acellular hyaline lining that may be surrounded by calcifications and chronic
inflammation are highly suggestive, especially in the appropriate clinical
context. Given the ease and frequency of modern day international
travel, pathologists should remember echinococcosis as a diagnostic possibility
when encountered with a cystic lesion, whether intra- or
extrahepatic. Prompt diagnosis can be important, particularly in the
setting of an intraoperative consultation in a clinically unsuspected case, as
this may facilitate treatment and prevent anaphylaxis from intraperitoneal
spillage of cyst contents.
Deniz K, Moreira RK, Yeh
MM, Ferrell LD. Am J Surg Pathol. 2017;41(2):277-281.
Distinguishing benign
hepatocellular lesions from hepatocellular carcinoma can be a difficult
diagnostic challenge for pathologists. Steatohepatitis-like changes
(SLC) in focal nodular hyperplasia (FNH) may have similar features with the
steatohepatitic variant of hepatocellular carcinoma (HCC). The
authors reviewed FNH resections from 3 institutions to determine the frequency
of SLC in FNH and their concurrence with other findings that are typically
thought to be associated with HCC, mainly hepatocellular rosettes and/or
widened hepatic cell plates (> 3 cells in thickness). SLC were
defined as the presence of ballooned hepatocytes and/or Mallory-Denk
bodies. Of the 33 FNH cases, 54% showed SLC, 70% showed
hepatocellular rosettes (almost half of these cases also showed SLC), and 42%
showed widened hepatic cell plates (over one-third also showed SLC) but all 3
features tended to be focal in extent. The fibrosis pattern in
steatotic FNH was different than the steatohepatitic variant of HCC: thick
fibrous bands with radiating smaller septa and thick-walled vessels are seen in
the former, and a “chicken-wire,” pericellular pattern is seen in the
latter. In conclusion, pathologists need to be aware that SLC,
hepatocellular rosettes and widened hepatic plates can be seen in FNH and
caution needs to be exercised in limited biopsy material as to not
over-diagnose these lesions as the steatohepatitic variant of HCC.
Gastroenterology
Elmasry S, et al.
Gastroenterology. 2017 Feb;152(3):550-553.
Detection of HCV in
liver or peripheral blood in the setting of negative serum HCV RNA is referred
to as occult hepatitis C. This is a prospective study comprising 134 hepatitis
C cases, who underwent DAA treatment and developed recurrent HCV infection
after liver transplantation. Transaminases were abnormal in >10% of the
patients who achieved SVR12 (n=14). Of the 9 of these 14 cases, 5 (55%) had
occult HCV based on detection by reverse transcription quantitative PCR. The
authors conclude that occult HCV infection is present in a subset of patients
with abnormal liver enzymes after achieving SVR.
Koutsoudakis G, et al.
Gastroenterology. 2017 Feb;152(3):472-474.
This is an editorial
that accompanies the previous article.
Gut
Garnelo, M., Tan A, Her
Z., et al. Gut 2017;66(2):342-351.
The interaction between
tumor cells and the immune system has been the subject of extensive research in
the past few years. In this study, Garnelo et al examine the role of
tumor infiltrating lymphocytes in the progression of hepatocellular carcinoma. Using
immunohistochemistry, immunofluorescence, PCR, and flow cytometry from human
hepatocellular carcinoma they demonstrate that the presence of tumor
infiltrating T-cells and B-cells correlates with improved
outcomes. They demonstrate that the density of tumor infiltrating
B-cells correlates with T-cell and NK cell activation and decreased tumor cell
viability.
Prepared by:
Editor, Daniela
Allende, MD, Cleveland Clinic
Oyedele Adeyi, MD;
University of Toronto
Wenqing Cao, MD; New
York University
Sanjay Kakar, MD; University
of California, San Francisco
Jingmei Lin, MD, PhD;
Indiana University
Rish Pai, MD, PhD;
Mayo Clinic Arizona
Eric Yee, MD;
University of Oklahoma
Nafis Shafizadeh, MD;
Southern California Permanente Medical Group
