I NTRODUCTION
Multiple myeloma (MM) is a hematological neoplasm characterized by the presence of clonal plasma cells within the bone marrow. The diagnostic requirement for MM is the presence of one or more myeloma-defining events in addition to evidence of either 10% or more clonal plasma cells in bone marrow or a biopsy-proven plasmacytoma.[ 1 ]
Relatively, pleural effusion is a rare finding in myeloma patients and is usually caused by nephrotic syndrome, congestive heart failure secondary to amyloidosis, pulmonary embolism, and infection. Myelomatous pleural effusion (MPE) is an even rarer finding, occurring in <1% of cases, and seldom is a presenting feature.[ 2 , 3 , 4 ] Pleural effusion usually indicates a poor prognosis for myeloma with a survival duration of <4 months.[ 5 ]
Extramedullary multiple myeloma (EMM) is characterized by clonal proliferation of plasma cells outside of the bone marrow spaces or microenvironment, in patients meeting the criteria of MM.[ 6 ] Plasma cell leukemia (PCL) can be considered a variant of aggressive EMM characterized by rapid progression, drug resistance, and short survival.[ 7 ] MM with CNS involvement (CNS-MM) is a rare form of EMM characterized by plasma cell infiltration in CNS, leptomeninges, or cerebrospinal fluid (CSF) but carries a very poor prognosis.[ 8 ]
Here in our study, we have described our experience of neoplastic plasma cell involvement in body cavity effusion fluids and CSF in a tertiary care cancer center, over 10 years.
M ATERIALS AND M ETHODS
This was a retrospective study conducted at the oncopathology department of a tertiary state cancer center over 10 years (July 2013–July 2024). The data were retrieved from the online database of our institute. All cases of plasma cell neoplasms showing body cavity fluid and CSF involvement were included in the study. Plasma cell infiltration in known cases of lymphoma were excluded. We studied the epidemiological data, duration between primary diagnosis and involvement in body fluid/CSF, bone marrow findings, serum protein electrophoresis and immunofixation, immunoglobulin type and amount, along with hyperCalcemia, Renal insufficiency, Anemia and Bone lesion (CRAB) features, levels of serum beta 2 microglobulin, immunohistochemistry or flow cytometry findings if any, treatment history, and follow-up data.
R ESULTS
A total of 16 cases of myelomatous involvement of fluid were identified [details in Tables 1 and 2 ].
Table 1
Demographical data, biochemical findings, effusion type, and electrophoresis findings
M = male, F = female, MM = multiple myeloma, PCL = plasma cell leukemia, SPEP = serum protein electrophoresis, IF = immunofixation, NA = not available, CSF = cerebrospinal fluid
| Case no | Age (years) | Sex | Primary diagnosis | Body fluid/CSF | Duration (months) | SPEP/IF | Heavy chain (mg/dL) | K/L ratio | B2 microglobulin (mg/L) |
| 1 | 56 | M | MM | CSF | 3 | Normal | 627 | 1.06 | NA |
| 2 | 62 | F | MM | CSF | 21 | IGG(L) | 2193 | 0.29 | 2.7 |
| 3 | 46 | F | MM | Pleural | 6 | IGG(K) | 1163 | 33.26 | 14.1 |
| 4 | 53 | M | MM | Pleural | 1 | IGG(L) | 6547 | 0.04 | 10.6 |
| 5 | 43 | F | PCL | Pleural | 1 | NORMAL | 693 | 4.48 | 34.2 |
| 6 | 69 | F | MM | Pleural | 10 | IGG(K) | 2519 | 34.6 | NA |
| 7 | 55 | F | MM | CSF | 10 | NORMAL | 491 | 1.96 | NA |
| 8 | 53 | M | Plasmacytoma | CSF | 15 | IGG(L) | 1808 | 0.42 | 5.7 |
| 9 | 30 | M | Plasmacytoma | Pleural | 60 | Normal | 819 | 0.53 | 8.6 |
| 10 | 65 | M | PCL | Pleural | 0 | IGA(L) | 4151 | 0.22 | NA |
| 11 | 59 | M | MM | Pleural | 2 | Normal | 569 | 0.4 | 35.1 |
| 12 | 48 | F | Plasmacytoma | Pleural | 15 | M band—73% | NA | NA | 3.5 |
| 13 | 60 | F | Plasmacytoma | Pleural | 3 | NA | NA | NA | 1.5 |
