Thursday, May 23, 2019

HPHS Journal Watch: March/April 2019

American Journal of Surgical Pathology

Cholangiolocellular Carcinoma With “Ductal Plate Malformation” Pattern May Be Characterized by ARID1A Genetic Alterations
Sasaki M, Sato Y, Nakanuma Y. Am J Surg Pathol. 2019 Mar;43(3):352-360.

This study evaluated a number of genes for mutations and defects in protein expression in 77 primary liver tumors with a cholangiolocellular carcinoma (CLC) component. Tumors were further subdivided for analysis based on their proportion of a CLC component. The degree of ductal plate malformation (DPM) growth pattern in each tumor was also scored to determine any association with genetic alterations. The investigators found that loss of ARID1A expression was present in 20.8% of tumors with a CLC component and was seen more frequently in tumors with a higher proportion of a CLC component; 68.8% of this subset showed an extensive DPM-pattern. These findings suggest differences in CLC and provide data to support the possibility of molecular-morphologic classification of primary liver tumors in the future. More detailed information on additional genetic mutations and associations with morphologic findings are available in the manuscript.

Intrasinusoidal Spread of Hepatic Epithelioid Hemangioendothelioma: Implications for the Diagnosis in Minimal Samples
Agostini-Vulaj D, Pehlivanoglu B, Weiss SW, et al. Am J Surg Pathol. 2019 Apr;43(4):573-579

The authors examined 18 cases of hepatic epithelioid hemangioendothelioma (EHE) and found that 17 showed tumor cells within sinusoids that appeared histologically separate, but within 1 to 8 mm, from the main mass. These intrasinusoidal tumor cells did not have the classic epithelioid or dendritic cell appearance of EHE, but rather showed hyperchromatic, cerebriform-like nuclei with multinucleation that in some cases mimicked megakaryocytes in over one-third of cases. Pathologists should be mindful of this phenomenon, as needle biopsies may only sample the periphery of mass lesions. Recognition of these intrasinusoidal tumor cells in limited samples can prevent misdiagnosis as non-lesional hepatic parenchyma. Immunohistochemical stains for CAMTA1, ERG, and sometimes CAM5.2 can assist in highlighting tumor cells.

Clinical Gastroenterology and Hepatology

Nonalcoholic Steatohepatitis Is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant Candidates
Younossi Z, Stepanova M, Ong JP, et al. Clin Gastroenterol Hepatol. 2019 Mar;17(4):748-755.

The authors used the Scientific Registry of Transplant Recipients (2002–2016) to estimate the trends in prevalence of HCC in liver transplant candidates with the most common types of chronic liver disease: alcoholic liver disease (ALD), chronic hepatitis B (CHB), chronic hepatitis C (CHC), and NASH. The proportions of HCC accounted for by CHC and ALD remained stable (both trend P > .10), the proportion of CHB decreased 3.1-fold (P < .0001), while the proportion of NASH in HCC increased 7.7-fold (from 2.1% to 16.2%; P < .0001). Over the study period, CHC was still the most common etiology for HCC (65%).

Cost Effectiveness of Transplanting HCV-Infected Livers Into Uninfected Recipients With Preemptive Antiviral Therapy
Bethea ED, Samur S, Kanwal F, et al. Clin Gastroenterol Hepatol. 2019 Mar;17(4):739-747.

Transplanting hepatitis C virus (HCV)-infected livers into HCV uninfected recipients is a controversial topic that is still not supported by current Guidelines. Direct-acting antivirals (DAAs) can be used to treat donor-derived HCV infection. The cost of DAA therapy may be a limitation. The authors evaluated the cost effectiveness of transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy. Using a Markov-based mathematical model, they found that transplanting HCV-positive livers into HCV-negative patients with planned DAA therapy after transplantation was a cost-effective strategy that could improve health outcomes. It is important for pathologists who review liver transplant biopsies to be aware that under these circumstances, histopathologic features of HCV may still need to be evaluated.

Journal of Gastroenterology and Hepatology

Clinical and histopathological features of immunoglobulin G4‐associated autoimmune hepatitis in children
Aydemir Y, Akcoren Z, Demir H, et al. J Gastroenterol Hepatol. 2019 Apr;34(4):742-746.

They reviewed frequency and the characteristics of immunoglobulin G4 (IgG4)‐associated autoimmune hepatitis in 40 pediatric patients with autoimmune hepatitis who had liver biopsies. IgG4‐associated autoimmune hepatitis was defined as presence of more than 10 IgG4‐positive plasma cells/high‐power field. They found a positive correlation between IgG4‐positive plasma cell count and degree of portal (r: 0.406, P: 0.009) and lobular inflammation (r: 0.37, P: 0.019), grade of interface hepatitis (r: 0.33, P: 0.03), and fibrosis (r: 0.318, P: 0.046). Time required for normalization of liver transaminases and serum IgG level was significantly shorter in IgG4‐associated autoimmune hepatitis.

