Introduction

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease which can affect multiple organ systems. This disease is usually associated with high serum IgG4 levels and specific histopathological features.

The concept of IgG4-RD was first introduced by Hamano et al. in 2001. It is associated with increased serum IgG4 levels in patients with autoimmune pancreatitis (AIP)[1]. The etiology and triggering factors are still unknown. The condition occurs most often in middle-aged or older men. A single study from Japan reported a low male to female ratio of 1: 0.77 [2]. Involvement of almost all anatomical regions has been reported, but most commonly affected areas are the pancreas, lacrimal gland, salivary gland, retroperitoneum, orbit, lymph nodes, kidneys, and lungs [1]. IgG4-RD is often discovered incidentally during radiological or histopathological examination of tissues. The diagnosis is made by combined evaluation of clinical, radiological, and histopathological findings. The course of the disease is usually characterized by remission and recurrent attacks, which can lead to fibrosis, destructive tissue damage, and if not promptly treated, it can cause organ failure. It also causes compression findings, secondary sclerosis, and obstruction due to neoplastic lesions [3,4]. Correct identification is essential to avoid unnecessary major surgery and to institute corticosteroid therapy [2].

Case History

A 31 years old female with no co-morbidities presented with complaints of pain in the left thigh for 1 month, difficulty in weight bearing and pain while walking for 5 days duration, which was insidious in onset, gradually progressive, aggravated on weight bearing associated with radiating pain to back and left thigh. Local examination revealed tenderness and swelling in the middle 1/3^rd of left thigh. There was no local rise of temperature and overlying skin was normal. Terminal flexion movement was painful at left hip and left knee joint. She was unable to perform straight leg raising test but no neurovascular deficit was noted.

X ray left thigh showed a lytic lesion in upper 1/3rd of left femur with unicortical pathological fracture (Fig 1a). The CT angiogram and MRI showed an expansile lytic lesion measuring 9 x 3 cm involving the proximal shaft of left femur with adjacent marrow and soft tissue edema. Minimal fluid collection with mild soft tissue thickening was noted adjacent to the lesion Fig 1b). PET scan revealed a well-defined osteolytic lesion measuring 2.5 x 2.6 x 11.1 cm in the mid and distal 1/3^rd of shaft of femur with significant cortical thinning and cortical erosion noted with increased uptake (Fig 2 a-f). The clinical differentials considered were mainly Giant cell tumour, infective osteomyelitis and malignancy. Laboratory investigations showed mild anemia (Hb – 9 gm/dl) with neutrophilic leukocytosis (TLC- 12,400/cumm) with mild left shift of neutrophils. Initial imaging guided biopsy from the osteolytic lesion showed only xanthogranulomatous inflammation with histiocytes and dense lymphoplasmacytic infiltrate extending between skeletal muscles with areas of necrosis and granulation tissue (Fig 3 a-c).

Figure 1(a): X-ray showing lytic lesion in upper 1/3rd of left femur with unicortical pathological fracture (b) CT Angiogram -Well defined, lobulated, eccentrically located lytic lesion in diaphysis of left femur measuring 23 x 27 x 88 m with cortical destruction.

Fig 2 (a) Maximum Intensity Projection (MIP) image of 18 F-Fluorodeoxy Glucose (FDG) PET showing focus of increased tracer concentration in the region of left thigh. Fig 2 (b, c, d): Fused coronal, (2e) axial image, (2 f) fused sagittal image of 18 F-FDG PET-CT showing a metabolically active soft tissue component in the left thigh adjacent to an expansile lytic lesion involving the upper and mid 1/3rd diaphysis of left femur with significant cortical thinning and endosteal scalloping.

Fig 3 (a) dense inflammatory infiltrate comprising of neutrophils, lymphocytes, plasma cells, giant cells and histiocytes; (b) Storiform type fibrosis; (c) Obliterative phlebitis.

