Splenic Marginal Lymphoma and Glomerulonephritis: Case Report and Review of the Literature

Abstract

Malignant lymphomas can affect kidneys in several ways. They may precipitate acute renal failure by causing ureteral or renal vascular obstruction, or by direct renal parenchymal infiltration. Furthermore, they may insult renal function via paraneoplastic mechanisms such as hypercalcemia. Lymphomas only rarely can cause glomerulonephritis (GN). We report a case of a 72-year-old male who presented with mild renal function impairment, proteinuria, and microscopic hematuria, suggesting active glomerulonephritis, and pancytopenia of immune origin. A bone marrow biopsy led to a diagnosis of splenic marginal zone lymphoma. Although a kidney biopsy was not performed, glomerulonephritis was attributed to the lymphoma and splenic marginal zone lymphoma-related glomerulonephritis was the final diagnosis. The course of splenic marginal zone lymphoma is extremely indolent. The first manifestation in some patients can be immune cytopenia or other autoimmune phenomena. These patients may respond well to corticosteroids. Therefore, our patient was started on prednisolone resulting in a good hematologic response. Renal function also improved and proteinuria and hematuria disappeared, suggesting a lymphoma-related origin of the GN. Two years after full steroids withdrawal, the patient remained stable with a good renal function and daily protein excretion less than 300 mg. Lymphomas rarely are the cause of secondary glomerulonephritis; however, with a lack of an apparent cause, the clinician should be aware of them, particularly in the elderly with autoimmune manifestations.

Keywords:

• cryoglobulins
• glomerulonephritis
• lymphoma
• renal failure
• splenic marginal lymphoma

INTRODUCTION

Malignant tumors and especially lymphomas affect kidneys in several ways. They may precipitate acute renal failure by causing ureteral or renal vascular obstruction, or by direct renal parenchymal infiltration. Paraneoplastic manifestations and treatment-related factors often cause renal function impairment. Lymphomas can also cause glomerulonephritis (GN) via unknown mechanisms.^[1] We report the case of a 72-year-old male with splenic marginal zone lymphoma who presented with mild renal function impairment, proteinuria, and microscopic hematuria, suggesting glomerulonephritis. The diagnosis, management, and clinical course of the patient are discussed. We also reviewed the literature and summarize the possible mechanisms involved in lymphoma-induced GN.

CASE PRESENTATION

A 72-year-old male was admitted in the nephrology department for proteinuria (3.1 gr/24 h) and impaired renal function (serum creatinine 1.5 mg/dL, eGFR MDRD = 40 mL/min/1.73m²). Past medical history included acute pancreatitis four months earlier, attributed to choledocholithiasis and treated by cholecystectomy. Hypertension was absent. Upon physical examination, the patient appeared pale with ankle edema and normal blood pressure (130/75 mmHg). Liver and spleen were not palpable.

Laboratory evaluation showed a total leucocyte count of 3840/mm³ (neutrophils 41%, lymphocytes 49%), hemoglobin 11.8 gr/dL, platelets 91,000/mm³, serum albumin 2.94 gr/dL. Liver function tests were normal, and there was no evidence of hepatitis B or C virus infection. Erythrocyte sedimentation rate (ESR) was 33 mm. Serum electrophoresis showed hypergammaglobulinemia but no monoclonal (M) protein. C3 measured 46.1mg/dL (normal values 63–158 mg/dL) and C4 12 mg/dL (normal values 15–33mg/dL). Cryoglobulins were not detected in serum. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, and antibodies to extractable nuclear antigens were absent. Urine microscopic examination showed 40–50 red blood cells per high power field but no red blood cell casts. Ultrasonic evaluation showed a marked discrepancy in kidney size with a right kidney of 6.6 cm and a left kidney of 9.5 cm in length. Further evaluation by computed tomography revealed a small degree of spleen enlargement. Because of the small size of the right kidney, contributing only 20% to the overall renal function (as revealed by scintigraphic evaluation), along with left kidney of diminished size, a renal biopsy was not performed.

Pancytopenia with splenomegaly justified further evaluation by bone marrow biopsy; the pathologists reported “lymphocytic infiltration 10–15% by small lymphocytes with a luminous cytoplasm. The infiltration exhibits an intra-sinusoidal pattern. Immuno-histochemical staining was positive for CD20 and CD45.” Therefore, a final diagnosis of glomerulonephritis associated with splenic marginal zone lymphoma was established.

