HPHS Journal Watch: January/February 2020


Immunomorphology and molecular biology of mixed primary liver cancers: is Nestin a marker of intermediate‐cell carcinoma?
Malvi D, de Biase D, Fittipaldi S, et al. Histopathology. 2020 Jan 76(2): 265-274.

Primary mixed liver cancers (PLCs), combined hepatocellular-cholangiocellular (cHCC-CC) and intermediate-cell carcinomas are rare tumours characterised by different molecular mechanisms. Nestin is a marker of progenitor cells with a promising application in human tumours. The aims of this study were (i) to determine the expression of Nestin in mixed PLCs; and (ii) to correlate the PLC immunoprofile with the gene expression in each tumour component. The authors selected 28 mixed PLCs, 13 (46.4%) cHCC-CC and 15 (53.6%) intermediate-cell carcinomas. The immunohistochemistry panel consisted of keratin 7, keratin 19, CD56 and Nestin. Next-generation sequencing analysis was performed on 17 cases (27 specimens) using a multi-gene custom panel. The differentiated HCC and CC components of cHCC-CC were negative for Nestin in all cases. The intermediate areas of cHCC-CC were immunoreactive for Nestin in 92.3% of cases, for CD56 in 76.9% and for K7/K19 in all cases. The immunoprofile of the intermediate-cell carcinomas showed 73.3% of cases positive for Nestin and 66.7% for CD56. TP53 and TERT were the most frequently mutated genes (31.3% and 17.6% of samples, respectively). Mutations were also found in IDH1, IDH2, PIK3CA and NRAS genes. Intermediate and HCC areas of cHCC-CC seemed to share the same mutational profile, and both harboured different mutations than the CC component. The authors conclude that nestin was not expressed by hepatocellular or cholangiocellular-cell components, but was expressed by most of the intermediate cells in PLCs, and therefore could be considered in the differential diagnosis of PLCs, together with mutational profile.

Liver Transplantation

Increased Frequency of Heterozygous Alpha‐1‐Antitrypsin Deficiency in Liver Explants From Nonalcoholic Steatohepatitis Patients.
Cheeney G, Pac LJ, Gopal P, et al. Liver Transpl. 2020 Jan 26(1): 17-24.

Cirrhotic explanted livers occasionally have unexpected periodic acid-Schiff-diastase (PASD)-positive globules within the hepatocyte cytoplasm. It is often unclear whether this finding is a nonspecific consequence of cirrhosis or is indicative of an underlying alpha-1-antitrypsin deficiency (A1ATD) contributing to the cirrhosis. In this study, the authors retrospectively evaluated liver explant specimens for histopathology (including PASD status with confirmatory alpha-1-antitrypsin [A1AT] immunohistochemistry [IHC]), and chart review provided etiology of liver failure and general clinical parameters. Real-time polymerase chain reaction was used to detect A1AT genotype (SERPINA1 S and Z alleles) by melting curve analysis on liver explant tissue from selected cases. Of 196 explanted livers, 21 (11%) had PASD+ globules, which were significantly enriched in patients with a clinical diagnosis of nonalcoholic steatohepatitis (NASH; 47%) compared with other causes (P < 0.001). IHC confirmed all PASD+ globules were A1AT+, with 20 of 21 cases demonstrating diffuse A1AT staining. In an expanded NASH cohort, 42% (14/33) of explants had PASD+ globules, 92% of which were homozygous (n = 1) or heterozygous (n = 11) for the SERPINA1 Z allele, corresponding to nearly 40% of all NASH patients. Overall, the Z allele was present in 10% of all tested liver explants, with 85% of PASD+ cases genotyping homozygous (n = 2) or heterozygous (n = 20), which is far in excess of the estimated 2% in the general population. The authors conclude that PASD+ A1AT globules (with confirmatory genotyping showing at least 1 Z allele) are commonly observed in NASH, suggesting a synergistic relationship toward liver fibrosis. In addition, the high frequency of SERPINA1 Z alleles in liver transplantation patients supports the utility of pretransplant genotyping.

Journal of Hepatology

Milestones in the pathogenesis and management of primary liver cancer.
Nault JC, Cheng AL, Sangro B, Llovet JM. J Hepatol. 2020 Feb 72(2): 209–214.

Liver cancer is a major global health problem and its incidence is on the rise. This issue of JOH addresses the milestones in the medical history of primary liver cancer and its most recent developments. It is an excellent review of its pathogenesis, early detection, diagnosis, staging and treatment . It also describes the landscape of molecular aberrations driving both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), as well as its prevention, surveillance and treatment.

