Publications by authors named "Yoh Zen"

307 Publications

The Acute Onset of Autoimmune Hepatitis During Pregnancy in the Absence of Hypergammaglobulinemia and Autoantibodies.

Intern Med 2021 Apr 12. Epub 2021 Apr 12.

Department of Internal Medicine, Japanese Red Cross Kochi Hospital, Japan.

The onset of autoimmune hepatitis (AIH) during pregnancy is rare and often poses a diagnostic challenge. A 29-year-old Japanese woman experienced epigastric pain and nausea during the third trimester of her third pregnancy. Three days after the symptom onset, an emergency Caesarean section was performed because of suspected acute fatty liver of pregnancy; however, the patient's liver dysfunction worsened afterward. Despite normal serum IgG concentration and absence of autoantibodies, biopsy-proven severe hepatitis with centrilobular zonal necrosis and good biochemical response to corticosteroids led to a diagnosis of AIH. Therefore, AIH should be included in the differential diagnosis of liver dysfunction during pregnancy.
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http://dx.doi.org/10.2169/internalmedicine.7155-21DOI Listing
April 2021

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.

Sci Rep 2021 Mar 5;11(1):5303. Epub 2021 Mar 5.

Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19 (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 (n = 105) patients, there were no significant differences between FGF19 (n = 21) and FGF19 (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.
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http://dx.doi.org/10.1038/s41598-021-84117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935880PMC
March 2021

Developmental histology of the portal plate in biliary atresia: observations and implications.

Pediatr Surg Int 2021 Mar 1. Epub 2021 Mar 1.

Department of Paediatric Surgery, Kings College Hospital, Denmark Hill, London, SE5 9RS, UK.

Purpose: The key characteristic of biliary atresia (BA) is obliteration of the extrahepatic bile ducts at the level of the porta hepatis. We aimed to relate the immunohistochemical features of remnant biliary ductules at the porta hepatis with clinical features and outcomes.

Methods: Samples were immunostained with anti-cytokeratin 20 (CK20), vimentin and alpha-smooth muscle actin (aSMA). Primary outcome was set as clearance of jaundice (bilirubin ≤ 20 μmol/L) following Kasai portoenterostomy (KPE).

Results: Eighty-two cases were classified into syndromic BA (n = 10), cystic BA (n = 7), CMV IgM+ BA (n = 9) and isolated BA (n = 56). CK20 expression was confirmed in 40/82 (49%), and vimentin expression in 19/82 (23%). aSMA was negative in all cases studied. CK20 expression was less common in isolated BA (n = 20/56, 36%) compared to CMV IgM+ BA (n = 8/9, 89%), cystic BA (n = 7/7, 100%) (isolated BA vs non-isolated BA, P = 0.0008). There was no difference in vimentin expression among the sub-groups (isolated BA vs. non-isolated BA; P = 0.39). CoJ was achieved in 52/82 (63%) overall with significant difference depending simply on sub-group [e.g. syndromic BA 9/10 (90%)]. CK20 expression was associated with a diminished rate of CoJ in the entire cohort [CK20+ 32/56 (57%) vs. CK20- 20/26 (77%); P = 0.04]. By contrast no correlation was observed between vimentin expression and CoJ (P = 0.13).

Conclusion: CK20+ expression was associated with reduced clearance of jaundice in BA and a trend towards reduced native liver survival.
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http://dx.doi.org/10.1007/s00383-021-04861-xDOI Listing
March 2021

An update on the pharmacological management of autoimmune hepatitis.

Expert Opin Pharmacother 2021 Mar 26:1-14. Epub 2021 Mar 26.

Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom.

: Autoimmune hepatitis (AIH) is an immune mediated, inflammatory disease affecting the liver as a result of environmental triggers in susceptible individuals leading to loss of self-tolerance. The immunopathogenesis of AIH is not fully understood, which limits targeted therapeutic options.: In this review, the authors provide an overview of current practice in the management of AIH, which include induction therapy with corticosteroids (± thiopurines), followed by maintenance therapy. Lack of early response to treatment may serve as a predictor of those at risk of requiring treatment escalation to second- and third-line agents such as mycophenolate mofetil (MMF), calcineurin inhibitors or biologics. Evidence for third-line agents from small retrospective studies or individual centers are reviewed. The nuances of AIH treatment in pregnancy, overlap syndromes, and drug induced liver injury (DILI) warrant further consideration.: Augmenting the balance of regulatory T cells (Treg) and effector T cells is an appealing therapeutic target with a multitude of agents in development. Many of the challenges in AIH research are due to its rarity and lack of randomized data. Management of AIH should strive towards individualized care through risk stratification and use of the best therapeutic modality for each patient.
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http://dx.doi.org/10.1080/14656566.2021.1895747DOI Listing
March 2021

Neuroendocrine carcinoma and mixed neuroendocrine‒non-neuroendocrine neoplasm of the stomach: a clinicopathological and exome sequencing study.

Hum Pathol 2021 Apr 21;110:1-10. Epub 2021 Jan 21.

Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Institute of Liver Studies, King's College Hospital & King's College London, London SE5 9RS, UK. Electronic address:

The gene mutation profiles of gastric neuroendocrine neoplasms are incompletely understood. The purpose of this study was to characterize the molecular pathology of poorly differentiated neuroendocrine carcinoma (NEC) and mixed neuroendocrine‒non-neuroendocrine neoplasm (MiNEN) of the stomach. Surgical cases of gastric NEC (n = 7) and MiNEN (n = 6) were examined by clinical review, immunohistochemistry, microsatellite instability (MSI) analysis and whole-exome sequencing. NEC cases consisted of small- (n = 2) and large-cell types (n = 4). All cases of MiNEN were histologically composed of large-cell type NEC and tubular adenocarcinoma. Whole-exome sequencing analysis detected recurrent mutations in TP53 in 8 cases (62%), and they were more frequently observed in MiNEN than in NEC (100% vs. 29%). Frameshift mutations of APC were observed in two cases of MiNEN. One case of large-cell type NEC had a frameshift mutation with loss of heterozygosity in RB1. The other mutated genes (e.g., ARID1 and KRAS) were detected in a single case each. A high level of MSI was confirmed in one case of MiNEN, which harbored mutations in two well-differentiated neuroendocrine tumor (NET)-related genes (MEN1 and ATRX1). In cases of MiNEN, two histological components shared mutations in TP53, APC and ZNF521, whereas alterations in CTNNB1, KMT2C, PTEN and SPEN were observed in neuroendocrine components only. In conclusion, TP53 is a single, frequently mutated gene in gastric NEC and MiNEN, and alterations in other genes are less common, resembling the mutation profiles of gastric adenocarcinomas. Gene mutations frequently observed in well-differentiated NET were uncommon but not entirely exclusive.
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http://dx.doi.org/10.1016/j.humpath.2020.12.008DOI Listing
April 2021

An immunostaining panel of C-reactive protein, N-cadherin, and S100 calcium binding protein P is useful for intrahepatic cholangiocarcinoma subtyping.

Hum Pathol 2021 Mar 13;109:45-52. Epub 2020 Dec 13.

Institute of Liver Studies, King's College Hospital & King's College London, SE5 9RS, London, UK. Electronic address:

This study aimed to establish an immunohistochemical panel useful for subclassification of intrahepatic cholangiocarcinoma (iCCA) into small- and large-duct types. Fifty surgical cases of iCCA consisting of small- (n = 31) and large-duct types (n = 19) were examined. To imitate liver needle biopsies, tissue microarrays were constructed using three tissue cores (2 mm in diameter) obtained from one representative paraffin block of each case. Immunostaining for C-reactive protein (CRP), N-cadherin, tubulin beta-III (TUBB3), neural cell adhesion molecule (NCAM), and S100 calcium binding protein P (S100P) was conducted. Most cases of small-duct iCCA were immunoreactive to CRP and N-cadherin, whereas expressions of these markers were markedly less common in large-duct iCCA (CRP, 97% vs. 5%, P < 0.001; N-cadherin, 87% vs. 16%, P < 0.001). TUBB3 and NCAM were also more frequently expressed in small-duct iCCA (65% vs. 32%, P = 0.006; 58% vs. 5%, P < 0.001), but their sensitivities were lower than those of CRP and N-cadherin. S100P was more commonly expressed in large-duct iCCA than in small-duct iCCA (95% vs. 29%, P < 0.001), and diffuse expressions were observed in 17 of 19 cases of large-duct iCCA (90%). All cases with a CRP+/S100P- immunophenotype were of small-duct type, whereas all but one case with a CRP-/S100P+ immunophenotype were of large-duct type. Of 10 cases with a double-positive or double-negative immunophenotype, 7 were appropriately classified based on immunoreactivity to N-cadherin. In conclusion, CRP, N-cadherin, and S100P form a useful immunohistochemical panel for iCCA subclassification, and correct subclassification was possible in 92% of cases based on a proposed, simple algorithm.
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http://dx.doi.org/10.1016/j.humpath.2020.12.005DOI Listing
March 2021

Primary biliary cholangitis with normal alkaline phosphatase: A neglected clinical entity challenging current guidelines.

J Autoimmun 2021 Jan 20;116:102578. Epub 2020 Nov 20.

Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom.

Background & Aim: The diagnosis of primary biliary cholangitis (PBC), an uncommon immune-mediated cholestatic liver disease, is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum alkaline phopsphatase (ALP) levels. Timely initiation of treatment with ursodeoxycholic acid prevents progression to cirrhosis and liver failure. We aimed at investigating liver histology in patients with normal ALP level and positive AMA and/or PBC-specific ANA.

Methods: We searched the Swiss PBC Cohort Study database, which includes subjects with positive PBC autoimmune serology and normal ALP levels, for patients who underwent a liver biopsy. Histological slides were centrally reviewed by an expert liver pathologist, and sera were centrally re-tested for AMA and ANA.

Results: 30 patients were included; 90% females, median age 53 (range 27-72) years. Twenty-four (80%) had liver histology typical for (n = 2), consistent with (n = 16) or suggestive of (n = 6) PBC, including three of four AMA-negative ANA-positive patients. Among 22 ursodeoxycholic acid treated patients, 14 had elevated GGT levels before treatment; a significant decrease of the median GGT level between pre- (1.46 x ULN) and post- (0.43 x ULN) treatment (p = 0.0018) was observed.