Patient underwent currettage with bone grafting and open reduction internal fixation by nailing. The curettage bony tissue was sent for histopathology which showed skeletal muscle bundles infiltrated by numerous plasma cells, lymphocytes, neutrophils and histiocytes. The stromal tissue showed degenerated bony bits with surrounding areas of storiform fibrosis and occasional blood vessels showing obliterative phlebitis (Fig 3 a-c). Areas of necrosis along with xantho-granulomatous changes & foreign body giant cell reaction was also noted. No frank evidence of malignancy was noted.

Based on the microscopic findings, the probability of infective osteomyelitis was considered. Tuberculosis was ruled out as no granulomas or any caesous necrosis was seen. No Acid-Fast Bacilli was noted on ZN stain. Fungal cause was ruled out by Pas stain and Grocott stain showing no fungal elements.

Since the tissue did not exhibit any typical histomorphology that would support a giant cell tumor, the clinical suspicion of a giant cell tumor was ruled out. IHC for CD1a was negative, ruling out Langan's cell histiocytosis. Negative ALK expression on IHC excluded inflammatory myofibroblastic tumor while negative CD34 expression excluded Dermato Fibrosarcoma Protuberans. Sarcoma was ruled out because there were no malignant osteoid or chondroid regions, no large cells in the backdrop of mononuclear cells, and IHC was negative for vimentin, desmin, calponin, S-100, and BCL2. PANCK negativity ruled out metastatic deposits from epithelial malignancy.

At this point, we thought about the possibility of an IgG4-related illness, but as there were no publications in the literature about this condition affecting long bones, it was seen as a lower differential diagnosis and was only taken into consideration after all other options had been ruled out. Immunohistochemistry revealed increased number of plasma cells highlighted by CD 138, and these plasma cells showed no kappa or lambda restriction highlighting their polyclonal nature. These plasma cells showed strong positivity with IgG4 (>30/hpf) >40% ratio of IgG and IgG4 plasma cells. Further serum IgG4 studies showed elevated levels (282 mg/dl) against a normal of 135 mg/dl.

Discussion

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that affects multiple systems. Three diagnostic criteria are included in the Comprehensive diagnostic (CD) criteria for IgG4-RD (revised 2020 version)[5]: organ involvement (diffuse/localized swelling); serum IgG4 concentration >135 mg/dl; microscopy demonstrating significant plasma cell infiltration (>10 IgG4+ cells/HPF) and a >40% ratio of IgG4+/IgG + cells, along with fibrosis on biopsy. Cases which met all three criteria were diagnosed with definite IgG4-RD; those who met the first and last criteria but did not have elevated serum IgG4 concentration were diagnosed with probable IgG4-RD; and those who met the first two criteria but had negative histopathology results or no histopathologic examination were diagnosed with possible IgG4-RD.[5,6] Organ-specific criteria may be used to re-diagnose patients with a suspected or probable diagnosis of IgG4-RD.

Although elevated serum IgG4 levels is a distinctive finding and frequently seen in IgG4-RD, it’s not the gold standard for diagnosing the condition. Due to its low sensitivity of 51% and low specificity of 60%, serum IgG4 concentration has been questioned in few studies.[7] As a result, a serum IgG4 cutoff level of 135 mg/dl was included in the initial CD criteria for IgG4-RD along with additional organ-specific criteria because it was thought to be a distinct and trustworthy sign predictive of IgG4-RD, and was included in the original CD criteria for IgG4-RD as well as other organ-specific criteria.[5 ]

Dense infiltration of lymphocytes, plasma cells, and fibrosis are frequent histopathologic features of IgG4-RD. In addition to lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis are considered to be distinctive and characteristic features for IgG4-RD.[5,6] Additional pathological criteria - obliterative phlebitis and storiform fibrosis were included in the 2020 RCD criteria as these were common histological findings seen in IgG4-RD. Obliterative phlebitis is characterized by the obliteration of the vascular lumen with inflammatory cells and fibrosis, while storiform fibrosis is defined as cart wheel arrangement of spindle-shaped cells.

