Tuesday, November 27, 2018

HPHS Journal Watch: September / October 2018


Nault JC, Couchy G, Caruso S, et al. Hepatology 2018; 68(3): 964-976.

Argininosuccinate Synthase 1 (ASS1) has been proposed as a marker for high risk of hemorrhage in hepatocellular adenomas (HCA). The authors studied 408 HCA and found ASS1 overexpression was significantly associated with sonic hedgehog HCA (shHCA) compared to other HCA molecular subgroups. ASS1 expression was found in the periportal region and was maintained in shHCA, but downregulated in all other HCA subtypes. ASS1 expression was not associated with specific clinical features.

Graham RP, Lackner C, Terracciano L, et al. Hepatology 2018; 68(4): 1441-1447.
Almost all fibrolamellar carcinomas have a heterozygous 400-kb deletion that leads to the fusion of DNAJB1 and PRKACA. The resulting fusion transcript activates protein kinase A by dysregulation of its catalytic portion. In contrast, PRKAR1A encodes one of the regulatory subunits of protein kinase A. Because the loss of function of PRKAR1A could also lead to protein kinase A activation, and because PRKAR1A mutations underlie the Carney complex, the authors searched their archives for liver tumors in individuals with Carney complex. They identified 3 cases of fibrolamellar carcinoma in Carney complex patients with typical morphologic and immunohistochemical findings. FISH was negative for PRKACA rearrangements, but as hypothesized, 2 of 2 cases with successful sequencing identified pathogenic mutations in PRKAR1A. All 3 cases were negative for PRKAR1A protein expression. The authors thus report two novel and interesting findings: 1) fibrolamellar carcinoma is part of the Carney complex and 2) rare cases of fibrolamellar carcinoma may be due to PRKAR1A mutations rather than the classic gene fusion. 


Hirschfield GM, Dyson JK, Alexander GJM, et al. Gut 2018;67:1568-1594.

This is a very helpful, well referenced,  review of PBC with a very strong section on the role of liver biopsy which includes a review of the histological changes (which emphasizes how focal the pathological changes can be) and brief, but helpful,   critical review of the available scoring systems (including Nakanuma) .
The recommendations with reference of the role of liver biopsy are:
  • Recommendation 5 “We recommend liver biopsy is not usually required in the diagnosis of PBC or for monitoring of disease progression unless its use is within the context of clinical trials. (Strong; High).”
  • Recommendation 7 “We recommend that, in the presence of cholestatic serum liver tests but an absence of diagnostic autoantibodies, the confirmation of PBC requires a liver biopsy. (Strong; Moderate).”
  • Recommendation 8 “We recommend that liver biopsy can be considered if there is a clinical suspicion of co-existing disease (eg, additional injury from non-alcoholic fatty liver disease (NAFLD), viral hepatitis or alcohol use) or the presence of overlapping autoimmune hepatitis, either at diagnosis or during follow-up. (Strong; Moderate).”

Clinical Gastroenterology and Hepatology

Ajmera V, Belt P, Wilson LA, et al.  Clin Gastroenterol Hepatol 2018, 16(9):1511-1520.

Modest alcohol use has a beneficial impact on mortality in general by decreasing cardiovascular disease. As cardiovascular death is the most common cause of death for nonalcoholic fatty liver disease, it is unclear whether or not modest alcohol use would be detrimental or beneficial. This longitudinal cohort study evaluated paired liver biopsies of patients from the nonalcoholic steatohepatitis clinical research network. It sought to compare modest alcohol use (n=168) to abstinence (n=117) on liver histology over time. Modest drinking was defined as monthly or less frequent drinking, with 1 or 2 drinks on a drinking day. More improvement of steatosis was seen in nondrinkers compared to the modest drinking group, but changes in inflammation, ballooned hepatocytes, and fibrosis stage was not statistically significant. Fourteen nondrinkers drank modestly on follow up and 55 modest drinkers stopped drinking. Those who stopped drinking were more likely to have resolution of NASH, whereas modest drinkers who continued were significantly less likely to have resolution of NASH. This suggests that counseling against alcohol may be beneficial for advanced fatty liver disease patients.


Burt AD, Alves V, Bedossa P, et al. Histopathology 2018;73(3):369-385.

The International Collaboration on Cancer Reporting (ICCR) is an alliance with the aim of developing an evidence‐based reporting data set for each cancer site. They describe the development of a cancer data set for the reporting of malignant liver tumours and present the ‘required’ and ‘recommended’ elements to be included in the report. This data set incorporates definitions and classifications in the most recent World Health Organization (WHO) publication on hepatic malignancies (4th edition) and the recently published tumour–node–metastasis (TNM) 8th ed. staging system. The required 11 elements are agreed unanimously by the panel to be essential for histological diagnosis, clinical management, staging and/or prognosis. The recommended 9 elements are non‐mandatory and defined as clinically important and recommended as good practice, and should ideally be included in the report, but which are not yet validated by evidence or used regularly in patient management. ICCR data sets are designed to be as concise as possible to encourage uptake, facilitate future translation, limit the burden on reporting pathologists and avoid jurisdictional pitfalls through the inclusion of non‐essential information. The ICCR is also supportive of the inclusion of additional free text or narrative where it is important to ensure clarification or nuance of the information provided in the data set report.

Rudini N, Novello C, Destro A, et al. Histopathology. 2018;73(4):601-611.

Nodule-in-nodule (N/N) hepatocellular carcinoma (HCC) is a convincing proof of multistep hepatocarcinogenesis. Here, an inner HCC develops within an outer, more differentiated, tumour, which can be rapidly taken over by the former so that N/N HCC is rarely detected.
The authors report the phenotypic and molecular profile of 10 resected N/N HCCs, arising in cirrhotic background and characterized: (i) as outer lesions by early (n = 3) and G1 (n = 7) HCC; (ii) as inner lesions by G1 (n = 3) and G2 (n = 7) HCC. They studied vascular (CD34 and endocan), hepatocellular (VEGF, GS, GPC3, HSP70 and CHC) and molecular (TERT promoter and β-catenin) changes taking place from the outer neoplastic compartment to the inner neoplastic compartment (INC). A diffuse pattern of CD34+ capillarized vessels and focal endocan immunoreactivity were major distinctive features acquired in the INC; VEGF immunoreactivity was inversely related to CD34 staining. A gain in the number of cells immunoreactive for GPC3, HSP70, and CHC, but not of GS-immunoreactive cells, also occurred in the INC. TERT promoter mutations were seen in half of the cases in both compartments, whereas β-catenin mutations were more rarely detectable. The authors conclude that major phenotypic changes take place in the INC of N/N HCC. TERT promoter mutations take place frequently and very early, and, in contrast to β-catenin mutations, do not appear to be acquired during N/N growth. These findings suggest that inner nodules represent a step further along the pathway of tumour progression, in contrast to earlier, simply initiated, lesions, and that complete neovascularization predicts a change in HCC biology.

Liver transplantation 

Welling TH, Eddinger K, Carrier K, et al. Liver Transplantation. 2018;24(9):1233-1242.

