Tuesday, March 28, 2017

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

Thursday, February 23, 2017

Hans Popper Hepatopathology Society Reception 2017

Hans Popper Hepatopathology Society Members,

You are invited to the Hans Popper Hepatopathology Society Reception

Saturday March 4th
6:00-8:00 PM

Hilton Palacio Del Rio, Room H-2093
200 S. Alamo St
San Antonio TX 78205

Telephone number to hotel front desk: 210-222-1400

Looking forward to seeing you!

Wednesday, February 22, 2017

President’s Message February 2017

As promised, this president’s message will continue on a “tour” of the Hans Popper Hepatopathology Society structure. The executive committee has been working very hard on writing and adopting SOPs for each of the offices and committees of the HPHS.  We hope to have these finished very soon, at which point they will be posted on the HPS website, available to anyone who like to view them. The Executive Committee hopes this will help make the HPHS more accessible to all by making it easier to understand all of the “moving parts” of the society and how the committees and offices are interrelated.  SOP is short for standard operating procedure (sometimes also called “standing operating procedure”). SOPs function in societies like the HPHS as a template, describing the duties and roles for each committee and officer. While SOPs tend to be a bit dry to talk about, not nearly as exciting as a liver biopsy, they are important to make sure societies function smoothly and are especially important as societies become larger.  Because the HPHS has grown so successfully over the past years, it’s a great time to put into place more formal SOPs.

In the last message, we reviewed the Executive Committee and its function.  This time we will review the Membership Committee.  Members are the most important element of the HPHS—in fact the mission of the HPHS is to serve its members through educational offerings in the art and science of liver pathology.  Thus, the Membership Committee is of particular importance.  The Committee has a chairperson and 5 members, each who serve for three years.  The start/end times for each are staggered in order to maintain a smooth transition as new members rotate on/off.  The Membership Committee is responsible for reviewing and approving membership applications, including associate members and emeritus members.  Associate membership is extended to individuals still in training programs (residency/fellowship) and lasts for 2 years, renewable as needed.  The Chair of the Committee presents the list of new members at the annual HPHS Business Meeting during the USCAP annual meeting.  The Membership Committee Chair also maintains (working closely with the secretary-treasurer) the full list of all members with their contact information.  Finally, this important committee is also in charge of actively seeking new members for the HPHS—the society grows and thrives by recruiting new members who have an interest in liver pathology.  

Please don’t forget to mark your calendars for the Hans Popper Reception in San Antonio (Saturday night).

Hans Popper Hepatopathology Society Reception
Saturday March 4th
Time: 6:00-8:00 PM
Room H-2093
Hilton Palacio Del Rio
200 S. Alamo St
San Antonio TX 78205
Telephone to hotel front desk 210-222-1400

Michael Torbenson, MD
President, Hans Popper Hepatopathology Society

Wednesday, January 25, 2017

Journal Watch November-December 2016

American Journal of Gastroenterology

Vitamin D is not associated with severity in NAFLD: Results of a paired clinical and gene expression profile analysis
Patel YA, Henao R, Moylan CA, Guy CD, Piercy DL, Diehl AM, Abdelmalek MF. Am J Gastroenterol 2016;111:1591-1598.

Vitamin D deficiency is associated with obesity, sedentary lifestyle, and insulin resistance.  Recent studies have implicated vitamin D in the pathogenesis of NAFLD.  The authors of this study correlated vitamin D levels with clinical, histologic, and gene expression differences in patients with NAFLD.  Vitamin D levels decreased with increased BMI but no differences were seen in vitamin D levels between patients with NAFLD and control patients.  There was no association between vitamin D levels and steatosis, lobular inflammation, ballooning, or overall NAS score.  Interestingly, vitamin D levels increased with increasing fibrosis up to stage 3 but were decreased in cirrhotic patients.  When comparing stage 0-1 to stage 3-4 patients, there only minor differences in expression of genes associated with vitamin D metabolism.


