Myelomatous pleural effusion: A rare case in posttransplant myeloma

INTRODUCTION

Multiple myeloma (MM) is defined by the neoplastic proliferation of plasma cells, resulting in an aberrant immunoglobulin (Ig) produced by neoplastic plasma cells manifesting as monoclonal M protein on protein immunoelectrophoresis and reduced or normal concentrations of normal Ig.¹ Pleural effusions are rare in multiple myeloma and most often indicate a concurrent disease process, like amyloidosis.² Malignant myelomatous pleural effusions (MPEs) are even more rare, occurring in less than 1% of cases of multiple myeloma.^1,2

Here we report the case of a patient with multiple myeloma presenting with a MPE and skin nodules at disease relapse post-autologous bone marrow transplant.

CASE REPORT

A 52-year-old female presented with complaints of severe headache and back pain. Evaluated and noted to have hypercalcemia with A:G reversal. She was worked up for this and was diagnosed with multiple myeloma (R-ISS, high risk, double-hit myeloma).

Started on the DARA + VRD (daratumumab, bortezomib, lenalidomide, and dexamethasone) regimen, following which her end-of-treatment bone marrow trephine biopsy showed no detectable plasma cells, and her paraprotein had reduced significantly.

Post 4 cycles, she underwent autologous stem cell transplantation followed by 2 cycles of the DARA + VRD (daratumumab, bortezomib, lenalidomide, and dexamethasone) regimen and was on maintenance with lenalidomide. Day 100 post-transplant, the marrow was assessed, and the patient was in remission with no evidence of plasma cells. Later, after 10 months of transplantation, she developed erythematous cutaneous lesions of varying sizes on her abdomen [Figure 1]. A skin biopsy was performed which revealed metastatic neoplasm confirmed with CD 138 Immunohistochemical studies and lambda light chain restriction [Figures 2,3 and 4]. Therefore, in view of relapsed disease started on the KPD (carfilzomib, pomalidomide, dexamethasone) regimen, post 3 injections, cutaneous lesions were significantly reduced. She developed a sudden onset of shortness of breath (SOB), and clinically, there was a decrease in breath sounds on bilateral lungs, but there was no fever. Her peripheral blood showed anemia, normal white blood cell counts, and adequate platelets. CT (computed tomography) scan showed a pleural effusion, and an intercostal drain was placed. The fluid was sent for cytology, which revealed numerous mature and immature plasma cells, along with binucleate and multinucleate forms. The cell block of the fluid also showed infiltration of cells with plasma cell morphology [Figure 5]. Pleural fluid analysis revealed an IgG lambda concentration of 81.2 g/dL.

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Figure 1:

Skin lesions presented after 8 months post-transplant.

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Figure 2:

Skin biopsy showing diffuse infiltration with plasmacytoid cells (H&E, 400x). H&E: Hematoxylin and eosin stain.

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Figure 3:

Plasma cells highlighted with CD 138 (IHC, 400X). IHC: Immunohistochemistry.

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Figure 4:

Plasma cells showing lambda chain restriction (IHC, 400X). IHC: Immunohistochemistry.

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Figure 5:

Cell block of pleural fluid showing plasma cell infiltration (H&E, 400x). H&E: Hematoxylin and eosin stain.

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The patient was continued with the KPD (carfilzomib, pomalidomide, dexamethasone) regimen. A PET CT scan was performed, which revealed progression of the disease. The family was explained about the prognosis.

DISCUSSION

The occurrence of pleural effusion in multiple myeloma is very unusual. The incidence of pleural effusions in patients with multiple myeloma is 6%, as reported by Kintzer et al.³ The first case of pleural effusion in multiple myeloma was reported in 1994 by Rodriguez et al.⁴ MPEs arise either from the spreading of chest wall plasmacytomas or invasion by nearby skeletal lesions or directly from affected pleura called as pleural plasmacytomas. Pleural effusions are typically caused by concurrent diseases such as cardiac failure, amyloidosis, pulmonary embolism, pneumonia, or a secondary neoplastic etiology rather than as a direct effect of the disease process itself.⁵ Of all the factors listed above, myelomatous involvement of pleural and adjacent tissues was the most common one, which brought about pleural exudates in one series by Zang et al.⁶

IgA paraproteins are the most common type (in up to 80% of cases) associated with the MPE.⁷ Sasser et al. reported 56 cases of MM with the involvement of the serous cavities, and in 30 cases, the most common site of involvement was the pleural cavity, and among them, half of the cases were associated with the presence IgA paraprotein type.⁸ Our case showed IgG paraprotein on immunoelectrophoresis.

