Medical mirroring: granulomatosis with polyangiitis (formerly Wegener's) mimicking immunoglobulin‐G4 related disease

Granulomatosis with polyangiitis (GPA; formerly Wegener's) can present with clinical and histopathological features similar to those of immunoglobulin‐G4 related disease (IgG4‐RD), a recently described fibro‐inflammatory condition. The ability of these two distinct entities to mimic each other closely creates significant pitfalls in diagnosis. We present a unique case in which GPA presented as a peri‐aortic fibrotic mass in the retroperitoneum. The patient's other clinical features also overlapped with classic IgG4‐RD disease manifestations, but the histopathology in two organs and the serological data confirmed the diagnosis of GPA. Rigorous histopathological review remains the gold standard for the diagnosis of GPA and the distinction of this entity from IgG4‐RD and other mimickers.     

IgG4‐related disease and lymphocyte‐variant hypereosinophilic syndrome: A comparative case series

Chronic lymphocytic leukaemia (CLL) is a chronic B‐cell lympho‐proliferative disorder in which lymphomatous transformations occur in 5%‐15% of patients. Histologically these cases resemble diffuse large B‐cell lymphoma, or Richter's transformation, in over 80% of cases. Rare cases of transformation to Hodgkin lymphoma (HL) have been reported in the literature with an estimated prevalence of 0.4%. We report a case of a 67‐year‐old female with CLL treated with the novel Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib, who subsequently presented with intractable fevers. Bone marrow trephine, and lymph node biopsy revealed classical HL with negative immuno‐histochemistry for Btk in HL cells, on a backdrop of CLL. The patient commenced treatment with Adriamycin, Vinblastine and Dacarbazine (AVD), which resulted in an excellent response. Hodgkin transformation of CLL is rare with a single retrospective study of 4121 CLL patients reporting only 18 cases. Btk expression in HL cells is recently recognised in classical HL; however, the majority of HLs are Btk negative. Given that Btk inhibitors have recently been shown to induce genomic instability in B cells, in the context of their widespread use, such emerging cases are increasingly relevant.     

Diagnostic usefulness of precise examinations with intraductal ultrasonography,peroral cholangioscopy and laparoscopy of immunoglobulin G4‐related sclerosing cholangitis

Herein, a case of immunoglobulin G4 (IgG4)‐related sclerosing cholangitis is reported. IgG4 was diagnosed based on observations from peroral cholangioscopy and laparoscopy, and these methods are proposed for definitive and precise diagnosis of this disease. A 76‐year‐old male patient with inguinal Paget's disease had intrahepatic bile duct dilatations detected with computed tomography at his periodic check‐up. Magnetic resonance cholangiography showed stenosis of the upper common bile duct and poststenotic dilatation of left intrahepatic bile ducts. The portal tract and bilateral intrahepatic bile ducts were surrounded by a low‐density area, facing a tumor‐like lesion at segment 2. Cytological examinations of the stenotic and dilated lesions revealed no cellular atypia. Histological examination of the tumor showed normal liver tissue with infiltration of lymphocytes, indicating an inflammatory pseudotumor. Peroral cholangioscopy excluded the possibility of biliary cancer and indicated that the stenotic legion was of submucosal, not mucosal, origin. Laparoscopic observations showed discoloration with wide yellowish‐white lobular markings and wide depressed lesions at segments 2 and 7. Liver histology showed mild cholangitis with infiltration of IgG4‐positive plasma cells around the bile ducts. Serum IgG4 levels were elevated. From these findings, the patient was diagnosed with IgG4‐related sclerosing cholangitis. After treatment with prednisolone, blood liver enzymes and IgG4 rapidly normalized, bile duct dilatations improved, and the hepatic pseudotumor disappeared. The cholangitis did not recur. In this case, biliary cancer was ruled out by observation with peroral cholangioscopy, and the spread of cholangitis in the liver periphery was verified with laparoscopy; this information could not be obtained with other modalities.     

Incidence and outcome of lung involvement in IgG4‐related autoimmune pancreatitis

We evaluated the incidence and outcome of lung involvement in 35 patients with autoimmune pancreatitis (AIP). Our results indicate that lung involvement is commonly observed in AIP (40%). In addition, corticosteroid treatment improved the lung lesions and appeared to reduce the probability of relapse compared with pancreatic lesions (0% vs 36%). This is the first report to assess the long‐term outcome of lung involvement in AIP (52 ± 33 months).     