| 14 | 55 | M | Plasmacytoma | Pleural | 0 | NA | NA | NA | 14.5 |
| 15 | 56 | M | MM | Pleural | 9 | NA | NA | NA | 23.8 |
| 16 | 70 | F | MM | Pleural | 4 | NA | NA | NA | 6.6 |
Table 2
Bone marrow findings, immunohistochemistry findings, treatment history, and survival data
IHC = immunohistochemistry, RT = radiotherapy, NA = not available
| Case no | Bony lytic lesion | Bone marrow plasma cell (%) | Flow/IHC | Treatment | Survival (months) |
| 1 | Absent | 65 | Bone marrow biopsy-IHC-CD38, CD138, and lambda—positive | 2D RT curative (with Orfit) photon and/or electron Cytarabine Methotrexate Bortezomib Zoledronic acid Cyclophosphamide | 1 |
| 2 | Present | 32 | RT | 1 | |
| 3 | Present | 70 | Bone marrow biopsy-IHC-CD38 and CD138—positive | Cyclophosphamide | 1 |
| 4 | Present | 20 | RT | 1 | |
| 5 | Present | 80 | Flow-PBS-CD38: 97% moderate positive CD138: 95% moderate positive CD19: 00% negative CD117: 00% negative CD20: 00% negative sKappa: 00% negative sLambda: 00% negative cKappa: 10% dim positive cLambda: 00% negative | Bortezomib | 1 |
| 6 | Absent | 52 | Bortezomib Cyclophosphamide | 3 | |
| 7 | Absent | 25 | Bortezomib Zoledronic acid Cyclophosphamide | 3 | |
| 8 | Absent | 4 | Nasal cavity-IHC-CD38—positive CD138—Negative MUM1—positive AE1—negative | Lenalidomide bortezomib Zoledronic acid cytarabine Methotrexate | 1 |
| 9 | Present | 1 | Lumbosacral mass-IHC-CD38—negative CD138—positive MUM1— positive AE1—negative CD20—negative | RT palliative Thalidomide Bortezomib | 6 |
| 10 | Present | 30 | Bortezomib | 1 | |
| 11 | Present | 12 | Bortezomib Thalidomide | 2 | |
| 12 | Absent | 9 | Rib: IHC: CD38—positive CD138—positive CD20—negative | Zoledronic acid melphalan thalidomide | 1 |
| 13 | Present | 3 | IHC-CD138—positive EMA—negative CD20—negative | RT palliative | 2 |
| 14 | Absent | — | Sacrum: IHC: CD38—positive CD138—positive CD20—negative | RT palliative | 1 |
| 15 | Present | 56 | Zoledronic acid melphalan Thalidomide lenalidomide | 5 | |
| 16 | Absent | 27 | Bortezomib | NA |
The age of the patients ranged between 30 and 70 years. There were eight male and eight female patients. Out of the 16 cases, 9 cases were known cases of MM, 5 cases were known cases of plasmacytoma, and 2 cases were known cases of PCL. Out of 16 cases, 12 cases involved pleural fluid, and 4 cases involved CSF. Among the four cases that involved CSF—three were cases of MM and the remaining one was a known case of plasmacytoma. Duration between primary diagnosis and secondary involvement ranged from 1 to 60 months barring two cases where concurrent fluid involvement was found.
The diagnostic findings of the cases included in our study are detailed below.
Serum electrophoresis reports of 12 cases were available, which demonstrated the M band in seven cases. Furthermore, immunofixation revealed immunoglobulin (Ig)G(L), IgG(K), and IgA(L) association in three cases, two cases, and one case, respectively. All five known cases of plasmacytoma were confirmed by immunohistochemistry on a biopsy where a cluster of differentiation (CD)38, CD138, or MM antigen 1 (MUM1) showed positivity. Flow cytometry confirmation was done in one case of PCL where CD38, CD138, and cKappa showed dim to moderate positivity.
Serum marker beta 2 microglobulin was elevated in nine cases with a peak value of 35.1 mg/L. Nine cases had the presence of CRAB features (hypercalcemia, renal impairment, anemia, and bony lytic lesion). Out of 16 cases, a bone marrow examination of 9 cases of MM showed up to 80% plasma cells on differential count. Bone marrow in five cases of plasmacytoma demonstrated <10% plasma cells, hence uninvolved, and two cases of PCL showed around 18% plasma cells in peripheral blood and 60%–70% plasma cells in bone marrow on differential count.