Conclusions: In our series, a high proportion of AMA positive patients with normal ALP levels have PBC. For the first time we show histological diagnosis of PBC in AMA-negative/PBC-specific ANA-positive subjects and the potential role of GGT as a biomarker in PBC patients with normal baseline ALP levels. Current guidelines for the diagnosis of PBC do not cover the whole extent of PBC presentation, with important clinical implications in terms of timely treatment initiation.
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http://dx.doi.org/10.1016/j.jaut.2020.102578DOI Listing
January 2021

[Benign bile duct stricture:pathology and potential etiologies].

Authors:
Yoh Zen

Nihon Shokakibyo Gakkai Zasshi 2020;117(8):667-673

King's College Hospital, Institute of Liver Studies.

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http://dx.doi.org/10.11405/nisshoshi.117.667DOI Listing
September 2020

Secondary Hemochromatosis and Hepatocellular Carcinoma Developed from Immunoglobulin G4-Related Disease with Hepatopathy: A Case Report.

J Nippon Med Sch 2020 Aug 1. Epub 2020 Aug 1.

Department of Surgery, Nippon Medical School.

Immunoglobulin G4 (IgG4) -related disease (IgG4-RD) is a recently characterized entity in which lymphocytes and plasma cells infiltrate various anatomical sites. IgG4-hepatopathy, which is the manifestation of IgG4-RD, is a broader term covering various patterns of liver injury. The clinical course including the malignant potential of IgG4-RD remains unclear. Here we report the first case of secondary hemochromatosis and hepatocellular carcinoma (HCC) developed from IgG4-hepatopathy. A 67-year-old man was admitted to our hospital due to deteriorated glucose tolerance. Blood test results showed hypergammaglobulinemia, especially IgG4. He was readmitted 2 months later with dyspnea due to lung disease and pleural effusion, with elevated transaminase levels. He underwent liver and lung biopsies and was diagnosed with IgG4-RD, and received steroid therapy, which improved his serum IgG4 levels and imaging abnormalities. A follow-up computed tomography (CT) scan conducted 38 months later demonstrated a 50-mm-diameter tumor segments 7 and 8 of the liver. The resected specimen revealed HCC and abundant siderosis in the background liver, leading to a diagnosis of hemochromatosis. IgG4-positive cells were scarce, probably due to corticosteroid therapy. In the present case, IgG4-RD was well controlled with prednisolone (PSL) and immunosuppressive agent, and chronic hepatitis was not so severe, even though the patient subsequently developed HCC. However, extensive siderosis consistent with hemochromatosis was unexpectedly noted. It is suggested that secondary hemochromatosis and HCC developed during IgG4-RD with hepatopathy. Here we report the present case because it contributes to our understanding of IgG4-RD.
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http://dx.doi.org/10.1272/jnms.JNMS.2021_88-306DOI Listing
August 2020

Steatohepatitis-Like Changes in Hepatocellular Adenoma.

Am J Clin Pathol 2020 09;154(4):525-532

Department of Pathology, University of Washington School of Medicine, Seattle.

Objectives: Our aim was to investigate the frequency of steatohepatitic morphology in hepatocellular adenoma (HCA) and correlate with its clinical parameters and risk factors underlying nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

Methods: We examined a series of 41 liver resection specimens diagnosed with HCA for steatohepatitic changes. Background nonneoplastic liver was also evaluated. Clinical records were reviewed for risk factors of NAFLD/NASH.

Results: Six steatohepatitic HCAs (SH-HCAs) were identified, with an overall prevalence of six (14.6%) of 41, of which three were HNF1α inactivated and three were inflammatory, but none were β-catenin mutated. Five of the six patients with SH-HCA had at least one known risk factor for NAFLD/NASH, including obesity (n = 4; 66.7%), diabetes (n = 5; 83.3%), hypertension (n = 3; 50%), and dyslipidemia (n = 1; 16.7%). Compared with the patients without SH-HCA, the patients with SH-HCA had a higher frequency of type 2 diabetes, obesity, and hypertension. Of the six SH-HCAs, background nonneoplastic liver showed significant steatosis in three (50%) cases and steatohepatitic changes in one (16.7%) case.

Conclusions: Approximately 15% of HCAs in our series demonstrated steatohepatitic changes. Lack of such morphology in β-catenin-mutated subtype suggests reassurance in this morphologic variant of HCA.
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http://dx.doi.org/10.1093/ajcp/aqaa075DOI Listing
September 2020

Clinicopathological characteristics of intraductal papillary neoplasm of the bile duct: a Japan-Korea collaborative study.

J Hepatobiliary Pancreat Sci 2020 Sep 2;27(9):581-597. Epub 2020 Jul 2.

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: The prevalent location and incidence of intraductal papillary neoplasm of the bile duct (IPNB) and invasive carcinoma associated with them have varied markedly among studies due to differences in diagnostic criteria and tumor location.

Methods: IPNBs were classified into two types: Type 1 IPNB, being histologically similar to intraductal papillary mucinous neoplasm of the pancreas, and Type 2 IPNB, having a more complex histological architecture with irregular papillary branching or foci of solid-tubular components. Medical data were evaluated.

