Differentiating Immunoglobulin G4-Related Sclerosing Cholangitis from Hilar Cholangiocarcinoma

Background/Aims

Few studies have differentiated immunoglobulin G (IgG) 4-related sclerosing cholangitis (IgG4-SC) from hilar cholangiocarcinoma (CC). Thus, we sought to investigate useful features for differentiating IgG4-SC from hilar CC.

Methods

We retrospectively compared clinical, serological, imaging, and histological features of six patients with IgG4-SC and 42 patients with hilar CC.

Results

In patients with hilar CC, obstructive jaundice was more frequent (p<0.01), serum total bilirubin levels were significantly higher (p<0.05), serum CA19-9 levels were significantly higher (p<0.01), and serum duke pancreatic monoclonal antigen type 2 levels were frequently elevated (p<0.05). However, in patients with IgG4-SC, the serum IgG (p<0.05) and IgG4 (p<0.01) levels were significantly higher and frequently elevated. The pancreas was enlarged in all IgG4-SC patients but only in 17% of hilar CC patients (p<0.01). Salivary and/or lacrimal gland swelling was detected in only 50% of IgG4-SC patients (p<0.01). Endoscopic retrograde cholangiography revealed that the hilar or hepatic duct was completely obstructed in 83% of hilar CC patients (p<0.01). Lower bile duct stenosis, apart from hilar bile duct stenosis, was more frequent in IgG4-SC patients (p<0.01). Bile duct wall thickening in areas without stenosis was more frequent in IgG4-SC patients (p<0.01).

Conclusions

An integrated diagnostic approach based on clinical, serological, imaging, and histological findings is necessary to differentiate IgG4-SC from hilar CC.     

Immunoglobulin G4-Related Disease Mimicking Unresectable Gallbladder Cancer

Immunoglobulin G4 (IgG4)-related disease is a novel disease entity that can involve diverse organs, causing specific diseases, including autoimmune pancreatitis, sclerosing cholangitis, cholecystitis, inflammatory aortic aneurysm, and inflammatory pseudotumor. IgG4-related disease is characterized by elevated serum IgG4 concentrations, abundant IgG4 lymphoplasmacytic infiltration, and dramatic steroid responses. It is clinically important to differentiate this rare disease from primary sclerosing cholangitis and cholangiocarcinoma, because the treatment and prognosis of these two diseases are completely different. However, the preoperative diagnosis is challenging, and the disease is frequently misdiagnosed. If the serum level of IgG4 is within the normal range, the diagnosis of IgG4-related disease is more difficult. This article reports on a 59-year-old man with IgG4-related disease mimicking unresectable gallbladder cancer with normal serum IgG4 concentrations.     

Recurrent Stent Thrombosis Secondary to Immunoglobulin G4-Related Disease

Immunoglobulin G4-related disease (IgG4-RD) is an insidiously progressive multiorgan disease. However, lack of familiarity with IgG4-RD results in patients often being undiagnosed and undertreated. IgG4-RD can affect any organ, and manifests as aortitis within the cardiovascular system. Cardiac involvement is less common, and myocardial infarction is rarely reported. We report the first case of a patient with multiple myocardial infarctions caused by recurrent stent thrombosis associated with IgG4-RD, which resolved upon treatment of IgG4-RD. This case highlights the importance for cardiologists to consider IgG4-RD as a rare but possible association with stent thrombosis.     

Punctate Purpura Complicated with Immunoglobulin G4-related Disease

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition affecting multiple organs; however, the involvement of skin lesions is rare. We herein report a 65-year-old man who presented with pruritic punctate purpura on both legs and elevated liver enzyme levels. Computed tomography showed enlargement of the pancreas and thickening of the bile duct wall. Magnetic resonance cholangiopancreatography showed diffuse irregular constriction of the main pancreatic duct, stricture of the lower common bile duct, and dilation after confluent stricture. A histopathologic examination of the pancreas and his enlarged salivary gland showed infiltration of IgG4-positive plasma cells. Ultimately, the patient was diagnosed with IgG4-RD.     