The authors aimed to define HCC-specific prognostic factors affecting recurrence in a contemporary, multicenter cohort of HCC patients undergoing OLT and specifically whether local-regional therapies limited recurrence. Their cohort included 441 patients undergoing OLT for HCC at 3 major transplant centers from 2008 to 2013. "Bridging" or "downstaging" therapy was used in 238 (54%) patients with transarterial chemoembolization (TACE) being used in 170 (71%) of treated patients. The survival rate after OLT was 88% and 78% at 1 and 3 years, respectively, with HCC recurrence (28% of deaths) significantly increasing the mortality rate (hazard ratio [HR], 19.87; P < 0.001). Tumor size, not tumor number, either at presentation or on explant independently predicted HCC recurrence (HR, 1.36 and 1.73, respectively; P < 0.05) with a threshold effect noted at 4.0-cm size. Local-regional therapy (TACE) reduced HCC recurrence by 64% when adjusting for presenting tumor size (HR, 0.36; P < 0.05). Explant tumor size and microvascular invasion predicted mortality (HR, 1.19 and 1.51, respectively; P < 0.05) and pathologic response to therapy (TACE or radiofrequency ablation) significantly decreased explant tumor size (0.56-1.62 cm diameter reduction; P < 0.05). The authors concluded that HCC tumor size at presentation or explant is the most important predictor for HCC recurrence after OLT. Local-regional therapy to achieve a pathologic response (decreasing tumor size) can limit HCC recurrences after OLT.

American Journal of Surgical Pathology

Joseph NM, Brunt EM, Marginean C, et al. AJSP 2018; 42(9):1201-1207.

Hepatic small vessel neoplasm (HSVN) is rare and considered a benign or low-grade neoplasm. HSVN shows no cytologic atypia, but because of the histologic density of its thin-walled vascular spaces and propensity to show an infiltrative border, it can be mistaken for angiosarcoma (AS). These investigators previously identified GNAQ mutations in 2 HSVNs, but sought to expand the understanding of its molecular pathogenesis in this current study. 8 HSVN, 7 cavernous hemangioma (CH), and 4 variant lesions (VL) that had features of both CH and HSVN were evaluated. All 8 HSVN showed either an activating or missense mutation in GNAQ or GNA14; 2 VL also showed GNAQ mutations and all 6 CH were negative for known pathogenic GNAQ mutations. GNAQ, GNA11, and GNA14 mutations have been shown in a number of vascular malformations and benign neoplasms, but not in AS. This study supports the belief that HSVN is indolent or benign. For clinical application, molecular analysis may be helpful in challenging cases to differentiate HSVN from AS.

Swanson EA, March JK, Clayton F, et al. AJSP 2018; 42(10):1346-1352.

In recent years, a number of publications have described Cystoisospora belli infection in gallbladder specimens occurring in immunocompetent hosts. However, studies to date have been based on morphologic exam on H&E and histochemical stains that show cytoplasmic inclusions that are consistent with C. belli. The investigators gathered 8 cholecystectomy cases in which a diagnosis of C. belli infection had been suggested and performed PCR testing for C. belli and also performed a number of histochemical stains to better characterize the inclusions. 3 small bowel biopsies from patients with an established diagnosis of AIDS, diarrhea, and C. belli infection were used as positive controls and normal small bowel biopsies were used as negative controls. Molecular testing showed amplification of a known internal transcribed spacer in the C. belli ribosomal gene cluster in all 3 positive controls, but none of the 8 gallbladder specimens showed amplification of the same template. Furthermore, Periodic-acid-Schiff with diastase (PAS-D) and Grocott-Gomori’s methenamine silver (GMS) showed a diffuse pattern of staining in the cytoplasmic inclusions in the gallbladder specimens while PAS highlighted capsular outlines and punctate internal structures of parasite forms of C. belli and GMS was negative in the small bowel biopsies. The findings from this study indicate that these epithelial inclusions may represent a mimic rather than true parasite forms of C. belli, especially in gallbladder specimens.

Sigel CS, Drill E, Zhou Y, et al. AJSP 2018; 42(10):1334-1345.

A recent study from Japan proposed classifying intrahepatic cholangiocarcinoma (ICC) into two subtypes, large duct (LD) and small duct (SD) ICC, given potentially different clinicopathologic behavior. The investigators in the present study sought to further delineate ICC into 4 subtypes, explore immunophenotypic expression patterns, and correlate pathologic features to clinical outcomes in a retrospective patient cohort from a major North American referral center. ICC subtypes included: large duct (LD), predominantly tubular SD, predominantly anastomosing/cholangiolar SD, and indeterminate. A number of immunostains as well as albumin RNA in situ hybridization (AR ISH) were also evaluated on tissue microarrays and select whole tissue sections. A very detailed analysis was performed. SD subtype was the most common (84%). LD was associated with primary sclerosing cholangitis, mucin production, and perineural invasion. AR ISH was positive in 71% of SD and 18% of LD ICC. No significant difference in disease-specific or recurrence-free survival was observed among ICC subtypes. Therefore, reporting ICC subtypes does not appear to be clinically relevant at this time, but further studies are needed.

Archives of Pathology and Laboratory Medicine

Lin CC, Yang HM. Arch Pathol Lab Med. 2018;142(9):1141-1145.

This is a short review on fibrolamellar carcinoma that includes clinicopathologic features, molecular genetics, differential diagnosis, and outcome information.

Schechter S, Lamps L. Arch Pathol Lab Med. 2018;142(10):1191-1195.

This is a review on EBV hepatitis with a focus on microscopic features and ancillary testing and a brief discussion of the differential diagnosis.

Ettel MG, Appelman HD. Arch Pathol Lab Med. 2018;142(10):1186-1190.

This is a special article discussing an approach to liver biopsies that are performed on patients with liver enzyme abnormalities, but with minimal changes on microscopic exam. The authors briefly review literature on this topic and offer their opinion. 

Human Pathology

Zhao CL, Hui Y, Wang L, et al. Hum Pathol. 2018 Oct;80:76-81.

Alanine-glyoxlate aminotransferase 1 (AGXT1) is exclusively expressed in the liver.  This study assesses the utility of AGXT1 immunohistochemistry and compares the use of this marker with arginase-1, an established marker with relatively high sensitivity and specificity. Immunostains for AGXT1 and arginase-1 were performed on tissue microarrays of 139 HCCs and 374 gastrointestinal and non-gastrointestinal carcinomas. Sensitivities of AGXT1 for all HCCs were 90.0% compared to 87.8% for arginase-1. Sensitivity increased to 92.1% when the presence of either marker was considered positive. With the exception of 5 cases of cholangiocarcinoma, both AGXT1 and arginase-1 were negative in all non-HCC tumors with specificities of 98.7%. The authors’ data support the consideration of AGXT1 as a novel hepatocellular marker with equally high specificity and slightly higher sensitivity as compared to arginase-1.

Chen Q, Wang M, Wang M et al. Hum Pathol. 2018;80:130-137.

The authors retrospectively reviewed over 1000 HCCs and identified 37 small HCCs.   This study describes morphologic features that may aid the pathologist in identifying such HCCs. The authors proposed that in the background of chronic hepatitis and cirrhosis, histologic features including crowdedness of hepatocytic trabeculae and the expansile invasive growth pattern may strong evidence for the diagnoses of small HCC.


Asrani SK, Kouznetsova M, Ogola G et al. Gastroenterology 2018;155(3):719-729.