Zhou S, Venkatramani R, Gomulia E, Shillingford N, Wang L. Histopathol 2016; Nov;69(5):822-830

The authors studied the diagnostic and prognostic utility of SALL4 in hepatoblastomas (HB). This marker was present in 100% and 41% respectively of embryonal and fetal components of HB, but not in the small cell or mesenchymal components. Also SALL4 expression correlated with poor overall survival and other prognostic indices.
AIMS: To investigate the expression of spalt-like transcription factor 4 (SALL4), a regulator of embryonal development, in three epithelial components of hepatoblastoma (HB) and the relationship between SALL4 expression levels and patients' clinicopathological features.
METHODS AND RESULTS:  A total of 115 specimens from 79 patients with HB were selected for immunostaining of SALL4. Nuclear staining was semi-quantified using the immunoreactive score (IS; range: 0-12). SALL4 expression was seen in all embryonal components (mean IS = 8.58) and in 41% of fetal components (mean IS = 0.78). No SALL4 expression was seen in either small cell undifferentiated or mesenchymal components of HB. Neither chemotherapy nor metastasis altered SALL4 expression significantly. High SALL4 expression levels were associated significantly with decreased overall survival (OS) (P = 0.004), event-free survival (EFS) (P = 0.003) and the presence of metastasis (P = 0.049) on univariate analysis. Multivariate analysis identified SALL4 as an independent prognostic predictor for OS (P = 0.029).
CONCLUSIONS:  SALL4 is useful for subtyping HB, and high SALL4 expression is associated with decreased survival in HB.

Piotti KC, Yantiss RK, Chen Z, Jessurun J. Histopathol 2016; Dec;69(6):937-942

AIMS:  Serum amyloid A is an acute phase reactant that is produced by hepatocytes in response to either inflammatory or neoplastic conditions. Because inflammatory adenomas produce this protein, serum amyloid A immunohistochemistry has been used in the evaluation of hepatocellular neoplasms. However, studies evaluating the expression of this protein in hepatitis are lacking. The aim of this study was to perform serum amyloid A immunostains on medical liver biopsy specimens of patients with common chronic liver diseases and correlate them with disease activity and stage.
METHODS AND RESULTS:  We performed serum amyloid A immunostains on 160 medical liver biopsies, including 100 cases of hepatitis C virus infection at different stages (20 cases of each) and 20 cases each of hepatitis B viral infection, steatohepatitis and autoimmune hepatitis. The extent and location of staining was recorded and correlated with grade, stage and laboratory values (transaminases, bilirubin and viral load). Data were analyzed using the Cochran-Mantel-Haenszel χ2 test for trend. Serum amyloid A staining was present in 130 (81%) cases and was limited to zone 3 perivenular hepatocytes in 66 (41%). Biopsy specimens with less fibrosis and/or mild portal inflammation showed significantly more staining than those with cirrhosis (P < 0.001), or at least moderate inflammatory activity (P < 0.001). There was no significant association between lobular inflammation (P = 0.06), bilirubin levels or viral load and immunohistochemical staining for serum amyloid A.
CONCLUSIONS:  Our results show that liver biopsy specimens with mildly active chronic hepatitis, early fibrosis and normal serum transaminases show more serum amyloid A immunopositivity compared with cases with more inflammatory activity, fibrosis or transaminitis. These findings indicate that serum amyloid A is expressed primarily in the early phases of disease and might influence progression and/or response to treatment.

Shalaby A, Hajhosseiny R, Zen Y, Davenport M, Quaglia A. Histopathol 2016; Dec;69(6):943-949

Aims: Orientation and digital analysis of the biliary remnants in the resected porta hepatis in infants with biliary atresia.
Methods and results:  Samples were orientated intra-operatively then stained with haematoxylin and eosin and immunostained for cytokeratin 7 (CK7). Sections were then digitized and analysed. Most proximal transected surface area was defined as the porta hepatis area (PHA) and the biliary epithelial area was defined as ‘BEA’. Data are quoted as median (range). Non-parametric statistical comparisons were made as appropriate. P < 0.05 was regarded as significant. Thirty-eight infants underwent surgery [median age 53 (16–120) days]. Eight specimens were excluded from the study due to technical reasons, leaving 30 specimens as the study cohort. Median PHA was 70 (30–133) mm2, median BEA 0.57 (0.07–5.5) mm2 (r = 0.51; P < 0.002). The median BEA/PHA ratio was 9.6 × 10−3 (1.9–104 × 10−3). There was a marked correlation of PHA with plasma γ-glutamyl transpeptidase (r = −0.51; P = 0.001). Both total BEA and the BEA/PHA ratio correlated with alkaline phosphatase (r = −0.35; P = 0.03 and r = −0.47; P = 0.005, respectively). Age at surgery correlated inversely with BEA (r = −0.44; P = 0.01) but not PHA (P = 0.1).
Conclusions: Precise quantification of biliary remnants is possible and correlates with biochemical variables. Values for BEA were associated with and declined demonstrably with increasing age at surgery.

