Immunoglobulin G4-related sclerosing cholecystitis presenting as gallbladder cancer: a case report
© Takahashi et al. 2015
Received: 5 June 2015
Accepted: 25 November 2015
Published: 3 December 2015
Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic inflammatory syndrome, and an understanding of its characteristics is currently evolving. IgG4-related cholecystitis is a manifestation of IgG4-related sclerosing disease in the gallbladder. This case report describes the clinical, radiographic, and histopathological findings in a young male patient who presented with a synchronous mass in the gallbladder. Serum levels of IgG4 and the IgG4/IgG ratio were normal, and there was no associated autoimmune pancreatitis. Therefore, establishing a preoperative diagnosis of IgG4-related cholecystitis was very difficult, and a differential diagnosis of gallbladder cancer infiltrating the liver was suggested. Postoperative histopathological examination established a diagnosis of IgG4-related cholecystitis definitively. A preoperative diagnosis of IgG4-related cholecystitis, although possible, would have been highly challenging in this case. It is difficult to establish whether surgical intervention is necessary in IgG4-related cholecystitis. Because malignant tumors are frequently suspected with this clinical presentation, surgical intervention should be undertaken only after due deliberation.
Immunoglobulin G4 (IgG4)-related sclerosing disease, a systemic inflammatory syndrome characterized by obliterative phlebitis and extensive infiltration of IgG4-positive plasma cells and lymphocytes with fibrosis in the pancreas, gallbladder, bile duct, salivary gland, kidney, retroperitoneum, and esophagus [1–5], has been increasingly recognized in the past few years.
IgG4-related cholecystitis does not present with characteristic symptoms of cholecystitis and is often accompanied by IgG4-related sclerosing cholangitis (IgG4-SC). The major clinical symptoms of IgG4-related cholecystitis or IgG4-SC are obstructive jaundice, nausea, fatigue, loss of appetite, and yellowish discoloration of the skin and frequently lead to bile duct stenosis.
IgG4-related sclerosing disease generally displays a preponderance in elderly males, frequent elevation of serum IgG4 levels, and dramatic response to steroid therapy. In most patients with this disease, serum IgG4 levels are elevated but can be normal . A serum IgG4 within the normal range makes it more difficult to diagnose IgG4-related sclerosing disease. Moreover, it is difficult to discriminate a malignancy based on lymphadenopathy and mass-forming lesion. Making a preoperative diagnosis proves challenging, and the disease is frequently misdiagnosed. As malignant tumors are frequently suspected on the basis of radiologic imaging and clinical symptoms, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgical intervention. However, in the current clinical scenario, in cases where the serum IgG4 level is within the normal range and a malignancy cannot be ruled out on preoperative diagnostics, surgical intervention becomes necessary.
To date, there have been several reports in the literature of IgG4-SC misdiagnosed as biliary cancer. However, IgG4-related cholecystitis mimicking gallbladder cancer has been rarely reported [7–9]. Here, we report the rare case of an 18-year-old man with IgG4-related cholecystitis mimicking gallbladder cancer and presenting with normal serum IgG4 levels.
An 18-year-old man was referred to our hospital with acute onset of painless obstructive jaundice, nausea, fatigue, loss of appetite, and icterus but no fever or past history of similar complaints.
Laboratory tests revealed the following results (values in parentheses indicate normal range): white blood cell count 5270/mm3 (3500–9700/mm3), hemoglobin 14.5 g/dL (13.6–18.3 g/dL), hematocrit 43.2 % (40.4–51.9 %), platelet count 295,000/mm3 (140,000–379,000/mm3), aspartate aminotransferase 214 IU/L (0–40 IU/L), alanine aminotransferase 314 IU/L (5–45 IU/L), alkaline phosphatase 2367 IU/L (104–338 IU/L), total bilirubin 8.1 mg/dL (0.3–1.2 mg/dL), direct bilirubin 6.0 mg/dL (0–0.4 mg/dL), amylase 74 U/L (39–134 U/L), total protein 8.1 g/dL (6.5–8.2 g/dL), albumin 4.4 g/dL (3.7–5.5 g/dL), and urine bilirubin 3+ (negative). Serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) levels were within normal limits as was the serum IgG4 (40 mg/dL; range, 4–108 mg/dL) and IgG (1055 mg/dL; range, 820–1740 mg/dL) levels.
The postoperative course was uneventful, there was no added steroid therapy, and the patient was discharged 17 days after the surgery without any additional treatment. At the 1-year follow-up, the patient had no symptoms or signs of the disease.
