Coexistence of IgG4-Related Disease and Renal Anastomosing Hemangioma: A Rare Diagnostic Challenge

Abstract

IgG4-related disease (IgG4RD) is a chronic inflammatory condition that can mimic malignancies. This report describes an 83-year-old male diagnosed with IgG4RD, in whom a left kidney mass was incidentally discovered. Despite glucocorticoid treatment for IgG4RD, the mass did not shrink, and imaging could not exclude malignancy, prompting surgical resection. Pathological examination revealed a rare benign tumor, renal anastomosing hemangioma (AH) with numerous IgG4-positive cells surrounding it. This case raises the possibility that chronic interstitial inflammation associated with IgG4RD may contribute to the development of renal AH, underscoring the need for further research with additional cases to better understand this relationship.

Introduction

IgG4-related disease (IgG4RD) is a chronic inflammatory condition that affects multiple organs over time, often presenting as masses that may mimic malignancies (1). Previous studies have indicated that patients with IgG4RD have a higher prevalence of malignancies than the general population, highlighting the need for ongoing tumor surveillance, even after diagnosis (1). This report describes a case where a mass in the left kidney was incidentally identified during the diagnosis of IgG4RD. Imaging findings and the clinical course could not exclude malignancy, prompting surgical resection, which revealed a rare benign tumor, renal anastomosing hemangioma (AH), upon pathological examination.

Case Report

An 83-year-old male presented with swelling of the bilateral upper eyelids for 5 months and swelling of the bilateral submandibular regions for 2 months, leading him to seek care at a previous hospital. Magnetic resonance imaging (MRI) of the head and neck revealed bilateral enlargement of the lacrimal and submandibular glands. Additionally, a low-signal area was observed from the pituitary stalk to the posterior lobe. Based on these findings, he was referred to our hospital for further evaluation and treatment. On admission, vital signs were as follows: heart rate, 64 bpm; blood pressure, 112/67 mmHg; and body temperature, 36.5°C. Physical examination revealed swelling of the bilateral upper eyelids and elastic masses in the submandibular regions, with no abnormalities in the chest or abdomen and no rash. Symptoms such as thirst, polydipsia, and polyuria were absent.

Investigation

The laboratory data are shown in Table 1. Urinalysis revealed no proteinuria, hematuria, or abnormal casts, but renal function was impaired, with a creatinine concentration of 1.34 mg/dL and an estimated glomerular filtration rate of 39.6 mL/min/1.73 m². IgG and IgG4 concentrations were elevated at 2,453 mg/dL and 1,010 mg/dL, respectively. The anti-nuclear-antibody test was positive (homogeneous/speckled pattern), but specific autoantibodies, including SS-A, were not detected.

Table 1.

Laboratory Date.

[Urinalysis]				[Biochemistry]				[Immunology]
Protein	(-)			HbA1c	5.8	%		IgG	2,453	mg/dL
Blood	(-)			TP	7.7	g/dL		IgA	200	mg/dL
Glucose	(-)			Alb	3.9	g/dL		IgM	49	mg/dL
Urinary cast	(-)			LDH	157	IU/L		IgG4	1,010	mg/dL
UPCR	0.19	g/g･Cr		AST	17	IU/L		C3	107	mg/dL
β2-MG	89	μg/L		ALT	8	IU/L		C4	23	IU/mL
				γ-GTP	17	IU/L
[Complete blood cell count]				ALP	54	IU/L		[Autoantibody]
WBC	5,380	/μL		Crn	1.34	mg/dL		Antinuclear antibody	×160
Neutro	3,170	/μL		eGFR	39.6	mL/min/1.73m2		(Homo/speckled pattern)
Lymph	1,750	/μL		BUN	25	mg/dL		Anti-SS-A antibody	<1.0	U/mL
Eosino	188	/μL		Na	139	mEq/L		MPO-ANCA	<1.0	U/mL
RBC	342×104	/μL		K	4.5	mEq/L		PR3-ANCA	<1.0	U/mL
Hb	11.0	g/dL		Cl	104	mEq/L		Anti ARS antibody	<1.0	U/mL
Plt	17.1×104	/μL		CK	173	U/L
				CRP	0.10	mg/dL
[Coagulation]
PT-INR	1.03
APTT	25.6	s
D dimer	2.2	μg/mL

Contrast-enhanced computed tomography (CT) of the head, chest, and abdomen revealed swelling of the orbital and salivary glands, thickening of the descending aortic wall, and soft tissue shadows around the common iliac arteries. Although contrast-enhanced CT did not reveal any typical areas of poor enhancement, an incidental mass with enhanced contrast and a pseudo-capsular structure were also detected in the left kidney (Fig. 1A). Contrast-enhanced MRI of the kidney showed early enhancement and washout patterns, consistent with the CT findings. The lesion demonstrated high intensity on heavily T2-weighted imaging, suggesting free water, and maintained a high intensity on T2 fat suppression, effectively ruling out angiomyolipoma. Based on the morphology, clear cell renal carcinoma or an IgG4RD-related renal lesion was suspected (Fig. 1B).