Fujikura K, Fukumoto T, Ajiki T, Otani K, Kanzawa M, Akita M, Kido M, Ku Y, Itoh T, Zen Y. Histopathol 2016; Dec;69(6):950-961.

Aims: The aim of this study was to achieve a better definition of intraductal papillary neoplasms of the bile duct (IPNBs).
Methods and results: Biliary tumours that showed predominantly intraductal papillary growth were provisionally classified as IPNBs (n = 25) and papillary cholangiocarcinomas (n = 27). IPNB was defined as a neoplasm that is confined to the epithelium or is regularly arranged in a high-papillary architecture along thin fibrovascular stalks, whereas the term ‘papillary cholangiocarcinoma’ was used for tumours with more complex papillary structures (e.g. irregular papillary branching or mixed with solid–tubular growth). In our consecutive cohort of biliary neoplasms, 5% were classified as IPNBs, and 10% as papillary cholangiocarcinomas. IPNBs differed from papillary cholangiocarcinomas by less advanced invasion, gross mucin overproduction (72% versus 7%), and their prevalent location (84% of IPNBs in intrahepatic/hilar ducts; 70% of papillary cholangiocarcinomas in extrahepatic ducts). Gastric-type and oncocytic-type tumours were only detected in IPNBs. Expression of mucin core proteins and cytokeratin 20 significantly differed between the two groups. KRAS and GNAS were wild-type genotypes in all but one case of KRAS-mutated IPNB. Patients with IPNB had better recurrence-free survival than those with papillary cholangiocarcinoma (P = 0.007). In multivariate analysis, in which several other prognostic factors (e.g. stromal invasion and lymph node metastasis) were applied, the classification of the two papillary tumours was an independent prognostic factor (P = 0.040).
Conclusions: Given the significant contrast in clinicopathological features between IPNBs and papillary cholangiocarcinomas, it may be more appropriate to use the diagnostic term ‘IPNB’ for selected tumours that show regular papillary growth, separately from papillary cholangiocarcinomas.

Chan AW, Yu S, Yu YH, Tong JH, Wang L, Tin EK, Chong CC, Chan SL, Wong GL, Wong VW, Chan HL, Lai PB, To KF. Histopathol 2016; Dec;69(6):971-984.

Aims: Steatosis in hepatocellular carcinoma (HCC) has been recognized for decades and found most commonly in small, well-differentiated HCC. However, the clinicopathological features and pathogenesis of HCC with steatosis is not well characterized. There are few data concerning whether HCC with steatosis should be regarded a distinct histological variant, steatotic HCC.
Methods and results: A retrospective cohort of 516 patients undergoing curative surgery for primary HCC was recruited. The median follow-up was 45.5 (range: 0.2–166.0) months. Steatotic HCC was defined as HCC with significant steatosis (≥5% of tumour cells). Associations with immunohistochemical expression of fatty acid binding protein-1 (FABP1), sonic hedgehog (SHH) and gene polymorphism of patatin-like phospholipase 3 (PNPLA3) were analysed. Steatotic HCC was found in 21.1% of patients and was associated with higher metabolic risks [diabetes mellitus (36.7% versus 18.2%) and hypertension (44.0% versus 28.7%)], underlying fatty liver (60.6% versus 37.8%), steatohepatitis (30.3% versus 13.0%), smaller tumour size, lower frequency of major vessel (1.8% versus 11.3%) and microvascular invasion (20.2% versus 32.4%), earlier tumour stages and lower serum alpha-fetoprotein. It was associated with developing late tumour relapse (hazard ratio 2.15, P = 0.002) independently of underlying cirrhosis and non-anatomical excision. Steatotic HCC did not differ from HCC without significant steatosis in immunohistochemical expression of FABP1 and SHH and PNPLA3 gene polymorphism.
Conclusion: Steatotic HCC is a common histological variant of HCC with distinct association with underlying fatty liver, steatohepatitis and metabolic risks. Despite more favourable baseline tumour features, it was associated with late tumour relapse.

