Pathologists play a central role in the diagnosis and classification of intrahepatic cholangiocarcinoma (iCCA). iCCA is currently classified into small- and large-duct types. Small-duct iCCA is ...characterized by a mass-forming gross appearance, mucus-poor ductule-like histology, and frequent association with chronic parenchymal liver diseases (eg, cirrhosis). Large-duct iCCA is an infiltrative duct-forming adenocarcinoma with a fibrotic stroma, similar to perihilar cholangiocarcinoma. Chronic cholangiopathies (eg, primary sclerosing cholangitis, liver flukes) are associated with an increased risk of large-duct iCCA. Alterations in IDH1/2, BAP1, or FGFR2 are characteristic molecular features of small-duct iCCA, whereas mutations in KRAS and SMAD4 and the amplification of MDM2 are mainly observed in large-duct iCCA. C-reactive protein and N-cadherin are commonly expressed in small-duct iCCA, and S100P is a good marker for large-duct iCCA. In addition to well-known subtypes (eg, cholangiolocellular carcinoma), uncommon variants are recognized. A tubulocystic variant is often misinterpreted as a benign neoplasm. Mucoepidermoid and enteroblastic variants are under-recognized and pose a diagnostic challenge. Cholangioblastic cholangiocarcinoma characterized by inhibin-A expression was recently found to have an NIPBL-NACC1 gene fusion. Despite significant advances in hepatobiliary pathology, there are still controversial premalignant entities that require large comprehensive studies. There are morphological overlaps between biliary adenofibroma and the tubulocystic variant of iCCA. Type 2 intraductal papillary neoplasm of the bile duct (IPNB) is typically associated with invasive malignancy at the initial presentation and lacks unique molecular features. Therefore, some pathologists prefer the term “papillary cholangiocarcinoma” over type 2 IPNB.
•Small- and large-duct types of iCCA have distinct clinical and molecular features.•Immunohistochemistry for CRP, N-cadherin, and S100P is useful for iCCA classification.•A tubulocystic variant of iCCA is often misinterpreted as a benign neoplasm.•Further studies are needed to better characterize biliary adenofibroma and type 2 IPNB.
Autoimmune pancreatitis (AIP) has attracted much attention in the last two decades, and due to the diagnostic value of immunoglobulin G4 (IgG4), the number of cases diagnosed in clinical practice has ...markedly increased. However, in contrast to prototypic IgG4-related type 1 AIP, a minor subtype of AIP, referred to as type 2 AIP, is less widely known and has thus not yet been characterized in detail. Type 2 AIP is unrelated to IgG4 and is a completely distinct entity from type 1 AIP. One confusing factor is that the two types of AIP share patterns of clinical presentation (e.g., acute pancreatitis and painless jaundice) and imaging abnormalities (e.g., diffuse or segmental enlargement). Since there are currently no established serum markers, the diagnosis of type 2 AIP is highly challenging and requires the tissue confirmation of neutrophilic injury to the pancreatic ducts, a finding designated as a granulocytic epithelial lesion. Approximately one-third of cases are associated with inflammatory bowel disease, particularly ulcerative colitis; however, the pathological relationship between these two conditions has not yet been clarified. Unanswered questions relate to its pathophysiology, the potential development of a similar granulocytic injury in other organs, and the characteristics of pediatric cases. This review summarizes consensus and controversies surrounding type 2 AIP, with the aim of increasing awareness and highlighting the unmet needs of this underrecognized condition.
Immunoglobulin G4-related disease (IgG4-RD) in the pancreatobiliary system manifests as sclerosing cholangitis (SC), hepatic inflammatory pseudotumors, and type 1 autoimmune pancreatitis (AIP). The ...pathology of IgG4-RD involves an inflammatory process and fibrogenic pathway, the combination of which damages the affected organs. Fibroinflammatory injury is characterized by three microscopic findings: a diffuse lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, obliterative phlebitis, and storiform fibrosis. Although the diagnosis of IgG4-related pancreatocholangitis is relatively straightforward in surgical specimens, the current clinical requirement is to diagnose patients using biopsy samples, which remains challenging. Histological differential diagnoses include primary SC, follicular cholangitis/pancreatitis, SC with granulocytic epithelial lesions, and type 2 AIP. Although the massive infiltration of IgG4-positive plasma cells is a histological hallmark of IgG4-RD, many other immune cells (e.g., Th2 lymphocytes, regulatory T cells, and M2 macrophages) appear to be strongly involved in orchestral immune reactions.