In recent years, IgG4-related sclerosing disease has become an increasingly intriguing clinicopathologic entity. The pathology involves diffuse or focal organ enlargement and mass-forming or thickening lesions, caused by heavy infiltration of IgG4-positive plasma cells and lymphocytes with fibrosis [10–12], in various organs, with resultant autoimmune pancreatitis, sclerosing cholangitis, cholecystitis, sialadenitis, retroperitoneal fibrosis, inflammatory aortic aneurysm, or inflammatory pseudotumors. However, the exact pathogenesis and pathophysiology of IgG4-related sclerosing disease remains unclear. As a malignancy is frequently suspected on the basis of clinical symptoms and radiologic findings in such cases, IgG4-related sclerosing disease should be included as a differential diagnosis. In the present case, diseases contributing to stenosis of the bile duct included cholangiocarcinoma, infiltration of the bile duct by gallbladder cancer, PSC, IgG4-related sclerosing disease, ischemic bile duct stenosis, and an amputation neuroma. In most cases, the diagnosis is easily established; however, a preoperative diagnosis is difficult to establish in a few patients.
Three major histopathological features and international pathological consensus minimal criteria for diagnosing IgG4-related disease in a new organ/site
The three major histopathological features associated with IgG4-related disease
①Dense lymphoplasmacytic infiltrate
②Fibrosis, arranged at least focally in a storiform pattern
Other histopathological features associated with IgG4-related disease are as follows:
①Phlebitis without obliteration of the lumen
Minimal criteria for IgG4-related disease in a new organ/site
①Characteristic histopathological findings with an elevated IgG4 plasma cells and IgG4/IgG ratio
②High serum IgG4 concentrations
③Effective response to glucocorticoid therapy
④Reports of other organ involvement that is consistent with IgG4-related disease
Most IgG4-related sclerosing diseases are associated with autoimmune pancreatitis (AIP) , which was not the case in our patient. This case was unique in that the patient was considerably younger and had IgG4-related cholecystitis mimicking gallbladder cancer with a normal IgG4 concentration. Normal serum IgG4 levels in IgG4-related sclerosing disease have been reported only in a few articles [7, 9, 16], and the sensitivity and specificity of serum IgG4 for IgG4-related SC is reported to be 50 and 60 %, respectively . In cases with suspected IgG4-related cholecystitis, other benign gallbladder diseases such as xanthogranulomatous cholecystitis etc., gallbladder cancer should be a differential diagnosis. Therefore, serum IgG4 should be assessed. However, serum IgG4 and the IgG4/IgG ratio were normal in this case, and without the associated AIP, a preoperative diagnosis was very difficult and a histopathological diagnosis was necessary for a definitive diagnosis. Bile cytology indicated no malignancy in this patient. However, bile cytology is often normal in cholangiocarcinoma. We tried endoscopic ultrasonography fine-needle aspiration (EUS-FNA). However, we did not succeed. EUS-FNA was useful for diagnosing IgG4-related sclerosing disease. In AIP, EUS-FNA provided tissue samples adequate for histopathological evaluation and greatly contributed to the histological diagnosis . We did not perform other pathological examinations because the patient was developing worse obstructive jaundice rapidly in a short time. In general, other diagnostic approaches include biopsies of the gallbladder, bile duct, and liver. A previous study suggested that biopsies of the gallbladder, bile duct, and liver are useful for diagnosing IgG4-related cholecystitis [19–22]. Biopsies of the bile duct and gallbladder, although technically difficult, could provide the full spectrum of morphologic changes. In general, fibroinflammatory involvement is mainly observed in the submucosa of the gallbladder and bile duct wall, whereas the epithelium of these structures was intact in the present case. Cytological examinations were often useful in establishing a differential diagnosis of gallbladder cancer, although it was difficult to obtain biopsy samples adequate for establishing characteristic histopathological findings of IgG4-related cholecystitis . Liver biopsies have the lowest diagnostic potential, although sometimes useful in the diagnosis of IgG4-related cholecystitis in cases of intrahepatic bile duct involvement . Therefore, we thought EUS-FNA or biopsy was useful for a differential diagnosis between gallbladder cancer and IgG4-related cholecystitis. We did not conduct other pathologic examinations in the present case because of the technical difficulty involved in performing a biopsy as well as the inadequacy of the tumor mass required for a biopsy. The quality of biopsy samples depends on the experience of the endoscopists undertaking the procedure; moreover, biopsy samples were sometimes small or had artificial degeneration. We did not perform PET in the present case as a report of PET that revealed an elevated standardized uptake value, associated with malignant tumor, has been published previously  and was not considered beneficial to establish a differential diagnosis.