Walter D, Herrmann E, Winkelmann R, Albert JG, Liese J, Schnitzbauer A, Zeuzem S, Hansmann ML, Peveling-Oberhag J, Hartmann S. Histopathol 2016; Dec;69(6):962-970.

Background and aims: CD15 is expressed by various cancer types; among these are intrahepatic and perihilar cholangiocarcinoma (CCA). The aim of this study was to elucidate CD15 expression in distal CCA as well as in dysplastic biliary tissue and to determine its prognostic significance.
Methods and results: Tissue samples from patients with intrahepatic (iCCA, n = 22), perihilar (pCCA, n = 7) and distal CCA (dCCA, n = 15), who underwent surgical resection in the period from 2010 to 2015 were evaluated for CD15 expression. Tissue of synchronous lymph node metastasis (n = 13), CCA-associated dysplasia (n = 20), dysplasia in intraductal biopsies (n = 10) and benign proliferations (n = 12), as well as inflammatory biliary lesions (n = 28) and non-inflammatory bile ducts (n = 23), were evaluated equally for CD15 expression. CD15 was found to be expressed highly in iCCA (81.8%), pCCA (85.7%), dCCA (73.3%), CCA-associated dysplasia (70.0%), dysplasia in intraductal biopsies (100%) and metastatic tissue (84.6%). CD15 expression was negative in 58 of 64 benign bile duct alterations resulting in an overall sensitivity and specificity of CD15 in CCA of 80.7 and 90.6% patients, respectively. CD15 expression was correlated significantly with a decreased overall survival in patients with CD15-positive CCA associated dysplasia (P = 0.003). However, CD15 expression in the invasive tumour component was not correlated with clinical outcome.
Conclusion: CD15 is a sensitive and specific marker for intraepithelial and invasive neoplasias of the bile duct. Therefore, it can be helpful in the delineation of dysplastic and neoplastic biliary cells from non-neoplastic tissue, which frequently causes a diagnostic problem in indeterminate biliary stricture.

Modern Pathology

Hale G, Liu X, Hu J, Xu Z, Che L, Solomon D, Tsokos C, Shafizadeh N, Chen X, Gill R, Kakar S. Mod Pathol 2016; Nov; 29(11):1370-1380.

The study examines the correlation between glutamine synthetase staining patterns and β-catenin mutations in 15 typical hepatocellular adenomas, 5 atypical hepatocellular neoplasms and 60 hepatocellular carcinomas. Glutamine synthetase staining was classified as: (1) diffuse homogeneous: moderate-to-strong cytoplasmic staining in >90% of lesional cells, without a map-like pattern, (2) diffuse heterogeneous: moderate-to-strong staining in 50-90% of lesional cells, without a map-like pattern, and (3) patchy: moderate-to-strong staining in <50% of lesional cells (often perivascular), or weak staining irrespective of the extent, and all other staining patterns (including negative cases). Sanger sequencing of CTNNB1 exon 3 was performed in all cases. Of hepatocellular tumors with diffuse glutamine synthetase staining (homogeneous or heterogeneous), an exon 3 β-catenin mutation was detected in 33% (2/6) of typical hepatocellular adenoma, 75% (3/4) of atypical hepatocellular neoplasm and 17% (8/47) of hepatocellular carcinomas. An exon 3 mutation was also observed in 15% (2/13) of hepatocellular carcinomas with patchy glutamine synthetase staining. The results show a modest correlation between diffuse glutamine synthetase immunostaining and exon 3 β-catenin mutations in hepatocellular adenoma and hepatocellular carcinoma with discrepancy rates >50% in both hepatocellular adenoma and hepatocellular carcinoma. The interpretation of β-catenin activation based on glutamine synthetase staining should be performed with caution, and the undetermined significance of various glutamine synthetase patterns should be highlighted in pathology reports.