Recent reviews emphasize that the pathogenesis of IgG4-RD is rooted in immune dysregulation, particularly in interactions between T follicular helper cells, regulatory T cells, and cytotoxic CD4+ T lymphocytes. These cellular populations drive both the inflammatory (proliferative) and fibrotic phases of disease. While the classic view focused on a predominant role for IgG4 antibodies, new data highlights the central contribution of cytotoxic T cells and their secreted fibrogenic cytokines, such as IL-4, IL-10, and TGF-β, which mediate organ fibrosis.[7]

The case presented here involving the femur adds to the limited cases of long bone involvement, which is likely the first reported case in literature. Bone lesions due to IgG4-RD pose significant diagnostic challenges because they can radiologically and histologically mimic infections, malignancies, or other inflammatory disorders.

In the current case, features like storiform fibrosis, obliterative phelbitis and a high proportion of IgG4-positive plasma cells (40% of all IgG-positive plasma cells) substantiated the diagnosis after ruling out all possible infectious and neoplastic causes on thorough IHC panel and by special stains. In our study, the presence of elevated serum IgG4 supports systemic activity, though levels are not exclusively diagnostic since increased serum IgG4 can occur in other conditions.[8]

Epidemiological trends indicate IgG4-RD is likely underdiagnosed, especially in its fibrotic phenotype, which can slowly cause irreversible tissue damage. Bone involvement remains unusual, with a few documented cases affecting the cranial, temporal, and long bones. This rarity can delay recognition and definitive management, highlighting the need for broad differential diagnoses and multidisciplinary input.

From a therapeutic perspective, corticosteroids remain the cornerstone for acute management. However, rates of relapse and steroid dependence are considerable, prompting the adoption of B-cell depletion therapy such as rituximab. This targets CD20+ B cells and has shown sustained remission rates in multi-organ IgG4-RD, particularly in cases with extensive or relapsing disease.

Newer agents inhibiting T-cell or cytokine signaling including IL-4/IL-13 and Bruton’s tyrosine kinase inhibitors are now in clinical trials, reflective of the shifting understanding of IgG4-RD pathogenesis.[7,8]

Follow-up is essential, given the tendency for chronic fibrosis to progress even after immunosuppressive therapy. Recent reports now recommend regular clinical assessment, imaging, and serological monitoring to optimize long-term outcomes and minimize irreversible tissue damage.

Conclusion

This case of IgG4-RD involving a long bone and presenting as an osteolytic lesion illustrates the inherent complexity of the disease. It reinforces that IgG4-RD, though rare in bone, should be considered in the differential diagnosis of lytic skeletal lesions with compatible histology and serology. The literature strongly suggests that early, accurate diagnosis and a tailored immunosuppressive approach are critical for good patient outcomes, especially in atypical presentations.

Advances in understanding the cellular and molecular underpinnings of IgG4-RD particularly the roles of cytotoxic T cells and targeted biologic therapies are likely to shape the next generation of management paradigms. Sustained multidisciplinary collaboration and continued research into predictive biomarkers will further enhance care for patients with this enigmatic and multifaceted condition.

References

1. Nambiar S, Oliver TI. IgG4-Related Disease. 2023 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan.
2. Hirabayashi K, Zamboni G. IgG4-related disease. Pathologica. 2012 Apr;104(2):43-55.
3. Nizar, AH, Toubi E. IgG4-related disease: case report and literature review. Autoimmun Highlights 2015;6:7–15.
4. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N. High serum IgG4 concentrations in patients with sclerosing pancreatitis. New England Journal of Medicine. 2001;344:732–738.
5. Umehara H, Okazaki K, Kawa S et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Mod Rheumatol 2021; 31:529–533.
6. Deshpande V, Zen Y, Chan JK et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012; 25:1181–1192.
7. Perugino CA, Mattoo H, Mahajan VS, Maehara T, Wallace ZS, Pillai S, Stone JH. Emerging Treatment Models in Rheumatology: IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies. Arthritis Rheumatol. 2017 Sep;69(9):1722-1732.
8. Chen LYC. IgG4-related disease for the hematologist. Hematology Am Soc Hematol Educ Program. 2024 Dec 6;2024(1):594-603.