Chronic liver disease (CLD) is a common and expensive condition, and studies of CLD-related hospitalizations have underestimated the true burden of disease. The authors analyzed data from a large, diverse health care system to compare time trends in CLD-related hospitalizations with those in congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD).  Data on hospitalizations related to CLD (n = 27,783), CHF (n = 60,415), and COPD (n = 34,199) were collected. Annual hospitalization rates (per 100,000) and compared hospital course, inpatient mortality, ancillary services, and readmissions were calculated. Patients with CLD, compared with selected other chronic diseases, had increasing rates of hospitalization, longer hospital stays, more readmissions, and, despite these adverse outcomes, less access to postacute care. Disease management models for CLD are greatly needed to manage the anticipated increase in hospitalizations for CLD.

Kim D, Li AA, Gadiparthi C et al.  Gastroenterology. 2018;155(4):1154-1163.

The authors studied trends in age-standardized mortality of chronic liver diseases in adults at least 20 years old in the United States from 2007 through 2016.  Data was collected from the US Census and National Center for Health Statistics mortality records and identified individuals with HCV infection, alcoholic liver disease (ALD), nonalcoholic fatty liver disease, or hepatitis B virus infection using ICD-10 codes.  In this population-based analysis of chronic liver disease mortality in the United States, the decrease in HCV-related mortality coincided with the introduction of direct-acting antiviral therapies, whereas mortality from ALD and nonalcoholic fatty liver disease increased during the same period. Minorities in the United States have disproportionately higher mortality related to chronic liver disease. 

Modern Pathology

Wang B, Sun Y, Zhou J, et al. Mod Pathol. 2018;31(10):1567-1577.

Hepatitis B (HBV)-related fibrosis can be reversed after effective antiviral therapy. However, detailed changes of collagen characteristics during fibrosis regression remain unclear. Paired biopsy from chronic HBV patients were imaged with second harmonic generation/two photon excitation fluorescence (SHG/TPEF)-based microscopy. Four different outcomes after 78-week antiviral therapy were identified: fast reverse (9%), reverse (63%), stable (15%), or progress (13%) on fibrosis. The most prominent fibrosis reversion occurred in the “septal” area, followed by the “fibrillar” area, but not in the “portal” area (P < 0.001). Four parameters correlated with fibrosis reversion: average width, maximum width, number of fibers, and number of cross-link fibers (P < 0.001). Average septal width was independently associated with regressive septa (odds ratio (OR) = 5.22, 95% confidence interval (CI): 4.17–6.53; P < 0.001), with an AUROC of 0.96 (95% CI: 0.95–0.97).

Journal of Gastroenterology and Hepatology

Wang Q, Wang G, Wang Y, et al. J Gastroenterol Hepatol 2018; 33: 1617-1625.

The mammalian AlkB homolog protein family has been reported to promote tumor cell invasion and metastasis of human cancer. They investigated expression status and clinical significance of AlkB homolog 3 (ALKBH3) in hepatocellular carcinoma (HCC). They found that high expression of ALKBH3 in HC Cis correlated with poor disease free and overall survival.

Hamoir C, de Vos M, Clinckart F, et al. J Gastroenterol Hepatol. 2018;33(10):1695.

This is a case report of drug induced cholangiopathy. Even though the pathology findings are limited, the article may raise awareness about this possibility. 

Journal of Hepatology

Londoño MC, Souza LN, Lozano JJ, et al. J Hepatol. 2018 Sep;69(3):626-634.

Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies, the pathogenesis remains unclear. All liver recipients, >10 years post-transplant, were screened and those with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Transcriptome profiling was performed on RNA extracted from 49/67 biopsies employing a whole genome next generation sequencing platform. The most frequent histological abnormality was portal inflammation with different degrees of fibrosis (45 biopsies, 67%). Two modules of 102 and 425 co-expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. The authors concluded that a large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients' liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage.

Prepared by (in alphabetical order):
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; Mayo Clinic, Rochester
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Maria Westerhoff MD; University of Michigan
Eric Yee MD; University of Arkansas for Medical Sciences

Thursday, November 15, 2018

Steatohepatitis Survey

Dear HPHS members,

There has been a good response to the survey, but we would like to obtain more responses to make sure that the results are representative of the practices of our members.

The date of the survey has been extended till Wed, Nov 21. Please send your response if not already submitted.

Click HERE to take survey.

Sanjay Kakar
(on behalf of the HPHS Executive Committee)

Friday, November 2, 2018

President's Message October 2018

Dear Friends and Fellow Hepatophiles,

The Society has grown in recent years and we currently have more than 100 members. The updated website and online payment of dues has facilitated this process. I would like to highlight the role played by the Membership Committee in the growth of the Society. The committee has been in the forefront in welcoming members at the Hans Popper reception, reaching out to non-members to join the society, and to current members to renew the membership. This effort was spearheaded by Dr. Larry Burgart, when the first Hans Popper reception was held. In the last 3 years, Dr. Dhanpat Jain has been the committee chair and has done a stellar job along with 4 committee members in streamlining the functioning of the membership committee. If you have any suggestions regarding membership, please send it to the Membership Committee.

The Society had conducted a survey last year about the practice of using special stains in liver biopsies. Another survey has been sent to the members to determine the practice characteristics of assessment of fatty liver disease in liver biopsies. The goal is increase awareness among members about the spectrum of assessing various features of fatty liver disease, which can help enable improvements in practice. Please complete the survey and send by Nov 5, 2018. The results will be shared with the members and highlighted at the Hans Popper reception at the 2019 USCAP meeting.
Continue your active participation in the Society by volunteering for a committee, contributing to case of the month and by sending your feedback. Best wishes for the forthcoming holiday season.

Sanjay Kakar, MD
President, Hans Popper Hepatopathology Society

Interesting Case: October 2018

Case contributed by:
Suntrea Hammer, MD, Assistant Professor, University of Texas Southwestern Medical Center, Dallas, TX

Clinical History
A 41-year-old woman with a history of interstitial lung disease, obesity, and polysubstance abuse presented with mildly, but persistently elevated transaminases (AST 53, ALT 38) and mild thrombocytopenia (113,000/uL).

Abdominal ultrasound demonstrated massive hepatosplenomegaly with normal hepatic contours and hepatopetal flow.
Chest CT revealed bilateral upper lobe pulmonary fibrosis concerning for sarcoidosis, infection, or hypersensitivity pneumonitis. There was also pulmonary artery enlargement, consistent with pulmonary arterial hypertension.

Figure 1: H&E 20x

Figure 2: Trichrome 20x
Figure 3: H&E 10x

Figure 4: H&E 40x

Figure 5: H&E 40x polarized light microscopy

Liver Biopsy Findings
The liver biopsy has mild central zone and sinusoidal dilatation (Figure 1) with delicate perisinusoidal fibrosis on trichrome stain (Figure 2), consistent with the patient’s history of pulmonary hypertension. There is minimal macrovesicular steatosis and no significant lobular inflammation (Figure 3). The portal tracts are remarkable for a prominent histiocytes with a pale gray, grainy cytoplasm and a wrinkled “tissue paper” appearance (Figure 4). The histiocytes are illuminated on polarization demonstrating polarizable crystalline material (Figure 5).