Results: Among 694 IPNB patients, 520 and 174 had Type 1 and Type 2, respectively. The levels of AST, ALT, ALP, T. Bil, and CEA were significantly higher in patients with Type 2 than in those with Type 1. Type 1 IPNB was more frequently located in the intrahepatic bile duct than Type 2, whereas Type 2 was more frequently located in the distal bile duct than Type 1 IPNB (P < 0.001). There were significant differences in 5-year cumulative survival rates (75.2% vs 50.9%; P < 0.0001) and 5-year cumulative disease-free survival rates (64.1% vs 35.3%; P < 0.0001) between the two groups.

Conclusion: Type 1 and Type 2 IPNBs differ in their clinicopathological features and prognosis. This classification may help to further understand IPNB.
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http://dx.doi.org/10.1002/jhbp.785DOI Listing
September 2020

De novo perihilar cholangiocarcinoma arising in the allograft liver 15 years post-transplantation for biliary atresia.

Pathol Int 2020 Aug 29;70(8):563-567. Epub 2020 Apr 29.

Institute of Liver Studies, King's College Hospital, London, UK.

Most primary liver cancers diagnosed in allograft livers are recurrent tumors of the native liver origin, while donor-derived primary liver cancers are markedly less common. A 21-year-old woman who had liver transplantation for post-Kasai biliary atresia was recently referred for post-transplant biliary stricture. Her transplantation was performed at the age of 6 years using the whole liver graft from a 10-year-old donor and choledocho-jejunostomy. The post-transplant course was uneventful in the first 15 years until she presented with obstructive jaundice. The stricture was located at the level of the hepaticojejunostomy, and required percutaneous transhepatic drainage and bile duct dilatation. She underwent an exploratory laparotomy, which suggested a neoplastic process widely involving the extrahepatic and intrahepatic large bile ducts. The histological examination of the resected extrahepatic bile duct confirmed infiltrating moderately differentiated adenocarcinoma. Molecular tests of multiple short tandem repeat loci confirmed the donor origin of the tumor. After four cycles of chemotherapy with gemicitabine and cisplatin, she is currently on radiotherapy in view of potential re-transplantation. De novo, post-transplant cholangiocarcinoma of graft origin is extremely uncommon with only three other cases reported. Two were associated with recurrent primary sclerosing cholangitis, and all had choledocho-jejunostomy at the time of transplantation.
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http://dx.doi.org/10.1111/pin.12944DOI Listing
August 2020

Rethinking fibrinogen storage disease of the liver: ground glass and globular inclusions do not represent a congenital metabolic disorder but acquired collective retention of proteins.

Hum Pathol 2020 06 21;100:1-9. Epub 2020 Apr 21.

Department of Diagnostic Pathology, Steel Memorial Hirohata Hospital, Himeji 671-1122, Japan. Electronic address:

Three types of intracytoplasmic inclusions immunoreactive to fibrinogen are collectively diagnosed as hepatic fibrinogen storage disease. This study aimed to better characterize ground glass (type II) and globular (type III) fibrinogen inclusions by the pathological examination of 3 cases and a literature review. Three adults (age: 32-64 years; male/female = 2:1) were unexpectedly found to have fibrinogen-positive ground glass changes (type II inclusions) by liver needle biopsy, against a background of acute hepatitis E, resolving acute cholangitis, or severe lobular hepatitis of unknown etiology. One patient also had fibrinogen-positive intracytoplasmic globules (type III inclusions) in the first biopsy, but they were not present in a second biopsy. None had coagulation abnormalities or hypofibrinogenemia. On immunostaining, both inclusions were strongly positive for not only fibrinogen but also C-reactive protein and C4d. Ultrastructurally, ground glass changes corresponded to membrane-bound cytoplasmic inclusions containing amorphous, granular material. The pathological features of type II fibrinogen inclusions were identical to those of pale bodies in hepatocellular carcinoma. The literature review suggested that type I fibrinogen inclusions characterized by a polygonal appearance are strongly associated with mutations in fibrinogen genes, coagulopathy, and family history, whereas type II/III inclusions are immunoreactive to multiple proteins and typically develop in cases of other unrelated liver diseases. In conclusion, type II and III fibrinogen inclusions do not represent a true hereditary storage disease but instead the collective retention of multiple proteins. Given the lack of clinical significance, a less specific name (e.g., pale body) may be more appropriate for those inclusions.
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http://dx.doi.org/10.1016/j.humpath.2020.04.004DOI Listing
June 2020

Clinicopathological differential diagnosis of IgG4-related disease: A historical overview and a proposal of the criteria for excluding mimickers of IgG4-related disease.

Pathol Int 2020 Jul 20;70(7):391-402. Epub 2020 Apr 20.

The Research Program for Intractable Disease by Ministry of Health, Labor and Welfare, Japanese Pathology Study Group of IgG4-related Disease, Tokyo, Japan.

