A rare case of co-occurrence of lupus nephritis and lymphoma

Abstract

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder known to increase the risk of lymphomas, typically after prolonged immunosuppressive therapy. We report a rare case of a 45-year-old woman who presented with fever, polyarthritis, and anasarca, and was concurrently diagnosed with lupus nephritis and marginal zone lymphoma without prior immunosuppression. Initial evaluation revealed hematologic abnormalities, renal involvement, and axillary lymphadenopathy. Kidney biopsy confirmed class III and V lupus nephritis, while lymph node biopsy unexpectedly revealed low-grade B-cell non-Hodgkin lymphoma. The patient was treated successfully with chemotherapy and supportive lupus therapy, showing marked clinical and laboratory improvement. This case underscores the importance of thorough evaluation of lymphadenopathy in SLE patients, even at initial presentation, and raises awareness of rare concurrent diagnoses. It highlights the complex relationship between autoimmune disease and malignancy, suggesting shared pathogenic mechanisms and the necessity for vigilant, long-term multidisciplinary management.

Introduction

Systemic Lupus Erythematosus (SLE) presents with various clinical features and complications from both disease activity and treatment side effects. A well-established link exists between SLE and lymphoma, with studies showing a higher incidence of lymphoma in SLE patients compared to healthy individuals.^[1–3] Although lymphoma, particularly Non-Hodgkin’s lymphoma, is commonly observed in later stages of SLE after prolonged immunosuppressive therapy, we report a case where a patient had concurrent diagnosis of lupus nephritis and marginal zone lymphoma without prior immunosuppressive exposure.

Case Presentation

A 45-year-old woman with no significant medical history presented in October 2022 with a three-month history of fever, inflammatory polyarthritis, and anasarca. Examination revealed left axillary lymphadenopathy and splenomegaly. Laboratory tests showed anemia (Hemoglobin – 7.9 gm/dl), thrombocytopenia (65,000/mm³), hematuria (Urine: RBC-14), and proteinuria (2.03 gram/day), Hypoalbuminemia (2.2 gm/dl), and normal serum creatinine (0.8 mg/dl). Additional tests included ANA (2+ homogenous pattern), elevated dsDNA (668 IU/ml), and low complement levels (C3- 41.5 mg/dl and C4 <7.42 mg/dl). Viral markers for Hepatitis-B, Hepatitis C, and HIV were negative. She was diagnosed with SLE per Systemic Lupus International Collaborating Clinics (SLICC 2019) criteria and underwent a kidney biopsy revealing focal and membranous lupus nephritis (classes 3 and 5) with Activity index: 0/24, chronicity score: 3/12 and mild tubulo-interstitial scarring. Immunofluorescence showed full house pattern [see Figure 1a and b].

Figure 1.

(a) Glomeruli showing segments of capillary wall thickening. Haematoxylin and Eosin stain, original magnification x400. (b) Glomerulus with Segmental endocapillary hypercellularity is also noted (BOLD arrow), Haematoxylin and Eosin stain, original magnification x400.

Prior to starting immunosuppression, we investigated the etiology of her axillary lymphadenopathy, suspecting an infection like tuberculosis. A biopsy of the left axillary lymph node unexpectedly revealed low-grade B-Non Hodgkin lymphoma, with marginal zone lymphoma as a possibility [see Figure 2a-h]. Bone marrow studies were negative for lymphoma.

Figure 2.

(a) Left axillary lymph node biopsy – showing (Bold arrow) dense capsular fibrosis with effacement of architecture of the lymph node due to a lymphoid neoplasm, Haematoxylin and Eosin stain (b) comprising atypical small lymphoid cells with irregular nuclear membranes, inconspicuous nucleoli and scant cytoplasm. The germinal centres appear regressed., Haematoxylin and Eosin stain, original magnification x40 (c-h) Immunohistochemcity positive for CD3, CD5, CD20 A,CD23, BCl2 and MIB1 with proliferation idex 10-15%

She was treated with R-CVP (Rituximab, Cyclophosphamide, Vincristine, and Prednisolone) chemotherapy under Hematologist supervision. After six cycles over six months, she showed symptomatic improvement and positive changes in laboratory parameters. An interim PET scan showed no significant lymphadenopathy. She experienced Herpes labialis and septic shock during during the first and fifth cycles, of chemotherapy respectively, both managed successfully. Hydroxychloroquine (HCQ) and ACE inhibitors were added for lupus nephritis. By the end of six months, there was a significant reduction in hematuria, proteinuria and improvement in lupus serology [see Table 1].

