Abstract
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that commonly affects multiple organs and may be misdiagnosed when presenting at atypical sites. We report an example of IgG4-RD involving the uterus and abdominopelvic lymph nodes and review the literature to clarify clinical, pathological and laboratory features. A 51-year-old female patient presented with prolonged menstruation and underwent PET/CT that revealed hypermetabolic masses in the uterus and multiple abdominopelvic lymph nodes, initially suggesting malignancy. She underwent a total hysterectomy and lymph node biopsy. Histopathology showed storiform fibrosis, obliterative phlebitis and dense lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells. Serum IgG4 and IgG levels were markedly elevated, supporting the diagnosis of IgG4-RD. Postoperative therapy with a regimen comprising dexamethasone, cyclophosphamide and bortezomib resulted in a substantial reduction in serum IgG4 levels, indicating effective disease management. This case report emphasizes the need to consider IgG4-RD in unusual anatomical locations, to enhance clinical awareness, and to apply comprehensive diagnostic criteria to improve patient outcomes.
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a rare, immune-mediated disorder that may affect multiple organ systems.1,2 The clinical symptoms of IgG4-RD often lack specificity, leading to diagnostic challenges.3–5 The pathological features include dense lymphoplasmacytic infiltration (rich in IgG4-positive plasma cells), storiform fibrosis and obliterative phlebitis. Commonly affected organs are the submandibular glands, lacrimal glands, and lymph nodes. 6 However, there are limited reports regarding the reproductive system,7–11 particularly concerning the uterus, with only one example reported to date. 12 In this report, we present a patient of IgG4-RD involving the uterus, aiming to improve diagnosis accuracy and inform management strategies for this exceptionally rare condition.
Patient History
A 51-year-old female patient presented with a 10-month history of prolonged menstruation, reporting no change in menstrual cycle or volume, and occasional dizziness and fatigue. PET/CT at our hospital demonstrated a hypermetabolic mass in the uterine cavity, along with multiple hypermetabolic lymph nodes in several regions, including the retroperitoneum, bilateral iliac regions, posterior left diaphragmatic crus, anterior diaphragmatic group, and bilateral paravertebral areas. Focal thickening with increased uptake (metabolic activity) was also noted in the mesentery, omentum, and peritoneum. These findings were suggestive of widespread dissemination or metastasis of malignancy, with the uterine lesion likely representing the primary site (Figure 1A).
(A) PET/CT imaging demonstrated a hypermetabolic mass within the uterine cavity and multiple hypermetabolic lymph nodes inferior to the transverse septum. (B) Gross view of the uterus showing a submucosal nodule measuring 5.0 cm × 4.0 cm × 4.0 cm protruding into the uterine cavity.
Under general anesthesia, she underwent a total hysterectomy with bilateral salpingo-oophorectomy, along with biopsies of mesenteric and omental nodules as well as the right obturator lymph node.
Pathological Examination
Gross examination identified a submucosal nodule protruding into the uterine cavity, measuring 5.0 cm × 4.0 cm × 4.0 cm (Figure 1B). Sectioning revealed a grayish-white, firm, poorly circumscribed mass. Multiple lymph nodes (ranging in diameter from 0.5 to 1.0 cm) were retrieved from the right pelvic cavity, mesentery, and greater omentum; these nodes were grayish-white and firm on cut section. Microscopic examination of the uterine lesion revealed fibrous tissue proliferation with focal storiform fibrosis, characterized by cells with eosinophilic cytoplasm, short spindle-shaped or oval nuclei with visible nucleoli, and mitotic figures at a frequency of 1 per 10 high-power field (HPF) (Figure 2A, C, D). There was dense infiltration of lymphocytes and plasma cells with lymphoid follicle formation (Figure 2E), and perivascular lymphocyte infiltrates with focal obliterative phlebitis (Figure 2B). Abdominopelvic lymph nodes exhibited variably sized lymphoid follicles with germinal centers (Figure 2F). Storiform-like fibrosis (Figure 2G) with increased lymphocytes and plasma cells in fibrous septa and follicular regions (Figure 2H) was also observed. Immunophenotyping of the uterine mass showed CD38+, CD138+, MUM1+, and IgG+ plasma cells (Figure 3A, B, C, and E, respectively); and abundant IgG4+ plasma cells (124 IgG4+ cells/HPF; IgG4/IgG ratio 60%, Figure 3D). CD20+ (Figure 3F) B cells and CD3+ (Figure 3G) T cells were also present. Negative markers comprised CD21 (Figure 3H), BCL2, BCL6, CD10, CD30, CD15, CD5, MYC, PAX5, CD34, ALK, and SMA in the lesional parenchymal cells. A subset of plasma cells co-expressed kappa and lambda light chains, indicating polyclonality; EBER in situ hybridization was negative. Lymph nodes similarly demonstrated CD20+ B cells; CD38+ and CD138+ plasma cells; abundant IgG4+ plasma cells (106/HPF; IgG4/IgG ratio 75%); and negative for CD3. The histomorphology of both the uterus and lymph nodes was concordant with the immunophenotypic profile. Based on these findings, serological tests were recommended and the result revealed elevated serum IgG4 (5650 mg/dL; reference range 3-201 mg/dL) and IgG (6010 mg/dL; reference range 751-1560 mg/dL). By integrating histopathologic, serologic, and clinical data, the final diagnosis was IgG4-RD involving the uterus and abdominopelvic lymph nodes.