The patient was started on 50 mg prednisolone daily leading to initial good response in proteinuria reduction and renal function improvement (serum creatinine 1.0 mg/dL). However, two months later, steroids tapering resulted in proteinuria relapse, in mild decrease of C3 and C4 complement concentration and in renal function impairment (serum creatinine 1.4 mg/dL); therefore, he was continued on 50 mg for another month with a good response. Unfortunately, he manifested proximal myopathy and depression, which were attributed to steroids. Tapering of the dosage over a four-week period was attempted again, and the patients' condition improved. Two years after full steroids withdrawal, the patient remained stable with a serum creatinine of 1.1mg/dL and daily protein excretion less than 300 mg. Urine microscopic examination showed fewer than eight red blood cells per high-power field. C3 and C4 complement levels returned to normal, and hyper-gammaglobulinemia disappeared.

DISCUSSION

Malignant lymphomas affect kidneys in several ways. They may precipitate acute renal failure by compressing the ureters and causing obstruction, by compromising renal arteries or veins, or by direct renal parenchymal infiltration. Many tumor-related conditions such as paraneoplastic hypercalcemia, sepsis, and hemolysis can cause acute renal failure. Treatment related factors such as tumor lysis syndrome, nephrotoxicity of anti-tumor chemotherapeutic agents, or radiation commonly cause renal function impairment. Finally, lymphomas can cause glomerulonephritis via unknown pathways.^[1] It was in 1922 when the concept of paraneoplastic glomerulopathy was first introduced by Galloway.^[2] Nowadays, the association of glomerulonephritis and malignancies is generally accepted and considered as an example of the broad spectrum of paraneoplastic disorders. The most commonly associated forms of malignancies are carcinoma and Hodgkin's disease. Membranous nephropathy is usually found in patients with solid tumors and minimal change nephrotic syndrome in Hodgkin's disease.^[3–^5] A smaller number of patients with non-Hodgkin's lymphoma (NHL) and glomerular injury have also been described, but renal pathology is much more heterogenous.^[6,7] This fact led some reviewers to express doubts about the relationship between them.^[8] Indeed, glomerular disease is an uncommon manifestation of non-Hodgkin's lymphomas. Nael Da'as et al., in a retrospective study of 700 patients with non-Hodgkin's lymphoma and leukemia, described 66 patients with renal involvement. Only four of them, representing a percentage less than 0.6%, had glomerulonephritis.^[7] However, impaired renal function is more common in NHL patients with renal involvement. Rault et al., in a review of the literature, described 27 cases of NHL-associated glomerulonephritis. Renal function was impaired in 19 patients, and four of them presented with rapidly progressive glomerulonephritis.^[9]

The most common glomerulopathy in patients with NHL is membranoproliferative (MPGN) and extracapillary proliferative GN (ExGN). From a total of 47 patients, nearly 26 percent had MPGN and 26 percent had ExGN. Minimal change disease (MCD), the most prominent form of glomerulopathy in Hodgkin's disease, represents in NHL patients only a percentage around 10%. Other, less frequent glomerulopathies include membranous nephropathy (MGN), IgA GN, FSGS, and amyloidosis (see Table 1).^[10]

Table 1  Glomerular diseases associated with non-Hodgkin's lymphoma (NHL)^[10]

Glomerular lesions in NHL patients	Number of patients
MPGN	12
ExGN	12
MGN	5
MCD	5
FSGS	3
Other PGN	3
IgA GN	3
Immunotactoid GN	4
Amyloidosis	2
Total	47

Clinical presentation includes acute renal failure, nephrotic syndrome or isolated proteinuria, and hematuria. The order of presentation of renal disease and lymphoma is not invariable. Although they are usually diagnosed simultaneously, many cases of glomerulopathies are detected several months before lymphoma presentation.^[11] Resolution of GN following successful treatment of lymphoma by systemic chemotherapy or local radiotherapy, especially in sites distant from the kidney, suggests that GN may indeed represent a paraneoplastic phenomenon. This theory is enhanced by the observed recurrence of GN when lymphoma relapses.^[12,13] However, renal function improvement is not always achieved. In 1992, Rault et al. described the response of 21 patients following lymphoma therapy; the most commonly used chemotherapeutic agents were corticosteroids (18 patients), cyclophosphamide (12 patients), and vincristine (12 patients), usually in combined regimens. Proteinuria improved in 13 patients and remained unchanged in four patients. No details about proteinuria in response to treatment were given in the remaining cases. Renal function improved in 10 patients, remained unchanged in three, and worsened in two.^[9]