Classification and Diagnostic Criteria for IgG4-Related Sclerosing Cholangitis

IgG4-related sclerosing cholangitis (IgG4-SC) can be classified into four types based on cholangiographic findings and regions of biliary stricture. This cholangiographic classification is useful to differentiate IgG4-SC from mimickers including cholangiocarcinoma, primary sclerosing cholangitis, and pancreatic cancer. Autoimmune pancreatitis (AIP) is a valuable clue for the diagnosis of IgG4-SC because the two are frequently found in association with each other. Two sets of diagnostic criteria for IgG4-SC have been proposed. In Japan, the clinical diagnostic criteria 2020 were recently developed. These clinical diagnostic criteria include narrowing of the intrahepatic and/or extrahepatic bile duct, thickening of the bile duct wall, serological findings, pathological findings, other organ involvement, and effectiveness of steroid therapy. When these criteria are applied, IgG4-SC is initially classified as associated or not associated with AIP, and cholangiographic classification is used for differential diagnosis. In most instances, IgG4-SC can be diagnosed on the basis of clinical diagnostic criteria. However, it is challenging to diagnose isolated IgG4-SC or IgG4-SC not associated with AIP. Here, we review the classification and diagnostic criteria for IgG4-SC, specifically focusing on the clinical diagnostic criteria 2020 and a large IgG4-SC case series from a nationwide survey in Japan.     

IgG<Subscript>4</Subscript>-Related Sclerosing Disease: A Novel Mimic of Inflammatory Bowel Disease

High levels of IgG4-positive plasma cells are commonly seen in autoimmune pancreatitis. It has recently become evident that autoimmune pancreatitis is one component of a larger multi-system disease. IgG4-positive plasma cells have been identified in many extrapancreatic tissues, including the colon, biliary tract, liver, and lungs, and thus the term “IgG4-related sclerosing disease” has been proposed. Awareness of IgG4-related sclerosing disease is important, as it has been shown to mimic other conditions like malignancy. This review discusses IgG4-related colitis and its potential for mimicking inflammatory bowel disease.     

Extensive Metastatic Cholangiocarcinoma Associated With IgG4-Related Sclerosing Cholangitis Misdiagnosed as Isolated IgG4-Related Sclerosing Cholangitis: A Case Report and Literature Review

As cholangiographic features of IgG4-related sclerosing cholangitis (IgG4-SC) resemble those of cholangiocarcinoma, it is highly confusing between the 2 conditions on the basis of cholangiographic findings. This study presents a case of extensive metastatic cholangiocarcinoma with IgG4-SC misdiagnosed as isolated IgG4-SC, and reviews recent studies of the 2 diseases.A 56-year-old man with no family history of malignant tumors or liver diseases presented with recurrent mild abdominal pain and distention for 3 months. Magnetic resonance cholangiopancreatography showed a 3.7 cm nodular lesion with unclear boundary in segment VI of the liver. Serum IgG4 and CA19-9 were slightly elevated. Histopathological examination was consistent with the consensus statement on the pathology of IgG4-SC. IgG4-SC was thus considered. Due to his mild symptoms, glucocorticoid was not given at first. However, 3 months after his first admission, he had more severe abdominal pain and further elevated serum CA19-9. Actually he was found suffering from extensive metastatic cholangiocarcinoma with IgG4-SC by exploratory laparotomy.The present case serves as a reminder that extensive metastatic cholangiocarcinoma with or without IgG4-SC may be misdiagnosed as an isolated IgG4-SC case if one relies solely on elevated serum and tissue IgG4 levels. We emphasize on the importance of repeated core needle biopsy or exploratory laparoscopy/laparotomy before immunosuppressive drugs are given, and on follow-up of imaging findings and serum CA19-9 once immunosuppressive therapy is started.     

Immunoglobulin G4-related Pleuritis Complicated with Minimal Change Disease

A 70-year-old woman with bilateral pleural effusion and respiratory failure was admitted to our hospital. Nephrotic syndrome due to minimal change disease had been diagnosed four months before admission. Because blood tests and a pleural fluid analysis did not reveal the etiology of her condition, we performed a video-assisted thoracoscopic pleural biopsy. No specific thoracoscopic findings were noted. The pathological findings revealed an increase in immunoglobulin G4 (IgG4)-positive cells; IgG4-related pleuritis was diagnosed. Her pleuritis improved with oral corticosteroid therapy. A further investigation was performed on previous kidney samples; however, the etiology of the nephrotic syndrome was not IgG4-related disease but minimal change disease.     

