Initial disease presentation with myelomatous pleural effusion is an ominous sign for multiple myeloma: report of a case emphasizing cytological features and ancillary studies

Abstract

Multiple myeloma (MM) is a marrow-based, multi-focal neoplastic proliferation of clonal plasma cells. Myelomatous pleural effusion (MPE) is considered a distinctive form of extramedullary disease and usually develop in disease progression or recurrence, but rarely at initial disease presentation of MM. Herein we report a 47-year-old male patient with MM who presented initially with MPE. The typical cytological features (eccentric nuclei and amphophilic cytoplasm with paranuclear hof), flow cytometric immunophenotyping, and cell block preparation with immunohistochemistry confirmed MPE. After establishing the diagnosis of stage III myeloma through bone marrow study, laboratory and radiological corrections, the patient was treated with chemotherapy and palliative radiotherapy. Unfortunately his disease progressed and he passed away in six months. Our case illustrated the importance of detailed cytological examination with ancillary studies for the challenging diagnosis of an extremely rare initial disease presentation of MM with MPE, which is an ominous sign.

INTRODUCTION

Multiple myeloma (MM) is a marrow-based, multi-focal neoplastic proliferation of clonal plasma cells and is usually associated with monoclonal paraprotein (M protein) in the serum and/or urine and the presence of the CRAB features (hypercalcemia, renal impairment, anemia, and lytic bone lesions).¹ Extramedullary disease (EMD), defined by the presence of clonal plasma cells outside the marrow, is not a common feature at presentation, with an incidence between 7 and 18% and is more frequent in cases with plasmablastic/pleomorphic morphology.^2,3 Myelomatous pleural effusion (MPE) is a distinctive EMD and usually develops at a median of 12 months from diagnosis of MM.⁴ MPE represents end-stage disease with a poor prognosis.^4,5 MPE as the initial presentation of MM is rare.^6–8 Herein, we report a case of MM with MPE as the initial disease presentation.

CASE REPORT

A 47-year-old male patient was referred from an orthopedic clinic with the chief complaints of bone pain and a chest wall tumor for months in early August, 2024. He was admitted on August 10^th, 2024. Imaging studies, including MRI, revealed multiple bony and soft tissue tumors involving the rib cage and thoraco-lumbar spines, pathological fractures of the sternum and bilateral ribs, and bilateral pleural effusion (Fig. 1).

Fig. 1.

Imaging findings at disease presentation. A, Chest X ray shows increased lung infiltration and bilateral pleural effusions. B, MRI shows multiple T2 hyperintense soft tissue lesions involving bilateral ribs.

Pigtail was inserted for drainage of the pleural effusion and cytological examination revealed atypical plasmacytic infiltration indicating myelomatous effusion. Laboratory examination of the serum showed elevated creatinine level (2.1 gm/dL), calcium (13.8 mg/dL), and beta 2 microglobulin (15,856 μg/L), with a low level of albumin (2.5 g/dL). Serum free kappa and lambda levels were 52.1 and 557 mg/L, respectively, with a ratio of 0.09. Immunoelectrophoresis revealed an M protein of IgG lambda. Sternal and bone marrow biopsies confirmed MM. Biochemical analysis of the pleural effusion fluid showed glucose level at 131 mg/dL and total protein at 5.8 g/dL.

The patient was diagnosed with International Staging System (ISS) stage III myeloma and was treated with bortezomib, thalidomide and dexamethasone (VTD), palliative radiotherapy, and daratumumab. His clinical course was complicated by pneumonia and he passed away with progressive disease and pneumonia on February 9^th, 2025, six months after diagnosis.

CYTOLOGICAL FINDINGS

Pleural effusion cytology showed abundant mature and atypical plasma cells admixed with some reactive mesothelial cells, histiocytes, and small lymphocytes. The atypical plasma cells exhibited eccentric nuclei with a higher than normal nuclear/cytoplasmic ratio and an amphophilic cytoplasm with paranuclear hof (Fig. 2). Some cells exhibited significant nuclear enlargement and prominent nucleolus. Scattered multinucleated giant cells and plasmablast-like cells were also present. Flow cytometric immunophenotyping and cell block preparation with subsequent immunohistochemistry confirmed the diagnosis of MPE.

Fig. 2.

Pleural effusion. A & B, A few clusters of atypical plasma cells showing eccentric nuclei and amphophilic cytoplasm with paranuclear hof (A, x200 and B, close-up from x1000; Diff-Quik stain). C & D, multinucleated atypical plasma cells (C, x1000 and D, close-up from x1000; Papanicolaou stain). E, Cell block section showing atypical plasma cells with small reactive lymphocytes in the background (x1000; H&E stain). F, Immunohistochemical stain shows that the atypical plasma cells are positive for CD38 (x1000).

PATHOLOGICAL FINDINGS

Biopsy from the sternum showed a florid proliferation of oval to round-shaped tumor cells with eccentric nuclei, fine chromatin and basophilic cytoplasm in a fibrous stroma. These tumor cells were immunoreactive for CD138 and were monotypic for lambda light chain expression. They were negative for cytokeratin (AE1/AE3), CD3 and CD20. Plasmacytoma was diagnosed. The subsequent bone marrow biopsy showed a hypercellular (70%) marrow with a markedly decreased normal hematopoiesis (Fig. 3). Around 80% of the marrow cells were mature and atypical plasma cells. Immunohistochemically, these plasma cells expressed CD38 and CD138, but not CD56 or CD117. Flow cytometric immunophenotyping revealed plasma cells with monotypic immunoglobulin lambda light chain expression, with co-expression of CD38, CD43, and cytoplasmic CD138. These findings confirmed the diagnosis of MM.

