Minimal change disease associated with newly diagnosed mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is a rare but aggressive form of non-Hodgkin’s lymphoma. Involvement of the kidney is an infrequent occurrence in patients with MCL and can be the result of direct infiltration or paraneoplastic glomerulopathy. Proliferative glomerulonephritis, membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis have previously been reported in association with MCL. We report a 55-year-old woman who developed nephrotic syndrome due to biopsy proven minimal change disease (MCD) in association with MCL. Proteinuria decreased with prednisolone treatment and MCD remains in remission without any immunosuppressant after the treatment of the underlying MCL.

• Mantle cell lymphoma
• minimal change disease
• nephrotic syndrome
• paraneoplastic glomerulopathy

Introduction

Mantle cell lymphoma (MCL) is a relatively rare but aggressive form of B-cell non-Hodgkin’s lymphoma, accounting for 5–10% of all lymphomas in North America and Europe. MCL is associated with high relapse rates and has the worst prognosis among lymphomas with a median survival of 3–4 years.1

Patients with lymphoma can present with nephrotic syndrome, glomerulopathy or acute kidney injury (AKI).2 Lymphoma can directly induce AKI by obstructing the ureters or renal artery, inducing renal vein thrombosis and also causing acute tubulo-interstitial nephritis. Other causes of AKI in the setting of lymphoma include hypercalcemia, sepsis, hemolysis, tumor infiltration, glomerulonephritis and paraproteinemia with deposition of paraprotein.2

Various types of renal involvement in patients with MCL have been reported in case reports.2–12 We report a novel case of nephrotic syndrome due to biopsy proven minimal change disease (MCD) in a patient with newly diagnosed MCL.

Case report

A 55-year-old woman presented with a 3-week history of increasing generalized edema and retro-orbital pain in her left eye. Her medical history included Graves’ disease treated with radioiodine therapy. Her only medication at the time of presentation was thyroxine 100 μg daily.

Examination revealed mild bilateral proptosis but no ophthalmoplegia. She had severe peripheral pitting edema but there was no evidence of lymphadenopathy, hepatomegaly or splenomegaly. Urinalysis showed fine granular casts on microscopy.

Investigations revealed a hemoglobin of 136 g/L (115–155), white cell count 8.0 × 10⁹ cells/L (4.0–11.0 × 10⁹), lymphocytes count 5.20 × 10⁹ cells/L (1.00–3.50 × 10⁹) and platelet count 198 × 10⁹ cells/L (150–400 × 10⁹). Biochemistry revealed a serum urea of 8.7 mmol/L (2.7–8.0), creatinine 100 µmol/L (50–100), estimated glomerular filtration rate 50 mL/min/1.73 m² and albumin 15 g/L (34–48). The urinary protein was 9.94 g/24 h (<0.22). Protein electrophoresis, serum complement C3 and C4 levels were normal. Immunoglobulin (Ig) G level was low (2.93 g/L; 6.5–17.0) while IgA and IgM were normal. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, antiglomerular basement antibodies and cryoglobulins were all negative. Renal ultrasound showed that the kidneys were of normal size and appearance with no hydronephrosis. Magnetic resonance imaging (MRI) of her orbits revealed bilateral proptosis and an 8 mm × 9 mm conglomerate of hyperdense intraconal soft tissue nodule on the left side (Figure 1).

Figure 1. MRI orbits shows an ill-defined hyperdense enhancing nodule in the left intraconal region (arrow).

An ultrasound-guided renal biopsy showed up to 10 normal viable glomeruli (Figure 2A) but on electron microscopy there was diffuse effacement of the podocytes with mild thinning of the glomerular basement membranes, consistent with MCD. No immune-complex type electron dense deposits were identified (Figure 2B). Immunofluorescence was negative.

Figure 2. The light microscopic features of the renal biopsy are normal (A). Electron microscopy of glomeruli showed diffuse effacement of the podocytes (B). There is diffuse but mild thinning of the glomerular basement membranes. No immune-complex deposits are identified. The appearance is in-keeping with minimal change disease.

Whilst considering the secondary cause of MCD, mild lymphocytosis was noted. A flow cytometry was performed which revealed monoclonal proliferation of B lymphocytes expressing lambda light chain, CD5/CD19+, CD20+, CD23−, CD38+, suggestive of MCL. Bone marrow biopsy showed bone marrow infiltration with small mature B cell collections and cytogenetics revealed the cyclin D1 translocation typical of MCL. Biopsy of the left intraconal lesion revealed lymphocytic proliferation with the B cell markers CD20 and CD5 as well as coexpression of cyclin D1. 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) revealed an asymmetrical uptake in the left superolateral orbit and a slight increase in the spleen.

The MCD was initially treated with prednisolone 60 mg daily with gradual tapering until the diagnosis of MCL was confirmed. Her MCD was in complete remission after 10 weeks of prednisolone treatment. The patient was then commenced on induction chemotherapy with dose-intense cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), prednisolone (CHOP) and methotrexate for myeloablation. Repeat 18-FDG-PET showed no evidence of residual lymphoma. She proceeded to have autologous hemopoietic stem cell transplantation (HSCT). The MCD remained in complete remission after treatment of the MCL without any immunosuppressant in the follow-up outpatient 1 month ago.