IgG4-related disease (RD) is a relatively new entity, which was first proposed in 2001. Since then, clinical and pathological characteristics of the disease have been investigated. As IgG4-RD has been studied extensively, the diagnostic criteria for IgG4-RD of each organ and the comprehensive diagnostic criteria for IgG4-RD have also been developed. However, one of the biggest challenges in the field is distinguishing between IgG4-RD and mimickers, which show overlapping features with IgG4-RD. It is now known that some non-IgG4-RDs may meet the diagnostic criteria of IgG4-RD and can be misdiagnosed as IgG4-RD. However, accurate diagnosis is crucial, as the treatments for IgG4-RD and those for other diseases that may be misdiagnosed as IgG4-RD are different. This prompted us to create and propose comprehensive exclusion criteria for IgG4-RD. In this review, we have described the comprehensive exclusion criteria for IgG4-RD, with a historical overview of the disease. These exclusion criteria were recently created by the Research Program for Intractable Disease of the Ministry of Health, Labor, and Welfare of Japan, All Japan IgG4 team, to support correct and accurate diagnosis of IgG4-RD.
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http://dx.doi.org/10.1111/pin.12932DOI Listing
July 2020

Pathological characteristics and diagnosis of IgG4-related disease.

Authors:
Yoh Zen

Presse Med 2020 Apr 28;49(1):104014. Epub 2020 Mar 28.

Institute of Liver Studies, King's College Hospital & King's College London, London, UK. Electronic address:

IgG4-related disease (IgG4-RD) has been accepted as a distinct entity in various fields. It is being increasingly diagnosed and treated in routine practice. However, difficulties are still associated with the diagnostic process. Serum IgG4 elevations and imaging studies are useful, but not entirely diagnostic for this condition. Therefore, a pathological examination still plays an important role. Three characteristic microscopic changes are dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. IgG4 immunostaining reveals many IgG4-positive plasma cells and an IgG4/IgG-positive cell ratio of more than 40%. In addition to the number and ratio of IgG4-positive plasma cells, the diffuse distribution of positive plasma cells needs to be confirmed because IgG4-positive plasma cells may focally aggregate in many other conditions. In small biopsy samples, it is important to recognize not only characteristic findings, but also microscopic changes that are unlikely to occur in IgG4-RD because the identification of the latter findings leads to the exclusion of this condition. Another challenging field regards the diagnosis of long-standing disease. Along with disease progression, inflammatory infiltrate decreases, while storiform fibrosis and obliterative phlebitis are suspected to persistently exist. Therefore, the recognition of the latter two findings will be a diagnostic clue. Given the general suspicion that IgG4-RD has recently been over-diagnosed, precise tissue examinations based on the proposed standards and close clinicopathological correlations are crucial.
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http://dx.doi.org/10.1016/j.lpm.2020.104014DOI Listing
April 2020

Biliary intraductal tubule-forming neoplasm: a whole exome sequencing study of MUC5AC-positive and -negative cases.

Histopathology 2020 Jun 15;76(7):1005-1012. Epub 2020 May 15.

Institute of Liver Studies, King's College Hospital & King's College London, London, UK.

Aims: Biliary intraductal tubular neoplasms that are non-mucinous and negative for mucin 5AC (MUC5AC) are called intraductal tubulopapillary neoplasms (ITPNs). Intraductal tubular neoplasms with mucinous cytoplasm and MUC5AC positivity also occur and their nature remains unclear, although some pathologists may classify these as 'intraductal papillary neoplasms of the bile duct (IPNBs) of gastric type'. This study aimed to elucidate genetic features of biliary intraductal tubular neoplasms.

Methods And Results: Six resected cases of biliary intraductal neoplasm with >70% tubular configuration were characterised by clinicopathological examination and whole exome sequencing, and the findings obtained were compared between MUC5AC-negative (n = 2) and -positive cases (n = 4). The intraductal tumours consisted of the pancreatobiliary-type epithelium with high-grade dysplasia arranged in back-to-back tubules. Both of the two MUC5AC-negative cases were non-invasive neoplasms and developed in the liver, whereas all MUC5AC-positive cases had invasive carcinoma and were present in the intrahepatic (n = 2), perihilar (n = 1) and distal bile ducts (n = 1). In an exome-sequencing study, MUC5AC-negative cases harboured mutations in CTNNB1, SF3B1, BAP1 and BRCA1 (one case each). KRAS mutations were observed in three of four MUC5AC-positive cases (75%) but none of the MUC5AC-negative neoplasms. Compared to published data, known driver genes of other intraductal neoplasms of the pancreatobiliary system (e.g. APC, CTNNB1, STK11, GNAS and PIK3CA) were wild-type in all but one MUC5AC-negative case with CTNNB1 mutation. Chromatin modifiers (ARID1A, BAP1 and KMT2C) were also altered in MUC5AC-positive cases, similar to usual cholangiocarcinomas.

Conclusions: This exome-sequencing study suggested that MUC5AC-negative biliary ITPNs are genetically distinct from pancreatic ITPNs and IPNBs. They may also biologically differ from MUC5AC-positive tubular neoplasms despite morphological resemblance.
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http://dx.doi.org/10.1111/his.14103DOI Listing
June 2020

Proposal of a liver histology-based scoring system for bile salt export pump deficiency.

Hepatol Res 2020 Jun 25;50(6):754-762. Epub 2020 Mar 25.

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.

Aim: Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition.

Methods: After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined.

Results: Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8-11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4-phenylbutyrate, histological changes were evaluated as improved or unchanged.

