Isolated IgG4-related cholecystitis mimicking locally advanced gallbladder cancer: a case report

Abstract

Immunoglobulin G4 (IgG4)-related disease is a fibroinflammatory condition that can involve multiple organs. Isolated involvement of the gallbladder is exceptionally uncommon and often radiologically indistinguishable from gallbladder carcinoma, resulting in diagnostic uncertainty before surgery. A 77-year-old man presented with right upper abdominal discomfort lasting 1 month. Cross-sectional imaging revealed irregular gallbladder wall thickening with contrast enhancement, raising suspicion for resectable gallbladder cancer. The patient underwent a radical cholecystectomy with partial hepatectomy. Histopathological analysis demonstrated dense lymphoplasmacytic infiltration, storiform fibrosis, and marked infiltration of IgG4-positive plasma cells exceeding established diagnostic thresholds, consistent with IgG4-related cholecystitis. The postoperative course was uneventful, and no additional treatment was required. IgG4-related cholecystitis should be considered in the differential diagnosis of gallbladder malignancy, particularly in atypical or indeterminate cases. However, when imaging findings strongly suggest carcinoma, radical surgical resection remains an appropriate oncologic approach.

INTRODUCTION

Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory condition characterized by tissue infiltration of IgG4-positive plasma cells and variable degrees of fibrosis [1,2]. The disease can affect multiple organs, most commonly the pancreas, biliary tract, salivary glands, and lymph nodes, often presenting as mass-forming or sclerosing lesions [3]. Gallbladder involvement in IgG4-RD is uncommon, and cases limited exclusively to the gallbladder are particularly rare. When present, IgG4-related cholecystitis typically manifests as diffuse or focal gallbladder wall thickening, a finding that closely resembles gallbladder carcinoma on imaging studies [2,3]. As a result, distinguishing between these entities before surgery is often difficult, and many patients undergo radical resection for suspected malignancy, with the correct diagnosis established only after histopathological evaluation [4]. Given that IgG4-RD generally shows a favorable response to corticosteroid therapy, accurate recognition of this disease entity is clinically important [5]. Awareness of IgG4-related cholecystitis may help avoid unnecessary surgical intervention in selected patients. Herein, we describe a case of isolated IgG4-related cholecystitis that radiologically mimicked gallbladder carcinoma and discuss the diagnostic challenges associated with this rare condition.

CASE REPORT

A 77-year-old man presented with a 1-month history of right upper quadrant discomfort. The symptom was mild and persistent, without associated fever, weight loss, or jaundice. He had no prior history of pancreatitis, jaundice, or similar symptoms. Laboratory investigations, including complete blood count and liver function tests, were within normal ranges. Tumor markers were also within normal limits, with carcinoembryonic antigen of 1.1 ng/mL and carbohydrate antigen 19–9 of 24 U/mL. Contrast-enhanced computed tomography (CT) revealed gallbladder wall thickening with arterial enhancement and multiple gallstones, without pancreatic or extrabiliary abnormalities (Fig. 1A). Magnetic resonance imaging (MRI) demonstrated asymmetric mural thickening abutting the liver (Fig. 1B) and homogeneous wall enhancement on contrast-enhanced T1-weighted sequences (Fig. 1C). Diffusion-weighted imaging with apparent diffusion coefficient (ADC) mapping confirmed restricted diffusion (Fig. 1D and E). Fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) showed intense uptake in the gallbladder lesion, with a maximum standardized uptake value of 7.9 (Fig. 1F). The patient was admitted for further evaluation, and surgical management was planned based on imaging findings suggestive of malignancy. Surgery was performed approximately 1 month after the initial imaging studies. After multidisciplinary discussion, the lesion was considered highly suspicious for resectable gallbladder carcinoma, and the patient underwent radical cholecystectomy with hepatic resection of segments 4b and 5. Histological examination revealed dense lymphoplasmacytic infiltration with periductal sclerosis but no evidence of malignancy (Fig. 2A and B). Immunohistochemistry demonstrated more than 100 IgG4-positive plasma cells per high-power field and an IgG4/IgG ratio exceeding 40% (Fig. 2C and D), confirming the diagnosis of IgG4-related cholecystitis. The postoperative course was uneventful, and the patient was discharged on postoperative day 8 without adjuvant therapy. No steroid therapy was administered, as the patient remained asymptomatic after surgery. The patient remained asymptomatic without evidence of recurrence or other organ involvement during 5 years of follow-up, after which routine follow-up was discontinued.

