Unusual metastatic microcalcification in IgG4-related disease detected by Tc-99m MDP SPECT/CT: a case description

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is a systemic condition characterized by immunoglobulin G4 (IgG4)-positive plasma cell infiltration, elevated serum IgG4 levels, multi-organ involvement, and a favorable response to glucocorticoid therapy (1,2). The main laboratory findings are elevated serum IgG4, hypergammaglobulinemia, and eosinophilia. The pathogenesis remains unclear; however, interactions between B cells and T lymphocytes, particularly follicular helper T cells, drive IgG4 class switching, T helper type 2 cell cytokine overexpression, and regulatory T-cell activation, leading to inflammatory cell infiltration and organ damage (3). IgG4-RD commonly affects organs such as the pancreas, kidneys, and lymph nodes, but its association with hypercalcemia is rare. In this article, we report a rare case of IgG4-RD complicated by hypercalcemia, with widespread metastatic calcifications in the lungs and stomach detected via technetium-99m methylene diphosphonate single-photon emission computed tomography/computed tomography (Tc-99m MDP SPECT/CT). Biopsies confirmed the diagnosis, and the patient improved significantly after corticosteroid therapy.

Case presentation

A 60-year-old Chinese man was urgently admitted to hospital due to severe hypercalcemia and renal insufficiency. The patient complained of weakness, and a physical examination suggested anemia. Laboratory findings showed renal dysfunction and severe hypercalcemia (blood urea nitrogen of 18.31 mmol/L, serum creatinine of 330 µmol/L, and serum calcium of 3.67 mmol/L). Serum immunoglobulin G (IgG) was 2,533.0 mg/dL (reference range: 860.0–1,740.0 mg/dL), and serum IgG4 subclass was 241 mg/dL (reference range: 3–201 mg/dL). Serum whole parathyroid hormone (PTH) was low at 9.2 pg/mL (reference range: 15–65 pg/mL). Serum markers specific to bone formation, including N-terminal mid-fragment (>300 ng/mL) and N-terminal propeptide of type I procollagen (>1,200 µg/L), were elevated, indicating heightened turnover. Peripheral blood analysis revealed anemia (red blood cell count: 2.74×10¹²/L, hemoglobin: 87 g/L), eosinophilia (2.74×10⁹/L), and hypoalbuminemia (serum albumin: 32.3 g/L). Urinalysis showed mild proteinuria (0.221 g/L). Autoantibody tests, including antinuclear antibodies, anti-extractable nuclear antigen antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies (ANCAs), and phospholipase A2 receptor antibodies, were all negative.

Based on the clinical presentation of hypercalcemia with suppressed PTH and the absence of malignancy evidence on the initial workup, Tc-99m MDP SPECT/CT was performed to exclude occult osteolytic metastases and evaluate metastatic calcifications resulting from calcium-phosphate dysregulation. A Tc-99m MDP SPECT/CT scan (740 MBq [20 mCi], imaging at 180 minutes post-injection) demonstrated increased tracer uptake in the stomach and lungs (Figure 1), indicative of extensive metastatic calcification. Chest computed tomography (CT) showed bilateral pulmonary exudative changes and mildly enlarged lymph nodes in the axillary and mediastinal regions, suggestive of inflammation; thus, empiric anti-infective therapy was initiated.

Figure 1 Images from Tc-99m MDP SPECT/CT scan. (A,B) Whole-body anterior (A) and posterior (B) bone scintigraphy demonstrating skeletal tracer distribution; (C) axial chest CT image revealing diffuse ground-glass opacities (as indicated by the arrows) in bilateral lung fields; (D,F) SPECT/CT fusion images in axial (D) and coronal (F) planes showing pathological radiotracer uptake in the stomach and lungs; (E) axial abdominal CT imaging highlighting gastric wall thickening with focal hyperdensity, suggestive of calcific deposition. CT, computed tomography; Tc-99m MDP SPECT/CT, technetium-99m methylene diphosphonate single-photon emission computed tomography/computed tomography.

To confirm the diagnosis, bronchoscopy and lymph node biopsy were performed. The bronchoscopic evaluation revealed chronic inflammation with eosinophil infiltration and diffuse mucosa microcalcifications (Figure 2). Histopathology of the left axillary lymph node excluded hematologic malignancy, but showed prominent IgG4-positive plasma cell infiltration [approximately 40 per high-power field (HPF)], IgG4⁺/IgG⁺ ratio >40% (Figure 2). The bone marrow biopsy showed markedly reduced hematopoietic hyperplasia, with the intramedullary hematopoietic component accounting for approximately 20% of the cellularity. Microscopic examination demonstrated the presence of granulocytic, erythroid, and megakaryocytic lineages, accompanied by abundant eosinophilic infiltration and scattered lymphoplasmacytic cells. Immunohistochemical staining showed diffuse positivity for IgG and focal positivity for IgG4. The renal biopsy findings demonstrated global glomerulosclerosis in approximately 25% of glomeruli and multiple microcalcifications within renal tubular epithelial cells. Multifocal plasma cell infiltration and fibrous tissue hyperplasia were observed in the renal interstitium. Electron microscopy revealed diffuse and irregular thickening of the basement membrane, occasional electron-dense deposits in the mesangial region, and the widespread effacement of the podocyte foot processes. Immunostaining highlighted abundant IgG4-positive plasma cell infiltration (>10 per HPF). Collectively, these features fulfilled the diagnostic criteria for immunoglobulin G4-related tubulointerstitial nephritis (IgG4-TIN).