Journal of Hepatology

Solà E, Kerbert A, Verspaget HW, et al. J Hepatol 2016; 65:914-920.

Clinical decompensation of cirrhosis is mainly related to a progressive increase in portal hypertension and circulatory dysfunction. Copeptin is the C-terminal fragment of the vasopressin (AVP) precursor and is secreted from neurohypophysis together with AVP. This prospective study included 321 patients and investigated the level of copeptin in disease progression and prognosis of cirrhosis.  The plasma copeptin level showed a significant correlation with plasma AVP level and endogenous vasoactive systems in cirrhotic patients. Compared to the patients with compensated cirrhosis, the patients with decompensation showed significantly higher plasma copeptin levels. Multivariate analysis revealed plasma copeptin was an independent predictor of development of complications of cirrhosis and 3-months mortality. The data suggests that copeptin is reliable marker for disease progression, decompensation and poor prognosis in patients with cirrhosis.

Pais R, Barritt AS 4th, Calmus Y, Scatton O, Runge T, Lebray P, Poynard T, Ratziu V, Conti F. J Hepatol 2016; 65:1245-1257.

NAFLD has become one of the most frequent cause of chronic liver disease, cryptogenic cirrhosis, and hepatocellular carcinoma, and is the second leading cause of liver transplantation (LT) in the United States. In this review article, the authors discuss the multifaceted impact of NAFLD on liver transplantation and how to optimize the outcome of NAFLD patients undergoing LT. Several key points are raised: patients with NAFLD listed for LT are more often removed from the waiting list because of associated comorbidities and older age; the shortage of liver grafts will increase in the future and the use of fatty liver grafts will require optimization of surgical and preservation techniques; patients with NAFLD are at higher risk of cardiovascular morbidity and mortality following LT; NAFLD recurrence is frequent after LT.

American Journal of Surgical Pathology

Russo P1, Magee JC, Anders RA, Bove KE, Chung C, Cummings OW, Finegold MJ, Finn LS, Kim GE, Lovell MA, Magid MS, Melin-Aldana H, Ranganathan S, Shehata BM, Wang LL, White FV, Chen Z, Spino C; Childhood Liver Disease Research Network (ChiLDReN). Am J Surg Pathol 2016; Dec;40(12):1601-1615.

Given variability in data and limitation to single institution cohorts in previous studies, the goal of this project was to better define which histologic features are the strongest predictors of biliary atresia (BA) and identify parameters that may be of prognostic significance.  This study utilized data and slide review from cholestatic infants that were prospectively enrolled in the multicenter ChiLDReN network to determine which histologic features: (1) could distinguish BA from non-BA causes of cholestasis [N=227]; (2) varied with respect to clinical parameters (including age); and (3) correlated with clinical outcome in BA patients after hepatoportoenterostomy (HPE) [N=316].  Except for patient age, central review pathologists were blinded to all clinical information and scored 26 histologic features based on consensus.  Bile plugs in portal tracts and portal tract edema, when seen without bile duct paucity or features of idiopathic neonatal hepatitis (giant cell transformation and extramedullary hematopoiesis), were most associated with BA (diagnostic accuracy 90%).  With regard to clinical outcomes, elevated bilirubin 6 months after HPE was associated with older age, but showed no strong correlation with histologic changes.  Advanced fibrosis (Batts-Ludwig stage ≥3 fibrosis), ductal plate malformation, bile duct injury, older age at HPE, and elevated INR were associated with an increased risk for transplantation.  In contrast to previous literature, this study found that age was not a significant factor in assigning the biopsy to the correct category of disease (BA vs. non-BA), and that there was substantial variability in the range of histologic changes in cases of BA that were clinically well-characterized.  Common causes of misinterpretation of findings in BA cases as non-BA included an overestimation of bile duct paucity and underestimation of portal tract edema as well as known mimickers of BA (cystic fibrosis and α-1 antitrypsin deficiency) in needle biopsies.

Archives of Pathology and Laboratory Medicine

Ainechi S, Lee H. Arch Pathol Lab Med 2016; Nov;140(11):1285-1289.