Role of endoscopy in the diagnosis of autoimmune pancreatitis and immunoglobulin G4‐related sclerosing cholangitis

Autoimmune pancreatitis (AIP) must be differentiated from pancreatic carcinoma, and immunoglobulin (Ig)G4‐related sclerosing cholangitis (SC) from cholangiocarcinoma and primary sclerosing cholangitis (PSC). Pancreatographic findings such as a long narrowing of the main pancreatic duct, lack of upstream dilatation, skipped narrowed lesions, and side branches arising from the narrowed portion suggest AIP rather than pancreatic carcinoma. Cholangiographic findings for PSC, including band‐like stricture, beaded or pruned‐tree appearance, or diverticulum‐like outpouching are rarely observed in IgG4‐SC patients, whereas dilatation after a long stricture of the bile duct is common in IgG4‐SC. Transpapillary biopsy for bile duct stricture is useful to rule out cholangiocarcinoma and to support the diagnosis of IgG4‐SC with IgG4‐immunostaining. IgG4‐immunostaining of biopsy specimens from the major papilla advances a diagnosis of AIP. Contrast‐enhanced endoscopic ultrasonography (EUS) and EUS elastography have the potential to predict the histological nature of the lesions. Intraductal ultrasonographic finding of wall thickening in the non‐stenotic bile duct on cholangiography is useful for distinguishing IgG4‐SC from cholangiocarcinoma. Endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) is widely used to exclude pancreatic carcinoma. To obtain adequate tissue samples for the histological diagnosis of AIP, EUS‐Tru‐cut biopsy or EUS‐FNA using a 19‐gauge needle is recommended, but EUS‐FNA with a 22‐gauge needle can also provide sufficient histological samples with careful sample processing after collection and rapid motion of the FNA needles within the pancreas. Validation of endoscopic imaging criteria and new techniques or devices to increase the diagnostic yield of endoscopic tissue sampling should be developed.     

IgG4‐related disease with hypergammaglobulinemic hyperviscosity and retinopathy

Immunoglobulin G4‐related disease (IgG4‐RD) is a recently described entity with protean manifestations. We describe a novel case of IgG4‐RD with hypergammaglobulinemic hyperviscosity responsive to fludarabine and rituximab. A 33‐year‐old Asian man developed bilateral lacrimal gland and submandibular salivary gland swelling with cervical lymphadenopathy. Biopsies of the affected tissues revealed reactive follicular hyperplasia. Seven years later, he presented with bilateral retinal hemorrhages due to hyperviscosity syndrome from profound polyclonal increase in IgG, including marked IgG4 elevation. Despite plasmapheresis, overproduction of IgG continued and he was refractory to systemic steroids, azathioprine, interferon alpha, and cyclophosphamide. IgG4‐RD was suspected following a myocardial infarction and detection of aneurysmal coronary arteries indicating large vessel vasculitis. Review of the cervical lymph node and lacrimal gland biopsies with immunohistochemical staining for IgG4‐positive plasma cells confirmed IgG4‐RD. B‐cell depletion with rituximab produced a partial response, but clinical symptoms and elevated protein levels persisted. Fludarabine was added to rituximab to suppress T‐cell activity, and this resulted in an excellent clinical and biochemical response. Combination therapy with fludarabine and rituximab in IgG4‐RD has not previously been reported and can be considered in patients with severe refractory disease.     

Original article: Impact of 18‐fluorodeoxyglucose positron emission tomography on computed tomography defined target volumes in radiation treatment planning of esophageal cancer: reduction in geographic misses with equal inter‐observer variability

Target volume definition in modern radiotherapy is based on planning computed tomography (CT). So far, 18‐fluorodeoxyglucose positron emission tomography (FDG‐PET) has not been included in planning modality in volume definition of esophageal cancer. This study evaluates fusion of FDG‐PET and CT in patients with esophageal cancer in terms of geographic misses and inter‐observer variability in volume definition. In 28 esophageal cancer patients, gross, clinical and planning tumor volumes (GTV; CTV; PTV) were defined on planning CT by three radiation oncologists. After software‐based emission tomography and computed tomography (PET/CT) fusion, tumor delineations were redefined by the same radiation‐oncologists. Concordance indexes (CCI's) for CT and PET/CT based GTV, CTV and PTV were calculated for each pair of observers. Incorporation of PET/CT modified tumor delineation in 17/28 subjects (61%) in cranial and/or caudal direction. Mean concordance indexes for CT‐based CTV and PTV were 72 (55–86)% and 77 (61–88)%, respectively, vs. 72 (47–99)% and 76 (54–87)% for PET/CT‐based CTV and PTV. Paired analyses showed no significant difference in CCI between CT and PET/CT. Combining FDG‐PET and CT may improve target volume definition with less geographic misses, but without significant effects on inter‐observer variability in esophageal cancer.