Rare Isolated Renal Involvement with Marginal Zone B Cell Lymphoma: A Case Report with Literature Review of Contemporary Management Strategies

Marginal zone B cell lymphomas are divided into nodal, extranodal and splenic types. Renal involvement by extranodal B cell lymphoma is extremely rare with an incidence of about 0.1%. We present a case of a 79-year-old Caucasian male with progressive renal failure and isolated left renal extranodal marginal zone lymphoma. Asymptomatic immunoglobulin (Ig) M monoclonal gammopathy along with bone marrow involvement by lymphoma was observed. Contemporary management options including radiotherapy (RT), chemotherapy, immune-modulating agents and novel chemotherapy-free regimens.


Introduction
Marginal zone lymphomas (MZL) are low-grade non-Hodgkin B cell lymphomas (NHL) classified into three subcategories such as extranodal marginal zone lymphoma (EMZL), also called mucosal-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone lymphoma (NMZL) and splenic marginal zone lymphoma (SMZL). EMZLs account for 8% of all NHL cases [1]. Most commonly, the EMZLs are found in the stomach, followed by spleen, eye, adnexa, lungs, skin, salivary glands, thyroid, small intestine, breast, synovium, dura and soft tissues. As kidneys lack the lymphoid tissues, renal involvement with EMZLs is extremely rare. Only a handful of such cases have been reported [2]. B cell lymphomas also present with paraproteinemia [3]. We report a case of a Caucasian male who presented with a progressive decline in renal function associated with isolated left renal involvement with marginal zone B cell lymphoma and asymptomatic immunoglobulin (Ig) M monoclonal gammopathy. Moreover, we reviewed the contemporary management options for MZLs.

FIGURE 1: Interstitial inflammation with lymphocytes
Immunohistochemical staining showed atypical lymphocytes that were positive for CD20 and negative for CD5, CD10, CD19, CD22 and CD23. Molecular testing revealed an Ig heavy chain gene rearrangement; these findings were consistent with marginal zone B cell lymphoma. Furthermore, immunofluorescence (IF) microscopy demonstrated seven glomeruli with diffuse pseudo-linear staining of the glomerular capillary loops for albumin (1+). Glomerular staining for IgG, IgA, IgM, C3, C1q and kappa or lambda light chain was negative. Interstitium stained positive for fibrinogen, while protein casts were stained positive for IgA (3+), kappa light chain (3+) and lambda light chain (3+). By electron microscopy (EM), the glomerular basement membrane had a normal trilaminar structure, the mean thickness was within the normal range without electron-dense deposits or tubuloreticular inclusions and the majority of podocytes foot processes were intact ( Figure 2). No immune complexes were detected by IF or EM.  Figure  3). One dose of vincristine and prednisone was given at that time, but renal function declined further. The patient was offered bortezomib/dexamethasone or ibrutinib for further treatment consideration, which he declined.

Discussion
Renal infiltration by lymphoma is rare, and such cases are often clinically silent [2]. EMZLs are more common than NMZLs or SMZLs and are subdivided into gastric and non-gastric types.
The gastric EMZLs are caused by sustained inflammation with bacterial infection (Helicobacter pylori). Etiologies for non-gastric EMZLs include Borrelia burgdorferi infection in cutaneous EMZLs, Chlamydophila psittaci infection in ocular EMZLs and Campylobacter jejuni infection in small intestinal EMZLs. A higher prevalence of hepatitis C virus (HCV) infection has also been reported in patients with MZLs, particularly of the splenic and nodal types, suggesting a possible causative role of the HCV in MZLs [1].
As no lymphatic tissues are present in the renal parenchyma, the theories about the renal involvement with lymphoma suggest that either the lymphocytes migrate from the lymphatics in the renal capsule or the presence of chronic inflammation provides a platform for longstanding antigenic stimulation, thereby attracting the lymphoid cells and developing into a lymphoma. Mostly, the MZLs present as Ann-Arbor stage IE disease, and BM and peripheral lymph node involvement are rather uncommon. BM involvement has been reported in up to 20% of cases of MZLs [3].
EMZLs are indolent and have a tendency to remain localized to the site of origin for an extended period of time. It has the potential for a systematic spread and can transform to an aggressive B cell lymphoma. Histological transformation to large B cell lymphoma has been reported in approximately 10% of the cases [3]. Patients with EMZL have a relatively good prognosis with a median survival >10 years. Our patient had an indolent clinical behavior of MZL but was diagnosed with isolated left renal involvement at the time of diagnosis.
Treatment options depend on the site of organ involvement. For gastric EMZLs, options include H. pylori eradication therapy, radiotherapy (RT), chemotherapy and immune-modulating agents. For early-stage H. pylori-positive EMZL, H. pylori eradication therapy is recommended, followed by endoscopic surveillance. For advanced-stage H. pylori-positive gastric EMZL, treatment with H. pylori eradication therapy is recommended, followed by observation until the development of symptoms at which time chemotherapy is initiated. Initial treatment with local RT is recommended in patients with early-stage H. pylori-negative gastric EMZL.
Non-gastric EMZLs treatment depends on the organ involved and the stage of the disease. Limited-stage EMZL is generally treated with locoregional RT or managed expectantly. Surgery is typically used for diagnostic purposes only but may play a role in the treatment of tumors in areas not conducive to RT (e.g. localized lesion in the lung). Single-agent rituximab is an alternative for the treatment of sites that cannot be treated with RT. Advanced-stage diseases are treated with rituximab or combination chemotherapy. Chemotherapy or chemoimmunotherapy is given to newly diagnosed patients who show no response to singleagent rituximab or have disease relapse.
Ibrutinib, a Bruton's tyrosine kinase inhibitor, is the first oral therapy approved by the Food and Drug Administration (FDA) for the management of relapsed/refractory (R/R) marginal zone lymphoma. It acts by inhibition of the B cell receptor (BCR) signaling pathway, an important pathway responsible for lymphoma genesis. A phase II study included 63 patients having R/R MZLs treated with ibrutinib. About 50% of the patients had EMZL, and about a quarter patients had SMZL. Ibrutinib has shown excellent efficacy in these patients with an ORR of 48% and median PFS of 14.2 months [8].

Conclusions
We report a case of marginal zone B cell lymphoma with isolated left renal involvement in a patient with progressive renal failure and asymptomatic IgM monoclonal gammopathy. MZLs are currently being treated with RT, chemotherapy and chemoimmunotherapy. Recently, chemotherapy-free regimens and other novel agents have gained importance. These agents are currently under development in various phases of clinical trials and may play an important role in the future management of MZLs and other B cell malignancies.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.