This resident short review summarizes current terminology and disease concepts for precancerous lesions of the biliary tract.  Normal biliary tract histology, categories and features of biliary neoplasia (biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, intraductal tubular neoplasm, mucinous cystic neoplasm, differences in immunophenotype), geographic differences in disease incidence and risk factors for biliary neoplasia are discussed in this manuscript.


Happaerts S, Foucault A, Billiard JS, Nguyen B, Vandenbroucke-Menu F. Hepatol 2016; 64(5): 1800-1802.

The authors report a case of a 27 year-old woman with a past medical history of tetralogy of Fallot and Abernathy malformation (congenital extrahepatic portosystemic shunt), who had a 22 cm combined hepatocellular-cholangiocarcinoma (HCC-CC) resected.  Non-neoplastic tissue adjacent to the carcinoma showed FNH-like reaction, consistent with the pre-operative imaging studies which suggested nodular regenerative hyperplasia, FNH, and FNH-like lesions in addition to the carcinoma. Such lesions, including hepatocellular carcinoma (HCC), have been reported in the past, but this is the first report of HCC-CC in the setting of Abernathy malformation. Of particular interest is a 2011 paper referenced by the authors, which describes in detail the various histologic findings seen in Abernathy malformation. These include absence of portal veins in small portal tracts, hypoplastic portal veins in larger portal tracts, lobular unpaired arterioles, hepatic artery hypertrophy, and nodular regenerative hyperplasia, all changes which likely reflect the absence of a portal venous system with compensatory hepatic artery buffer response.

Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C, Luciani A, Zafrani ES, Laurent A, Azoulay D, Lafdil F, Pawlotsky JM. Hepatol 2016; 64(6): 2038-2046.

The authors investigated the PD-L1 status of 217 hepatocellular carcinomas. PD-L1 expression by neoplastic cells was associated with elevated serum AFP, satellite nodules, lymphovascular space invasion, poor differentiation, and CK19 expression. PD-L1 expression by inflammatory cells associated with the tumor was associated with elevated serum AFP, lymphovascular space invasion, poor differentiation, and lymphoepithelial histologic subtype of HCC. No association was seen with B-catenin nuclear staining or with diffuse glutamine synthetase expression.

Rebouissou S, Franconi A, Calderaro J, Letouzé E, Imbeaud S, Pilati C, Nault JC, Couchy G, Laurent A, Balabaud C, Bioulac-Sage P, Zucman-Rossi J. Hepatol 2016; 64(6):2047-2061.

This paper is by the French group which has reported much of the data on hepatocellular adenoma (HA) subtypes. In this study, the authors investigated B-catenin mutation status and B-catenin activity levels on fresh frozen tissue from 220 HAs, 373 HCCs, and 17 borderline HA/HCC lesions. Overall B-catenin activity was higher in HCCs than HAs, and this was related to mutation type. In their HAs, they divided the B-catenin activation into three categories, which was related to specific mutations:
1) Weak activation: S45, K335, and N387 mutations.
2) Moderate activation: T41 mutations.
3) High activation: Exon 3 deletions (most commonly seen in borderline lesions) and D32-S37 mutations.
Tumors with highly active mutations demonstrated strong and homogenous GS staining. Weak mutants demonstrated heterogenous and patchy GS staining. Also, highly active mutants typically showed nuclear B-catenin IHC staining, whereas weakly active mutants did not. Thus, weak mutants would not show typical high risk IHC staining, whereas highly active mutants would. S45, however, is a notable exception which was a mutation seen in both HAs and HCCs. Although this mutation could be seen in malignancy, particularly if duplicated, GS IHC staining would not pick it up. In HCCs with weakly active mutations, the authors demonstrated B-catenin to be activated through additional events, such as loss of heterozygosity (LOH) at 3p or a second B-catenin mutation. Overall, the study is the largest to date correlating B-catenin mutation status with GS IHC staining pattern.

Prepared by:
Editor, Daniela Allende, MD, Cleveland Clinic
Oyedele Adeyi, MD; University of Toronto
Wenqing Cao, MD; New York University
Cindy Guy, MD; Duke 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