Journal Watch: January – February 2017

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).


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.”


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.
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.
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.
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.


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.


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

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