Fig. 1.

Imaging findings of isolated immunoglobulin G4-related cholecystitis. (A) Contrast-enhanced computed tomography (CT) demonstrates marked gallbladder wall thickening (arrow) with gallstones. (B) Axial T2-weighted magnetic resonance imaging shows asymmetric wall thickening (arrow) abutting the adjacent liver. (C) Axial contrast-enhanced T1-weighted image demonstrates homogeneous wall enhancement (arrow). (D, E) Diffusion-weighted imaging (b=1,000 sec/mm²) and the corresponding apparent diffusion coefficient map reveal restricted diffusion (arrow). (F) Fluorodeoxyglucose (FDG) positron emission tomography/CT shows intense FDG uptake in the gallbladder lesion (arrow; maximum standardized uptake value=7.9).

Fig. 2.

Histopathological findings of isolated immunoglobulin G4 (IgG4)-related gallbladder. Dense lymphoplasmacytic infiltration is observed in the gallbladder wall (A: hematoxylin and eosin [H&E] staining, ×4; B: H&E, ×200). The specimen shows both an absolute increase (>100 IgG4-positive plasma cells per high-power field) and a relative increase (IgG4/IgG plasma cell ratio >40%) (C: IgG, ×200; D: IgG4, ×200).

DISCUSSION

A definitive diagnosis of IgG4-related disease is established primarily through histopathological evaluation rather than clinical or radiologic findings alone. IgG4-RD is known to affect a wide range of organs, including the pancreas, biliary system, gallbladder, retroperitoneum, and vascular structures, and may manifest as autoimmune pancreatitis, sclerosing cholangitis, or mass-forming inflammatory lesions [1,2]. In the present case, microscopic examination of the resected specimen revealed prominent lymphoplasmacytic infiltration accompanied by fibrosis (Fig. 2). Immunohistochemical staining demonstrated numerous IgG4-positive plasma cells with an elevated IgG4/IgG ratio, fulfilling established diagnostic thresholds. Although serum IgG4 levels can provide supportive information, they lack sufficient diagnostic reliability when used in isolation. In IgG4-related sclerosing cholangitis, reported sensitivity is approximately 50%, with overall diagnostic accuracy around 60% [4]. Consequently, distinguishing IgG4-related cholecystitis from gallbladder carcinoma before surgery remains challenging. Reported cases of isolated IgG4-related cholecystitis mimicking gallbladder cancer are summarized in Table 1 [6–11]. In this case, IgG4-related disease was not initially suspected preoperatively, as the imaging findings were highly suggestive of gallbladder malignancy. Therefore, serum IgG4 measurement was not performed as part of the routine preoperative evaluation, which represents a limitation of this report.

Table 1.

Clinical and pathological features of reported cases of isolated IgG4-related cholecystitis mimicking locally advanced gallbladder cancer