Conclusions: The proposed histology-based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.
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http://dx.doi.org/10.1111/hepr.13494DOI Listing
June 2020

Patient-Derived Scaffolds of Colorectal Cancer Metastases as an Organotypic 3D Model of the Liver Metastatic Microenvironment.

Cancers (Basel) 2020 Feb 5;12(2). Epub 2020 Feb 5.

First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.

The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent need for new tissue culture models to study colorectal cancer liver metastasis (CRLM) as current models do not mimic the biological, biochemical, and structural characteristics of the metastatic microenvironment. Decellularization provides a novel approach for the study of the cancer extracellular matrix (ECM) as decellularized scaffolds retain tissue-specific features and biological properties. In the present study, we created a 3D model of CRC and matched CRLM using patient-derived decellularized ECM scaffolds seeded with the HT-29 CRC cell line. Here, we show an increased HT-29 cell proliferation and migration capability when cultured in cancer-derived scaffolds compared to same-patient healthy colon and liver tissues. HT-29 cells cultured in CRLM scaffolds also displayed an indication of epithelial-mesenchymal transition (EMT), with a loss of E-cadherin and increased Vimentin expression. EMT was confirmed by gene expression profiling, with the most represented biological processes in CRLM-seeded scaffolds involving demethylation, deacetylation, a cellular response to stress metabolic processes, and a response to the oxygen level and starvation. HT-29 cells cultured in cancer-specific 3D microenvironments showed a reduced response to treatment with 5-fluorouracil and 5-fluorouracil combined with Irinotecan when used at a standard IC (as determined in the 2D culture). Our 3D culture system with patient-derived tissue-specific decellularized ECM better recapitulates the metastatic microenvironment compared to conventional 2D culture conditions and represents a relevant approach for the study of CRLM progression and assessing the response to chemotherapy agents.
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http://dx.doi.org/10.3390/cancers12020364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072130PMC
February 2020

Clinical and Pathological Characteristics of IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis Diagnosed Based on Experts' Diagnosis.

Ann Vasc Dis 2019 Dec;12(4):460-472

Department of Cardiology, Osaka Medical College, Takatsuki, Osaka, Japan.

IgG4-related disease is a systemic disease, characterized by elevation of serum IgG4 and, histopathologically, massive infiltration of IgG4+ lymphocyte and plasma cell infiltration, storiform fibrosis, causing enlargement, nodules or thickening. It may affect various organs simultaneously or metachronously. Here we analyzed the clinical and pathological characteristics of 99 patients diagnosed with IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. Of 99 patients (women/men, 15/84; mean age 67.3±9.5 years), 33 were diagnosed based on the histopathological findings of perivascular/retroperitoneal lesions, 50 were diagnosed based on the characteristic imaging findings of perivascular/retroperitoneal lesions and the presence of definitive IgG4-related disease in other organ(s), and the remaining 16 patients were diagnosed by experts based on the characteristic imaging findings of perivascular/retroperitoneal legions, serological findings, response to glucocorticoid treatment, and/or the presence of suspected IgG4-related disease in other organ(s). According to the new organ-specific criteria proposed by experts, 73 (73.7%) diagnoses were categorized to be definitive, and 6 (6.1%) and 17 (17.2%) diagnoses were categorized to be probable and possible, respectively. Further analyses are needed to clarify the optimal diagnostic and therapeutic strategy of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. (This is a translation of J Jpn Coll Angiol 2018; 58: 117-129.).
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http://dx.doi.org/10.3400/avd.oa.19-00085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957903PMC
December 2019

The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease.

Ann Rheum Dis 2020 01 3;79(1):77-87. Epub 2019 Dec 3.

Massachusetts General Hospital Rheumatology Unit, Harvard Medical School, Boston, Massachusetts, USA

IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises; existing literature; derivation and validation cohorts of 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiological and basic science investigations.
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http://dx.doi.org/10.1136/annrheumdis-2019-216561DOI Listing
January 2020

The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease.

Arthritis Rheumatol 2020 01 2;72(1):7-19. Epub 2019 Dec 2.

Massachusetts General Hospital, Boston.

Objective: IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD.

Methods: An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included.

Results: A 3-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval [95% CI] 97.2-99.8%) and a sensitivity of 85.5% (95% CI 81.9-88.5%). In the second, the specificity was 97.8% (95% CI 93.7-99.2%) and the sensitivity was 82.0% (95% CI 77.0-86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds.

Conclusion: ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.
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http://dx.doi.org/10.1002/art.41120DOI Listing
January 2020

Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis.

Sci Rep 2019 11 19;9(1):17075. Epub 2019 Nov 19.

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.

Progressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0-3.0;P = 0.003) and 2.4-fold (95% CI, 1.7-3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.
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http://dx.doi.org/10.1038/s41598-019-53628-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863819PMC
November 2019

Comparison of a 22-gauge Franseen-tip needle with a 20-gauge forward-bevel needle for the diagnosis of type 1 autoimmune pancreatitis: a prospective, randomized, controlled, multicenter study (COMPAS study).

Gastrointest Endosc 2020 02 22;91(2):373-381.e2. Epub 2019 Oct 22.