Representative histopathological staining of the uterus and abdominopelvic lymph nodes. (A) Multifocal lymphoplasmacytic infiltrates and fibrous tissue proliferation in the uterine myometrium (40×; Scale bar: 200 μm). (B) Occlusive phlebitis around uterine vessels (100×; Scale bar: 100 μm). (C) Fibrous tissue proliferation in the uterine myometrium (200×, Scale bar: 100 μm). (D) Storiform fibrosis in the myometrium (400×; Scale bar: 50 μm). (E) Fibrosis with dense plasma-cell infiltration in the myometrium (600×; Scale bar: 20 μm). (F) Fibrous tissue proliferation in the abdominopelvic lymph node (40×; Scale bar: 200 μm). (G) Storiform fibrosis with lymphocytic infiltration in the lymph node (400×; Scale bar: 50 μm). (H) Increased plasma cells in the lymph node (1000×; Scale bar: 10 μm).
Representative immunohistochemical staining of the uterus. (A) CD38, (B) CD138, (C) IgG, (D) IgG4, (E) MUM1, (F) CD20, (G) CD3, (H) CD21 (400×; Scale bar: 50 μm).
Clinical Treatment and Follow-Up
The patient received dexamethasone, cyclophosphamide and bortezomib regimen supplemented by symptomatic therapy. She underwent regular outpatient follow-up. Fourteen months post-surgery, serum IgG4 and IgG levels had declined to 1390 mg/dL and 2360 mg/dL, respectively, and imaging demonstrated regression of abdominal lesions, indicating a significant treatment response. The patient's condition remained stable under long-term maintenance therapy.
Discussion
IgG4-RD is characterized by immune dysfunction and its exact pathogenesis remains unclear.5,13,14 However, allergic mechanisms, genetic susceptibility, environmental exposures, and microbial infections have been implicated2,5,13,14 . Epidemiologically, serum IgE levels are elevated up to 90% of patients, and 32.8% exhibit peripheral eosinophilia. Both findings correlate positively with IgG4 levels, 15 suggesting that allergy contributes to disease onset. 16 In affected tissues, dense lymphoplasmacytic infiltrates, storiform fibrosis, and obliterative phlebitis are observed; these changes may be mediated by immune-complex deposition. 17
IgG4-RD of the uterus is exceedingly rare and often presents atypically, which may delay diagnosis or lead to misdiagnosis. 12 The principal diagnostic frameworks are the 2020 revised comprehensive diagnostic criteria (RCD, originally published 2011)18,19 from Japan and the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. 20 The specificity of RCD is reduced when serum IgG4 is borderline or biopsy material is limited. 21 By contrast, the weighted system of 2019 ACR/EULAR criteria rewards broader evaluation and multisite involvement, yielding higher composite scores and greater diagnostic confidence. 20 In the present patient, ACR/EULAR component scores included atypical-site involvement (0 points), concordant pathological morphology in the uterus and lymph nodes (13 points), matching immunohistochemical profiles (14 points), serum IgG4 > five times the upper limit of normal (11 points), and a favorable response to glucocorticoid therapy provided supportive evidence. This yielded a total score of 38, exceeding the diagnostic threshold of 20. However, an elevated serum IgG4 level (> 1350 mg/dL) is supportive but neither specific nor definitive for the diagnosis 3 . Histopathological criteria—namely an IgG4+/IgG+ plasma cell ratio exceeding 40% and more than 10 IgG4+ plasma cells per HPF—are valuable diagnostic markers.
Despite meeting diagnostic criteria, several important differential diagnoses must still be considered. Key differential diagnoses include inflammatory myofibroblastic tumor, 22 mucosa-associated lymphoid tissue, 23 Castleman disease, systemic autoimmune disorders, and inflammatory pseudotumor5,19,20 (Table 1). Histology, immunophenotyping, and testing (eg, light-chain restriction and B-cell receptor gene rearrangement) aid in distinguishing these entities. Therapy for IgG4-RD should be individualized and targeted to control inflammation, limit fibrosis, and preserve organ function. Involvement of critical organs or symptomatic disease warrants prompt systemic glucocorticoids, whereas indolent superficial involvement may be managed conservatively with active surveillance.24,25 Collectively, these diagnostic and therapeutic considerations underscore the importance of accurate pathological recognition.
Differential Diagnosis of Immunoglobulin G4-Related Disease (IgG4-RD).
Conclusion
In conclusion, the presence of dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis should prompt consideration of IgG4-RD, even in unusual anatomical locations. Combining the RCD and ACR/EULAR classification criteria with clinical, imaging, laboratory, and histopathological data improves diagnostic accuracy and facilitates timely, effective treatment.
Footnotes
Ethics Approval
The data reported here were obtained in agreement with the Ethics Committee (2025-165).
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
The data used in this case report are available as described in the manuscript.
Trial Registration
Not applicable, because this article does not contain any clinical trials.