Diffuse large B-cell lymphoma with rapid kidney enlargement after induction of hemodialysis in a patient with IgG4-related disease

Abstract

A 76-year-old Japanese man was incidentally diagnosed with a pancreatic head tumor on computed tomography after surgery for colon cancer. He underwent pancreatoduodenectomy and was diagnosed with IgG4-related autoimmune pancreatitis. Concurrent chronic kidney disease gradually progressed and chronic hemodialysis was introduced 2 years later. Six months after the introduction of hemodialysis, follow-up abdominal computed tomography revealed marked enlargement of bilateral kidneys compared with previous images. Blood tests revealed persistent high IgG and IgG4 levels, and IgG4-related kidney disease was suspected. Thus, percutaneous kidney biopsy was performed. No evidence of IgG4-related kidney disease was detected, and a diagnosis of diffuse large B-cell lymphoma was made. Six courses of combination chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone was effective, and the patient achieved and maintained complete remission for five years. This case highlights the need to consider the possible development of malignant lymphoma within several years after IgG4-related disease, especially in cases of autoimmune pancreatitis.

Introduction

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a disease of unknown etiology that is characterized by marked infiltration and fibrosis of lymphocytes and IgG4-positive plasma cells, resulting in organ enlargement, nodules, and thickened lesions. IgG4-RD is common in middle-aged men aged 50–70. In addition to pancreatic and renal lesions, salivary and lacrimal gland lesions have been reported [1]. The disease was initially thought to be steroid-responsive; however, it can lead to end-stage kidney disease in patients with irreversible fibrosis. The long-term prognosis of patients with IgG4-RD after the induction of dialysis is unknown. There are increasing reports regarding malignancies in IgG4-RD patients [2]. In general, chronic dialysis patients, cancer in the kidney, liver and lung are well-known malignancies, while malignant lymphoma is relatively rare [3].

Here, we describe a patient with IgG4-RD initially diagnosed with autoimmune pancreatitis who developed rapid enlargement of bilateral kidneys after induction of hemodialysis. The final diagnosis was malignant lymphoma, and the patient was successfully treated with chemotherapy.

Case report

A 76-year-old Japanese man on chronic hemodialysis was admitted to our hospital because of bilateral kidney enlargement on abdominal ultrasonography. He had been treated for hypertension and diabetes mellitus for more than 20 years and was diagnosed with chronic kidney disease (serum creatinine level of 2.4 mg/dL) 6 years prior. Both kidneys showed cortical atrophy and the clinical diagnosis was chronic kidney disease because of hypertensive nephrosclerosis at that time. Three years later, he was found to have sigmoid colon cancer. Abdominal computed tomography (CT) revealed no evidence of metastasis in other organs, and the patient underwent a colectomy. Follow-up CT performed 6 months after the curative surgery for colon cancer revealed a nodular lesion of 1.5 cm in the pancreatic head. Both kidneys remained atrophic, and there were no specific findings in other organs. Since pancreatic cancer was suspected, pancreaticoduodenectomy was immediately performed. The nodular lesion in the pancreas head (Fig. 1A) showed loss of pancreatic tissue, and inflammatory cell infiltration accompanied by storiform fibrosis was detected (Fig. 1B and C). Immunohistochemical staining revealed that most of the cells were CD138-positive plasma cells and also positive for IgG and IgG4 (Fig. 1D–F). Serum IgG and IgG4 levels were elevated at 1,886 mg/dL and 689 mg/dL, respectively. Therefore, the diagnosis of IgG4-associated autoimmune pancreatitis was made. Renal dysfunction was progressive thereafter, and the patient was confirmed with end-stage kidney disease requiring hemodialysis at the age of 75. Six months after the introduction of hemodialysis, abdominal CT was performed as a follow-up one year after the pancreatoduodenectomy. We unexpectedly found marked enlargement of bilateral kidneys compared with previous images (Fig. 2A and B). The patient was admitted for kidney biopsy for histologic diagnosis.

Fig. 1.

Macroscopic and microscopic findings of the pancreas nodule. A Macroscopic specimen of the excised pancreas shows a white nodular lesion (arrow). B Loss of pancreatic structure and inflammatory cell infiltration in kidney tissue (H&E staining). C Inflammatory cell infiltration was accompanied by storiform fibrosis (Elastica-Van Gieson’s staining). D Immunohistochemical staining revealed that most of the infiltrating cells in the kidney were positive for CD138. E The infiltrating cells were positive for IgG. F The infiltrating cells were positive for IgG4

Fig. 2.