Figure 1.

Contrast-enhanced CT (A, B, C) and contrast-enhanced MRI images (D, E). (A) Wall thickening of the descending aorta. (B) Soft tissue shadow at the branching of the common iliac artery. (C) Mass in the left kidney with a capsular structure extending towards the renal sinus (arrow). (D) Heavy T2-weighted image and (E) T2 fat-suppressed image showing a contrast-enhanced high-signal area in the left kidney with a pseudocapsule (arrows). Early enhancement and washout observed.

Labial biopsy showed an IgG4/IgG-positive cell ratio of 52% and 18 IgG4-positive plasma cells per high-power field. Based on the 2020 Comprehensive Diagnostic Criteria for IgG4RD, the presence of multiple organ masses, hyper-IgG4emia, and pathological findings, a diagnosis of IgG4RD was confirmed. The renal lesion remained indistinguishable from IgG4RD-related kidney disease (IgG4RKD) or renal cell carcinoma based on imaging findings.

Treatment

Given the potential for tumor shrinkage with glucocorticoid treatment in patients with IgG4RD, 30 mg (0.5 mg/kg) of prednisone was initiated for remission induction, and its effectiveness was monitored using blood tests and imaging. Over 3 months, the dose was tapered to 10 mg, and the serum IgG4 concentration decreased to 285 mg/dL. There were no findings from urinalysis or imaging that strongly suggested interstitial nephritis. However, the improvement in renal function after glucocorticoid treatment and the persistence of inflammatory cell infiltration in the interstitium on renal histology are consistent with IgG4RD-related interstitial nephritis. Follow-up CT demonstrated significant shrinkage of the aortic wall thickening and other suspected IgG4RD lesions. In contrast, no reduction in the renal mass was observed, further supporting the suspicion of renal cell carcinoma, particularly the clear cell subtype. This prompted a partial nephrectomy (Fig. 2).

Figure 2.

Clinical course and changes in images.

The histopathological findings describe hemangioma-like vascular structures positive for CD34, consistent with renal AH (Fig. 3A-C). Despite treatment, infiltration of IgG4-positive cells was observed around the lesion (Fig. 3D, E), whereas no infiltration was identified within the AH lesion itself. In the surrounding non-tumor tissue, interstitial fibrosis and sclerosis of multiple glomeruli were identified (Fig. 3F).

Figure 3.

Histological findings of Hematoxylin and Eosin (H&E) staining and immunohistochemistry. H&E staining revealed hemangioma-like vascular structures (low magnification: A, high magnification: B). These structures were positive for CD34 (C). Marked infiltration of inflammatory cells was observed in the tubulointerstitial area (D), which contained many IgG4-positive cells (E). Additionally, interstitial fibrosis and sclerotic glomeruli were noted (F) (Scale bars: A, 1,000 μm; B-F, 100 μm).

Discussion

IgG4RKD represents renal manifestations of IgG4RD, sometimes resulting in the formation of tumor-like lesions. Typical pathological findings include lymphoplasmacytic infiltration of the renal interstitium with IgG4-positive cells, along with characteristic imaging features, such as renal enlargement, wedge-shaped hypoperfusion areas, or multiple renal masses (2). Differentiating IgG4RKD from malignancies is often challenging, as renal malignancies have been reported in IgG4RD cases (3,4). In this case, the imaging findings of a hyperintense lesion surrounded by a pseudocapsule did not exclude the possibility of malignancy, requiring additional diagnostic investigation.

AH, a rare benign vascular tumor, has been documented in various organs, such as the kidney, liver, adrenal gland, and retroperitoneum (5). Among AH cases, the kidney is the most commonly affected organ, with over 60 cases reported to date (6). However, its overall prevalence remains unknown due to its rarity. Its etiology remains unclear; however, two-thirds of cases are associated with renal dysfunction, and many have been reported in patients with end-stage renal disease (ESRD) (6,7). While AH lesions are typically solitary, multifocal and bilateral lesions have also been observed in patients with ESRD (6). Renal AH often mimics renal cell carcinoma (RCC) in imaging findings, exhibiting early enhancement and washout patterns on CT or MRI (6). Given these overlapping features, histopathological examination played a crucial role in differentiating AH from other potential diagnoses in this case. A summary of the clinical, imaging, and histopathological features of renal AH, IgG4-RKD, and RCC is presented in Table 2, highlighting key points useful for differential diagnosis (6,8,9).

Table 2.

Summary of Clinical, Imaging, and Histopathological Features of Diseases Presenting with Renal Mass Lesions.