Talc related portal histiocytosis in an intravenous drug abuser
Mild congestive hepatopathy secondary to pulmonary hypertension

Major Learning Points
  • Talc presents in the liver as polarizable, needle-shaped crystals within portal macrophages. Granulomata are rare, unlike the reactions seen in the lung.
  • Talc histiocytosis can present along-side chronic viral hepatitis or congestive hepatopathy in patients with concomitant lung related injuries.
  • The presence of talc alone is not reported to lead to chronic liver injury or fibrosis, and the talc may persist long after drug use has ceased.

Talc is an insoluble crystal present in many pharmaceuticals as a “filler” substance. When these pharmaceuticals are ground down for intravenous injection, the talc particles are distributed around the body, most commonly in the lung, but also in the liver in as many as 63% of users (1). [i]
Unlike cases of pulmonary deposition, talc deposition in the liver is devoid of giant cells and well-formed granulomas. Typical talc deposits are seen as infiltrates of hypertrophied macrophages with gray cytoplasm and indistinct cytoplasmic crystals within the portal tracts, and occasionally, in Kupffer cells.[ii] These infiltrates can be associated with inflammatory infiltrates and fibrosis, usually in the setting of chronic viral hepatitis. In this case, the patient had talc induced pulmonary fibrosis, which led to pulmonary hypertension and right heart dysfunction, the sequela of which can be identified in the liver as vascular outflow obstruction.
The histologic features of talc induced histiocytosis are subtle and can easily be mistaken for debris laden macrophages. Unlike classic debris laden macrophages, the cytoplasm has a “wrinkled tissue paper” quality, which suggests the presence of cytoplasmic crystals. These differ from the polarizable crystalline deposits in porphyria, which demonstrate a “Maltese cross” pattern.[iii] The cytoplasm in glycogen storage diseases can also take on a “wrinkled tissue paper” quality, but this will be primarily within hepatocytes rather than histiocytes.iii 

[i] Allaire GS, Goodman ZD, Ishak KG, Rabin L. Talc in liver tissue of intravenous drug abusers with chronic hepatitis. A comparative study. Am J Clin Pathol. 1989 Nov;92(5):583-8.
[ii] Kringsholm B, Christoffersen P. The nature and the occurrence of birefringent material in different organs in fatal drug addiction. Forensic Sci Int. 1987 May-Jun;34(1-2):53-62.
[iii] Burt A, Portmann B, Ferrell L. MacSween’s Pathology of the Liver. 6th edition. Churchill Livingston Elsevier; 2012. Chapter 4, Genetic and Metabolic Diseases.

Monday, September 24, 2018

HPHS Journal Watch: July/August 2018

Advances in Anatomic Pathology

An Update on the Clinicopathologic Features and Pathologic Diagnosis of Hepatitis E in Liver Specimens.
Lenggenhager D,  Weber A. Adv Anat Pathol 2018;25:273–281.

This review paper highlights how to diagnose hepatitis E (HEV) on liver specimens. Once thought to be a self-limiting waterborne infection restricted to developing countries where it had its worst impact on pregnant women, it has become clear for nearly a decade that HEV is more common in industrialized countries than previously known. The seroprevalence is 30% in France and up to 21% in the US. Molecular detection of HEV RNA in the blood is over a short viremic period of about 3 weeks. In stool samples, the virus is detectable for an additional 2 weeks. Molecular detection is more robust than antibody-based serological testing. Acute HEV infection can be in the typical acute hepatitis pattern. The cholestatic pattern can show swollen hepatocytes, rosette formation and bilirubinostasis. Immunocompromised patients may get chronic HEV infection with rapid progression to cirrhosis. Chronic HEV can look similar to those of chronic viral HBV or HCV. Ancillary tools are necessary to help make the diagnosis given the nonspecific and overlapping morphologic histologic features. PCR targeting the ORF2 and 3 gene region of the virus can be done on formalin-fixed paraffin embedded tissues. In situ RNA testing is specific but less sensitive than PCR. Immunohistochemistry using ORF2 antibody can be useful particularly in immunocompromised patients.

Clinical Gastroenterology and Hepatology

Nonalcoholic Fatty Liver Disease Associates With Increased Overall Mortality and Death From Cancer, Cardiovascular Disease, and Liver Disease in Women but Not Men.
Hwang YC, Ahn HY, Park SW, Park CY. Clin Gastroenterol Hepatol 2018;16:1131–1137.

Using a large health study database of 318,224 people from Korea, followed for a median of 5.7 years, the causes of mortality were identified in subjects with NAFLD. The prevalence of NAFLD determined by ultrasound was 26%. The cumulative mortality rate was 0.51%, with cancer being the highest cause of death. In men, having NAFLD at baseline was not associated with overall cardiovascular or liver associated death. Women with NAFLD at baseline had higher cancer related and liver related mortality. Having liver fibrosis had an additional risk of death compared to NAFLD alone in women as well. In men, neither obesity nor NAFLD alone was associated with cancer-related mortality. Cardiovascular-related mortality was increased in men who had either obesity or NAFLD alone. In women, having either obesity or NAFLD alone was associated with increased overall and cancer related mortality, although the combination of the 2 conditions did not confer additional predictive power for mortality. In women, cardiovascular and liver related mortality was increased when they had both obesity and NAFLD. The study concludes that the impact of NAFLD appears stronger in women than in men, with NAFLD associating more closely with obesity metabolic syndrome and inflammation in women than in men, which may explain the higher mortality rate.

High Prevalence of Liver Fibrosis Among European Adults With Unknown Liver Disease: A Population-Based Study.
Caballería L, Pera G, Arteaga I, et al. Clin Gastroenterol Hepatol 2018;16:1138–1145.
This population-based, cross-sectional study investigated the prevalence of liver fibrosis as evaluated by transient elastography using Fibroscan with M probe. Three thousand fourteen participants were randomly chosen from a total of 162,950 subjects between 18-75 years. Those with a history of liver disease were excluded. In 92 subjects, a liver biopsy was performed and assessed by 2 liver pathologists blinded to the liver stiffness measurement. Risk factors associated with increased liver stiffness included male gender, abdominal obesity, type 2 diabetes, serum glucose level, triglyceride levels, and increased AST or ALT levels. Comparing biopsy to liver stiffness measurement, patients with F0 to F1 had measurement of 8.4, whereas those with F4 had a measurement of 30.8kPa. Per the table listed in the article, 53% of those with F0 had liver stiffness measurement of greater than 8.0kPa. The authors state that using a cutoff of >6.8kPa, 32% of the the patients had significant liver fibrosis, but using a cutoff of >9.0 kPa, 65% of the patients had significant liver fibrosis (defined by F1-F4). This gave a sensitivity of 93%, specificity of 78%, and predictive accuracy of 83%. They propose a screening algorithm that starts with a detailed medical history identifying risk factors for liver fibrosis, followed by calculating fatty liver index, and then screening with transient elastography for only those with risk factors and a fatty liver index >60. They suggest that transient elastography can be useful for screening for liver fibrosis in the community.


Hepatic elastin content is predictive of adverse outcome in advanced fibrotic liver disease.
Kendall TJ, Dolman GE, Duff CM, et al. Histopathol 2018;73(1):90-100.

