Bilateral Testicular Plasmacytoma Preceding Multiple Myeloma with Extramedullary Renal Involvement: A Case Report

Abstract

Multiple myeloma (MM) is a clonal proliferation of plasma cells in the bone marrow, with criteria including bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma with myeloma-defining events. Solitary plasmacytoma (SP) represents a singular clonal plasma cell lesion without myeloma-defining events, while extramedullary disease (EMD) is an aggressive form of MM characterized by independent growth outside the bone marrow microenvironment. We present a unique case of a 64-year-old patient with bilateral testicular plasmacytoma anteceding the development of Immunoglobulin G (IgG) kappa-type MM, featuring extramedullary renal involvement.

Background

Multiple clinical manifestations of plasma cell neoplasms are present. Solitary plasmacytoma (SP), a rare early-stage plasma cell malignancy characterized by a solitary lesion of clonal plasma cells without myeloma-defining events. ¹ It can present either in soft tissue or bone and patients with SP are at risk for progression to multiple myeloma (MM). Solitary plasmacytoma differs from extramedullary disease (EMD) in the absence of a diagnosis of MM. ² EMD represents an aggressive form of MM which can be found at the time of MM diagnosis or relapse. It is characterized by the presence of plasmacytomas that result from the hematogenous spread. ³

Herein we present a patient with bilateral testicular plasmacytoma without bone marrow involvement and myeloma-defining events preceding IgG kappa-MM with extramedullary renal disease.

Case Report

A 64-year-old male patient was admitted to our hospital after a left radical orchiectomy for a 34 × 20 mm heterogenous and hypervascularized mass with a pathological diagnosis of plasmacytoma. The patient's past medical history included coronary artery disease, hypertension, and hyperlipidemia. His bone marrow examination was normocellular with plasma cells < 5%. Serum hemoglobin, creatinine, and calcium levels were within the normal range and there was no lytic bone lesion. Additional laboratory tests were performed including serum and urine protein electrophoresis (sPEP and uPEP), serum immunofixation electrophoresis (SIFE), and quantitation of immunoglobulins (Igs). The sPEP demonstrated a 0.24 g/dL monoclonal peak in the gamma region, without monoclonal peak in uPEP, serum Ig G was 1220 mg/dL (normal values: 751–1560), serum free light chain (sFLC) ratio was 1.27 (normal values: 0.26–1.65), serum kappa free light chain (sKFLC) was 19.8 mg/L (normal values: 3.3–19.4) and urine kappa free light chain (uKFLC) was 24.01 mg/L (normal values: 0.39–15.1). Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed no evidence of any other lesion of bone or soft tissue, and the diagnosis of solitary plasmacytoma was confirmed. A month later, a right radical orchiectomy was performed for a 5 × 4.5 mm testicular mass detected incidentally during urology follow-up, confirming the plasmacytoma diagnosis. The kappa and lambda immunohistochemistry (IHC) was positive for kappa and negative for lambda. The analysis of the gene mutations did not reveal any result relevant to MM. Postoperative serum hemoglobin, creatinine, and calcium levels were within the normal range.