Clinicopathological features	Anastomosing hemangioma	IgG4-related kidney disease	Renal cell carcinoma (RCC)
Frequency	Rare	Rare	Common
Clinical manifestations	None or hematuria, flank pain	Renal dysfunction, mass lesions, proteinuria	Hematuria or bask pain, palpable mass
Histopathology	Benign vascular proliferation with anastomosing sinusoidal-like spaces	Dense lymphoplasmacytic infiltrate, storiform fibrosis, IgG4-positive plasma cells	Malignant epithelial cells forming glandular or solid structures
Immunohistochem-istry	CD31, CD34 positive	IgG4-positive plasma cells	PAX8, RCC marker positive
Radiological findings	Hypoattenuation, arterial enhancement on CT	Diverse lesions such as wedge-shaped areas	Hypervascular mass, often with necrosis on CT/MRI
Treatment	Surgical resection	Immunosuppressive therapy	Surgical resection, targeted therapy, immunotherapy

RCC: Renal cell carcinoma

Patients with IgG4RD have an elevated risk of malignancy compared to the general population (10). Chronic inflammation caused by IgG4RD may promote tumorigenesis, although the exact mechanism is unclear (11). In this case, a benign tumor, renal AH, was found instead of a malignant tumor. A search for the coexistence of renal AH and autoimmune diseases did not confirm any association with IgG4RD. However, three cases of end-stage renal failure resulting from lupus nephritis have been reported (12-14). Including this case, four cases where a pathological diagnosis was made through surgical intervention were compared in terms of age, sex, and comorbidities (Table 3). Generally, renal AH is known to be prevalent in older men with ESRD (15). Although the three cases of lupus nephritis occurred at relatively young ages, all three had ESRD. This case, involving an older male with stage 3b chronic kidney disease, aligns with the profile of the occurrence of renal AH. Despite prior glucocorticoid treatment in this case, interstitial inflammatory cell infiltration and numerous IgG4-positive cells were observed around the renal AH. Chronic interstitial inflammation has been implicated in the pathogenesis of renal fibrosis in conditions such as lupus nephritis, which is known to increase the risk of ESRD (16). Similarly, chronic inflammation associated with IgG4RD may have played a role in the development of renal AH. While AH is benign vascular tumor, its potential association with IgG4RD remains unreported. Given that renal AH is an extremely rare condition, the possibility that IgG4RD-related inflammation contributed to its development cannot be ruled out. However, due to the rarity of renal AH, the possibility of a coincidental coexistence also remains. Further research with additional cases is needed to better understand this relationship.

Table 3.

Summary of Previous Cases of Pathologically Diagnosed Anastomosing Hemangioma with Autoimmune Disease.

PMID	Age/sex	Symptoms	Organ	Treatment	Comorbidities	Autoantibody	Reccurrence
34256731	35/Female	Back pain	Right kidney	Nephrectomy	Lupus nephritis, ESRD (dialysis)	Not mentioned	None
28118845	47/Male	Back pain	Left kidney	Nephrectomy	Lupus nephritis, ESRD (dialysis), HT	Not mentioned	None
31687349	39/Male	Hematuria	Bilateral kidney right adrenal grand	Adrenal-nephrectomy	Lupus nephritis (Type V), ESRD (dialysis), HT, DL, anemia	Not mentioned	None
This case	83/Male	None	Left kidney	Partial nephrectomy	IgG4RD, CKD, HF, HT, enlarged prostate	ANA (homo/speckled pattern)	None

ESRD: end stage renal disease, HT: hypertension, DL: dyslipidemia, HF: heart failure, ANA: anti-nuclear antibody

Glucocorticoid therapy is generally effective for IgG4RD (17). In this case, the aortic lesions responded well to treatment, but the renal mass did not, suggesting that the renal mass lesion was not directly associated with IgG4RKD. However, the presence of chronic interstitial inflammation surrounding the lesion raises the possibility that IgG4RKD-related inflammation contributed to the development of renal AH. The appropriate approach to managing masses suspected of malignancy at the time of IgG4RD diagnosis remains a subject of discussion, particularly regarding whether therapeutic intervention should be determined after evaluating glucocorticoid responsiveness. Collaboration with urologists from the time of diagnosis and regular imaging assessments are essential to determine the optimal timing for surgical resection while continuing treatment.

Conclusions

IgG4RD can present with tumor-like lesions and is known to have a higher association with malignancies compared to the general population. In this case, we identified the incidental coexistence of renal AH, a rare benign tumor, during the evaluation of IgG4RD. The clinical insights gained from the diagnostic and therapeutic processes in this case highlight the importance of distinguishing between benign and malignant lesions in patients with IgG4RD. This report underscores the need for multidisciplinary approaches in managing such cases and contributes to understanding the potential relationship between IgG4RD and tumor formation.

The authors state that they have no Conflict of Interest (COI).