IgG4-related Disease Concomitant with Diffuse Large B-cell Lymphoma

Abstract

A 77-year-old man presented with right inguinal lymphadenopathy and swollen parotid and submandibular glands bilaterally. Histopathology revealed germinal center B-cell type diffuse large B-cell lymphoma (DLBCL) in the inguinal lymph node. Lymphocyte and plasma cell infiltration in the submandibular gland with elevated serum IgG4 levels (13 g/L) prompted a diagnosis of IgG4-related disease (IgG4-RD). Systemic chemotherapy for DLBCL led to shrinkage of the lymph nodes and disappearance of the submandibular gland swelling, as confirmed by fluorodeoxyglucose-positron emission tomography/computed tomography. Although concomitant IgG4-RD and lymphoma have been reported, their simultaneous diagnosis is rare; therefore, a biopsy of all involved organs is crucial in cases with unusual organ involvement.

Introduction

IgG4-related disease (IgG4-RD) is a polyclonal lymphoproliferative disorder characterized by elevated serum IgG4 levels and mass-forming lesions in various organs due to the proliferation of IgG4-producing plasma cells. IgG4-RD is associated with an increased risk of malignant diseases, particularly malignant lymphoma (1,2). While there have been many reports of IgG4-RD preceding malignant lymphoma (3-10), few cases have been reported in which both were diagnosed simultaneously (11).

We herein report a case of IgG4-RD disease concomitant with diffuse large B-cell lymphoma (DLBCL).

Case Report

A 77-year-old man was referred to the Department of Hematology & Immunology, Kanazawa Medical University, in September 2020, with a 1-month history of right inguinal lymphadenopathy and swollen bilateral parotid and submandibular glands. He showed no B symptoms (fever, night sweats, or weight loss), dry eyes, dry mouth, or taste or smell abnormalities. The bilateral parotid glands measured 5 cm, the submandibular gland swelling was 3 cm, and the right inguinal lymph node measured 3 cm. Blood tests revealed elevated serum levels of IgG (2,469 mg/dL), IgG4 (1,250 mg/dL), and soluble IL-2R (1,220 U/mL) (Table). Retrospectively, serum IgG levels showed a slight increase from the reference value (1,853 mg/dL) in March 2015, although serum total protein and albumin levels were normal at 8.3 g/dL and 4.6 g/dL, respectively. In June 2020 total protein and albumin was both normal (7.4 g/dL and 4.0 g/dL). In September 2020, protein fractionation showed no M-peak or β-γ bridging. The γ-globulin level had increased from the reference value (27.7%). No data were available on immunoelectrophoresis when the patient was referred to our department.

Table.

Laboratory Findings upon Admission.

Item	Measure		Item	Measure
RBC	396×104	/μL	CRP	0.26	mg/dL
Hb	13.5	g/dL	Na	140	mmol/L
Hct	42.1	%	K	4.4	mmol/L
MCV	106.2	fL	BUN	14	mg/dL
WBC	5,780	/μL	Cre	0.93	mg/dL
Neut	48.3	%	TP	8.6	g/dL
Lym	39.3	%	Alb	4.5	g/dL
Plt	191,000	/μL	LDH	176	U/L
IgG	2,469	mg/dL	AST	27	U/L
IgG4	1,250	mg/dL	ALT	19	U/L
IgG4/IgG	51	%	γ-GTP	76	U/L
IgA	182	mg/dL	ALP	214	U/L
IgM	105	mg/dL	β2MG	2.0	mg/L
			sIL-2R	1,220	U/mL
			AMY	62	U/L
			Glu	98	mg/dL
			HbA1c	5.5	%

¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography (¹⁸FDG-PET/CT) showed an abnormal accumulation in the bilateral parotid and submandibular glands, as well as in the right inguinal lymph nodes (Fig. 1). The diagnosis of germinal center B-cell-type DLBCL was made based on the diffuse proliferation of large, atypical lymphocytes, which immunohistochemically tested positive for CD20, CD10, Bcl-6, and MUM-1 (Fig. 2). The lymphoma stage was Lugano I. In addition, the right submandibular gland exhibited prominent infiltration of lymphocytes and plasma cells, with a ratio of IgG4+/CD38+ plasma cells exceeding 70%. Fibrosis and obliterating phlebitis were also observed (Fig. 3). Furthermore, a high serum IgG4 level of 13 g/L led to a diagnosis of IgG4-RD.

Figure 1.