American Journal of Clinical Pathology

Diagnosis of Congenital Hepatic Fibrosis in Adulthood: A Multidisciplinary Approach.
Alsomali MI, Yearsley MM, Levin DM, Chen W. Am J Clin Pathol. Jan 153(1): 119–125.

This article addresses the clinicopathologic features of congenital hepatic fibrosis (CHF) that could aid the diagnosis of this relatively rare condition during adulthood. Five consecutive adult CHF cases identified in a single institution were studied. Disease associations, including Joubert syndrome, Caroli disease, polycystic kidney disease and congenital anomaly of hepatic vasculature were noted in 3 of 5 cases. No unique common radiologic findings were found. Histologically, all cases showed characteristic abnormal interlobular bile ducts embedded in fibrotic portal stroma, with varying degrees of liver fibrosis. Click on the link to learn more about a multidisciplinary approach to the diagnosis of congenital hepatic fibrosis.

Human Pathology

Pathology of liver disease: advances in the last 50 years.
Torbenson M, Washington K. Hum Pathol. 2020 Jan; 95: 78-98.

A trip down memory lane…a review discussing where we have been and where we are headed in key areas of liver pathology, including hepatitis C, non-alcoholic fatty liver disease, liver transplant, hepatic adenomas, hepatocellular carcinomas, and cholangiocarcinomas.

Journal of Gastroenterology and Hepatology

Human liver regeneration following massive hepatic necrosis: Two distinct patterns.
Dezső K, Nagy P, Paku S. 2020 Jan; 35(1): 124-134.

The authors describe two morphologic patterns of hepatic regeneration in patients who survived massive hepatic necrosis.


Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma.
Nault JC, Martin Y, Caruso S, et al. Hepatology. 2020 Jan;71(1):164-182.

The study aimed to describe the genomic profiling of HCC from early to advanced stages. 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) were analyzed for 190 gene expressions and for 31 gene mutations. Genomic profiling was correlated with tumor stages, clinical features, and survival. Cases were classified as: BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the entire cohort, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT-rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced-stage HCC (BCLC B/C) showed higher frequencies of SF3B1, TP53 and RB Transcriptional Corepressor 1 mutations. G1-G6 transcriptomic classification and the molecular prognostic 5-gene score (HN1, RAN, RAMP3, KRT19, and TAF9) showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5-gene score predicted survival in resection specimens (P < 0.0001), ablation (P = 0.01) and in advanced HCC (P = 0.04). Up to 22% of advanced HCC harbored potentially targetable genetic alterations. MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies.

Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma.
Renne SL, Woo HY, Allegra S, et al. Hepatology. 2020 Jan;71(1):183-195.

This study aims to investigate the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the CD34+ vessels that completely encapsulate tumor clusters (VETC), previously linked to HCC metastatic dissemination. 541 resected HCCs from multiple institutions were analyzed. VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and tissue microarray. VETC HCCs represented 18.9% of the whole series and were significantly associated with high alpha-fetoprotein level, size > 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (P = 0.023), disease-free survival (P = 0.002), and overall survival (P = 0.001). VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (β-catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype. Conclusion: The VETC pattern was found in a subset of HCC and correlated with survival. The study highlights the role of the microenvironment in the aggressiveness of HCC and heterogenous features of angiogenesis.

Evaluating Noninvasive Markers to Identify Advanced Fibrosis by Liver Biopsy in HBV/HIV Co-infected Adults.
Sterling RK, King WC, Wahed AS, Kleiner DE, et al. Hepatology. 2020 Feb;71(2):411-421.

Liver biopsies are rarely performed to evaluate advanced fibrosis in hepatitis B virus (HBV)-human immunodeficiency virus (HIV) co-infected patients receiving combined antiretroviral therapy. The aim of the study is to assess the accuracy of non-invasive methods. Fibrosis was staged by a central pathology committee using the Ishak fibrosis score (F). Dual cutoffs for three noninvasive biomarkers (aspartate aminotransferase-to-platelet ratio index, Fibrosis-4 index [FIB-4], and liver stiffness by vibration-controlled transient elastography or VCTE) with the best accuracy to exclude or confirm advanced fibrosis (F ≥ 3) were determined using established methodology. 108 with a liver biopsy and having at least one noninvasive biomarker were included: 22% had advanced fibrosis (≥ F3). The area under the curve for advanced fibrosis was 0.69 for APRI, 0.66 for FIB-4, and 0.87 for VCTE. VCTE cutoffs of 5.0 kPa or less (to exclude) and 8.8 kPa or greater (to confirm) advanced fibrosis had a sensitivity of 92.3% and specificity of 96.0%, respectively. Among the 34.9% with values between the cutoffs, 26.1% had advanced fibrosis. Considering APRI or FIB-4 jointly with VCTE did not improve the discriminatory capacity. Conclusion: VCTE is a better biomarker of advanced fibrosis. Using VCTE dual cutoffs, approximately two-thirds of patients could avoid biopsy to determine advanced fibrosis.

