IgG4‐related sclerosing cholangitis (IgG4‐SC) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4‐related ...disease. Although clinical diagnostic criteria of IgG4‐SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4‐SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions (CQs) with clinical statements were developed regarding diagnosis (14 CQs) and treatment (4 CQs). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4‐SC.
Highlight
IgG4‐related sclerosing cholangitis is recognized as a biliary manifestation of IgG4‐related disease, and differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Kamisawa and colleagues developed consensus guidelines using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4‐related sclerosing cholangitis.
Background & Aims No standardised definition exists for acute, severe AIH (AS-AIH). However, rapid identification of AS-AIH and early corticosteroid therapy may prevent the need for liver ...transplantation (LT). We set out to determine the clinical outcomes of patients with AS-AIH presenting to our institution with particular focus on the role of corticosteroids. Methods Retrospective analysis of a prospectively collated database identified patients presenting with AS-AIH from 1999 to 2009. We defined AS-AIH as an acute presentation with an INR of ⩾1.5 at any time without histological evidence of cirrhosis. Results 32 patients were identified with AS-AIH. Among the 32 AS-AIH patients 23 were treated with corticosteroids of whom 10 (48%) required LT, whilst all 9 untreated patients required LT ( p = 0.01). Untreated patients demonstrated higher MELD scores at presentation (34 vs. 28 p = 0.01) and a non-significant decrease in episodes of sepsis but no difference in sepsis or mortality was observed between untreated or treated patients (11% vs. 26% p = 0.6 and 22% vs. 17% p = 0.99 respectively). Among treated patients, no difference in MELD scores was observed between responders or failures. Despite 59% undergoing LT, six deaths (19%) occurred. Conclusion In a well characterised cohort of patients with AS-AIH, almost 60% required LT and 20% died. There was no difference in prognostic scores between steroid responders and failures and steroid exposure did not appear to jeopardise survival. Patients with AS-AIH should be considered for a trial of corticosteroids expediently whilst a thorough search for sepsis and assessment for LT should occur if clinical deterioration or encephalopathy develops.
Aims
The diagnosis of IgG4‐related disease (IgG4‐RD) requires a multidisciplinary approach, in which histology plays an important role. Although a diagnosis was previously established by the use of ...surgically resected specimens, there is increasing clinical demand to diagnose this systemic condition by the use of biopsies. The aim of the present study was to elucidate how useful transbronchial lung biopsies (TBLBs) are for this diagnostic purpose.
Methods and results
The study cohort consisted of 20 consecutive patients diagnosed with IgG4‐RD in other organs who underwent TBLB for potential pulmonary involvement. One case showing multiple granulomas suggestive of other conditions was excluded. Seven of the remaining 19 cases (37%) showed apparently normal lung tissue, indicating a sampling error, and 12 (63%) had microscopic abnormalities. Nine cases (47%) with a dense lymphoplasmacytic infiltrate met the number and ratio criteria for IgG4‐positive plasma cell infiltration (>20 cells/high‐power field, and an IgG4/IgG‐positive plasma cell ratio of >40%). Obliterative phlebitis and storiform fibrosis were observed in one case each. In 43 control cases of various inflammatory conditions, tissue IgG4 elevations appeared to be uncommon, with only two cases (5%) each meeting the number or ratio criterion, and one case (2%) fulfilling both. All control cases with tissue IgG4 elevations were of eosinophilic pneumonia.
Conclusions
Transbronchial lung biopsies provided histological findings that were supportive for the diagnosis of IgG4‐RD in 47% of cases, with 98% diagnostic specificity. Therefore, they have potential as a useful and acceptable diagnostic approach for IgG4‐related lung disease.
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.
Pancreatic ductal adenocarcinoma (PDAC) shows pronounced epithelial and mesenchymal cancer cell populations1-4. Cellular heterogeneity in PDAC is an important feature in disease subtype ...specification3-5, but how distinct PDAC subpopulations interact, and the molecular mechanisms that underlie PDAC cell fate decisions, are incompletely understood. Here we identify the BMP inhibitor GREM16,7 as a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse. Greml inactivation in established PDAC in mice resulted in a direct conversion of epithelial into mesenchymal PDAC cells within days, suggesting that persistent GREM1 activity is required to maintain the epithelial PDAC subpopulations. By contrast, Greml overexpression caused an almost complete 'epithelialization' of highly mesenchymal PDAC, indicating that high GREM1 activity is sufficient to revert the mesenchymal fate ofPDAC cells. Mechanistically, Greml was highly expressed in mesenchymal PDAC cells and inhibited the expression ofthe epithelial-mesenchymal transition transcription factors Snail (also known as Snail) and Snai2 (also known as Slug) in the epithelial cell compartment, therefore restricting epithelial-mesenchymal plasticity. Thus, constant suppression of BMP activity is essential to maintain epithelial PDAC cells, indicating that the maintenance ofthe cellular heterogeneity of pancreatic cancer requires continuous paracrine signalling elicited by a single soluble factor.
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.
Growing evidence has suggested that intrahepatic cholangiocarcinoma (iCCA) can be classified into small- and large-duct types. The present study aimed to elucidate how large-duct iCCA is similar and ...dissimilar to perihilar cholangiocarcinoma (pCCA).