Figure 2 Core diagnostic evidence of IgG4-related disease. (A) Bronchoscopy demonstrating an irregular nodular elevation in the bronchial mucosa; (B) axial CT image of the left axilla showing an enlarged lymph node; (C) hematoxylin and eosin staining of the lymph node biopsy (×100 magnification) revealing dense lymphoplasmacytic infiltration; (D) hematoxylin and eosin staining of the lymph node biopsy (×200 magnification) highlighting abundant lymphoplasmacytic infiltration. CT, computed tomography; IgG4, immunoglobulin G4.

Other potential diseases, including lymphoma, malignancy, sarcoidosis, and Castleman’s disease, were ruled out through differential evaluation. A final diagnosis of IgG4-RD, with concurrent hypercalcemia and renal insufficiency, was confirmed. The patient subsequently received intravenous methylprednisolone therapy (20 mg/day). Following treatment, the patient’s clinical status markedly improved, with restoration of normal renal function and serum calcium levels (serum urea nitrogen: 10.06 mmol/L, serum creatinine: 118 µmol/L, and serum calcium: 2.27 mmol/L).

All procedures in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s), and the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this article and the accompanying images. A copy of the written consent form is available for review by the editorial office of this journal.

Discussion

IgG4-RD is a systemic disorder capable of affecting nearly any organ. While over 90% of hypercalcemia cases stem from primary hyperparathyroidism or malignancy, IgG4-RD is exceedingly rare; patients often present with nonspecific symptoms, leading to referrals across multiple specialties. When IgG4-RD involves organs such as the kidneys, lungs, or bone marrow, it may mimic tumor-like lesions, necessitating differentiation from malignancies or other autoimmune conditions, such as ANCA-associated vasculitis, idiopathic multicentric Castleman disease (iMCCD), and Rosai-Dorfman disease. When IgG4-RD affects the kidneys, the primary manifestation is IgG4-TIN, characterized by interstitial inflammation rich in plasma cells (4,5). Key diagnostic features include elevated serum IgG4 levels, eosinophilic infiltration, hypergammaglobulinemia, sharply demarcated renal parenchymal lesions (with distinct margins between affected and unaffected areas), and immunoglobulin and complement deposition in the tubular basement membrane (6).

The therapeutic response to corticosteroids can help differentiate IgG4-RD from other disorders. Patients with IgG4-RD exhibit rapid improvement following glucocorticoid therapy, whereas patients with iMCCD demonstrate only partial responsiveness to steroids and, often require adjunctive immunosuppressant or anti-interleukin 6 (IL-6) therapy (7,8).

When IgG4-RD affects the lungs, it is termed immunoglobulin G4-related lung disease (IgG4-RLD), which often mimics other pulmonary disorder manifestations such as inflammatory pseudotumor, interstitial pneumonia, organizing pneumonia, and lymphomatoid granulomatosis, thereby complicating differential diagnosis (9). Histologically, both IgG4-RLD and iMCCD exhibit lymphoplasmacytic infiltration. However, IgG4-RLD is characterized by perivascular stromal fibrosis, eosinophilic infiltration, and obliterative phlebitis. Conversely, iMCCD lung lesions are typically localized to alveolar regions adjacent to the perilymphatic stromal compartments (10). Rosai-Dorfman disease typically presents with lymphadenopathy. Histopathologically, it is characterized by a predominance of histiocytes with abundant cytoplasm demonstrating emperipolesis (lymphocyte engulfment), also termed Rosai-Dorfman cells. These cells exhibit strong S-100 protein positivity and CD1a negativity, which reliably distinguishes the disease from IgG4-RD. While both IgG4-RD and Rosai-Dorfman disease may exhibit hypergammaglobulinemia, potential overlap between the two entities remains speculative (11).

In this case, the patient initially presented with renal dysfunction and hypercalcemia, prompting symptomatic management upon admission. Due to the nonspecific clinical features, establishing a definitive diagnosis proved challenging. Ultimately, bronchoscopy, lymph node biopsy, and renal histopathology confirmed IgG4-RD, complicated by hypercalcemia. This case highlights that IgG4-RD is a systemic chameleon capable of mimicking malignancies in virtually any organ system, including the gastrointestinal tract, nervous system, gynecologic organs, and non-renal urologic sites. This underscores the critical need to include IgG4-RD in differential diagnoses of tumor-like lesions across multiple specialties (12-15).

Hypercalcemia is predominantly attributed to primary hyperparathyroidism and malignancy, which account for over 90% of cases (16). Conversely, IgG4-RD represents a rare etiology of hypercalcemia, with only isolated case reports documented in the medical literature. PTH testing serves as the cornerstone for differentiating among the etiologies of hypercalcemia, which is broadly divided into PTH-dependent hypercalcemia and non-PTH-dependent hypercalcemia.