Fig. 3.

Marrow trephine shows extensive infiltration by atypical and immature plasma cells (A, x40 & B, x 1000; H&E stain), which are positive for CD138 (C, x400; immunohistochemistry).

DISCUSSION

According to the review of thoracic and pulmonary abnormalities of 958 cases with MM, 58 (6.1%) patients were found to have pleural effusion, with congestive heart failure secondary to amyloidosis as the most frequent cause.⁷ Only eight (0.8%) patients had MPE, including three (0.3%) at initial clinical presentation and five (0.5%) during disease progression. However, the authors suggested that the incidence of MPE might be higher if the cause of the effusion had been pursued in the 15 patients that were classified as “undermined”. Our case is unique with MPE as one of the initial disease presentations, rather than the more frequent scenario of developing MPE during disease progression or recurrence/relapse after treatment.^4,5

MPE may be the initial disease presentation of MM as in our case, or more frequently, during the disease course.^4,7,9,10 MPE, either primary or secondary, is associated with poor prognosis as it usually represents end-stage disease, with a highly proliferative and aggressive tumor and the median survival was less than four months.⁴ In a literature review of 16 cases of MM with MPE as an initial manifestation, Zhang L.L. et al. found that the overall survival of these patients were only four months, essentially the same as those with secondary MPE.^4,9 Our case was classified as ISS stage III for MM (Serum β2 microglobulin > 5.5 mg/L), indicating poor prognosis. Stage ISS III patients have a median survival about 29 months.¹¹ Stage ISS III patients with MPE were reported to have much inferior survival for less than four months.⁴ Although our patient was treated with VTD chemotherapy and palliative radiotherapy, his disease progressed and he passed away in less than six months. It is likely that MPE is not an independent prognostic factor. In the Revised ISS for myeloma (ISS-R), fluorescence in situ hybridization (FISH) after CD138 plasma cells purification and serum lactate dehydrogenase (LDH) were proposed to stratify newly diagnosed MM patients effectively with respect to the relative survival risk.¹² In the future, we might use MPE specimens for plasma cell purification and subsequent FISH assay for providing prognostic information in patients with MPE, either those as initial disease presentation or at relapse/progression.

When MPE presents as the initial manifestation of MM, cytologic diagnosis can be challenging. For the diagnosis of plasma cell-rich effusion specimens, our previously proposed guide for triaging lymphocyte-rich effusions for ancillary studies could be applied.¹³ The key factors include history and cellular atypia. Based on clinical information (an earlier history or current MM) and presence or absence of cellular atypia, the plasma cell-rich effusion samples could be triaged for ancillary studies. The key diagnostic clue lies in the typical cytological features of plasma cells, such as round nuclei and basophilic or amphophilic cytoplasm with a perinuclear hof. These features persist even in anaplastic or multinucleated plasma cells as highlighted in the current case. Ancillary studies on the effusion specimens, including flow cytometric immunophenotyping, cell block sections with immunohistochemistry, and clonality assay can help confirm MPE.¹³ If the atypical plasma cells are reactive, the underlying lesions might include infection, or even HHV8-associated multicentric Castleman disease,¹⁴ among others. If the atypical plasma cells are clonal, the next step would be trying to identify the underlying tumors, which could be plasmacytoma/MM, plasmablastic lymphoma,¹⁵ lymphoplasmacytic lymphoma,¹⁶ or other rare neoplasms. Incorporation of cytomorphology, correlation with clinical information, and appropriate application of various ancillary techniques is mandatory for a correct diagnosis. A final diagnosis of MM can be established through bone marrow examination, in conjunction with laboratory and radiological findings.

In addition to cytological examination and afore-mentioned ancillary studies, biochemical study of the effusion fluid including protein electrophoresis for paraprotein (M protein), free light chain ratio, glucose, total protein, β2-microglobulin, LDH, … etc. might offer diagnostic hints for MM.

MPE is considered a distinctive form of EMD and may stem from different modes of acquisition according to Megan H.: extension from adjacent plasmacytoma (continuous spread), infiltration of the pleura by circulating tumor cells (hematogenic spread), or mediastinal lymph node involvement (lymphatic spread).⁵ In our case, there were extensive osteolytic bony lesions (skull, facial bones, bilateral scapulae, bilateral clavicles, bilateral humeri, bilateral ribs, sternum, spine, sacrum, bilateral iliac bones, bilateral ischia, bilateral pubic bones, bilateral femora, bilateral tibiae, and right fibula), particularly in the rib cage. The MPE in our patient was most likely due to direct extension (continuous spread) from adjacent plasmacytoma of the chest into the pleura.

In conclusion, MPE is a rare initial presentation of MM and a rare underlying cause of pleural effusion. Recognizing the cytomorphology of atypical or neoplastic plasma cells, along with awareness of this rare etiology, is crucial for effectively triaging pleural effusion specimens for ancillary studies, ensuring an accurate and timely diagnosis.