Elastin is an extracellular matrix (ECM) protein conferring elastic recoil to tissues. The aim of this study was to determine if elastin content in needle core native liver biopsies was predictive of clinical outcome in patients with chronic hepatitis C virus-related chronic liver disease. The authors evaluated elastin contents in liver biopsies by image analysis and correlated it with outcome in patients with advanced (Ishak stage ≥5) chronic hepatitis C virus-related chronic liver disease. Elastin content (but not absolute scar content or Ishak stage) was predictive for future clinical outcomes. In a cohort of patients without sustained virological response, the median hepatic elastin content was 3.4%, and 17 patients (57%) progressed to a liver-related clinical outcome; 11 of the 15 patients (73%) with a hepatic elastin content of >3.4% progressed to a clinical outcome, as compared with only six of 15 (40%) with an elastin content of <3.4%. The difference in time to outcome was significant. This study describes a simple and reproducible method for elastin quantification in liver biopsies that provides potentially valuable prognostic information to inform clinical management.

Hepatic angiomyolipoma: mutation analysis and immunohistochemical pitfalls in diagnosis.
Yan Z, Grenert JP, Joseph NM, et al. Histopathol 2018;73(1):101-108.

Hepatic angiomyolipoma (AML) often shows epithelioid morphology with inconspicuous fat and can mimic hepatocellular adenoma (HCA) or carcinoma (HCC). This study examines the expression of commonly used markers for HCA or HCC in hepatic AML and highlights pitfalls in diagnosis. 16 resected cases of AML were stained with reticulin, LFABP, glutamine synthetase (GS), beta catenin, CD68 and CD117.  Sanger sequencing of exon 3 of CTNNB1 and next-generation sequencing (NGS) was also performed. High-risk histological features were often present in tumors with benign outcome: marked atypia (19%), mitoses (20%) and necrosis (33%). GS staining (≥10% of tumor) was seen in epithelioid components in 13 (87%) cases, and was diffuse (>50% of tumor) in six (40%) cases. LFABP staining or nuclear beta catenin staining was not seen in any case. Sanger sequencing and NGS did not reveal CTNNB1 mutation in any tested case. NGS demonstrated TSC2 mutations in all five cases tested. The authors conclude that absence of LFABP and presence of fat can be mistaken for HNF1a-inactivated HCA. Diffuse GS staining can be mistaken for b-catenin-activated HCA or HCC. Diffuse GS expression is not related to CTNNB1 mutation. All tested cases showed TSC2 mutation, supporting this as the driving genetic event for hepatic AML.

Hepatic granulomas: a 17-year single tertiary centre experience.
Gaspar R, Andrade P, Silva M, et al. Histopathol 2018;73(2):240-246.

The reported incidence of granulomas in liver biopsies ranges from 1 to 15%. The authors assess the clinical relevance, presenting features and underlying aetiology in a non-transplant, tertiary referral center. During the 17-year study period (January 1998–December 2014), 9374 biopsies were performed and granulomas were found in 297. Of these, 57 were excluded. Overall, the most common etiology was tuberculosis (35.8%), followed by primary biliary cholangitis (PBC) - 15.0%. In 30 patients (12.5%) granulomas were idiopathic. From 1998 to June 2006 there were 147 granulomas in 5304 biopsies (2.8%), a frequency that did not change significantly compared to the period from July 2006 to December 2014 (93 granulomas in 4070 biopsies, 2.3%, P > 0.05). However, for the majority of cases (61.9%) there was a shift in granuloma etiology during the former time-period that infectious diseases were responsible, whereas in the latter, autoimmune liver diseases (43%) were the main etiology. The authors conclude that hepatic granulomas can result from various infectious and non-infectious diseases. During recent years, an epidemiological shift regarding granuloma etiology was observed, from systemic infectious diseases to non-infectious, mainly immune-mediated primary liver disorders.

Liver transplantation

Morphological characterization of chronic antibody-mediated rejection in ABO-identical or ABO-compatible pediatric liver graft recipients.
Dao M, Habès D, Taupin JL, et al. Liver Transpl 2018;24(7):897-907.

This study aims to define the morphological profile associated with the presence of donor‐specific antibodies (DSAs) and/or C4d immunostaining in ABO‐identical or compatible pediatric liver grafts. The authors study a cohort of 53 cases with a 10‐year protocol biopsy aims to define the morphological changes associated with the presence of DSA and/or C4d immunostaining in liver grafts, in order to refine the diagnosis criteria of cAMR. All biopsies demonstrated fibrotic changes with a mean liver allograft fibrosis score (LAFSc) of 5.1 ± 2.2. A total of 31 (58%) biopsies exhibited C4d positivity. DSAs were detected in 20 (45%) patients. LAFSc, perivenular fibrosis and portal inflammation were significantly higher in the double‐DSA and C4d‐positive group versus the double‐negative group. The authors defined a histological scoring system from these results, which was integrated with the 2016 Banff definition and allowed reclassifying patients for the diagnosis of chronic active antibody‐mediated rejection (cAMR; 11/53 versus 13/53). Their study confirmed that perivenular fibrosis and portal inflammation in late pediatric liver graft biopsies are features of cAMR.

American Journal of Surgical Pathology

A Point-based Histologic Scoring System for Hepatocellular Carcinoma Can Stratify Risk of Posttransplant Tumor Recurrence.
Roberts DE, Kakar S, Mehta N, et al. Am J Surg Pathol 2018;42(7):855-865.

Eligibility for liver transplant in patients with HCC relies on tumor size and number that is based on radiographic assessment. However, the pre-operative radiographic impression and pathologic assessment of explanted livers for HCC has been shown to be discordant in up to 30% of cases. The goal of this study was to determine whether certain histologic features were associated with tumor recurrence after transplant. Evaluation of 109 explanted livers showed that scirrhous and solid growth patterns, nuclear pleomorphism, nuclear-to-cytoplasmic ratio, and cytoplasmic amphophilia were found to be high-risk histologic features. Assigning points based on these parameters, the total score was called the Recurrence Risk Assessment Score (RRAS). The authors then validated the RRAS performance in a separate cohort of 81 explants in predicting tumor recurrence. When compared against conventional tumor grade by WHO histologic criteria, the RRAS was superior in predicting HCC recurrence. This study provides further support that histologic evaluation may provide another useful, if not better, method of predicting HCC recurrence as compared to radiographic studies alone.

Archives of Pathology and Laboratory Medicine

Factors Impacting the Performance Characteristics of Bile Duct Brushings: A Clinico-Cytopathologic Analysis of 253 Patients.
Hacihasanoglu E, Memis B, Pehlivanoglu B, et al. Arch Pathol Lab Med 2018;142(7):863-870.

The goal of this study was to determine the performance of bile duct brushings (BDBs) in detecting malignancies over a span of 15 years at a major academic medical center. 253 cases with at least 18 months of histopathologic or clinical follow-up were reviewed. Overall, the authors found BDBs to have a sensitivity of 35%, specificity of 100%, positive predictive value of 100%, negative predictive value of 58%, and accuracy of 66% in detecting malignancy. In addition, a number of detailed analyses and statistics were generated, including various grouping of diagnostic categories (from benign, atypical, suspicious, and malignant), comparison of conventional smears to ThinPrep, accounting for stent effects, categorizing the type of carcinoma, and evaluating test performance over time. In brief, the finding that sensitivity nearly doubled and accuracy increased while specificity and positive predictive value only minimally decreased when atypical, suspicious, and malignant categories were combined suggests that further refinement in atypical and suspicious categories may be helpful. Also, in cases where patients had a history of stenting, the statistics generated suggest that cases were only diagnosed as malignant when cytologic features were unequivocal.