Journal of Hepatology

Fa(s)t assessment of the liver graft: Is it relevant?
Nahon P, Soubrane O. J Hepatol. 2019 Mar;70(3):346-347.

This editorial addresses the nuances in assessing the severity of fat involvement of liver grafts in transplantation, which in severe cases represents the main cause of donor livers being declined. It also emphasizes the yet unmet need for a fast, quantitative and reliable method to serve as an alternative to the current gold standard procedure of histological semi-quantitative evaluation performed on frozen biopsy section at the time of transplantation. Magnetic resonance spectroscopy, fibroscan devices, and user friendly non-invasive pocket spectrometer that can be administered by the harvesting surgeon to assess donor liver fat are being developed.

American Journal of Clinical Pathology

Portal Cavernoma Cholangiopathy: Histologic Features and Differential Diagnosis
Pittman ME, Kierans AS, Rao D, et al. Am J Clin Pathol. 2019 Mar(3):255-262.

This case series describes in detail the histopathological features of portal cavernoma cholangiopathy (PCC, formerly portal biliopathy), a type of biliary injury that occurs in association with a portal vein thrombus or cavernoma. Cases are noted to clinically mimic cholangiocarcinoma, cirrhosis, and may present as a hilar mass. Microscopic features are reminiscent of hepatoportal sclerosis and/or bile duct obstruction, and show obliterated or miniaturized portal veins, with ductular reaction, reactive epithelia atypia, and mixed inflammatory cell infiltrate and neutrophils.

Liver Transplantation

Not All Cellular Rejections Are the Same: Differences in Early and Late Hepatic Allograft Rejection
Jadlowiec CC, Morgan PE, Nehra AK, et al. Liver Transpl. 2019 Mar;25(3):425-435.

T cell–mediated rejection (TCMR) is common after liver transplantation (LT), and it is often thought to have a minimum impact on outcomes. The authors investigated the role of the timing of TCMR on patient and allograft survival and examined the risk factors for early and late TCMR. They reviewed protocol liver biopsies for 787 consecutive LT recipients with an 8.6‐year follow‐up. The incidence of early TCMR (≤6 weeks after LT) was 33.5% with nonalcoholic steatohepatitis patients having the lowest incidence. Younger recipient age (P < 0.01), number of human leukocyte antigen mismatches (P < 0.01), and use of deceased donor allografts (P = 0.01) were associated with increased risk of early TCMR, which had no impact on allograft (hazard ratio [HR], 1.02; 95% CI, 0.79‐1.32; P = 0.89) or overall survival (HR, 1.03; 95% CI, 0.78‐1.34; P = 0.86). Late TCMR (>6 weeks after LT) was less common (17.7%) and was associated with different risk factors. The majority of late TCMR (56.2%) episodes had no antecedent early TCMR, although moderate‐to‐severe early TCMR (HR, 2.85; 95% CI, 1.55‐5.23; P < 0.01) and steroid resistance (HR, 3.62; 95% CI, 1.87‐6.99; P < 0.01) were associated with late TCMR. Late TCMR increased risk of mortality (HR, 1.89; 95% CI, 1.35‐2.65; P = 0.001) and graft loss (HR, 1.71; 95% CI, 1.23‐2.37; P = 0.001). In summary, the majority of early TCMR episodes after LT are mild and do not appear to adversely impact long term patient or allograft survival, provided that they are treated adequately. By contrast, late TCMR may carry deleterious effects with associated long term risk of graft loss and decreased survival. The authors suggest that it is important to describe TCMR after LT in the context of its timing and histologic grade. Early moderate‐to‐severe or steroid‐resistant rejection may play a role in late TCMR as multiple or inadequately treated TCMR episodes are risk factors for chronic rejection. Patients with moderate‐to‐severe early TCMR are at an increased risk for late TCMR and warrant closer clinical follow‐up. The occurrence of late TCMR carries deleterious effects with increased long term risk of graft loss and decreased survival.


A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites
Martins-Filho SN, Alves VAF, Wakamatsu, et al. Histopathology. 2019 Apr;74(5):718-730.

Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies. This has precluded a thorough characterization of molecular drivers of HCC dissemination, particularly in relation to distant metastases. The authors evaluate 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules that were analyzed. The study included morphological assessment, immunohistochemistry and mutation status of the TERT promoter, which is the most frequently mutated gene in HCC. Immunohistochemistry (IHC) was performed for markers of hepatocyte differentiation (HepPar1 and arginase), WNT pathway (β‐catenin and glutamine synthetase), HCC progenitor cell features (K19, CD44 and EpCAM), markers of EMT (vimentin and claudin‐1) and cell proliferation (Ki67). Results for β‐catenin and glutamine synthetase IHC were combined as a proxy for WNT signaling pathway activation. Most of the patients were male (62 of 88, 70%), with background liver cirrhosis (79 of 88, 90%) due to hepatitis C virus (HCV) infection (47 of 88, 53%). The results of this study confirm a strong predilection of HCC for lung dissemination, including subclinical micrometastases (unrecognized during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; macrovascular invasion; high histological, nuclear and architectural grades; and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significantly higher CK19 and EpCAM expression than primary liver tumors. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule. Their study also illustrates how autopsies can go beyond their primary objective of defining the cause of death and help address biological questions.