Left: ¹⁸FDG-PET/CT findings informing the diagnosis of IgG4-related disease and diffuse large B-cell lymphoma. Abnormal accumulations are seen in the parotid (SUVmax: 8.08) and submandibular glands (SUV max: 9.57), and right inguinal lymph node (SUVmax: 15.18). Right: ¹⁸FDG-PET/CT findings after six courses of R-THP-COP chemotherapy. The abnormal accumulation in the bilateral parotid glands, bilateral submandibular glands, or lymph nodes had disappeared, indicating a successful complete metabolic response. ¹⁸FDG-PET/CT: ¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography

Figure 2.

Pathological findings in right submandibular gland. A) Hematoxylin and Eosin staining (×200), B) EVG (×200), C) IgG (×200), D) IgG4 (×200). Prominent lymphocytic and plasma cell infiltration with fibrosis and obliterating phlebitis are evident. Immunohistochemical staining reveals IgG4-positive cellular infiltration (IgG4/IgG >70%).

Figure 3.

Pathological findings in right inguinal lymph node. A) Hematoxylin and Eosin (H&E) staining (×40), B) H&E staining (×400), C) CD20 (×200), D) CD10 (×200), E) BCL-6 (×200), F) MUM-1 (×200). Diffuse proliferation of large atypical lymphocytes positive for CD20, CD10, Bcl-6 and MUM-1 immunohistochemically.

The patient was admitted to the hospital in November 2020 to undergo R-THP-COP chemotherapy consisting of rituximab (600 mg), pirarubicin (65 mg), cyclophosphamide (1,000 mg), and vincristine (1.9 mg) administered on day 1, along with prednisolone (65 mg) from days 1 to 5. He completed six courses of R-THP-COP chemotherapy in March 2021. Following the initiation of treatment, the enlarged bilateral parotid glands, submandibular glands, and right inguinal lymph nodes quickly decreased in size, and serum IgG and IgG4 levels returned to normal (Fig. 4). Subsequent ¹⁸FDG-PET/CT after treatment completion showed no abnormal accumulation in the bilateral parotid glands, bilateral submandibular glands, or lymph nodes, indicating a complete metabolic response. Furthermore, the patient's IgG4-RD remained in remission without the need for glucocorticoid (GC) maintenance treatment.

Figure 4.

Change in IgG and IgG4 levels during follow up.

Discussion

The diagnosis of IgG4-RD can be challenging because the involved organs vary from case to case, and lymph node involvement is uncommon. A diagnosis is usually made by a biopsy of representative tissues, such as the lacrimal glands, salivary glands, or pancreas. However, diagnosing IgG4-RD from a lymph node biopsy is difficult due to the variability in the histopathology of IgG4-related lymphadenopathy (12) and the rarity of cases involving only the lymph nodes. In cases where disease distribution involves both representative tissues and regional lymph nodes, it is generally considered to be the same disease. However, in instances such as this, where lymphadenopathy extends beyond regional lymph nodes, the possibility of a separate disease from that affecting the salivary glands cannot be ruled out. In the present case, PET-CT clearly showed stronger accumulation in the inguinal region [maximum standardized uptake value (SUVmax): 15.18] than in the bilateral parotid (SUVmax: 8.08) and bilateral submandibular (SUVmax: 9.57) glands, which suggested a possible malignant lymphoma. Therefore, PET-CT is recommended in cases of IgG4-RD with atypical disease distribution, even though it is not covered by Japanese health insurance.

The mechanism underlying the development of malignant lymphoma in IgG4-RD patients remains unclear. Possibilities include lymphoma development from chronic inflammation due to IgG4-RD, and IgG4-RD developing as a paraneoplastic syndrome of lymphoma. It has been reported that IgG and IgG4 may contribute to the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma (13). In addition, elevated levels of Th2 and Treg cytokines in ocular MALT lymphomas associated with IgG4-RD imply a potential role for Th1/Th2 in disease etiology (14). The present patient received R-THP-COP chemotherapy for DLBCL, which resulted in a rapid reduction in the size of the bilateral parotid and submandibular glands. The long-term remission of IgG4-RD without maintenance GC in this case may be attributed to the efficacy of not only GC therapy but also additional rituximab administration (15).

A biopsy of the most reliable site is the usual approach to diagnose IgG4-RD; however, in cases where the distribution of affected organs is unusual, biopsies from multiple organs may be necessary for an accurate diagnosis.

Author’s disclosure of potential Conflicts of Interest (COI).

Yasufumi Masaki received research grants from Kyowa Hakko Kirin Pharma, Astellas Pharma, Eisai Pharma, Ono Pharma, Pfizer Pharma, Asahi Kasei Pharma, MSD Pharma, Daiichi-Sankyo Pharma, Taisho Pharma, Taiho Pharma, Takeda Pharma, Chugai Pharma, Teijin Pharma, Nippon Kayaku and Mochida Pharma, outside the submitted work.