PTH-dependent hypercalcemia is usually caused by parathyroid adenoma and hyperplasia. Üsküdar et al. documented a patient with IgG4-RD who presented with parathyroid adenoma and biochemical evidence of hyperparathyroidism (elevated PTH and serum calcium). Postoperative histology revealed hallmark IgG4-RD features: dense lymphoplasmacytic infiltrates with IgG4/IgG >50%, suggesting the autoimmune targeting of parathyroid tissue (17). An alternative mechanism of PTH-dependent hypercalcemia involves autoantibodies targeting the calcium-sensing receptor (CaSR). A patient with polyautoimmunity presented with elevated serum calcium and PTH levels in response to glucocorticoids. Subtotal parathyroidectomy revealed the patchy lymphocytic infiltration of histologically normal glands, suggesting IgG4-mediated CaSR inactivation as the underlying cause of hypocalciuria hypercalcemia (18). Separately, Hasegawa et al. reported a unique presentation of IgG4-RD complicated by autoimmune hemolytic anemia (AIHA), with systemic involvement of the lymph nodes, liver, and salivary glands. The patient exhibited elevated serum calcium and intact PTH levels. However, Tc-99m methoxyisobutylisonitrile (MIBI) scintigraphy and thyroid ultrasonography revealed no abnormalities. Transient hypercalcemia in a patient with AIHA may therefore be associated with IgG4-RD (19).

The etiology of non-PTH-dependent hypercalcemia remains unclear. Kawakita et al. presented the case of a 40-year-old male hospitalized with renal dysfunction and severe hypercalcemia. Tc-99m MDP SPECT imaging demonstrated increased ectopic tracer uptake in the heart, lungs, stomach, and kidneys. Subsequent autopsy revealed bone marrow osteoclast proliferation. The patient was ultimately diagnosed with IgG4-RD complicated by osteolytic hypercalcemia (20). Parathyroid hormone-related peptide (PTHrP) is the most common mediator of malignancy-associated hypercalcemia. Hypercalcemia has also been documented in immune-mediated disorders such as childhood lupus nephritis and systemic lupus erythematosus. PTHrP shares significant homology with PTH in its N-terminal sequence and binds to the type 1 PTH/PTHrP receptor, which is highly expressed in bone and kidneys. This interaction mimics PTH activity, leading to elevated serum calcium levels (21-23).

Another proposed mechanism involves anti-PTH receptor antibodies, which activate PTH receptors, thereby inducing hypercalcemia despite suppressed PTH and PTHrP levels (23). As IgG4-RD is an autoimmune disease, it is hypothesized that PTHrP may contribute to its associated hypercalcemia. In this case, the patient’s subnormal PTH levels suggested non-PTH-dependent hypercalcemia, and the next step involved the potential malignancy evaluation. Through comprehensive laboratory tests, imaging studies, and histological examinations, we excluded other causes of hypercalcemia, such as solid tumors, lymphomas, multiple myeloma, and drug-induced effects. Therefore, the etiology of IgG4-RD associated with hypercalcemia warrants further investigation. Hypercalcemia and dysregulated calcium metabolism predispose patients to metastatic calcifications in an alkaline microenvironment. Elevated intracellular pH in organs such as the lungs, stomach, and kidneys facilitates calcium-phosphate deposition, increasing patient susceptibility to ectopic calcifications (24).

Tc-99m MDP SPECT/CT is a highly sensitive imaging modality for the early detection of extraosseous metastatic calcifications. Tc-99m MDP SPECT/CT provides unique diagnostic and therapeutic insights into hypercalcemia. Unlike conventional imaging, its ability to bind microcrystalline hydroxyapatite enables the early detection of metastatic calcification before CT/magnetic resonance imaging visibility, which is particularly critical in calcium-phosphate dysregulation with renal or autoimmune diseases. Simultaneously, it serves as a metabolic indicator: diffuse skeletal uptake suggests hyperparathyroidism, while focal osteoblastic lesions indicate malignancy with higher specificity than 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography for mineralizing tumors (25). In our IgG4-RD case, this dual capability excluded occult metastases and confirmed IgG4-related pulmonary/gastric calcification, thereby guiding a therapeutic shift from empiric chemotherapy to targeted immunosuppression due to suspected parathyroid-mediated hypercalcemia. Tc-99m MDP SPECT/CT quantifies the hypercalcemia treatment response through the serial maximum standardized uptake value tracking of the calcification burden, directing the real-time titration of dialysis and antiresorptive regimens when biomarkers equivocate. It not only quantifies the extent of calcifications but also aids in disease diagnosis, reducing reliance on invasive biopsies. For patients with renal insufficiency and hypercalcemia of unknown origin, IgG4-RD should be carefully considered in the differential diagnosis. Tc-99m MDP SPECT/CT plays a critical role in promptly identifying metastatic calcifications and guiding therapeutic interventions.

Acknowledgments

The authors thank the patient for allowing them to publish this case report.

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-794/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s), and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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