Table 1. Laboratory parameters at diagnosis, 3 months and 6 months.

Lab parameter	Diagnosis	At 6 months	At 12 months
Hemoglobin (gm/dl)	7.9	10.4	10.9
Total leucocyte count (mm3)	7200	12,000	7000
Platelet count (mm3)	65000	1,21,000	1,12,000
Urine RBC	14	3	Nil
Urine Protein	2+	1+	Negative
24 h urine protein (gm/day)	2.03	0.47	0.1
Serum Albumin (gm/dl)	2.2	3.8	4.3
Serum Creatinine (mg/dl)	0.88	0.87	0.63
dsDNA (IU/ml)	668	252	185
C3/C4 (mg/dl)	41.5/<7.42	99/9.17	89.8/<7.4
Imaging	CT abdomen and pelvis Splenomegaly -14.8 cm Borderline to significant abdominal lymph nodes	Whole body PET scan Splenomegaly - 13.1 cm No lymphadenopathy

CT - Computed Tomogrpahy, dsDNA - Double stranded Deoxy Ribonucliec Acid, PET - Positron Emission Tomography, RBC - Red Blood Cells

Discussion

Fever and lymphadenopathy can be seen in SLE, lymphoma, and infections complicating SLE. Early-stage lymphoma may mimic SLE symptoms, and lymphadenopathy occurs in up to 67% of SLE patients,^[4] often requiring biopsy or peripheral blood sampling for immunophenotyping to distinguish lymphoma from conditions like tuberculosis.

Lupus-like syndromes can arise from infections, hematological malignancies, or solid tumors.^[5] However, lupus nephritis as a complication of lymphoma is rare.^[6–10] Glomerulonephritis is an uncommon complication of hematological malignancies and non-Hodgkin lymphomas (NHLs).^[11–13] The first case of lupus nephritis secondary to lymphoma was associated with Mantle cell lymphoma was reported in 2018 by Horino T et al.^[8] A higher SLE risk in NHL patients, suggesting shared pathogenic mechanisms possibly involving similar genetic or triggering factors was noted by Wang et al.^[14] Research by Anders HJ et al. emphasized the significant roles of both T and B cells in SLE pathogenesis, particularly the production of hallmark autoantibodies by B cells and the activation of germinal center B cells by T follicular helper cells.^[10,15] The expansion of lymphoma cells may perturb the immune system, potentially contributing to SLE development in susceptible individuals.^[16]

Many SLE patients receive potent immunosuppressive drugs like Cyclophosphamide which was studied for its potential association with lymphoma development.^[17] Another drug, Mycophenolate mofetil (MMF) which compromises T cell function, possibly leading to dysregulated B cell proliferation in the context of chronic antigen stimulation. However, our patient did not receive any of these drugs in the past. The Epstein-Barr virus (EBV) infection is increasingly recognized as a possible contributor to lymphoma development. Moreover, SLE patients often experience frequent viral reactivations, as indicated by higher EBV seroconversion rates.^[17] The structural similarities between EBV antigens and certain SLE antigens noted, which cause positive lupus serology. Although EBV serology was not conducted in our patient, lymph node biopsy showed negative results for Epstein-Barr encoding region (EBER) in situ hybridization.

Our patient’s clinical presentation was dominated by lupus signs and glomerulonephritis, with lymphoma only diagnosed through lymph node biopsy. The long-term management of patients with both SLE and lymphoma requires ongoing follow-up to monitor for relapses. Currently, the patient remains stable after chemotherapy and may need further immunosuppressive therapy if lupus nephritis recurs.

Conclusion

This case highlights the complex interplay between rheumatic disorders and malignancies, influenced by immune system dysregulation. While lymphadenopathy is common in SLE, a biopsy is essential to identify concurrent conditions. The long-term course for patients with both SLE and lymphoma is not well understood and requires extensive monitoring.