Accuracy of the Liver Imaging Reporting and Data System in Computed Tomography and Magnetic Resonance Image Analysis of Hepatocellular Carcinoma or Overall Malignancy-A Systematic Review
van der Pol CB, Lim CS, Sirlin CB et al. Gastroenterology. 2019 Mar; 156(4):976-986.

The Liver Imaging Reporting and Data System (LI-RADS) categorizes observations from imaging analyses of high-risk patients based on the level of suspicion for hepatocellular carcinoma (HCC) and overall malignancy. However, the actual percentage of HCC and overall malignancy within each LI-RADS category is not known. The authors performed a systematic review to determine the percentage of observations in each LI-RADS category for computed tomography and magnetic resonance imaging that are HCCs or malignancies.  The authors searched the MEDLINE, Embase, Cochrane CENTRAL, and Scopus databases from 2014 through 2018 for studies that reported the percentage of observations in each LI-RADS v2014 and v2017 category that were confirmed as HCCs or other malignancies based on pathology, follow-up imaging analyses, or response to treatment (reference standard). Of 454 studies identified, 17 (all retrospective studies) were included in the final analysis, consisting of 2760 patients, 3556 observations, and 2482 HCCs. The pooled percentage of patients with HCC were 94% for patients who, on CT/MRI, had a lesion classified LR-5, 74% for LR-4, 38% for LR-3, 13% for LR-2, and 36% for LR-M. No malignancies were reported in the LR-1 category. Several potential variables associated with accuracy such as modality (CT vs. MRI) and lesion size could not be evaluated because of either lack of eligible studies or individual participant data. Understanding the accuracy of each LI-RADS category for liver cancer allows physicians to quantify and communicate risk associated with different findings on CT/MRI, allowing for more well-informed management decisions. LR 2 and 3 lesions had non-trivial cancer risks.

Human Pathology

Hepatic mast cell concentration directly correlates to stage of fibrosis in NASH
Lombardo J, Broadwater D, Collins R. et al. Hum Pathol. 2019 Apr;86:129-135.

Recent research has described an association between an increased concentration of mast cells in the liver and the severity of hepatic fibrosis in animal models. The role of mast cells in the liver with regard to fibrosis is not well understood. The authors retrospectively investigated whether a correlation exists between stages of fibrosis and mast cell concentrations. 106 tissue slides were collected from a large military hospital of known cases of unremarkable liver, non-alcoholic fatty liver disease (NAFLD), and each stage of NASH. Tryptase staining was used to highlight and quantify the mast cell concentration in each diagnostic category. Mast cells in five 400× fields (1 square mm) in both the periportal and parenchymal regions of each slide were counted.  The study demonstrated an increase in mast cells in NASH stage 3-4 fibrosis compared to unremarkable liver (35.48 versus 18.23, respectively, P < .001) and a direct correlation (r = 0.287) between the number of mast cells and the stage of fibrosis. Better characterization of the role of mast cells in the development of hepatic fibrosis may further develop our understanding of the pathophysiology of non-NASH NAFLD and NASH.

Steatotic and nonsteatotic scirrhous hepatocellular carcinomas reveal distinct clinicopathological features
Hatano M, Ojima H, Masugi  Y, et al. Hum Pathol. 2019 Apr;86:222-232.

The authors investigated the clinicopathological and molecular characteristics of scirrhous HCC.  120 resected HCC cases were evaluated, including tumor area containing fibrous stroma and the percentage of steatotic cells within the tumor.  37 cases with fibrous stroma making up > 50% of the largest tumor area were defined as scirrhous HCC (sHCC); the other 83 cases were categorized as common HCC (cHCC). Clinicopathologically, sHCC had fewer poorly differentiated tumors (p=0.037) and a higher percentage of cases with steatosis (p=.025) than cHCC.  sHCC cases were subsequently divided into two subgroups: those with > 5% steatotic cells (steatotic sHCC) and those with < 5% steatotic cells (nonsteatotic sHCC).  Steatotic sHCC tended to have a longer time to recurrence than nonsteatotic sHCC, and both sHCC subgroups exhibited different clinicopathologic and molecular features from cHCC.


Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis
Chen HY, Shen DT, Ji D, et al. Gut 2019;68:512-521.

It is well known that Hepatitis D virus is a defective virus that completes its life cycle only with hepatitis B virus. However, there is limited data on the global burden of HDV infection. A systematic review found that 11% of HBsAg carriers (without histories of either intravenous drug use or high-risk sexual behaviour) were coinfected with Hepatitis D virus, which is twice previous estimates. A significantly higher HDV prevalence was noted in intravenous drug users (38%) and high-risk sexual behaviour (17%).  Clearly, coinfection with HDV needs to be actively considered by histopathologists, as well as other clinicians, in patients with HBV, especially those in high risk groups.

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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