Nodular Regenerative Hyperplasia Associated With Primary Liver Malignancies.
Penrice D, Simonetto DA. Hepatology. 2020 Feb;71(2):760-761.

Nodular regenerative hyperplasia (NRH) is traditionally considered a benign process. Two cases associated with hepatocellular carcinoma (HCC) have been reported in the literature. This study reports two additional HCC cases and 2 cholangiocarcinomas in a large cohort of NRH patients.

American Journal of Surgical Pathology

Pathology of Echinococcosis: A Morphologic and Immunohistochemical Study on 138 Specimens With Focus on the Differential Diagnosis Between Cystic and Alveolar Echinococcosis.
Reinehr M, Micheloud C, Grimm F, et al. Am J Surg Pathol. 2020 Jan; 44(1):43-54.

There are overlapping morphologic features in two echinococcal diseases that occur in humans and cause a significant global health burden: cystic echinococcosis (CE) and alveolar echinococcosis (AE). Distinguishing between CE and AE is important because of differences in prognosis and treatment. This retrospective study utilized histologic, immunohistochemical (IHC), and molecular methods (PCR) to analyze 138 cases of echinococcosis and refine diagnostic criteria in discriminating between CE and AE. Six histologic criteria were found to distinguish between CE and AE in the majority of cases: smallest cyst size, largest cyst size, number of cysts, thickness of laminated layer, striation of laminated layer, and pericystic fibrosis. In cases with equivocal morphology, supplemental testing with IHC (using specialized antibodies mAbEmG3 and mAbEm2G11) and PCR (targeting mitochondrial 12S rRNA gene) can be pursued.

Archives of Pathology & Laboratory Medicine

Fatty Liver Disease: A Practical Approach.
Mostafa M, Abdelkader A, Evans J, et al. Arch Pathol Lab Med. 2020 Jan;144(1):62-70.

This special section article summarizes a diagnostic approach to pathologic interpretation and gives tips on frequently encountered situations in fatty liver disease.

American Journal of Gastroenterology

ACG Clinical Guideline: Disorders of the Hepatic and Mesenteric Circulation.
Simonetto DA, Singal AK, Garcia-Tsao, et al. Am J Gastroenterol. 2020 Jan;115(1): 18-40

Although this is a clinical review, this article contains much that will be of interest to histopathologists. This includes a summary of current views on the coagulation pathways, a review of the vascular anatomy of the liver, and a discussion of the causes of portal vein thrombosis.

Clinical Characteristics and Adverse Impact of Hepatotoxicity due to Immune Checkpoint Inhibitors.
Miller ED, Abu-Sbeih H, Styskel B, et al. Am J Gastroenterol. 2020 Feb;115(2): 251-261.

In a study of over 5000 patients receiving immune checkpoint inhibitors (ICIs) 2% developed hepatotoxicity, occurring in a higher proportion of recipients on combination therapy (9%) compared with monotherapy (2%). Although commoner, disease severity and clinical outcome were not worse in the group receiving combination therapy. ICIs were discontinued permanently in 69 and temporarily in 31 patients. 67 patients received steroids, 14% of whom had recurrent hepatotoxicity after steroid taper. 31 patients resumed ICIs after ALT improvement, 26% of whom developed recurrent hepatotoxicity. Characteristics of liver injury, response to steroids, and outcomes were similar between 38 individuals with a 62 without possible pre-existing liver disease.


Polyploidy spectrum: a new marker in HCC classification.
Bou-Nader M, Caruso S, Donne R, et al. Gut 2020 Feb;69:355-364.

The literature on HCC continues to grow and in this paper the authors explore polyploidy as a diagnostic and prognostic marker. They show that binuclear polyploid hepatocytes are the major components of the polyploid fraction in normal human liver parenchyma but that the quantification of cellular and nuclear ploidy is sufficient to distinguish between normal liver parenchyma and HCC. TP53 mutation is the factor accounting for a higher percentage of mononuclear polyploid hepatocytes when compared with both TERT promoter and CTNNB1 mutated HCC tumours. They also show that highly polyploid HCC tumours are associated with worse prognosis.

Prepared by:
Nafis Shafizadeh MD (Editor); Southern California Permanente Medical Group
Daniela Allende MD; Cleveland Clinic
Vishal Chandan MBBS; University of California Irvine
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
Heather Stevenson-Lerner MD PhD; University of Texas
Eric Yee MD; University of Arkansas

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