Author (year)	Age (yr)/sex	Clinical features	Diagnostic method	Histopathological features	Treatment	IgG4 IHC
						Cells/HPF	Ratio (%)
Shin et al. (2013) [6]	58/M	Suspected gallbladder cancer	Postoperative diagnosis	Lymphoplasmacytic infiltration, fibrosis	Radical cholecystectomy	15	NA
Feely et al. (2014) [7]	71/F, 53/M	Elevated CA19–9, mimicking biliary malignancy	Postoperative diagnosis	Lymphoplasmacytic infiltration, fibrosis	Radical cholecystectomy	98–104	79–81
Takahashi et al. (2015) [8]	18/M	Suspected gallbladder cancer	Postoperative diagnosis	Lymphoplasmacytic infiltration, fibrosis, obliterative phlebitis	Radical cholecystectomy	30–40	10–40
Kulkarni et al. (2019) [9]	55/F	Gallbladder mass with choledochal cyst, suspected carcinoma	Postoperative diagnosis	Lymphoplasmacytic infiltration, storiform fibrosis	Radical cholecystectomy + choledochal cyst excision	Approximately 80	>40
Jearth et al. (2020) [10]	57/M	Mimicking locally advanced gallbladder cancer	Steroid therapy followed by surgery	Lymphoplasmacytic infiltration, fibrosis	Steroid + cholecystectomy	93	40–50
Harada et al. (2022) [4]	82/M	Localized gallbladder wall thickening, suspected malignancy	Postoperative diagnosis	Lymphoplasmacytic infiltration, fibrosis, obliterative phlebitis	Laparoscopic cholecystectomy	10	>40
Kawakami et al. (2023) [11]	70s/M	Fundus lesion with stones, suspicious for malignancy	Transpapillary biopsy followed by surgery	Lymphoplasmacytic infiltration, fibrosis	Laparoscopic cholecystectomy	>10	>40
Present case	77/M	Mimicking locally advanced gallbladder cancer	Postoperative diagnosis	Lymphoplasmacytic infiltration, fibrosis, obliterative phlebitis	Radical cholecystectomy	100	>40

IgG4, immunoglobulin G4; IHC, immunohistochemistry; HPF, high-power field; NA, not applicable; CA19–9, carbohydrate antigen 19–9; M, male; F, female.

Radiologic findings, including diffuse or focal gallbladder wall thickening, frequently overlap with those of malignancy [2,3]. In our patient, contrast-enhanced CT demonstrated arterial-phase enhancement with gallstones, while MRI showed irregular mural thickening with homogeneous enhancement. Diffusion-weighted imaging with ADC mapping indicated restricted diffusion, and FDG-PET/CT revealed intense metabolic uptake, all of which favored a diagnosis of carcinoma (Fig. 1). In such cases, when imaging findings are highly suggestive of resectable gallbladder carcinoma, upfront surgical resection is generally considered appropriate without preoperative histologic confirmation, in accordance with current international consensus guidelines for gallbladder cancer management [5]. Preoperative tissue diagnosis is not routinely performed due to technical limitations and the potential risk of tumor seeding associated with percutaneous biopsy.

In the absence of systemic manifestations such as autoimmune pancreatitis, renal involvement, or retroperitoneal fibrosis, imaging studies alone have limited value for definitive diagnosis [2,3]. Although FDG-PET/CT may assist in identifying multiorgan involvement in IgG4-RD, inflammatory lesions can demonstrate increased uptake similar to malignant tumors [12]. As a result, most patients are managed surgically under the suspicion of gallbladder cancer [6–10]. While several reports have described the use of intraoperative frozen-section analysis to identify IgG4-related inflammation and permit less extensive surgery [4,11], the diagnosis is most often established only after definitive resection, as in our case. Previous studies have reported variability in immunohistochemical findings, with some cases failing to meet proposed consensus thresholds. In contrast, the histological features in our patient satisfied the criteria outlined in the 2012 International Consensus Statement [1], the 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria [13], and the 2020 revised Japanese diagnostic criteria [14]. Despite the availability of standardized diagnostic frameworks, histological and radiologic overlap with malignancy continues to pose a diagnostic challenge. The combined use of serum IgG4 measurement, preoperative biopsy, or cytologic evaluation may help reduce unnecessary radical resections in selected cases, particularly given the favorable response of IgG4-RD to corticosteroid therapy [5]. Nevertheless, in routine clinical practice, most cases are still diagnosed after surgical intervention [4]. This case highlights the difficulty of differentiating IgG4-related cholecystitis from gallbladder carcinoma. Despite comprehensive multimodal imaging (Fig. 1), malignancy could not be excluded preoperatively, and histopathological examination remained the only means of establishing the correct diagnosis (Fig. 2). Although isolated IgG4-related cholecystitis is rare, it should be considered in the differential diagnosis of gallbladder malignancy, especially in patients with equivocal or atypical imaging findings. In such cases, serum IgG4 measurement and evaluation for other organ involvement may improve preoperative diagnostic accuracy. However, when imaging findings strongly suggest malignancy, radical surgical resection remains an appropriate and often unavoidable oncologic approach.

Data Availability Statement

Data sharing is not applicable as no new data were created or analyzed in this study.