Saturday, May 26, 2018

HPHS Journal Watch: March/April 2018

American Journal of Surgical Pathology
MDM2 is an independent oncogene and also a negative regulator of p53. A recent whole-exome sequencing study identified MDM2 amplification in 5% of cholangiocarcinomas. The investigators sought to determine the frequency of MDM2-amplified intrahepatic cholangiocarciomas (iCCAs) and evaluate their clinicopathologic features. The study cohort consisted of surgical resections from Korean and Japanese patients. Tissue microarrays (TMAs) were constructed and tested for MDM2 amplification by in situ hybridization. Tumors that showed MDM2 amplification on TMA had whole tissue sections made and were re-tested to assess for heterogeneity in MDM2 amplification. In addition, all MDM2-amplified and 25 MDM2-nonamplified iCCAs were sequenced for KRAS and IDH1/2 mutations. All cases were tested for SMAD4 expression by immunohistochemistry.
MDM2-amplification was found only in iCCAs with large-duct type morphology and comprised 6% of cases; amplification was diffuse in 77% of iCCAs. KRAS and IDH1 mutations were only detected in MDM2-nonamplified iCCAs. Loss of SMAD4 expression was more frequent in MDM2-amplified iCCAs. Patients with MDM2-amplified iCCAs had a worse survival than those without MDM2-amplification (median survival 16 vs. 28 mo., median follow-up 39 mo.); however, when comparing only patients with large-duct type morphology iCCAs, MDM2-amplified and MDM2-nonamplified patients showed no statistically significant difference in survival. In summary, this study identified that MDM2-amplification is present in a subset of iCCAs and MDM2 inhibitor therapy may play a role in the future.

Liver Transplantation
This review summaries the use of radiation therapy for hepatocellular carcinoma, makes comparisons with other local ablative therapies, and addresses potential novel strategies for optimizing future utility.
Currently, normothermic machine perfusion (NMP) of donor livers using packed red blood cells and fresh frozen plasma is being used in clinical trials, and some suggest it will revolutionize organ transplantation. This paper discusses using NMP with a new synthetic solution created from a polymerized bovine hemoglobin-based oxygen carrier and a gelatin-based colloid suspension as an alternative to using scare and expensive human blood products. Included is a brief discussion, with photomicrographs, of NMP-related histopathologic ischemia-reperfusion injury changes.

This is a nice and fairly comprehensive review of the interplay between the gut microbiota and the liver in health and disease. 

Clinical Gastroenterology and Hepatology
Classically, in adults, the histologic findings of NASH include zone 3 steatosis, inflammation, and ballooned hepatocytes. In children, on the other hand, fatty liver disease may have fewer ballooned hepatocytes, more portal based inflammation, and can have zone 1 steatosis. The purpose of this study was to determine clinically relevant associations between zone 1 vs. zone 3 steatosis in children. Liver biopsies of 776 pediatric patients were scored for degree and location of steatosis, inflammation (lobular & portal), ballooned hepatocytes, and fibrosis.
19% had zone 1 steatosis, 31% had zone 3, and the remaining were panacinar (42%) or azonal (8%). Compared with children with zone 3 steatosis, those with zone 1 steatosis were younger, more likely to be Hispanic, have higher fasting triglyceride levels, male, and have higher AST. Children with zone 3 steatosis had higher waist circumference and blood pressure.
Biopsies with zone 3 steatosis had more ballooned hepatocytes than those with zone 1, higher NAFLD activity score, and NASH. Those with zone 1 steatosis had more portal inflammation and more fibrosis, with 2.34 times the odds of having advanced fibrosis compared to zone 3 steatosis patients.
In conclusion, zone 1 vs. zone 3 steatosis in pediatric NAFLD have informative risk differences in fibrosis and steatohepatitis, with zone 1 patients being more likely to be younger, Hispanic, and male; importantly they are more likely to have fibrosis.

The authors report a case of a 50-year-old woman presenting with concurrent erythema multiforme and autoimmune hepatitis. Despite the presence of several confounding factors, the authors do a convincing job of establishing the diagnosis. There is a brief discussion regarding the challenge of distinguishing lupus-related hepatitis from autoimmune hepatitis, and the clinical significance of doing so.

The authors report an unusual case of hepatocellular carcinoma (HCC) presenting as a lateral eyebrow skin metastasis in an 83-year-old man who was subsequently found to have alcoholic cirrhosis. There is a brief discussion on the limited literature on HCC cutaneous metastases.

American Journal of Pathology
This study evaluated the differences in progenitor cell niche activation between primary sclerosing cholangitis (PSC) (n=20), primary biliary cholangitis (PBC) (n=20), and healthy livers (n=5). Ductular reaction, progenitor cell phenotype, and signaling pathways were investigated by IHC and immunofluorescence. Ductular reaction was found to be more expansive and more proliferative in PBC than PSC. Ductular reaction correlated with fibrosis and clinical prognostic risk scores both in PSC and PBC. The ductular phenotype was predominantly biliary in PBC, as compared to signs of hepatocyte commitment in PSC.