Department of Gastroenterology, Yodogawa Christian Hospital, Osaka, Japan.

Background And Aims: Histologic diagnosis of autoimmune pancreatitis (AIP) using EUS-guided FNA (EUS-FNA) is difficult. To address this issue, new fine-needle biopsy (FNB) needles were recently developed. Here, we prospectively evaluated 2 newly designed EUS-FNB needles for histologic evaluation in patients with type 1 AIP.

Methods: This was a prospective, randomized, multicenter trial comparing biopsy specimens obtained with a 22-gauge Franseen needle or a 20-gauge forward-bevel needle in patients with suspected type 1 AIP. AIP was diagnosed according to international consensus diagnostic criteria. The primary endpoint was the sensitivity of EUS-FNB needles, and secondary endpoints were the amount of specimen obtained, histology of the pancreas based on evaluation of lymphoplasmacytic sclerosing pancreatitis (LPSP), and contribution of histologic findings to the diagnosis of AIP.

Results: One hundred ten patients were randomly assigned to the Franseen group (22-gauge Franseen needle) or the forward-bevel group (20-gauge forward-bevel needle). EUS-FNB sampling was successful in all patients. Nine patients were excluded because of diagnoses other than AIP. Compared with the forward-bevel needle, the Franseen needle obtained a significantly greater number of high-power fields. Of 101 patients, 39 patients (78%) in the Franseen group and 23 patients (45%) in the Forward-bevel group were diagnosed with level 1 or 2 LPSP (P = .001). Thirty-six patients could not be diagnosed with type 1 AIP without EUS-FNB specimen results.

Conclusions: The 22-gauge Franseen needle should be routinely used for histologic diagnosis of type 1 AIP. (Clinical trial registration number: UMIN 000027668.).
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http://dx.doi.org/10.1016/j.gie.2019.10.012DOI Listing
February 2020

Intracholecystic papillary neoplasm of the gallbladder protruding into the common bile duct: A case report.

Mol Clin Oncol 2019 Nov 9;11(5):488-492. Epub 2019 Sep 9.

Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK.

The current study indicates the case of intracholecystic papillary neoplasm (ICPN) protruding into the common bile duct (CBD) without superficial spread. A 58-year-old woman presented to hospital with a fever that lasted for three days. Laboratory tests revealed elevated hepatobiliary enzyme levels. CT, MRI and endoscopic ultrasonography revealed a polypoid, papillary tumor inside the gallbladder cavity, which also extended to the CBD. On peroral cholangioscopy, a papillary tumor with mucin production was found at the middle bile duct. Biliary biopsy and bile cytology indicated adenocarcinoma. Based on a diagnosis of ICPN extending to the CBD, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy and gallbladder bed resection. However, pathological examination revealed that the ICPN was confined to the gallbladder and cystic duct, whereas the CBD was tumor-free. The present case indicates that when ICPN increases in size, it may protrude into the CBD due to an increased intracholecystic pressure, which increases the risk of overestimation of tumor extension and may result in unnecessary additional bile duct resection.
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http://dx.doi.org/10.3892/mco.2019.1919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776826PMC
November 2019

Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes.

Histopathology 2020 Feb 1;76(3):470-480. Epub 2019 Dec 1.

Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.

Aims: Immune check-point inhibitors are known to cause immune-mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab.

Methods And Results: Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second-generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check-point inhibitor (3 days-1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab-treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab-treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8 /CD4 cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug-induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis.

Conclusions: Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8 lymphocytes and macrophages due to blockage of PD-1-PD-L1 interaction.
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http://dx.doi.org/10.1111/his.14000DOI Listing
February 2020

Sinusoidal-type Angiosarcoma of the Liver: Imaging Features and Potential Diagnostic Utility of p53 Immunostaining.

Am J Surg Pathol 2019 12;43(12):1728-1731

Department of Radiology, Kobe University Graduate School of Medicine Kobe, Japan.

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http://dx.doi.org/10.1097/PAS.0000000000001349DOI Listing
December 2019

Case of resected multiple hepatocellular adenomas in a young man with severe obesity.

Surg Case Rep 2019 Aug 13;5(1):131. Epub 2019 Aug 13.

Department of Surgery and Digestive Surgery, Kita-Harima Medical Center, 926-250, Ichiba-cho, Ono, 675-1392, Japan.

Background: Hepatocellular adenoma (HCA) is a rare liver tumor that has the potential for rupture and malignant transformation. Here, we report a case of multiple hepatocellular adenomas (HCAs) that were treated by surgical resection.

Case Presentation: An 18-year-old man was admitted to our hospital with proteinuria. His height was 176.5 cm, weight was 126 kg, and body mass index was 40 kg/m. A liver tumor was incidentally found on abdominal ultrasonography. Contrast-enhanced computed tomography and gadoxetic acid-enhanced magnetic resonance imaging revealed three hepatic tumors that were 68 mm, 16 mm, and 9 mm in segments 3/4, 8, and 1, respectively. A percutaneous needle biopsy of the largest tumor was performed, the diagnosis of unclassified type HCA was made, and laparoscopic partial liver resection was performed of all three. The postoperative course was uneventful, and the patient was discharged 12 days later. An immunohistochemical examination revealed positivity for serum amyloid A protein, no decrease in fatty acid-binding protein, and negativity for β-catenin, glutamine synthetase, and cytokeratin 7. Therefore, these tumors were diagnosed as inflammatory type HCAs.