Abdominal imaging of the kidney. A Abdominal computed tomography (CT) before induction of hemodialysis showing bilateral atrophic kidneys. B Abdominal CT 6 months after induction of hemodialysis showing marked enlargement of bilateral kidneys. C 18F-fluorodeoxyglucose positron emission tomography revealed consistent uptake in bilateral enlarged kidneys

On admission, his height was 177.0 cm, body weight 65.5 kg, body temperature 36.3 ℃, blood pressure 151/78 mmHg, and pulse 88/min. Physical examination revealed no remarkable abnormalities in the head and neck, chest, abdomen, and extremities. No swelling of parotid glands, submandibular glands, and lymphadenopathy in cervical, axillary, and inguinal areas were detected. Blood test results on admission are summarized in Table 1. Serum IgG level was 1,992 mg/dL, IgG4 598 mg/dL, IgE 1,817 IU/mL, complement (C) 3 100 mg/dL, C4 24.7 mg/dL, hemolytic complement activity (CH50) test 4.57 U/mL, and antinuclear antibody was negative. We did not find any abnormality on chest radiography. Further investigation with 18F-fluorodeoxyglucose positron emission tomography revealed consistent uptake in bilateral enlarged kidneys (Fig. 2C), spine, ribs, and mesenteric lymph nodes.

Table 1.

Laboratory findings on admission

Complete blood count			Biochemistry (cont.)
White blood cell count	5.0 × 103	/µL	Chloride	95	mmol/L
Neutrophil	60.2	%	Calcium	8.2	mg/dL
Lymphocyte	9.3	%	Phosphate	4.5	mg/dL
Monocyte	7.6	%	Total bilirubin	0.2	mg/dL
Eosinophil	22.7	%	Aspartate aminotransferase	7	U/L
Basophil	0.2	%	Alanine aminotransferase	4	U/L
Red blood cell count	2.61 × 106	/µL	Lactate dehydrogenase	238	U/L
Hemoglobin	8.5	g/dL	Alkaline phosphatase	251	U/L
MCV	102.3	fL	Serology
MCH	32.6	pg/mL	C-reactive protein	2.02	mg/dL
Platelet count	230 × 103	/µL	Immunoglobulin G	1992	mg/dL
Biochemistry			Immunoglobulin G4	598	mg/dL
Total protein	7.7	g/dL	Immunoglobulin A	200	mg/dL
Albumin	3.3	g/dL	Immunoglobulin M	93	mg/dL
Blood urea nitrogen	45.3	mg/dL	Immunoglobulin E	1817	IU/mL
Creatinine	10.96	mg/dL	Complement 3	100	mg/dL
Uric acid	7.6	mg/dL	Complement 4	24.7	mg/dL
Sodium	134	mmol/L	Hemolytic complement activity (CH50)	4.57	U/mL
Potassium	5.1	mmol/L	Anti-nuclear antibody	Negative

MCV mean corpuscular volume, MCH mean corpuscular hemoglobin

Ultrasound-guided percutaneous kidney biopsy was performed on the right kidney. Biopsy specimen showed diffuse infiltration of lymphoid cells, and kidney structure was replaced by those cells (Fig. 3A). The sampled tissue included 10 glomeruli, and all glomeruli showed global sclerosis with disruption of Bowman’s capsule by infiltrating cells (Fig. 3B). The tubulointerstitial area was severely damaged with disappearance of renal tubulus (Fig. 3C) and diffuse infiltration of large or medium sized atypical lymphoid cells with vesicular chromatin and many mitoses surrounded by fibrotic tissue (Fig. 3D and E). Immunostaining showed few IgG- and IgG4-positive cells, but the IgG4/IgG ratio was 30%–40% (Fig. 4A and B). While the morphology of fibrosis was similar to that in IgG4-RD, the infiltrating cells showed severe atypia, suggesting malignant lymphoma. We thus performed further immunohistochemical staining. The results demonstrated that the infiltrating cells were positive for CD20 and CD138 (Fig. 4C and D) and were Bcl-6 (+), MUM-1 (+), and CD10 (+), with a MIB-1 index of 80%. From these results, a diagnosis of diffuse B-cell lymphoma (DLBCL) was made. Analysis of peripheral blood smear and gastric biopsy performed after renal biopsy also suggested DLBCL.

Fig. 3.

Percutaneous kidney biopsy findings. A Diffuse infiltration of lymphoid cells, and kidney structure was replaced by those cells (H&E staining). B Glomerulus showing global sclerosis with disruption of Bowman’s capsule by infiltrating cells (H&E staining). C Tubulointerstitial area showed severely damaged renal tubulus and disappearance of renal tubulus (PAM staining). D–E Diffuse infiltration of atypical cells with enlarged nuclei, irregular nuclear shape, and unequal nuclei size surrounded by fibroblasts (H&E staining)

Fig. 4.

Immunohistochemical staining of intrarenal infiltrating cells. A Immunohistochemical staining showed few IgG-positive cells. B Immunohistochemical staining for IgG4; the IgG4/IgG ratio was 30%–40%. C Most infiltrating cells were positive for CD20. D There were a small number of CD138-positive cells

The patient received six courses of combination chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Follow-up 18F-fluorodeoxyglucose positron emission tomography showed disappearance of uptake in both kidneys, vertebral bones, ribs, and intraabdominal lymph nodes. Five years, the patient remains stable on maintenance hemodialysis without recurrence of DLBCL.

