Anaplastic extramedullary plasmacytoma resistant to novel therapies: a case report

Introduction

Solitary plasmacytoma (SP) is a rare type of plasma cell malignancy, presenting as a mass of monoclonal plasma cells with no signs of multiple myeloma (MM) [1]. SPs are separated into extramedullary plasmacytomas (EMP) and solitary bone plasmacytomas (SBP). The most common sites for EMP to occur are the nasal cavity, paranasal sinuses, and pharynx [2]. EMP has a risk of progression to MM. The treatment of choice for EMP is radiotherapy (RT). The benefit of additional chemotherapy (ChT) is controversial [3, 4].

Anaplastic EMP, caused by highly atypical plasma cells, is a rare disease with sporadic documentation [5], [6], [7], [8]. There is a lack of clinical recommendations due to the scant availability of case reports about these rare forms of SP. The benefit of additional systemic therapy to RT to prevent disease progression and progression to MM is currently under debate [5]. In this case report we present a case of anaplastic EMP with a poor response to RT and multiple lines of novel therapies.

Case report

A 66-year-old male presented with a 4-month history of difficulty breathing through his nose and swelling on the left side of his face. Magnetic resonance imaging (MRI) of the head and neck revealed a heterogenous 4.1 cm × 4.5 cm × 5.2 cm mass expanding in the left maxillary sinus and the middle and inferior nasal conchae with the destruction of the sinus walls and suspected perineural spread. A biopsy from the left maxillary sinus revealed a probable angiosarcoma. The questionable diagnosis demanded a repeated review of the biopsy samples. The repeated analysis revealed a cellular tumor tissue formed by highly polymorphic malignant plasma cells with a large, eccentrically located nucleus, rough chromatin, and a moderate amount of dark cytoplasm. The cells showed a strong positive reaction with plasmin, MUM1, CD79a, Bcl-2, a 30 % positive reaction with CD138, and a negative reaction with CD10, Bcl-6, Synaptophysin, Cyclin-D1, CD20, and PAX5. Areas with strong and questionable positivity for κ light chain markers were observed, while the reaction with λ light chain markers was negative (Figure 1). An anaplastic form of EMP was confirmed.

Figure 1:

Histopathologic image of left maxillary sinus biopsy tissue: Cellular tumor tissue formed by highly polymorphic malignant plasma cells (hematoxylin and eosin (H&E) stain, × 400) (a); strong positivity for plasmin (b), MUM1 (c); 30 % positivity for CD138 (d); strong (e) and questionable (f) positivity for κ light chain markers; negativity for λ light chain markers (g). Scale bars = 100 μm.

Initial laboratory evaluation revealed LDH within normal limits (101 U/l) and normal serum κ/λ free light chain (FLC) ratio of 1.64 (κ 20.3 mg/L; λ 12.4 mg/L). Monoclonal (M) protein was not found in serum protein electrophoresis (SPEP) and immunofixation. Positron emission tomography/computed tomography (PET/CT) revealed fluorodeoxyglucose (FDG) avid lesions in the left maxillary sinus (SUVmax 19.9) with an FDG avid retropharyngeal lymph node (SUVmax 15.8), and no other pathological FDG avid lesions (Figure 2).

Figure 2:

PET/CT showing FDG avid lesions in the left maxillary sinus (SUVmax 19.9) with an FDG avid retropharyngeal lymph node (SUVmax 15.8).

Examination of BM aspirate and biopsy revealed BM with normal hemopoiesis and sporadic plasma cells (1 %). On fluorescence in situ hybridization (FISH), del(17p), t(4;14)(p16;q32), t(14;16)(q32;16q23), t(11;14)(q32;q23), and t(14;20) were not detected. After the exclusion of MM, a diagnosis of anaplastic EMP was made.

Systemic treatment with Dara-VMP (daratumumab, bortezomib, melphalan, and prednisolone) regimen was initiated. After the first cycle, modest clinical regression of the disease was observed: the facial swelling subsided, and the patient could breathe easily. However, during the third cycle of Dara-VMP, the patient complained of having more difficulty breathing through the nose. M protein of immunoglobulin G (IgG) κ light chains was observed on serum immunofixation and the κ/λ FLC ratio was slightly elevated (2.88 (κ 22.1 mg/L; λ 7.67 mg/L)). Computed tomography (CT) showed a tumor progression: an infiltratively growing 6.0 cm × 4.5 cm × 5.0 cm tumor with the destruction of all the left maxillary sinus walls, spreading to all surrounding structures. After a failure to respond to immunochemotherapy, the biopsy was repeated for a suspected alternative diagnosis, revealing the same anaplastic EMP. Due to the aggressive progression of the tumor, RT to the plasmacytoma (a total of 50 Gy in 25 fractions) and ChT with BRd (bendamustine, dexamethasone, and lenalidomide) regimen were initiated.

After RT and 2 cycles of BRd, MRI was performed to evaluate the response. A moderate regression of the tumor size was observed. After the fourth cycle of BRd, the patient complained of swelling in his neck. Ultrasound revealed multiple pathological low-density lymph nodes on the left side of the neck. A biopsy of the mass on the neck confirmed EMP. BM aspiration and biopsy were repeated, showing no signs of MM. The disease was considered resistant to the BRd regimen and the fifth cycle was not administered. Instead, KRd (carfilzomib, lenalidomide, and dexamethasone) regimen was initiated. However, the first cycle was not completed because the patient was diagnosed with COVID-19.