Three months later whole-body low-dose computed tomography (WBLDCT) showed a 7 × 7 cm sized lesion with exophytic growth in the right renal lower pole. Contrast-enhanced abdominal computed tomography showed a 7.2 × 7.2 cm solid lesion with irregular borders and high contrast enhancement in the right renal lower pole and a 2 × 1.8 cm solid lesion with the same properties in the right renal hilum (Figure 1). Right radical nephrectomy and adrenalectomy were performed with a presumptive diagnosis of renal cell carcinoma. The histopathological examination revealed the diagnosis of plasmacytoma of both lesions. The diagnostic evaluation for multiple myeloma was performed with a bone marrow examination showing minimal marrow involvement with clonal BMPCs between 8%–10%. Serum protein electrophoresis (sPEP) demonstrated a 1.37 g/dL monoclonal peak in the gamma region, with monoclonal Ig G kappa light chain detected on serum immunofixation electrophoresis (sIFE). Serum Ig G was 1340 mg/dL (normal values: 751–1560), sFLC ratio was 3.75 (normal values: 0.26–1.65), sKFLC was 155.01 mg/L (normal values: 3.3–19.4) and uKFLC was 187.01 mg/L (normal values: 0.39–15.1). He had mild anemia with hemoglobin of 11.6 g/dL (normal values: 13.6–17.2) and mean corpuscular volume (MCV) of 85.8 fL (normal values: 80.7–95.5), his beta-2 microglobulin (B2 M) was 4937 ng/mL (normal values: 609–2366) and erythrocyte sedimentation rate (ESR) was 77 mm/hr (normal values: 0–20) but no other myeloma-defining events. When we evaluated the patient retrospectively, we considered renal plasmacytoma as extramedullary involvement of multiple myeloma. He was treated with the VD regimen (bortezomib, dexamethasone). We selected a doublet regimen (VD) instead of a triplet for first-line therapy because the disease did not exhibit aggressive features. After four cycles of treatment, we observed a negative IFE and a normocellular bone marrow examination with plasma cells less than 5%. Serum Ig G was 716 mg/dL, sFLC ratio was 1.12, sKFLC was 18.35 mg/L, B2 M was 2909 ng/mL and ESR was 24 mm/hr. Lenalidomide was indicated as maintenance therapy. We did not proceed with autologous stem cell transplant (auto-SCT) after VD and before maintenance with lenalidomide, but EMD is an aggressive form of MM and in the first-line setting, an aggressive approach with triplet regimens followed by consolidation with autologous stem cell transplantation is the standard of care. Twelve months later PET/CT revealed a pelvic mass of 8.8 × 7.2 cm extending from the surgical clips in the inferior of the nephrectomy lodge to the pelvis (Figure 2). Serum Ig G was 1870 mg/dL, sFLC ratio was 23.8, sKFLC was 1079.8 mg/L, B2 M was 3747×and ESR was 55 mm/hr. His hemoglobin was 11.5 g/dL with a mild elevation in his creatinine levels from 0.9 mg/dl baseline value to 1.35 mg/dl (normal values: 0.67–1.17). We treated progressive disease with the VDT-PACE regimen (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide). After the third cycle, he underwent stem cell harvest successfully with more than 2.2 × 10⁶/ kg of CD34 cells for auto-SCT. The lesion's size was reduced to 9 mm on PET/CT. We observed very good partial response (VGPR) according to the multiple myeloma response criteria.^4,5 Auto-SCT was performed with melphalan 140 mg/m² (MEL-140). Lenalidomide was indicated as maintenance therapy and ixazomib was added to increase progression-free survival. ⁶ We have observed durable remission on the same maintenance regimen for the past 15 months.

Figure 1.

Contrast-enhanced abdominal computed tomography showing a 7 × 7 cm sized lesion with exophytic growth in the right renal lower pole.

Figure 2.

PET/CT showing a pelvic mass of 8.8 × 7.2 cm extending from the surgical clips in the inferior of the nephrectomy lodge to the pelvis.

Discussion

MM is a mature B-cell neoplasm defined by the presence of clonal bone marrow plasma cells (BMPCs) ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma with one or more myeloma-defining events. ² Myeloma-defining events involve signs of end-organ damage (hypercalcemia, renal insufficiency, anemia, and bone lesions) or biomarkers of malignancy (clonal bone marrow plasma cells ≥60%, elevation of serum involved/uninvolved free light chain (FLC) ratio ≥100, magnetic resonance imaging (MRI) with more than one focal lesion. ⁷ SP is a solitary lesion of bone or soft tissue with biopsy-proven evidence of clonal plasma cells without myeloma-defining events. The presence of clonal BMPCs affects the prognosis of solitary plasmacytoma differently. Consequently, it is divided into two separate entities: solitary plasmacytoma (no clonal BMPCs) and solitary plasmacytoma with minimal marrow involvement (<10% clonal BMPCs). ⁸ Approximately 10% of solitary plasmacytoma progresses to MM within 3 years. ² If there is minimal bone marrow involvement this rate increases to 20% for soft tissue and 60% for bone plasmacytomas.^1,2,8 Before concluding that a patient has a solitary plasmacytoma, at least one advanced imaging scan (PET-CT, low-dose whole-body CT, or MRI of the whole body or spine) is advised for patients because the accurate diagnosis of MM is critical.^2,9 Depending on the clinical setting and available options, different imaging techniques may be selected. Patients with SP and ≥10% clonal BMPCs are considered to have multiple myeloma, also SPs should not be considered as EMD, since they occur in the absence of MM diagnosis.^1,3,10 The main approach to the treatment of SP is usually definitive local radiotherapy. ¹ Despite their locally destructive and aggressive features, SPs are highly sensitive to radiation. ¹¹ Treatment fields should include all sites of disease identified by imaging, with a margin of normal tissue. ¹¹ Radiation therapy is the primary treatment for SP, with surgery reserved for specific situations requiring urgent treatment, such as fracture fixation, decompressive laminectomy, or spinal stabilization. ¹ Radiation therapy can be delayed until after surgery, but is still necessary because tumor excision without subsequent radiation therapy results in a very high rate of local recurrence. ¹² It is important to monitor monoclonal protein levels after treatment, as reductions indicate a response to radiation. ¹³ However, persistent protein levels may indicate residual disease beyond the treated area. ¹¹ The role of adjuvant chemotherapy after radiotherapy in the treatment of SP remains controversial and cannot be definitively recommended. ¹