The study cohort consisted of iCCA (n = 58) and pCCA (n = 44). After iCCA tumors were separated into small- (n = 36) and large-duct (n = 22) types based on our histologic criteria, genetic statuses of the three types of neoplasms were compared. Locations of iCCA were plotted on a three-dimensional image and their distances from the portal bifurcation were measured.
Large-duct iCCA was distinct from small-duct iCCA in terms of frequency of bile duct reconstruction required, perineural infiltration, and survival, with these features more similar to pCCA. Large-duct iCCA and pCCA more frequently had the loss of SMAD4 expression and MDM2 amplifications than small-duct iCCA, whereas the loss of BAP1 expression and IDH1 mutations were mostly restricted to small-duct iCCA. From imaging analysis, most tumors of large-duct iCCA were present around the second branches of the portal vein.
Large-duct type iCCA shared the molecular features with pCCA, and it may be reasonable to expand the definition of pCCA to include cancers originating from the second bile duct branches.
Autoimmune pancreatitis (AIP) is classified into type 1 (IgG4-related) and type 2 (IgG4-unrelated) and the interpretation of pancreatic biopsy findings plays a crucial role in their diagnosis. Needle ...biopsy of type 1 AIP in the acute or subacute phase shows a diffuse lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and the infiltration of many IgG4-positive plasma cells. In a later phase, changes become less inflammatory and more fibrotic, making interpretations more challenging. Confirmation of the lack of ‘negative’ findings that are unlikely to occur in type 1 AIP (e.g., neutrophilic infiltration, abscess) is important to avoid an overdiagnosis. The number of IgG4-positive plasma cells increases to >10 cells/high-power field (hpf), and the IgG4/IgG-positive plasma cell ratio exceeds 40 %. However, these are minimal criteria and typical cases show >30 positive cells/hpf and a ratio >70 % even in biopsy specimens. Therefore, cases with a borderline increase in this number or ratio need to be diagnosed with caution. In cases of ductal adenocarcinoma, the upstream pancreas rarely shows type 1 AIP-like changes; however, the ratio of IgG4/IgG-positive plasma cells is typically <40 %. Although the identification of a granulocytic epithelial lesion (GEL) is crucial for type 2 AIP, this finding needs to be interpreted in conjunction with a background dense lymphoplasmacytic infiltrate. An isolated neutrophilic duct injury can occur in peritumoral or obstructive pancreatitis. Drug-induced pancreatitis in patients with inflammatory bowel disease often mimics type 2 AIP clinically and pathologically. IL-8 and PD-L1 are potential ancillary immunohistochemical markers for type 2 AIP, requiring validation studies.
Aims
The present study aimed to systematically compare clinicopathological and genetic features between keratin 19 (K19)‐expressing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma ...(iCCA).
Methods and results
Consecutive cases of HCC (n = 430) were classified into K19+ and K19− using immunohistochemistry. ICCA cases were also separated into small‐(S‐iCCA; n = 36) and large‐duct types (n = 22) based on recently proposed criteria, with the former being used in the present study. Mutational hot‐spots in TERT, CTNNB1, KRAS and IDH1 were sequenced. Twenty‐six cases (6%) of HCC expressed K19. K19+ HCC was more strongly associated with chronic hepatitis B than K19− HCC and S‐iCCA (46% versus 17% and 6%; both P < 0.001). Lymph node metastasis was observed in K19+ HCC (8%) and S‐iCCA (22%), but was exceptional in K19− HCC (1%). K19+ HCC had TERT promoter mutations less frequently than K19− HCC (31% versus 59%; P = 0.022), and lacked alterations in KRAS and IDH1. CTNNB1 mutations were similarly observed in K19+ and K19− HCC (23% and 19%, respectively), but rare in S‐iCCA (3%). The postoperative survival curve of K19+ HCC was almost identical to that of S‐iCCA in the first 5 years (approximately 50% at 5 years), and significantly worse than that of K19− HCC (P = 0.040). Extrahepatic recurrence was more common in K19+ HCC (50%) and S‐iCCA (35%) than in K19− HCC (15%) (P = 0.001).
Conclusions
Although K19+ HCC and S‐iCCA showed similar biological behaviours, they did not share any driver gene mutations, suggesting the possible involvement of epigenetic alterations in the iCCA‐like features of K19+ HCC.
There is no consensus as to whether or not metastatic nodules in the liver should be biopsied for tumor grading in cases of neuroendocrine tumors with ‘synchronous liver metastasis’. In this study, ...we compared the Ki‐67 labeling index between the primary tumor and synchronous liver metastasis in 30 patients, who had received simultaneous resections. Examined tumors were of the small bowel (n = 18) or pancreas (n = 12), and G1 or G2 in primary histologic grade. In 20 patients (67%), the Ki‐67 index was similar between the primary tumor and liver metastasis, but 10 (33%) showed an elevation of 3.4–14.4% in the liver, which increased the tumor grade in 4 cases. The Ki‐67 elevation in the liver was more common in G2 than G1 neoplasms (P = 0.002). The size, but not number, of liver metastases was significantly larger in patients with an elevated Ki‐67 index (P = 0.006). Using 40 mm as a provisional cutoff for the greatest diameter of liver metastases, the positive predictive value of this discriminator for elevated Ki‐67 was 56%, and the negative predictive value was 93%. In conclusion, synchronous liver metastases can yield a higher Ki‐67 labeling index than primary neuroendocrine tumours, particularly when the secondary is greater than 40 mm.
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