Human Pathology

Bim is an independent prognostic marker in intrahepatic cholangiocarcinoma.
Zhang H, Jenkins SM, Lee CT, et al. Hum Pathol. 2018;78:97-105.

Bim protein is an important cell apoptosis initiator that can be altered in tumorigenesis.  The authors analyzed the correlation of Bim expression by immunohistochemistry with various clinicopathological features and survival in a cohort of 56 patients with intrahepatic cholangiocarcinoma.  Nineteen of 56 (34%) tumors had high Bim expression (>10%).  Patients who had tumors with high Bim expression had significantly longer overall survival than those with low or no staining.  Additionally, high Bim expression correlated with low Ki-67 index and lack of lymph node metastasis at the time of surgery.  The study findings suggests Bim is an independent prognostic marker in intrahepatic cholangiocarcinoma.

Mucinous intrahepatic cholangiocarcinoma: a distinct variant.
Chi Z, Bhalla A, Saeed O, et al. Hum Pathol 2018;78:131-137.

In this retrospective study from a tertiary medical center with a large volume of hepatectomies, mucinous variant of intrahepatic cholangiocarcinomas (n=7) were compared to conventional intrahepatic cholangiocarcinomas (n=79).  This study describes demographic, histopathologic, immunohistochemical, and molecular findings specific to mucinous intrahepatic cholangiocarcinomas.  This variant presents at advanced stage upon diagnosis with shorter survival time compared with conventional type cholangiocarcinomas.

Resection of the largest reported hepatic small vessel neoplasm.
Walcott-Sapp S, Tang E, Kakar S, et al. Hum Pathol 2018;78:159-162.

A case report describing a large hepatic small vessel neoplasm with characteristic morphologic and staining features, which underscores consideration for his entity regardless of lesion size.


Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study. Costentin CE, Layese R, Bourcier V, et al. Gastroenterol 2018;155(2):431-442.

This multi-center study aimed to determine how compliance with hepatocellular carcinoma semi-surveillance guidelines affects survival times of patients with HCV and HBV-associated compensated cirrhosis who developed HCC.  216 patients with detected HCC with biopsy-proven viral cirrhosis were included.  After lead-time adjustment, overall survival time was longer in patients compliant with surveillance guidelines (53.2 months) than noncompliant patients (25.4 months).  This study offers the most robust evidence available of a survival benefit with six-month HCC surveillance and strongly supports the implementation of interventions aiming at improving patients’ compliance.

Incidence of Hepatocellular carcinoma in Patients with HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents.
Calvaruso V. Gastroenterol 2018;155(2):411-421.

Studies have produced conflicting results of the incidence of hepatocellular carcinoma (HCC) in patients with in hepatitis C virus (HCV)-associated cirrhosis treated with direct-acting antivirals (DAAs).  This was a large prospective study of 2, 249 consecutive patients with HCV-associated cirrhosis treated with DAAs were followed.  At 1 year after exposure to DAAs, HCC developed in 2.1% of patients with Child-Pugh class A with an SVR and 6.6% of patients with no SVR; and in 7.8% of patients with Child-Pugh class B with an SVR and 12.4% of patients with Child-Pugh class B.  This study demonstrated that the SVR to DAA treatment decreased the incidence of HCC over a mean follow-up of 14 months.


Macrotrabecular-Massive Hepatocellular Carcinoma: A Distinctive Histological Subtype with Clinical Relevance.
Ziol M, Pote N, Amaddeo G, et al. Hepatology 2018; 68(1): 103-112.

The authors report a series of “macrotrabecular-massive” hepatocellular carcinoma (MTM-HCC), defined as the presence of >50% macrotrabecular architecture (more than six cells thick). They retrospectively reviewed 237 HCC resections and 284 HCC biopsies, and identified MTM-HCC in 12% of the whole cohort. It was associated with poor prognostic factors, including tumor size, AFP level, satellite nodules, and vascular invasion. It was an independent factor of early and overall recurrence. There is an editorial on the paper by Dr. David Kleiner in the same issue.

cHCC-CCA: Consensus Terminology for Primary Liver Carcinomas With Both Hepatocytic and Cholangiocytic Differentiation.
Brunt E, Aishima S, Clavien PA, et al. Hepatol 2018; 68(1): 113-126.

This article is a consensus paper from an international group of pathologists, radiologists, and clinicians and gives recommendations for working terminology surrounding combined hepatocellular-cholangiocarcinoma (cHCC-CCA). They recommend the diagnosis be based on H&E, with immunostains being supportive of the diagnosis. Other recommendations include morphologically typical HCC with positive CK19 or other markers of “stemness” should NOT be called cHCC-CCA, and morphologically typical CCA with only immunohistochemical expression of hepatocytic or stem-cell markers should NOT be called cHCC-CCA. They also recommend “there should no longer be formal diagnostic subtypes based on the identification of stem/progenitor cells, but rather if stem/progenitor cell features are observed, they are noted in a comment as ‘stem/progenitor cell features present.’” The paper is essential reading for anyone who routinely diagnoses primary liver carcinomas.

Polycystic Liver Disease: Hepatic Venous Outflow Obstruction Lesions of the Noncystic Parenchyma Have Major Consequences.
Barbier L, Ronot M, Aussilhou B, et al. Hepatol 2018; 68(2): 652-662.

The authors retrospectively reviewed 125 cases (resection or transplantation) of polycystic liver disease and evaluated for features of hepatic venous outflow obstruction (HVOO), seen in 92% of the cases, and correlated the findings with clinical parameters.

Modern Pathology

Progression and regression of fibrosis in viral hepatitis in the treatment era: the Beijing classification.
Theise ND, Jia J, Sun Y, et al. Mod Pathol 2018; 31:1191–1200.

New staging system, the Beijing Classification, for assessment of liver biopsies from patients with treated chronic viral (B and C) hepatitis. The Beijing Classification includes extent (stage) of fibrosis, and adds quality of fibrosis to the staging in order to clarify presence of regressive vs progressive fibrosis.

Journal of Gastroenterology and Hepatology
Role of heat shock factor 1 expression in the microenvironment of intrahepatic cholangiocarcinomas.
Kawashita H, Morine Y, Saito Y, et al. J Gastroenterol Hepato 2018;33(7):1407-1412.

Clinical significance and biological effect of Heat shock factor 1 (HSF1) expression in intrahepatic cholangiocarcinoma (IHCC) remain unknown. Specimen from forty‐nine patients with intrahepatic cholangiocarcinoma (IHCC) who underwent hepatic resection was stained with HSF1 immunostain. HSF1 expression was significantly higher in tumors than in normal tissue. The overall survival rate was significantly lower in patients with high than low HSF1. Multivariate analysis showed that high HSF1 expression was a factor independently prognostic of patient survival.

American Journal of Clinical Pathology

Detection of Albumin Expression by RNA In Situ Hybridization Is a Sensitive and Specific Method for Identification of Hepatocellular Carcinomas and Intrahepatic Cholangiocarcinomas. 
Lin F, Shi J, Wang HL, et al.  Am J Clin Pathol, 150: 58–64.