EMD is an aggressive form of MM defined as the ability of a clone and/or subclone to survive and develop independently of the bone marrow microenvironment. ¹⁴ Extramedullary dissemination of MM may occur either at diagnosis or throughout the disease. The reported incidence for patients with newly diagnosed MM ranges from 0.5% to 4.8%, while the reported incidence for patients with relapsed or refractory MM is between 3.4% and 14%.^3,15–19 Both at the time of diagnosis and during follow-up, there has been a significant increase in extramedullar (EM) involvement in recent years.^17,20 This conclusion could partially be explained by the widespread use of more accurate imaging methods like MRI and CT scans. The other contribution to this conclusion is improved survival of MM patients with novel agents and better supportive care. The considerable rise in EM relapses during follow-up observed in recent years may therefore be due to patients increasing life expectancy.

EMD management is particularly difficult because of poor prognosis and clinical heterogeneity.^21,22 Our patient had bilateral testicular plasmacytoma without myeloma-defining events at first. FDG-PET/CT revealed no evidence of any other lesion of bone or soft tissue, his bone marrow examination was normocellular and there were no myeloma-defining events. During the follow-up anemia with extramedullary renal plasmacytoma confirmed the diagnosis of multiple myeloma even with minimal bone marrow involvement. We treated EMD with four cycles of VD regimen and lenalidomide maintenance therapy. Retrospectively, in the first line of treatment, an aggressive approach with triple regimens followed by consolidation with autologous stem-cell transplant should have been considered. After relapse treatment regimen was a multidrug anthracycline-containing VDT-PACE regimen. We observed VGPR according to the MM response criteria. VGPR in MM is characterized by detectable monoclonal protein via sIFE, but not on sPEP and uPEP, or by a reduction of ≥90% in serum monoclonal protein levels alongside urine monoclonal protein levels <100 mg per 24 h. Traditionally, response assessment relied on serum and urine monoclonal protein concentrations via protein electrophoresis or immunofixation.^23,24 However, the landscape has evolved with the substitution of monoclonal protein concentrations for synthetic rates, varied cutoffs, and the incorporation of sFLC values. ⁵ The International Myeloma Working Group introduced new response categories, including minimal residual disease negativity, aiming for consistent reporting across clinical trials. ⁴ Additionally, according to the latest criteria, a soft tissue plasmacytoma must decrease by more than 90% in the sum of the maximal perpendicular diameter SPD compared to baseline, aligning with observations in our patient. ⁴ We consolidated our treament with Auto-SCT performed with MEL-140. As EMD is associated with an adverse prognosis in newly diagnosed and relapsing MM patients experts agree on aggressive treatment if possible including induction treatment, Auto-SCT, consolidation, and maintenance treatment.^21,25

Conclusion

This case report highlights a rare presentation of bilateral testicular plasmacytoma preceding IgG kappa-type multiple myeloma with extramedullary renal involvement. Successful treatment involved the Vd regimen, lenalidomide maintenance, and later the VDT-PACE regimen with autologous stem cell transplantation. The case underscores the need for aggressive therapeutic strategies and warrants further investigation through prospective clinical trials dedicated to EMD in MM.