A diagnostic criterion of MPE includes the presence of monoclonal protein in the pleural fluid electrophoresis, the detection of atypical plasma cells in pleural fluid (cytology and, if possible, cell block), and also in pleural biopsy.⁹ Cytological examination of the pleural fluid shows malignant plasma cells; however, the morphology of the plasma cells in these patients can be quite variable. A morphologic diagnosis of MPE can be made if the cytological features are classical and distinctive, as in our case. Immunochemistry performed on the smears or immunohistochemistry (IHC) on the cell block may be useful when the there is a low number of plasma cells in the pleural fluid, or when the cells exhibit atypical morphological features, or when they resemble those in other malignancies. When atypical plasma cells are noted, differential diagnoses such as lymphoma or poorly differentiated malignancies must be considered and ruled out accordingly. Alternatively, when only mature plasma cells are observed, conditions such as chronic disorders, viral infections, and autoimmune conditions, which exhibit reactive plasmacytosis, should be excluded. Clonality can be established by immunohistochemical staining by using CD138, which is expressed in normal and neoplastic plasma cells,⁶ whereas CD56 is expressed in the majority of myeloma cases but not in reactive plasma cells.⁷ But when these malignant plasma cells spread to the extramedullary sites, CD56 is frequently not expressed within the extramedullary sites, but its expression is retained in the medullary part.¹⁰ The cytologic diagnosis may be further supplemented by immunophenotyping studies using flow cytometry for plasma cell markers (CD38 and CD138), as well as analysis of pleural fluid to demonstrate the monoclonal protein that is identical to that seen in patient serum.¹⁰ In our case neither IHC nor flow cytometric analysis of pleural fluid was done, and the diagnosis was established on a highly cellular smear revealing only plasma cells, including mature, immature, binucleate, and multinucleate forms (which excludes reactive etiology), in correlation with pleural fluid monoclonal protein-IgG lambda and skin biopsy findings (CD138 and lambda cytoplasmic positivity in tumor cells) and the clinical scenario.

Extramedullary involvement with neoplastic plasma cells indicates a poor prognosis, especially in recurrent MM cases, as in our case. Pleural infiltration by neoplastic plasma cells usually has a fatal outcome, with a median survival of 1.5–3 months. Therefore, in MM, involvement of the pleural cavities necessitates more aggressive chemotherapy regimens. Alternatively, a multimodality approach in some patients with a combination of radiation therapy, chemotherapy, and chemical pleurodesis resulted in clinical remission that lasted 6 months after diagnosis of the MPE.¹¹

Finally, it has been reported that the mean survival period after the diagnosis of MPE is approximately 4 months. However, chemotherapy using bortezomib has been found to be effective against extramedullary plasmacytomas, and also in which other modalities of treatment, including immunomodulatory drugs, are not effective.¹² Moreover, Zhong et al. reported that chemotherapy with bortezomib prolonged the overall survival of cases of MPE to 11.7 months.¹³ Our patient was also treated with bortezomib, but there was progression of the disease, which was fatal.

MM associated with MPE has a poor outcome, as it has been proposed to be a late manifestation in the natural history of the disease or may be a manifestation of an aggressive phase of the disease.¹⁴

CONCLUSION

The incidence of MPEs in multiple myeloma is rare, often indicating an advanced disease or an aggressive phase of the disease with poor prognosis, which requires prompt evaluation and appropriate treatment. Due to the varied etiologies of pleural effusion, diagnostic thoracentesis and a cytological examination of the pleural fluid, along with ancillary techniques, should be performed whenever feasible in myeloma patients, and the disease should be treated in accordance with the etiology. Chemotherapy is the main mode of treatment for MPE. However, the response rate is very low, with an overall median survival time of 4 months.