All the smears from pleural fluid cytology along with cell block showed a marked increase in the number of plasma cells along with lymphocytes and mesothelial cells in variable proportion. All the cases showed the presence of plenty of mature and immature plasma cells along with binucleated forms and Mott cells [Figure 1a – c ]. Immunohistochemistry (IHC) on one of the cellblocks of the pleural fluid showed membranous CD138 positivity [ Figure 1e ] and nuclear MUM1 positivity [ Figure 1f ] in plasma cells. Plasma cells were nonreactive for lambda monoclonal antibody [ Figure 1g ] and immunoreactive for kappa monoclonal antibody [ Figure 1h ].
Smears studied from cytospin preparation of CSF showed plasma cells, with binucleated forms, along with atypical forms with cleaved irregular nuclei, stippled chromatin, and occasional nucleoli in a proteinaceous background [ Figure 1d ].
Treatment details of the cases studied are as below.
A total of 10 patients received chemotherapy with bortezomib, cyclophosphamide, and dexamethasone or bortezomib, lenalidomide, and dexamethasone regimen, whereas four patients underwent palliative radiotherapy, one patient had palliative radiotherapy and chemotherapy and the single patient was treated with curative radiotherapy and chemotherapy. Despite this aggressive treatment, most patients succumbed to death with a mean survival of 2 months and a maximum survival of 6 months.
D ISCUSSION
Plasma cell myeloma comprises about 1% of all malignancies and 10% of hematologic malignancies.[ 4 ] The most common presenting symptoms like bone pains, fatigue, and recurrent infections can be due to the result of plasma cell infiltration as well as increased abnormal paraprotein secretion. Other less common, presenting symptoms and signs involve renal, cardiac, musculoskeletal, gastroenterological, neurological, and respiratory systems. Thoracic manifestations commonly include osseous lesions, plasmacytoma, rare pulmonary infiltrates, mediastinal lymphadenopathy, and pleural effusion.[ 5 ]
MPEs are one of the rarest complications of MM, occurring in <1% of patients.[ 9 ] Rodríguez et al .[ 10 ] reported the first case of MPE in 1994.
CNS-MM is diagnosed in <1% of MM patients with the reported median age of onset of CNS-MM being younger than the usual of classical MM diagnosis; however, age at presentation varies between studies. CNS-MM can be diagnosed by the presence of atypical plasma cells in the CSF by conventional cytology and flowcytometry or imaging evidence of intraparenchymal lesions or leptomeningeal/dural enhancement and/or direct tissue sampling, especially in doubtful cases. Diagnosis of CNS-MM still represents a challenge as neurological symptoms may be confounded and attributed to other clinical situations, such as hyperviscosity, paraproteinemia, hypercalcemia, uremia, bone damage, stroke, treatment-related neuropathy, or opportunistic infections.[ 8 ]
In our study, patients ranged in age from 30 to 80 years with a male-to-female ratio of 1:1. In a similar study by Gochhait et al .,[ 11 ] the age of the patients ranged between 26 and 78 years with a male preponderance.
In our study, 12 cases showed MPE. Of these, six patients had MM, four patients had plasmacytoma, and two patients had PCL as their initial diagnosis. Four cases had CSF infiltration by plasma cells. Of these, three cases had MM, and one case had plasmacytoma as the primary diagnosis. One patient with CSF involvement was simultaneously diagnosed with squamous cell carcinoma of the oral cavity.
Two cases of myelomatous pleural fluid involvement manifested simultaneously at the initial primary diagnosis whereas in the rest of the 12 cases, pleural fluid involvement was diagnosed within the range of 1–60 months after starting chemotherapy for primary plasma cell neoplasm.