Autoimmune pancreatitis (AIP) has attracted much attention in the last two decades, and due to the diagnostic value of immunoglobulin G4 (IgG4), the number of cases diagnosed in clinical practice has ...markedly increased. However, in contrast to prototypic IgG4-related type 1 AIP, a minor subtype of AIP, referred to as type 2 AIP, is less widely known and has thus not yet been characterized in detail. Type 2 AIP is unrelated to IgG4 and is a completely distinct entity from type 1 AIP. One confusing factor is that the two types of AIP share patterns of clinical presentation (e.g., acute pancreatitis and painless jaundice) and imaging abnormalities (e.g., diffuse or segmental enlargement). Since there are currently no established serum markers, the diagnosis of type 2 AIP is highly challenging and requires the tissue confirmation of neutrophilic injury to the pancreatic ducts, a finding designated as a granulocytic epithelial lesion. Approximately one-third of cases are associated with inflammatory bowel disease, particularly ulcerative colitis; however, the pathological relationship between these two conditions has not yet been clarified. Unanswered questions relate to its pathophysiology, the potential development of a similar granulocytic injury in other organs, and the characteristics of pediatric cases. This review summarizes consensus and controversies surrounding type 2 AIP, with the aim of increasing awareness and highlighting the unmet needs of this underrecognized condition. (Gut Liver 2022;16:357-365)
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.
Summary IgG4-related disease is a protean condition that mimics many malignant, infectious, and inflammatory disorders. This multi-organ immune-mediated condition links many disorders previously ...regarded as isolated, single-organ diseases without any known underlying systemic condition. It was recognised as a unified entity only 10 years ago. Histopathology is the key to diagnosis. The three central pathology features of IgG4-related disease are lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. The extent of fibrosis is an important determinant of responsiveness to immunosuppressive therapies. IgG4-related disease generally responds to glucocorticoids in its inflammatory stage, but recurrent or refractory cases are common. Important mechanistic insights have been derived from studies of patients treated by B-cell depletion. Greater awareness of this disease is needed to ensure earlier diagnoses, which can prevent severe organ damage, disabling tissue fibrosis, and even death. Identification of specific antigens and T-cell clones that drive the disease will be the first steps to elucidate the pathogenesis of IgG4-related disease.
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.
Our knowledge and experience of IgG4-related sclerosing cholangitis (ISC) have expanded in the last decade. ISC is one of the common organ manifestations of IgG4-related disease (IgG4-RD); ...approximately 60 % of patients with this systemic condition have ISC in the proximal and/or distal bile ducts. ISC needs to be discriminated from primary sclerosing cholangitis, cholangiocarcinoma, and other rare forms of lymphoplasmacytic cholangiopathy (e.g., follicular cholangitis and sclerosing cholangitis with granulocytic epithelial lesions). Its diagnosis requires a multidisciplinary approach, in which serology, histology, and imaging play crucial roles. Treatments with high-dose corticosteroids typically lead to the rapid and consistent induction of disease remission. Another promising therapeutic approach is B-cell depletion with rituximab. Although disease relapse is relatively common, provided that appropriate treatments are administered, ISC is considered a “benign” disease with a low risk of liver failure and biliary malignancy. Its molecular pathology is characterized by Th2-dominant immune reactions, regulatory T-cell activation, and CCL1-CCR8 interactions. Particular subsets of B cells such as plasmablasts and regulatory B cells also expand. A recent global proteomic study demonstrated that three significantly activated immunological cascades in ISC were all B-cell- or immunoglobulin-related (Fc-gamma receptor-mediated phagocytosis, B-cell receptor signaling pathway, and Fc-epsilon receptor I signaling pathway), suggesting the crucial roles of B cells in the underlying immune reactions. Despite the expansion of our knowledge of the pathophysiology of ISC, the exact role of IgG4 remains unclear. A better understanding of its immunopathology will offer some potential drug targets for this emerging biliary disease.
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.
Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ...ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.
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