Discussion

Glomerular disease in the setting of malignancy has been recognized for several decades. The glomerulopathy associated with solid malignancies is most commonly membranous nephropathy. On the other hand, MCD is most frequently associated with Hodgkin’s lymphoma but rarely with other hematological malignancies and solid tumors.13–15 This is the first report of a patient with MCL presenting with nephrotic syndrome caused by MCD.

Malignant lymphomas can affect the kidneys in a number of ways. Firstly, their effects may be direct with either compression of the ureters causing obstruction or direct infiltration of the renal parenchyma. Secondly, tumor-related conditions such as hypercalcemia and tumor lysis following therapy may cause AKI. Thirdly, the kidney can be directly invaded by tumor cells in hematological malignancies. Lymphoma may also give rise to paraneoplastic glomerulonephritis.16 In previous cases, MCL has been associated with proliferative glomerulonephritis,4,6 membranoproliferative glomerulonephritis,11 focal segmental glomerulosclerosis (FSGS),9 acute interstitial nephritis (AIN)7 and MCL infiltration of the kidneys (Table 1).2,8,10

Table 1. Reported cases of mantle cell lymphoma associated with renal disease.

Case	Age/sex	Type of kidney disease	Creatinine (μmol/L)	Proteinuria (g/day)	Treatment	Outcome	References
1	76/M	MCL infiltration	465	1.8	Chemotherapy, radiotherapy, methylprednisolone, thalidomide	Died 10 months after diagnosis of renal disease	Baldus et al.3
2	75/M	Segmental proliferative GN	573	ND	Short-term HD, cyclophosphamide, PN	Survived 3 years	Rerolle et al.4
3	68/M	Diffuse endocapillary proliferative GN	1043	ND	HD, PN, chlorambucil	Survived 3 years	Da’as et al.2
4	68/M	FSGS	899	18	Short-term HD, cyclophosphamide, plasma exchangeR-CVP for MCL	Survived till time of report (2 years)	Wu et al.5
5	69/M	MCL infiltration	981	1.1	HD, patient opted for no other treatment	Survived 12 months.	Karim et al.6
6	73/M	AIN	483	ND	HD	ND	Karim et al.6
7	69/M	AIN	707	1.3	PN	Renal function returned to normal but died 12 months later with progressive MCL	Colak et al.7
8	52/M	Diffuse proliferative GN	310	3.9	Short-term HD, solumedrol, adrimycin, cyclophosphamide, PN	Renal function returned to normal, survival ND	Davies et al.8
9	59/ND	Membranoproliferative GN	773	6.88	ND	ND	Wong et al.9
10	72/F	MCL infiltration	362	0.2	Short-term HD, PN, vincristine, prednimustine, mitoxantrone	Partial recovery; survived 7 months	Lee et al.10
11	77/M	Crescentic GN	572	1.5	Short-term HD, PN, 5 cycles of CHOP then aracytin	Renal function improved but died of other complications	Lubas et al.11
12	68/M	Membranoproliferative GN	282	ND	HD in short-term, R-Hyper-CVAD	Renal function improved; HD-free but lost to follow-up	Chu et al.12
13	55/F	MCD	100	9.94	PN, CHOP and autologous hemopoietic stem cell transplant	Survived till time of report (24 months)	Current

AIN, acute intersitial nephritis; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisolone; FSGS, focal and segmental glomerulonephritis; GN, glomerulonephritis; HD, haemodialysis; MCD, minimal change disease; MCL, mantle cell lymphoma; ND, not documented; PN, prednisolone; R-CVP, rituximab, cyclophosphamide, vincristine and prednisolone.

With the exception of two patients including the present one, all other reports of association between MCL and glomerulopathy were in male patients. This probably reflects the higher preponderance of males who develop MCL. In the presence of glomerulopathy, all patients were found to have nephrotic range proteinuria. The survival of patients with both MCL and kidney involvement is generally poor with the longest survival reported to be 3 years from the time of diagnosis of the renal disease. It remains unclear if the presence of kidney disease confers a poorer outcome or if the underlying MCL is the main determining factor. The patient in this case report has survived for 24 months since diagnosis of the MCD and her MCD remains in remission.

The parallel between renal function, proteinuria and lymphoma disease activity as well as the improvement in renal function following prednisolone or cytotoxic therapy for lymphoma in these patients would be consistent with a paraneoplastic mechanism for the MCD. Although the pathogenesis of paraneoplastic glomerulonephritis is uncertain, autoimmune mechanisms and T-lymphocyte dysfunction may be important in this respect.17 With MCD and Hodgkin’s lymphoma, clinical observations and experimental data suggest that both diseases are associated with an expansion of T cells polarized towards a Th2 phenotype.13 Cytokines, chemokines and other related factors produced by tumor cells or lymphoid tissues have been implicated. However, MCL involves B cells and monoclonal proteins may be involved in the pathogenesis.

In summary, we present a case of minimal change disease associated with mantle cell lymphoma. The nephrotic syndrome improved with prednisolone and MCD remained in remission without immunosuppression after the treatment of the underlying lymphoma. Recognition of paraneoplastic glomerulopathy and the subsequent detection of undiagnosed lymphoid malignancy are important, as demonstrated in this case.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.