Conclusions: We reported an extremely rare case of multiple resected HCAs in a young, obese Japanese man. Our findings suggest that HCA should be considered in the differential diagnosis of liver tumor in obese patients. Further studies that consider clinical and molecular risk factors are required to establish individualized treatment plans for HCA in obese patients.
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http://dx.doi.org/10.1186/s40792-019-0689-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692803PMC
August 2019

Immunoglobulin G4-related Liver Disease Overlapping with Non-alcoholic Steatohepatitis That Was Diagnosed Simultaneously with Autoimmune Pancreatitis: A Case Report and Review of the Literature.

Intern Med 2019 Dec 31;58(24):3537-3543. Epub 2019 Jul 31.

Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, Japan.

A 70-year-old woman was referred to our hospital due to symptoms of dry eyes, dry mouth, and epigastric pain. Computed tomography showed distal pancreatic swelling, liver edge dullness and surface irregularities. Serum anti-nuclear antibody titers, immunoglobulin G and IgG4 levels were elevated. Autoimmune pancreatitis (AIP) was diagnosed based on endoscopic findings and a histopathological examination. Her AIP improved after starting prednisolone treatment. A liver biopsy revealed interface hepatitis with lymphoplasmacyte and IgG4-positive plasma cell infiltration. In addition, non-alcoholic steatohepatitis (NASH) was diagnosed based on the presence of parenchymal steatosis, ballooning hepatocytes, and pericellular fibrosis. We experienced a unique liver disease case showing IgG4-related liver disease overlapping with NASH.
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http://dx.doi.org/10.2169/internalmedicine.3204-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949448PMC
December 2019

Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy.

Semin Diagn Pathol 2019 Nov 24;36(6):434-440. Epub 2019 Jul 24.

Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, United States; Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States. Electronic address:

Liver injury triggered by immune checkpoint inhibitors has been increasingly seen in clinical practice, and the incidence is likely to rise further in the next several years because of expanded indications for cancer immunotherapy. Tissue damage driven by disrupted immune tolerance against self-antigens is called an immune-related adverse event (irAE). irAEs in the liver histologically presents panlobular hepatitis (∼70%), isolated central zonal necrosis (∼20%), primarily granulomatous hepatitis (∼5%), and other minor forms of tissue injury (∼5%). Infiltrating cells are mainly lymphocytes and occasional eosinophils. Unlike classic autoimmune hepatitis (AIH), plasma cell infiltration is not conspicuous. Immunostaining reveals a large number of CD8+ T lymphocytes and a markedly smaller number of CD4+ cells or CD20+ B lymphocytes. The unique CD3+/CD20+ and CD4+/CD8+ ratios shifted in favor of CD8+ cytotoxic T lymphocytes are helpful to discriminate irAEs from other conditions (e.g., AIH, idiosyncratic drug-induced liver injury). Another hepatobiliary manifestation of irAEs is sclerosing cholangitis clinically characterized by elevations of biliary enzymes, diffuse duct wall thickening, and duct dilatation. Lymphocytic infiltration can be observed by endoscopic biopsies from the thick extrahepatic bile ducts, and liver needle biopsies may also show severe lymphocytic cholangitis resembling primary biliary cholangitis. An important differential diagnosis of irAEs is previously asymptomatic or subclinical liver disease unmasked by cancer immunotherapy, which is often challenging and requires close clinicopathological correlations.
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http://dx.doi.org/10.1053/j.semdp.2019.07.009DOI Listing
November 2019

Type 1 Autoimmune Pancreatitis with Imaging Appearance Similar to That of Malignant Cystic Tumor.

Case Rep Gastroenterol 2019 May-Aug;13(2):265-270. Epub 2019 Jun 14.

Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

A 79-year-old man was admitted with asymptomatic elevation of liver enzymes and tumor markers. Abdominal contrast-enhanced computed tomography demonstrated swelling of the pancreatic head, and additional blood test showed raised IgG4 levels. Histological examination by endoscopic ultrasonography (EUS)-guided fine needle aspiration for pancreatic head mass revealed storiform fibrosis and IgG4-positive plasma cell infiltration. We diagnosed this case as type 1 autoimmune pancreatitis (AIP). In addition, there was a cystic lesion in the pancreatic body apart from the pancreatic head mass. A mural nodule in the multilocular cyst was detected by EUS, and there was positive uptake of fluorodeoxyglucose in positron emission tomography/magnetic resonance imaging. The preoperative diagnosis of this cystic lesion was intraductal papillary mucinous carcinoma, and distal pancreatomy was performed. Histopathological findings showed various sizes of retention cysts caused by IgG4-positive plasma cell infiltration around the pancreatic branch ducts. The mural nodule was a fibrotic mass with diffuse infiltration of IgG4-positive cells. This cystic lesion mimicking malignant cystic neoplasm occurred in relation to AIP. This case provided important information helping to understand the mechanism of formation of mural nodules in multilocular cysts in patients with type 1 AIP.
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http://dx.doi.org/10.1159/000500477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600027PMC
June 2019