When encountering plasma cells in fluids, one needs to rule out reactive plasma cells. Features favoring a neoplastic etiology include an increased number of plasma cells and the presence of immature plasma cells with prominent nucleoli. A detailed clinical history such as the history of plasma cell neoplasm in other part/s of the body, symptoms of back pain or lytic lesions in the skull, serum biochemistry findings of hypercalcemia, and anemia, may be very helpful. Ancillary techniques such as flow cytometry and immunohistochemistry on fluid cell block with CD38, CD138, and MUM1 along with kappa/lambda light chain restriction establishing monoclonality help at arriving at the final diagnosis of MM involving effusion fluids/CSF. In addition, the other biochemical findings including information on monoclonal bands in urine and blood, and radiological findings are helpful features.[ 12 , 13 ] In the modern arena, IHC for light chains immunoglobulin is being replaced or associated with RNA in situ hybridization technique, which has been proven more sensitive to MM due to less background staining.[ 14 ]
In our study, nine cases had the presence of CRAB features (hypercalcemia, renal dysfunction, anemia, or lytic lesion in the skull). All our five cases of plasmacytoma were diagnosed by histomorphology with confirmation by immunohistochemical expression of CD38, CD138, or MUM1 on biopsies. In one case of PCL, flow cytometric analysis of peripheral blood revealed CD38, CD138, and cKappa with dim to moderate positivity. In our study, bone marrow examination of patients with myelomatous effusion showed the presence of plasma cells ranging from 12% to 80% in cases of MM and <10% in cases of plasmacytoma.
Some studies have noted the IgA kappa subtype to be associated with the majority of the pleural effusions.[ 5 , 13 , 15 ] Whereas other studies demonstrated IgG kappa subtype on immunofixation.[ 11 , 16 , 17 ] In our study, seven cases showed the presence of a monoclonal band on serum protein electrophoresis with the absence of an M band in four cases including two CSF cases. On further serum immunofixation, we found IgG(L) in three cases including two CSFs, IgG(K) in two cases, and IgA(L) in one case.
IgA myeloma represented 27% and 21% of CNS-MM cases in the multi-center study by Jurczyszyn et al .[ 18 ] and by Kyle et al .,[ 19 ] respectively. Overall, there is no consensus for associations between immunoglobulin type or light chain restriction in CNS-MM.[ 8 ]
The pathogenesis of myelomatous effusion is still unknown. Several possible mechanisms are postulated for MPE, such as infiltration of the pleural fluid by malignant plasma cells, direct infiltration of the pleural fluid from adjacent tissues, involvement by circulating plasma cells, or a lymph node infiltration leading to poor lymphatic drainage.[ 11 , 20 , 21 ]
MM with CNS involvement can develop by two pathways: one via hematogenous dissemination of malignant cells and the second by direct infiltration by the tumor. Very rarely CNS involvement can be due to the use of immunomodulatory drugs like lenalidomide used for the treatment of MM before CNS-MM progression.[ 8 ]
Cytopathologic evidence of plasma cell infiltration of the pleural fluid remains the gold standard for diagnosing MPE. Ancillary techniques such as flow cytometry/IHC of pleural fluid aid in the diagnosis.[ 17 ]
MPE predicts poor outcomes with a short survival time.[ 17 ] Systemic chemotherapy is the treatment of choice for eliminating myeloma, whereas symptomatic therapy, such as thoracentesis and pleurodesis diuretics, may provide some relief to improve the quality of life. Despite the reduction in serum paraprotein with bortezomib-based chemotherapy, the patients require multiple admissions for thoracentesis and pleurodesis for treating refractory effusion. In the era of novel agents, patients with extramedullary involvement respond poorly to therapy, indicating the biological differences between intramedullary and extramedullary diseases. Myeloma infiltration in the pleural cavity carries a short median survival of 1.5–3 months.[ 22 , 23 ] A study on CNS-MM survival data quotes their median survival of 4.5 months.[ 8 ] The presence of MPE, or any extramedullary disease, should be considered a high-risk myeloma and treated aggressively. For patients eligible for stem cell transplantation, a triplet induction therapy (one novel agent, immunomodulatory agent and/or proteasome inhibitor and/or monoclonal antibody followed by high-dose melphalan, and autologous blood stem cell transplantation), a triplet consolidation therapy, and maintenance treatment with at least by lenalidomide has been proposed.[ 24 , 25 ]
In our case series, 10 patients received a chemotherapy regimen of bortezomib, cyclophosphamide, or lenalidomide, four patients opted for palliative radiotherapy, one patient took palliative radiotherapy and chemotherapy, and one patient was treated with curative radiotherapy and chemotherapy. Despite this aggressive treatment, the mean survival time was 2 months with maximum survival reaching up to 6 months.
C ONCLUSION
Myelomatous involvement of fluid/CSF renders poor prognosis to the patients and calls for multidisciplinary robust research and studies to enable a better understanding of this disease entity.
Conflicts of interest
There are no conflicts of interest
Funding Statement
Nil.
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