Pathogenesis of malignancy related GN is not well understood. Several mechanisms have been proposed to explain the renal pathologic findings. It is well known that most of malignancies, especially hematologic, are accompanied by many immunologic abnormalities. In some cases, GN is clearly associated with the presence of cryoglobulins in patient's sera. The existence of type-I or type-II cryoglobulinemia is often associated with lymphoproliferative disorders^[14] in which the B-lymphocyte clone can be secretory. Cryoglobulins are believed to be immune complexes that are insoluble at low temperatures. In type II or type III cryoglobulinemia, the antigen is a polyclonal immunoglobulin, but in type I, it remains of undetermined nature. Gilboa et al. observed hypocomplementemia and type I cryoglobulinemia composed of an IgGκ M-component in two patients with chronic lymphocytic leukemia (CLL) associated with MPGN. Their finding that immunoglobulin eluted from both the glomeruli and the serum cryoglobulin, bound in vitro to patients' glomeruli but not to normal glomeruli, suggested that the monoclonal IgG κ was directed to non-glomerular antigens.^[15] The latter might be a lymphocyte antigen, as suggested by Day et al.^[16] In 1972, Oldstone et al. found in two patients with Burkitt's lymphoma that the IgG which was eluted from renal biopsy specimens contained antibodies that bound to Epstein-Barr virus antigens.^[17]

However, cryoglobulinemia is not always present. Monotypic immunoglobulin deposits can be found in the absence of cryoglobulinemia, with or without a circulating M-component. Some of these patients present with features typical of monoclonal immunoglobulin-deposition disease (MIDD) in which depositions exhibit a granular pattern.^[10,18] Fibrillary and immunotactoid GN have also been described.^[19,20] In 1983, Dosa et al. described a patient with acute myelomonocytic leukemia and circulating and renal immune complexes containing antibodies against antigens on the leukemic membranes.^[21] Tumor-related antigens or antibodies to these antigens have also been identified in glomerular deposits in several cases of tumor-associated MGN. An example would be the finding of the carcinoembryonic antigen in the glomeruli of a patient with bowel cancer.^22–24] A substantial number of reports of necrotizing glomerulonephritis in NHL patients exists. This type of lesion is common in Wegener's granulomatosis and microscopic polyangiitis. However ANCAs are not present in these patients. There is a case report of c-ANCA and angioimmunoblastic lymphoma with proteinuria 1.2 g per day and cutaneous leukocytoclastic vasculitis, but unfortunately neither renal biopsy nor an enzyme linked immunosorbent assay (ELISA) for MPO or PR3 antibodies was performed.^[25] In 1992, Davenport reported the association of a positive c-ANCA leukocytoclastic vasculitis and compatible clinical findings, leading to a misdiagnosis of Wegener's granulomatosis. A post-mortem examination disclosed a NHL without granulomatis vasculitis. No renal biopsy was performed.^[26]

Splenic marginal lymphoma (SMZL) has been considered a distinct clinicopathological entity since 1992. The term was introduced by Schmid et al. in relation to a study performed on a series of four cases.^[27] SMZL remains a rare entity accounting for around 2.5% of all NHL.^[28] The course of splenic marginal zone lymphoma is extremely indolent because of its slow progression. Survival is in excess of 70% at 10 years. It occurs at a median age of 65. The most relevant feature at presentation is splenomegaly with typically absent peripheral lymph node involvement. In the case of marked splenomegaly with cytopenias due to hypersplenism, the treatment of choice is splenectomy. Chemotherapy by alkylating agents or purine analogues is used in patients with clinical progression after splenectomy or when surgery is contraindicated. Rituximab may also be employed. However, the first manifestation in some patients can be immune hemolytic anemia or autoimmune thrombocytopenia. Other autoimmune phenomena are also commonly seen. These patients may respond well to corticosteroids.^[29–31]

Because of the limited extension of bone marrow infiltration and the small degree of splenomegaly, pancytopenia was considered as an autoimmune phenomenon, and splenectomy was ruled out as a potential treatment. Our patient had no substantial laboratory findings compatible with a particular pathologic type of GN, except for hypocomplementemia, which was consistent with membranoproliferative GN. Crescentic form of GN was excluded because the patient had no rapid progressive renal failure. Because membranoproliferative GN is the second most frequent form of NHL-related glomerulopathy, we decided to start him on a six-month steroid course as described above on case presentation. Moreover, prednisolone is a potent anti-lymphocyte medication. In our patient, two months after the therapy initiation, lymphocytosis disappeared, and hemoglobin and platelets levels also improved.

It becomes clear that pathogenesis of GN in hematologic malignancies involves a lot of immune mechanisms, which include cryoglobulinemia, immune deposits induced by tumor or viral antigens, tumor antigen implantation in glomeruli, and altered T-cell function. It is certain that the pathogenic mechanism needs further clarification, but the clinician should be aware of the possibility of an underlying hematologic malignancy, especially of B-cell origin, in almost every case of GN, particularly in the elderly with autoimmune manifestations.

DECLARATION OF INTEREST

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