IgG4-Related Disease and Hypertrophic Pachymeningitis

Hypertrophic pachymeningitis (HP) is an inflammatory condition in which the dura mater of the cranium or spine becomes thickened, leading to symptoms that result from mass effect, nerve compression, or vascular compromise. The differential diagnosis of HP includes immune-mediated conditions such as rheumatoid arthritis and vasculitis, malignancies, and infections. Many times, no diagnosis is reached; in such cases, the disease has been described as idiopathic HP. IgG4-related disease (IgG4-RD) is a recently described inflammatory condition known to cause tumefactive lesions at myriad anatomical locations. Both IgG4-RD and idiopathic HP share similar demographics, histopathology, and natural history. We hypothesized that IgG4-RD is a common cause of idiopathic HP.To investigate this hypothesis, we identified all pathology specimens diagnosed as noninfectious HP during 25 years at our institution. Fourteen cases had stained slides and paraffin blocks to permit review of the original hematoxylin and eosin stained slides as well as immunostaining of cell blocks. Recently published consensus guidelines describing characteristic histopathology and the necessary quantity of IgG4+ plasma cell infiltrate were used to diagnose IgG4-RD.Four cases (66.6%) that had been regarded previously as representing idiopathic HP were diagnosed as IgG4-RD; of all the reviewed cases, IgG4-RD represented 29% of cases. Of the remaining cases, 3 cases were associated with granulomatosis with polyangiitis (GPA), 2 with lymphoma, and 1 each with rheumatoid arthritis, giant cell arteritis, and sarcoidosis. Two of the cases could not be diagnosed more precisely and were classified as undifferentiated HP. Clinical history, serologic tests, cerebrospinal fluid studies, and radiology alone could not identify the cause of HP. Rather, biopsy with histopathology and immunostaining was necessary to reach an accurate diagnosis. Significant IgG4+ plasma cell infiltrates were observed in rheumatoid arthritis, granulomatosis with polyangiitis, and lymphoma, underscoring the importance of histopathology in making the diagnosis of IgG4-RD.This case series demonstrates that IgG4-RD may be the most common etiology of noninfectious HP and highlights the necessity of biopsy for accurate diagnosis.Abbreviations: ANCA = antineutrophil cytoplasmic antibodies, CNS = central nervous system, CSF = cerebrospinal fluid, CT = computed tomography, GPA = granulomatosis with polyangiitis, HP = hypertrophic pachymeningitis, HPF = high-power field, IgG4-RD = IgG4-related disease, MRI = magnetic resonance imaging, WBC = white blood cell     

Immunoglobulin G4-Related Aortitis and Severe Aortic Valve Stenosis Treated With Transcatheter Aortic Valve Replacement and Immunosuppression

IgG4-related disease is an immune-mediated fibro-inflammatory disorder with multisystemic involvement. Aortitis and peri-aortitis are the most common cardiovascular manifestations of the disease. We present the case of a 65-year-old man with symptomatic severe aortic stenosis and concomitant IgG4 aortitis. The diagnosis was confirmed by IgG4 serum levels, positive positron emission computed tomography (PET-CT) scans, and pathology from mediastinal dissection. Surgical aortic valve replacement (SAVR) was unfeasible owing to extensive mediastinal fibrosis, and transcatheter aortic valve replacement (TAVR) was successfully performed. As ascending aorta access for SAVR in IgG4 aortitis with long-run fibrosis entails a high risk of mortality, TAVR could be considered in certain suitable patients.     

IgG4相关性胆管炎

IgG4相关性胆管炎（IAC）是近年来才被人们认识的一种临床疾病,其特点是血清IgG4水平升高、胆管周围大量IgG4阳性浆细胞浸润以及对激素治疗敏感。IAC大多伴有自身免疫性胰腺炎（AIP）。本文就IAC的临床特征、诊断、治疗和预后作一综述。