Ever wonder what the data is regarding the detection of albumin expression by ribonucleic acid (RNA) in situ hybridization in HCC, ICCs, and carcinomas from various organs using manual and automated staining?  This original article addresses the utility of RNAscope (Advanced Cell Diagnostics, Hayward, CA) employing 482 cases on tissue microarray sections and on 22 cases of ICCs.  This study concludes that RNAscope for albumin is highly sensitive and specific for identifying HCCs and is highly specific and moderately sensitive for detection of ICCs.  Further, rare non-HCC and non-ICC, can also have aberrant expression of albumin. 

Journal of Hepatology

European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. 
Thursz M, Gual A, Lackner C, et al. J Hepatol. 2018 Jul;69(1):154-181.

The July publication of J. of Hepat contains the current clinical practice guidelines for alcohol-related liver disease.  While many clinical aspects are addressed, the article merits a closer read by pathologists specifically regarding the importance of our role in diagnosis, identification of co-morbidities, and in provision of prognostic pathological features. 

Hepatology Snapshot: Drug-induced chronic liver injury.
Dakhoul L, Ghabril M, Chalasani N.  J Hepatol. 2018 Jul;69(1):248-250.

Visit this extremely helpful, easy to use, and guaranteed to make your signouts more efficient tabular illustration of drug induced liver injury by causative agents detailing distinguishing histopathological findings and helpful clinicopathological features. 

Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; Mayo Clinic, Rochester
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Eric Yee MD; University of Arkansas for Medical Sciences
Maria Westerhoff MD; University of Michigan

Wednesday, September 19, 2018

Save the Date: HPHS Reception at USCAP 2019

Dear Members,

You are cordially invited to join the Hans Popper Hepatopathology Society reception at the USCAP national meeting.  Please save the date:

     Date: Saturday March 16, 2019 6:00-8:00 PM
     Location: National Harbor, Maryland

We look forward to seeing you!

Monday, July 30, 2018

HPHS Journal Watch: May/June 2018

Clinical Gastroenterology and Hepatology

Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple
Steatosis: A Systematic Review and Meta-analysis.

Verhaegh P, Bavalia R, Winkens B, et al. Clin Gastroenterol Hepatol. 2018;16(6):837-861.

This systematic review and meta-analysis studied whether noninvasive tests can differentiate nonalcoholic steatohepatis (NASH) from simple steatosis (SS). There were 122 studies evaluating 219 different blood markers and 22 other tests. Alanine aminotransferase had a pooled sensitivity of 63.5% and specificity of 74.4% to diagnose NASH. Ferritin had pooled sensitivity of 79.1%, specificity of 71.9%, and adinopectin had pooled sensitivity of 72.0% and specificity of 75.7%. The cleaved CK18-M30 as an assay had a pooled sensitivity of 68.4% and specificity of 74.2%. Of –omics approaches, the GlycoNASH test data had a pooled sensitivity of 67.1% and specificity of 63.8%. Scoring systems that combined blood markers, such as NASHTest (combining 10 markers with age, gender, weight, height, and SteatoTest positivity) showed specificity of 95.3% but sensitivity of 22.9% in differentially NASH from borderline NASH and SS. In summary, none of the pooled markers showed both sensitivity and specificity over 80%. More standardized study designs are needed as the majority of the studies contained only limited numbers of patients with significant fibrosis or did not provide the stages of fibrosis.

Acetaminophen-induced Acute Liver Failure Is More Common and More Severe in Women.
Rubin JB, Hameed B, Gottfried M, et al; Acute Liver Failure Study Group. Clin Gastroenterol Hepatol. 2018;16(6):936-946.

Acetaminophen overdose is the leading cause of acute liver failure (ALF) and acute liver injury (ALI), accounting for approximately 50% of all ALF cases. Previous data regarding drug-induced liver injury have shown that women are noted to be at increased risk for progressing to ALF and require subsequent transplant. From a national registry of 32 academic medical centers, 1162 patients with acetaminophen induced ALI (22%) or ALF (78%) were identified. Their presentation, clinical course, and overall survival between genders were studied. Sixty-eight percent (170) of acetaminophen induced ALI and 76% (864) of ALF patients were women. About half of patients with ALF had unintentional acetaminophen overdose and 40% were suicide attempts. More women than men co-ingested acetaminophen with sedating agents such as opioids or benzodiazepines (70% vs. 52%). On presentation, men had higher ALT, bilirubin, albumin, and MELD scores than women, but otherwise, weight-adjusted ALT was similar.  More women had severe clinical courses, including severe hepatic encephalopathy (68% women vs. 58% men), and need for critical care needs. However, transplant-free survival were similar between male and females.

Excellent Outcomes of Liver Transplantation Following Down-Staging of Hepatocellular Carcinoma to Within Milan Criteria: A Multicenter Study.
Mehta N, Guy J, Frenette CT, Dodge JL, et al. Clin Gastroenterol Hepatol. 2018;16(6):955-964.

This was a multi-center study using a standardized down-staging protocol (within Milan criteria) to assess outcomes of liver transplantation in such patients. The type of local regional therapy (LRT) was not standardized. Most received TACE alone or in combination with radio-frequency ablation.16% of patients were not down-staged to within Milan criteria. A factor predicting inability to achieve tumor down-staging was pre-treatment AFP≥1000. The number, size of tumors, MELD score, number of LRT sessions were not significant predictors of inability to be down-staged. Successful down-staging to Milan criteria was achieved in 83.4% (median 2.7 months). Majority were down-staged after a single LRT. Of those who were down-staged, 17% (28 of 156) had subsequent tumor progression and were dropped out of the waitlist. 58% of patients received liver transplant. Following transplant, the explanted liver showed tumor staging within Milan criteria in 45.9% of cases (T1/T2); 19.3% of cases turned out to be understaged by imaging and beyond Milan criteria (T3/T4). Median post-LT follow up was 4.3 years with a survival of 95% at 1 year and 80% at 5 years. HCC recurrence developed in 10% of patients at a median of 19.1 months from transplant. Predictors of recurrence included an AFP >500 and vascular invasion. Down-staging resulted in excellent overall 5-year post-LT survival of 80% and recurrence free probability of 87%. Only 7% had micro- or macro-vascular invasion. Treatment failure predictors included a pretreatment AFP of >1000 and Child’s B/C cirrhosis, suggesting that these patients should not be subjected to the risks of LRT.

Journal of Hepatology

Development of the liver: Insights into organ and tissue morphogenesis
Ober EA, Lemaigre FP.  J Hepatol 2018; 68 (5):1049-1062.

Employing the burgeoning modality of three dimensional imaging and distinct model organisms, this study illustrates the growing understanding of morphogenetic processes in the adult liver.  Stages from endodermal budding giving rise to an asymmetric liver, mechanisms leading to liver and lobe development, morphogenesis of the intra and extrahepatic bile ducts, its reaction to injury, and vascular development are discussed. 

Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors
De Martin E, Michot JM, Papouin B, et al. J Hepatol 2018; 68 (6): 1181-1190.   

The goal of this large scale and well organized study was to accurately evaluate the incidence of  hepatic immune related adverse events (IRAEs) in patients with metastatic cancer treated with anti-cancer anti-PD-1, anti-PDL1, and anti-CTLA-4 immunotherapy.  Using data gathered in 1,425 patients from August 2015 to August 2017 by the REISAMIC pharmacovigilance register, individuals who developed grade ≥3 hepatitis were identified according to the Common Toxicity Criteria for Adverse Events (CTCAE).  The severity of liver injury was classified according to the Drug-Induced Liver Injury Network (DILIN) 5-point scale.  Acute hepatitis due to cancer immunotherapy was reported in only 3.5% of treated patients.  Two distinct types of immune mediated hepatitis were described:  granulomatous hepatitis with fibrin depositis associated with anti-CTLA-4 mABs; and lobular, non-granulomatous hepatitis associated with anti-PD-1/anti-PDL1 mABs.  The authors concluded that liver biopsies have a key role in detailing the severity of injury and in providing guidance in treatment choices. 