In view of all of these aspects, establishing a preoperative diagnosis of IgG4-related cholecystitis was possible but highly challenging and it was too difficult to determine whether surgical intervention was actually necessary in this case. This patient was developing worse obstructive jaundice rapidly in a short time. We did not perform both PET and EUS-FNA. In this case, a preoperative diagnosis was difficult. We could not assess the benign region (xanthogranulomatous cholecystitis or IgG4-related cholecystitis) or cancer; therefore, we decided to perform operation and intraoperative consultation. Although there is much to be understood with regard to IgG4-related cholecystitis, it is conceivable that a trial of steroid therapy may be warranted if this disease entity is suspected before surgery. A poor response to steroid therapy should indicate the possibility of a diagnosis of gallbladder cancer with a need for re-evaluating the diagnosis. Thus far, there are several reasons why a definitive preoperative diagnosis cannot be established in such a case. Moreover, because malignant tumors were frequently suspected under these conditions, surgical intervention should be undertaken after due deliberation.
At present in Japan, there are no reports describing a presentation of IgG4-related cholecystitis without AIP. Herein, we report the first case in the literature of a young man with only IgG4-related cholecystitis and normal serum IgG4 concentrations.
In 2010, Leise et al. reported a case of an ill-defined tumor (6 cm) in the liver hilum that appeared to surround the gallbladder, which was established to be IgG4-related cholecystitis on examination of the surgical specimen . In 2005, Gumbs et al. reported the appearance of synchronous tumors in the pancreatic head and gallbladder that were preoperatively diagnosed as pancreatic ductal adenocarcinoma and gallbladder cancer . Postoperative histopathological examination established AIP with IgG4-related cholecystitis. Some other cases reported IgG4-related cholecystitis mimicking gallbladder cancer [7–9, 23, 24] (Table 2). A few cases of synchronous autoimmune pancreatitis and pancreatic ductal adenocarcinoma have also been reported [25, 26]. In addition, one report describes epithelial atypia in the common bile duct in the presence of bile duct involvement in autoimmune pancreatocholangitis . Previous reports have reported IgG4-SC occurring with cholangiocarcinoma, but no reports of IgG4-related cholecystitis with gallbladder cancer exist so far. We intend to continue the follow-up of the present case in the outpatient setting.
Previously reported cases of IgG4-related cholecystitis
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- Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Autoimmune pancreatitis. N Engl J. 2006;355:2670–6.View ArticleGoogle Scholar
- Kitagawa S, Zen Y, Harada K, Sasaki M, Sato Y, Minato H, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner’s tumor). Am J Surg Pathol. 2005;29:783–1.View ArticlePubMedGoogle Scholar
- Zen Y, Onodera M, Inoue D, Kitao A, Matsui O, Nohara T, et al. Retroperitoneal fibrosis: a clinicopathologic study with respect to immunoglobulin G4. Am J Surg Pathol. 2009;33:1833–9.View ArticlePubMedGoogle Scholar
- Lopes J, Hochwald SN, Lancia N, Dixon LR, Ben-David K. Autoimmune esophagitis: IgG4-related tumors of the esophagus. J Gastrointest Surg. 2010;14:1031–4.View ArticlePubMedGoogle Scholar
- Ohara H, Okazaki K, Tsubouchi H, Inui K, Kawa S, Kamisawa T, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci. 2012;19:536–42.View ArticlePubMedGoogle Scholar
- Inoue M, Sasaki T, Fujimoto Y. Significance of the ratio of serum IgG4 to IgG in differential diagnosis of autoimmune-related cholangitis. Tan to Sui. 2009;30:1289–93 (in Japanese).Google Scholar
- Shin SW, Kim Y, Jeong WK, Kim J, Kim MY, Oh YH, et al. Isolated cholecystitis mimicking gallbladder cancer: a case report. Clin Imaging. 2013;37:969–71.View ArticlePubMedGoogle Scholar