Discussion

IgG4-RD is diagnosed by high serum IgG4 levels and pathologic findings. It is a disease entity in which Japanese researchers have contributed greatly to the development of the concept and the establishment of diagnostic criteria [1]. CT and PET-CT scans of the current case showed no abnormal findings in the head and neck region, including salivary glands, lacrimal glands, and enlarged lymph nodes. It is important to perform histologic diagnosis to differentiate malignancies and other non-malignant diseases including Sjögren syndrome, primary sclerosing cholangitis, Castleman disease, secondary retroperitoneal fibrosis, granulomatosis polyangiitis, sarcoidosis, and eosinophilic granulomatosa with polyangiitis. When the revised comprehensive diagnostic criteria 2020 were applied to this case, the patient was diagnosed as a definite diagnosis group after pancreatoduodenectomy [4].

In recent years, there have been many reports on the association between IgG4-RD and malignant tumors, and the incidence of malignant diseases in patients with IgG4-RD is high [2]. Autoimmune pancreatitis, which was present in this case, is reported to be a potential risk factor for the development of subsequent malignancy in patients with IgG4-RD [5]. In a study of 118 patients with IgG4-related diseases, 12 patients (10.1%) developed malignant tumors, of which 4 (25.0%) were lymphomas, the most common type [6]. There have been more than a dozen reports of malignant lymphoma complications in IgG4-RD. Wang et al. published a literature review of patients with IgG4-RD that developed malignant lymphoma [7]. DLBCL developed in 12 of 25 cases (48.0%), and patients with autoimmune pancreatitis tended to develop DLBCL. In most cases, malignant lymphoma developed 2–5 years after the diagnosis of IgG4-RD [7], as observed in our case.

In this case, no malignant tissue was found in the resected pancreatic tissue, and the diagnosis of IgG4-related autoimmune pancreatitis was made. Since the patient was asymptomatic, and we did not find other organ involvement by CT and ultrasonography, the patient was not treated with corticosteroids and was closely monitored thereafter. It is an important clinical question whether steroid therapy for IgG4-RD can prevent subsequent development of malignant lymphoma. Although it is difficult to answer the question, Wang et al. described the case of DLBCL after the treatment of IgG4-RD [7]. The patient was treated with oral prednisolone and cyclophosphamide, and serum IgG4 levels decreased to the normal range. However, 16 months later, the patient developed sudden cervical lymph node enlargement with fever, and was diagnosed to have DLBCL. This report indicates that treatment of IgG4-RD might not necessarily suppress the development of malignant lymphoma.

The detailed pathogenic mechanisms of malignant lymphoma associated with IgG4-RD are unknown. One of the possible mechanisms is persistent B-cell activation from chronic inflammation and tumorigenesis of IgG4-positive cells. For example, in Sjögren syndrome, the incidence of DLBCL is high, with a relative risk of 2.0–6.57-fold, and chronic inflammation is thought to contribute to the increased risk of disease development [8, 9]. The pathogenesis is thought to be that IL-10 produced by regulatory T cells and IL-4 produced by helper T cells induce B-cell activation, which in turn promotes the production of IgG4 antibodies. In the current patient, persistent eosinophils were elevated even after removal of the pancreatic tumor, and proliferation of fine fibers similar to that observed in IgG4-related kidney disease was observed in the renal tissue that showed high IgG4 levels.

Renal infiltration of malignant lymphoma is relatively frequent, at 33.5% [10]. It is believed that there is no lymphoid tissue in the renal parenchyma, and malignant lymphomas that are first detected in the kidney are very rare, accounting for only 0.7% of all extranodal malignant lymphomas [11]. There have been 20 reported cases of solitary renal malignant lymphoma in Japan, and only one case was reported to have occurred in a patient on hemodialysis. Histopathologically, DLBCL accounted for the majority of cases [12]. In the current patient, we considered diabetic kidney disease as the primary cause of end-stage kidney disease. However, we could not confirm the diagnosis histopathologically before induction of dialysis as a result of severe kidney atrophy. As DLBCL in the kidney developed early after the induction of dialysis, it is possible that IgG4-RD lesions had been co-existent in both kidneys and in the pancreas when the pancreas nodule was found. Further analysis of more patients with IgG4-RD and malignant lymphoma in future will help elucidate the clinical picture and identify possible mechanisms of disease.

In summary, we described a case of DLBCL diagnosed by enlargement of bilateral kidneys after introduction of chronic hemodialysis. This case highlights the need to be aware that IgG4-related diseases may be associated with malignant tumors. In cases of autoimmune pancreatitis, development of malignant lymphoma within several years should be considered.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from the participant included in this study.