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