Clinicopathological Pearls and Diagnostic Pitfalls in IgG4-Related Disease: Challenging Case Series and Literature Review

Abstract

Background: IgG4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder characterized by lymphoplasmacytic infiltrates enriched in IgG4-positive plasma cells, storiform fibrosis, and frequently elevated serum IgG4 levels. Classic forms, such as pancreaticobiliary or retroperitoneal involvement, are often recognized early, whereas atypical manifestations mimic malignancy or inflammatory conditions, leading to delayed or inappropriate treatment. Case Series: A 30-year-old man presented with hyperemesis, proptosis, and gait instability. He was found to have colonic stenosis, stomach thickening, pachymeningitis, and polyserositis. Gastroenteric histology and serology confirmed IgG4-RD. Steroids were ineffective, but rituximab produced sustained clinical and radiologic improvement. A 35-year-old woman developed jaundice and cholestasis with a perihilar mass highly suggestive of cholangiocarcinoma. Histopathology revealed IgG4-RD, and rituximab therapy led to marked clinical and serological improvement. A 64-year-old woman with a submandibular mass underwent sialoadenectomy, with histology confirming IgG4-RD; she remained asymptomatic without systemic treatment. Literature Review: A literature review highlighted the diagnostic challenges of atypical IgG4-RD. Gastrointestinal involvement is rare and often misclassified as inflammatory bowel disease. Isolated biliary disease frequently mimics cholangiocarcinoma, while salivary gland involvement may be misdiagnosed as neoplasia. Serum IgG4 levels >135 mg/dL and IgG4/IgG ratio >0.21 may support clinical suspicion, but histopathology remains indispensable for definitive diagnosis and for excluding malignancy. Steroid responsiveness is a hallmark, though relapses after tapering are common, often necessitating B-cell-directed therapy. Conclusions: IgG4-RD should be considered in patients with unexplained, relapsing, or steroid-responsive conditions. Early recognition, multidisciplinary collaboration, and integration of histopathology with clinical features are essential to avoid misdiagnosis and optimize management.

Keywords: Atypical features of IgG4-RD; Dacryoadenitis; IgG4-related disease; IgG4-related sclerosing cholangitis; autoimmune pancreatitis; immune-mediated fibroinflammatory disease; immunoglobulin G4; lymphadenopathy; ocular and orbital inflammatory disease; retroperitoneal fibrosis and related disorders; salivary gland disease.

Figure 1

Histological features of gastric mucosae with foveolar hyperplasia H&E, 4× (A) and mild plasma cellular infiltrate H&E, 20× (B). The majority of IgG-positive plasma cells, immunostaining, 20× (C) appear positive for IgG4 20× (>10 plasma cells/HPF—ratio > 0.4), (D).

Figure 2

Histological features of IgG4-related sclerosing cholangitis typically show mild plasma cellular infiltrate H&E, 20× (A) with irregularity whorled pattern of fibrosis (storiform fibrosis), H&E, 20× (B). Majority of IgG4-positive plasma cells, immunostaining, 20× (C) appear positive for IgG4, 20× (>10 plasma cells/HPF—ratio > 0.4), (D).

Figure 3

Histological features of IgG4-related sialadenitis show a mass-forming lesions with atrophic ducts, periductal fibrosis, with obliterated vein and mild plasma cellular infiltrate H&E, 20× (A,B). Majority of IgG-positive plasma cells, immunostaining, 20× (C) appear positive for IgG4 20× (≈95/105 plasma cells/HPF—ratio > 0.4), (D).

Figure 4

Practical monocenter approach for typical and atypical IgG4-RD manifestations. For specific organ involvement refer to Table 2.