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. 
Wardell CP, Fujita M, Yamada T, et al. J Hepatol 2018; 68 (5): 959-969.

Biliary tract carcinomas (BTCs) are a heterogenous group frequently exhibiting poor response to treatment.  This study is a large-scale genome sequencing analyses of somatic and germline driver events and genomic landscape mapping to enhance comprehension of carcinogenesis, better classify, and improve treatment strategies of BTCs.  412 BTC samples were analyzed by whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing using subtypes of intrahepatic cholangiocarcinomas (ICCs), distal cholangiocarcinomas (DCCs), peri-hilar type cholangiocarcinomas (PHCs), and gallbladder or cystic duct cancers (GBCs/CDCs). 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some negatively affecting prognosis, were identified. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients.  Learn more and read about BTCs and their distinct genetic features including somatic events and germline predispositions.

Modern Pathology

Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury.
Zen Y, Yeh MM. Mod Pathol 2018; 31: 965–973.

The authors reviewed adverse effects of immune checkpoint inhibitors in liver and compared clinicopathologic features between checkpoint inhibitor-induced liver injury and acute autoimmune hepatitis or idiosyncratic drug-induced liver injury. They have seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2). They also performed IHC for B and T cell markers and found large numbers of CD3+ and CD8+ lymphocytes in immune checkpoint inhibitor treated livers. CD20+ B cells and CD4+ T cells were fewer in checkpoint inhibitor-induced liver injury than in autoimmune hepatitis or drug-induced liver injury. They conclude that liver injury caused by cancer immunotherapy shares some features with autoimmune hepatitis; however, there are obvious differences between the two conditions.

Journal of Gastroenterology and Hepatology

Individual and combined effects of hepatitis B surface antigen level and viral load on liver cancer risk
Yang Y, Gao J, Tan YT, et al. J Gastroenterol Hepatol 2018 ;33(5):1131-1137. 

Hepatitis B surface antigen (HBsAg) and viral load are both hallmarks of hepatitis B virus (HBV) infection. The authors carried out a nested case–control study including 211 liver cancer cases and 221 controls who were seropositive for HBsAg within two populationbased cohorts. They found that elevated levels of HBVDNA and HBsAg are associated with increased risks of liver cancer. Compared with subjects with HBVDNA < 2000 IU/ml, the adjusted ORs increased from 2.11 (95%CI: 0.99–4.50) to 10.47 (95%CI: 5.06–21.68) for those with HBVDNA level at 2000–19 999 to ≥ 20 000 IU/ml. Compared with subjects at a low level of HBsAg (0.05–99 IU/ml), the adjusted ORs increased from 1.82 (95%CI: 0.90–3.68) to 2.21 (95%CI: 1.10–4.43) for those with HBsAg level at 100–999 to ≥ 1000 IU/ml.


Histological assessment of the liver explant in transplanted hepatitis C virus patients achieving sustained virological response with direct-acting antiviral agents. 
Putra J., Schiano TD., Fiel MI. Histopathol 2018;72(6):990-996.

Direct-acting antiviral agents (DAAs) have transformed the management of patients with chronic hepatitis C virus, and treatments are now associated with sustained virological response (SVR) rates of > 95 %.  With the success of DAAs, histologic examination for hepatitis C has, at least anecdotally, become less commonplace.  This study evaluated the histologic findings of both inflammation and fibrosis, of HCV patients who achieved SVR after receiving DAA treatment and compared them to the histologic findings of a control group of HCV patients who did not achieve SVR and did not receive DAA treatment.  The authors report a lack of demonstrable association between histologic findings and SVR status and persistent inflammation in HCV patients with SVR despite receiving DAAs.

Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study. 
Sasami M, Kuo FY, Huang CC, et al. Histopathol 2018;72(7):1164-1171.

Cellular senescence plays a role in the pathogenesis of various non-neoplastic diseases, including primary biliary cholangitis and other adult cholangiopathies.  This study investigated the role of cellular senescence, through established senescence markers p16, p21, and NCAM, in patients with biliary atresia, the most common form of pediatric obliterative cholangiopathy.  The study examined expression of these markers in bile ducts and bile ductules at early (Kasai procedure) and late (transplant) stages of biliary atresia and compared them to a normal control group.  Study findings indicate that increased expression of senescence regulators may be involved in the progression of biliary atresia in a manner similar to that observed in adult cholangiopathies.  

American Journal of Pathology

Understanding Liver Regeneration: From Mechanisms to Regenerative Medicine.
Gilgenkrantz H, Collin de l’Hortet A. Am J Pathol 2018; 188(6): 1316-1327.

This review article summarizes the published data in the past five years in liver regeneration, discussing the mechanisms leading to regeneration disruption in chronic liver diseases.

Human Pathology

DJ-1 is a useful biomarker for invasive extrahepatic cholangiocarcinoma. 
Tabata Y., Nakanishi Y., Hatanaka Y., et al.  Hum Pathol. 2018;76:28-36.

Through a liquid -chromatography mass spectrometry-based proteomics approach, the authors previously reported that DJ-1 protein is up-regulated in cholangiocarcinoma compared with non-neoplastic bile duct epithelium.  Building on those findings, the authors evaluated expression of DJ-1 in patients with invasive extrahepatic cholangiocarcinoma (EHCC) by evaluating immunohistochemical (IHC) staining for anti–DJ-1 antibody and the impact of IHC staining score on postoperative survival.  Additionally, serum levels of DJ-1 in invasive EHCC patients with and without metastasis were compared.  Although limited by the number of patients studied, DJ-1 protein in IHC staining and serum examinations may offer a biomarker for prognosis in patients with invasive EHCC.

Low-level clonal FGFR2 amplification defines a unique molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population.
Pu XH., Ye Q., Yang J., et al. Hum Pathol. 2018; 76:100-109.

Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several tumor types, including intrahepatic cholangiocarcinoma (ICC).  Multiple clinical trials are under way for repurposing the drugs that target the FGF signaling pathway as an innovative ICC treatment.  In Western countries, the   frequency of FGFR2 fusions in ICC ranges from a reported 7%-45%.  This study assess the incidence of FGFR2 aberrations, including translocations and amplification, in Chinese patients.  122 ICCs were evaluated for translocations and amplifications of FGFR2 by fluorescence in situ hybridization as well as protein expression by immunohistochemistry.  The relationship between genetic aberrations and protein expression were then compared to clinicopathologic characteristics and prognostic outcomes.  Molecular aberrations were identified in 23/122 (19%) of tumors.  Low-level amplification of FGFR2 was twice as common as FGFR2 translocation; and these tumors were generally of lower stage and associated with better overall survival.

Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; Mayo Clinic, Rochester
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Cynthia Guy MD; Duke University
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Eric Yee MD; University of Arkansas for Medical Sciences
Maria Westerhoff MD; University of Michigan