- Lee YS, Lee SH, Lee MG, Lee SJ, Hwang JH, Shin E, et al. Immunoglobulin g4-related disease mimicking unresectable gallbladder cancer. Gut Liver. 2013;7:616–20.PubMed CentralView ArticlePubMedGoogle Scholar
- Feely MM, Gonzalo DH, Corbera M, Hughes SJ, Trevino JG. IgG4-related cholecystitis presenting as biliary malignancy: report of three cases. J Gastrointest Surg. 2014;18:1710–5.View ArticlePubMedGoogle Scholar
- Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22:1–14.PubMed CentralView ArticlePubMedGoogle Scholar
- Okazaki K, Uchida K, Koyabu M, Miyoshi H, Takaoka M. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol. 2011;46:277–88.View ArticlePubMedGoogle Scholar
- Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol. 2006;41:613–25.PubMed CentralView ArticlePubMedGoogle Scholar
- Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181–92.View ArticlePubMedGoogle Scholar
- Okazaki K, Kawa S, Kamisawa T, Shimosegawa T, Nakamura S, Shimatsu A, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Nihon Naika Gakkai Zasshi. 2012;10(101):795–804.Google Scholar
- Okazaki K, Yanagawa M, Mitsuyama T, Uchida K. Recent advances in the concept and pathogenesis of IgG4-related disease in the hepato-bilio-pancreatic system. Gut Liver. 2014;8:462–70.PubMed CentralView ArticlePubMedGoogle Scholar
- Mizutani S, Suzuki H, Yoshida H, Arima Y, Kitayama Y, Uchida E. Case of IgG4-related sclerosing cholangitis with a normal serum IgG4 level: report of a case. J Nippon Med Sch. 2012;79:367–72.View ArticlePubMedGoogle Scholar
- Lytras D, Kalaitzakis E, Webster GJ, Imber CJ, Amin Z, Rodriguez-Justo M, et al. Cholangiocarcinoma or IgG4-associated cholangitis: how feasible it is to avoid unnecessary surgical interventions? Ann Surg. 2012;256:1059–67.View ArticlePubMedGoogle Scholar
- Kanno A, Ishida K, Hamada S, Fujishima F, Unno J. Diagnosis of autoimmune pancreatitis by EUS-FNA by using a 22-gauge needle based on the International Consensus Diagnostic Criteria. Gastrointest Endosc. 2012;76(3):594–602.View ArticlePubMedGoogle Scholar
- Kawakami H, Zen Y, Kuwatani M, Eto K, Haba S, Yamato H, et al. IgG4-related sclerosing cholangitis and autoimmune pancreatitis: histological assessment of biopsies from Vater’s ampulla and the bile duct. J Gastroenterol Hepatol. 2010;25:1648–55.View ArticlePubMedGoogle Scholar
- Chandan VS, Iacobuzio-Donahue C, Abraham SC. Patchy distribution of pathologic abnormalities in autoimmune pancreatitis: implications for preoperative diagnosis. Am J Surg Pathol. 2008;32:1762–9.View ArticlePubMedGoogle Scholar
- Hirano K, Fukushima N, Tada M, Isayama H, Mizuno S, Yamamoto K, et al. Diagnostic utility of biopsy specimens for autoimmune pancreatitis. J Gastroenterol. 2009;44:765–73.View ArticlePubMedGoogle Scholar
- Zen Y, Nakanuma Y, Portmann B. Immunoglobulin G4-related sclerosing cholangitis: pathologic features and histologic mimics. Semin Diagn Pathol. 2012;29:205–11.View ArticlePubMedGoogle Scholar
- Leise MD, Smyrk TC, Takahashi N, Sweetser SR, Vege SS, Chari ST. IgG4-associated cholecystitis: another clue in the diagnosis of autoimmune pancreatitis. Dig Dis Sci. 2011;56:1290–4.View ArticlePubMedGoogle Scholar
- Gumbs AA, Kim J, Kiehna E, Brink JA, Salem RR. Autoimmune pancreatitis presenting as simultaneous masses in the pancreatic head and gallbladder. JOP. 2005;10(6):455–9.Google Scholar
- Inoue H, Miyatani H, Sawada Y, Yoshida Y. A case of pancreas cancer with autoimmune pancreatitis. Pancreas. 2006;33:208–9.View ArticlePubMedGoogle Scholar
- Witkiewicz AK, Kennedy EP, Kennyon L, Yeo CJ, Hruban RH. Synchronous autoimmune pancreatitis and infiltrating pancreatic ductal adenocarcinoma: case report and review of the literature. Hum Pathol. 2008;39:1548–51.View ArticlePubMedGoogle Scholar
- Oh HC, Kim JG, Kim JW, Lee KS, Kim MK, Chi KC, et al. Early bile duct cancer in a background of sclerosing cholangitis and autoimmune pancreatitis. Intern Med. 2008;47:2025–8.View ArticlePubMedGoogle Scholar