Small-RNA sequencing was used to profile miRNA expression in cirrhotic nodules (CNs), dysplastic nodules, early HCCs, and small progressed HCCs in 17 patients having chronic liver disease of various etiologies. An miRNA expression signature of 62 miRNAs distinguishing small progressed HCCs from matched CNs was identified. The authors suggest that identification of miRNAs discriminating CNs from neoplastic nodules may have relevant translational implications in early HCC diagnosis.

Modern Pathology
These authors shed much needed light on the difficult subject of diagnosing liver graft versus host disease by creating a three-tiered scoring system and histopathological algorithm. Their results show a high sensitivity, specificity and accuracy when compared to controls, including drug-induced liver injury cases. This is an exciting and “must read” paper.  

The aim of this study was to identify the relationship of xanthogranulomatous cholecystitis (XGC) with IgG4-related cholecystitis.  The histological features of 57 XGC cases were compared with those of 104 conventional chronic cholecystitis (CC) cases.  XGC cases showed increased gallbladder wall thickening and histiocytic infiltration as compared with CC cases.  XGC cases also more commonly showed dense lymphoplasmacytic infiltration, storiform fibrosis, and extensive IgG4+ plasma cell infiltration.  XGC demonstrated an increased mean number of IgG4+ plasma cells (35/hpf) as compared with CC (5/hpf) [p <0.001].  The XGC cases were further classified based on a cut-off of 50 IgG4+ plasma cells because this threshold was proposed for IgG4-related disease in the liver, pancreas, and bile duct.  IgG4-high XGC cases (n=16) had a mean number of 78 IgG4+ plasma cells compared to IgG4-low XGC cases (n =41) that had a mean number of 11 IgG4+ plasma cells.  Nine IgG4-high XGC cases (16%) had denser lymphoplasmacytic infiltration, fibrosis, and a higher IgG4/IgG ratio, suggesting that a subset of XGC cases share histological features with IgG4-related cholecystitis.  XGC cases with histological features suggestive of IgG4-related cholecystitis were also found to show clinical features such as extracholecystic involvement and mass-forming inflammation.  Of the nine IgG4-high XGC cases that had histologic features suggestive of an IgG4-related disease, only one case also had IgG4-related disease at another site.  The study findings suggest that XGC and IgG4-related cholecystitis have overlapping histologic features but are at best weakly associated with other typical organ manifestations of IgG4-related disease.

This is a prospective, biopsy-controlled, study conducted to compare 10 liver fibrosis markers in 289 patients [Enhanced Liver Fibrosis test (ELF), FibroTest, transient elastography, 2-D shear-wave elastography, and 6 indirect marker tests] in detection of advanced liver fibrosis (defined as Kleiner stage > F3).  The liver biopsy fibrosis stage was used as the reference standard.  The aim of the study was 1) to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease in primary and secondary health centers using a literature-established cutoff value of 10.5 as seen in the setting of NAFLD; and 2) to assess the diagnostic accuracy for significant fibrosis or cirrhosis and to determine whether combinations of fibrosis markers increases diagnostic yield.  The prevalence of advanced fibrosis by liver biopsy was 23% (66/289); 6% (8/128) in primary care and 36% (58/161) in secondary care. Both ELF and FibroTest identified advanced fibrosis with comparable high accuracy (AUROC of 0.92 and 0.90, respectively) in both primary and secondary care settings. ELF >10.5 correctly diagnosed advanced fibrosis in 79% of patients and absence of advanced fibrosis in 91%.  In the primary care setting, for an ELF score < 10.5, the negative predictive value to rule out advanced fibrosis was 98%, but the positive predictive value to affirm a diagnosis of advanced fibrosis was lower at 60%.  ELF better identified patients with advanced liver fibrosis than indirect markers.  However, combining ELF and FibroTest did not increase diagnostic yield of detecting advanced liver fibrosis and did not differ from transient elastography. The study suggests that ELF and FibroTest identified advanced liver fibrosis in alcoholic patients from primary and secondary care with high diagnostic accuracy (AUROC values of 0.90 or higher using biopsy as reference).

Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis) and pancreas (autoimmune pancreatitis). The sera of patients with IAC/AIP was compared control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies for reactivity against human H69 cholangiocyte lysates on immunoblot. The choice of PSC sera as one of the controls is interesting as it is recognized that in a subset of patients there is an overlap with IgG4-RD. Annexin A11 was identified as the main target antigen. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD and not in controls.  Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes. This suggests that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.

Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
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 

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