After the patient recovered from the infection, a conglomerate of lymph nodes in the neck and a mass in the abdominal wall were detected. Laboratory evaluation showed markedly increased LDH activity of 2578 U/l, β-2 microglobulin of 13.25 mg/L, and highly increased serum κ/λ FLC ratio of 117.1 (κ 1037.5 mg/L; λ 8.86 mg/L). Serum immunofixation revealed M protein of κ light chains of an unknown immunoglobulin class. The abdominal wall mass and the lymph node of the neck were excised and the progression of EMP was confirmed. Intensive salvage ChT was not suitable for the patient because of the poor performance status. Palliative management was started and the patient died one month after the last relapse (Figure 3).

Figure 3:

The course of the patient’s disease from the diagnosis to death. Dara-VMP: daratumumab, bortezomib, melphalan, prednisolone; BRd: bendamustine, dexamethasone, lenalidomide; KRd: carfilzomib, lenalidomide, dexamethasone; RT: radiotherapy.

Discussion

Anaplastic EMP is a rare and aggressive variant of plasma cell disorders that has only been documented in a few case reports. The diagnosis of SP is based on a biopsy confirming monoclonal plasma cell formation and the exclusion of MM [1]. The pathological diagnosis of anaplastic EMP may be challenging due to highly pleomorphic plasma cells and the resemblance to aggressive lymphomas, including plasmablastic lymphoma, ALK-positive large B-cell lymphoma, rhabdomyosarcomas, and other sarcomas [6, 8], [9], [10]. In the present case, the diagnosis of angiosarcoma was made primarily. Regarding the uncertainty of the diagnosis, the biopsy samples were repeatedly reviewed, confirming the anaplastic EMP.

The main therapeutic strategy for EMP is RT, as the tumors tend to be radiosensitive. According to expert opinion, MM ChT regimens are redundant, as RT alone is usually effective enough [3, 4]. However, it is unknown whether the treatment of the anaplastic form of EMP should be more aggressive. We overviewed the treatment and the clinical outcomes of the documented cases of anaplastic EMP (Table 1).

Some patients with anaplastic EMP were treated with RT only. RT of 40 Gy resulted in remission for a patient with anaplastic EMP of the nasopharynx [10]. On the other hand, Windfuhr et al. presented a patient to whom RT of 55 Gy was ineffective and who was successfully treated surgically [11]. In other cases, a combination therapy of RT and ChT was implemented. In a renal transplant patient with anaplastic plasmacytomas in multiple locations treatment with cyclophosphamide and prednisolone followed by RT resulted in remission [7]. Takeda et al. reported a patient with anaplastic EMP of the nasopharynx which was resistant to ChT regimens with vincristine, cyclophosphamide, doxorubicin, prednisolone, and etoposide but showed a great response to RT. After RT, an autologous stem cell transplantation was performed, resulting in a complete remission at 1-year follow-up after the diagnosis [6]. In the case of anaplastic cerebral EMP and anaplastic EMP of the soft tissues of the knee, the tumors failed to respond to RT. Despite the initiated melphalan and prednisolone, the patient died 5 months after the diagnosis [9].

Novel drugs such as monoclonal antibodies, proteasome inhibitors, immunomodulators, and their combinations have significantly changed the treatment of MM. To our knowledge, the present case is the first case in which ChT regimens Dara-VMP, KRd, and BRd concomitant with RT were used to treat a patient with anaplastic EMP. Initially, we administered the Dara-VMP regimen which is generally used for the treatment of patients with MM who are ineligible for transplantation [15]. Daratumumab is an IgG1 monoclonal antibody that binds to the CD38 molecule, which is expressed on plasma cells [16]. This is the first documented case in which a monoclonal antibody was administered to treat anaplastic EMP. BRd and KRd are ChT regimens used for relapsed or refractory MM [17, 18]. Bendamustine is an old anticancer drug. As its mechanism of action has the characteristics of both alkylating agents and antimetabolites, bendamustine has been rediscovered in the treatment of MM in recent decades [19]. Lenalidomide is one of the new-generation immunomodulatory drugs used in the treatment of MM that drastically changed the response rates [20]. Carfilzomib is a second-generation proteasome inhibitor that is more effective than proteasome inhibitor bortezomib in the treatment of relapsed or refractory MM [21]. In our case, even these novel therapies combined with RT were ineffective and were not able to stop the progression of the disease. Madi et al. reported a case of anaplastic EMP that was also resistant to an immunomodulatory drug and a proteasome inhibitor. Four cycles of lenalidomide and dexamethasone and 6 cycles of bortezomib and dexamethasone in addition to a subsequent RT were not effective, leading to the patient’s death 12 months after the first presentation [22]. However, we found documentation of a successful remission of testicular anaplastic EMP after treatment with 6 cycles of the immunomodulatory drug thalidomide, dexamethasone, and melphalan [23].

Conclusion

To conclude, we reported a patient with anaplastic EMP that was resistant to RT and ChT regimens with a monoclonal antibody, an immunomodulatory drug, and proteasome inhibitors. The review of the literature revealed that RT is not always effective for this form of EMP, and ChT could be considered as a treatment option. However, in this case, anaplastic EMP remained refractory even to treatment regiments containing novel agents. Thus, further research is required to determine the optimal management of anaplastic EMP.