(Chest. 2004;125:1546-1555.)
© 2004
American College of Chest Physicians
Pleural Effusions in Hematologic Malignancies*
Michael G. Alexandrakis, MD;
Freda H. Passam, MD;
Despina S. Kyriakou, MD and
Demosthenes Bouros, MD, FCCP
* From the Department of Hematology (Dr. Alexandrakis), University Hospital of Heraklion, and Medical School, University of Crete, Crete; Hematology Unit (Dr. Passam), Third Department of Medicine, Sotiria Hospital, Medical School, University of Athens, Athens; Department of Hematology (Dr. Kyriakou), University Hospital of Larisa, and Medical School of Thessaly, Thessaly; and Department of Pneumonology (Dr. Bouros), University Hospital of Alexandroupolis, and Medical School, University of Thrace, Thrace, Greece.
Correspondence to: Demosthenes Bouros, MD, FCCP, Department of Pneumonology, Medical School, University of Thrace and University Hospital, 1A Achilleos St, Athens 15342, Greece; e-mail: bouros{at}med.duth.gr
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Abstract
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Nearly all hematologic malignancies can occasionally present with or develop pleural effusions during the clinical course of disease. Among the most common disorders are Hodgkin and non-Hodgkin lymphomas, with a frequency of 20 to 30%, especially if mediastinal involvement is present. Acute and chronic leukemias, myelodysplastic syndromes, are rarely accompanied by pleural involvement. Furthermore, 10 to 30% of patients receiving bone marrow transplantation develop pleural effusions. In cases of hematologic pleural effusions, drug toxicity, underlying infectious, secondary malignant or rarely autoimmune causes should be carefully sought. In most cases, the pleural fluid responds to treatment of the primary disease, whereas resistant or relapsing cases may necessitate pleurodesis.
Key Words: leukemia • lymphoma • pleural fluid • pleural infiltration
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Introduction
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During everyday practice, physicians dealing with the diagnostic workup of pleural effusions occasionally discover an underlying hematologic malignancy. Pleural effusions may be the first presentation of a hematologic malignancy or may develop during the course of the disease. In the second case, expansion of the primary malignancy or related complications may result in pleural fluid accumulation. In order to review current knowledge regarding the hematologic entities associated with pleural disease, the diagnostic tests, and the treatment applied, a search was made of English-language literature using the PubMed database. Multiple references were found, and a selection of 134 articles was made.
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Pleural Effusions in Non-Hodgkin Lymphoma
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Pleural effusion is a relatively common finding in patients with non-Hodgkin lymphoma (NHL), with a frequency of up to 20%.1 In addition, up to 10% of malignant pleural effusions with a positive cytologic examination are due to NHL.2
Pleural fluid cytology is usually an early step in the diagnosis of the malignant origin of the fluid, followed by closed biopsy or thoracoscopic biopsy when cytology fails to delineate the cause of the effusion. These examinations are positive in 77% of malignant effusions of various etiologies.3 In lymphomatous effusions, positive cytology is reported in 14 to 88% of patients. However, malignant cells in pleural specimens may be so sparse that even experienced cytologists are unable to render a definite diagnosis.4 In the majority of patients with NHL and a pleural effusion, the fluid is associated with widespread disease (mainly associated with mediastinal involvement).56 The fluid may cause symptoms of dyspnea, cough, and pain, and may be accompanied by fever and superior vena cava syndrome.7 The amount of fluid accumulated in lymphomas may vary, ranging from blunting of the costophrenic angle on chest radiography and little or no respiratory symptoms, to severe respiratory distress with opacification of a whole hemithorax.89
The fluid may appear serous or serosanguineous. Pleural effusions in lymphomas are usually exudates.101112 In rare cases, especially in advanced stages of low-grade lymphomas with multiple-organ infiltration, the pleural effusion is a transudate due to venous compression, congestive heart failure, hypoalbuminemia, and renal failure.13 Transudative or exudative reactive pleural effusions have also been observed to accompany lung parenchyma involvement in lymphomas.141516 In 12% of the cases of pleural effusions in NHL, the fluid may be chylous.17
The possible mechanisms for the formation of pleural effusions in NHL patients include the following: (1) pleural infiltration by the tumor with shedding of malignant cells into the pleural space, (2) lymphatic obstruction due to lymphomatous infiltration of the pulmonary and mediastinal lymph nodes, and (3) obstruction of the thoracic duct that leads to chylothorax.1 Various studies have supported that malignant pleural infiltration is the most common cause of pleural effusion in lymphoma,17 although it may also be caused by infections (especially tuberculosis), pleural damage due to previous chest irradiation, chemotherapeutic agents, or infiltration by other neoplasms.1819
Occasionally, positive cytologic findings of a diagnostic thoracentesis may be the first indication of an underlying lymphoma.20 Malignant lymphocytes in the pleural fluid are usually identical to the cells in the involved lymph nodes and in the blood (in cases where there are circulating neoplastic cells).2102122 In the cases of reactive pleural effusions, the lymphocytes are small, mature, polyclonal, and predominantly of the T-cell subset.102324 Difficulties in distinguishing morphologically neoplastic from reactive lymphocytes arise in low-grade lymphomas in which the involved cell in both cases is a small mature lymphocyte and whenever a mixed population of neoplastic and reactive lymphocytes exists.917
Cytologic evaluation with immunophenotyping of the pleural fluid is usually diagnostic not only of malignancy but also of the subtype of the lymphoma.11 Therefore, the pleural fluid should be analyzed, wherever possible, by flow cytometry and cytogenetic study. Immunologic typing studies define the B- or T-cell origin and degree of maturation. Cytogenetic analysis may further support the diagnosis and define other specific types of NHL.91125 However, thoracoscopy remains an important diagnostic means for undiagnosed cases or for providing a definite diagnosis with tissue biopsy. The majority of cases of NHL with pleural effusion belong to the intermediate grade of malignancy, a small proportion belongs to the low grade, and an even smaller proportion belongs to the high-grade group.5626
The effect of the presence of pleural effusion on the prognosis of patients with NHL has not been determined. In patients with intermediate-grade NHL, the presence of pleural effusion at the time of presentation does not seem to have an adverse effect on survival, when appropriately treated.7 Regarding low-grade NHLs, there are conflicting data. In one case-controlled study,7 the evidence of pleural effusion had no effect on remission rate and survival; however, it included only four cases of low-grade NHL. However, in a retrospective study27 of 91 patients with follicular low-grade lymphoma, the presence of pleural fluid adversely influenced survival. In patients with high-grade NHL and pleural effusion, the prognosis is negatively affected.7282930 In a study31 including 57 patients with high-grade NHL of the mediastinum, the presence of pleural effusion was a significant predictor of relapse and survival; 82% of patients with NHL and a pleural effusion relapsed vs 40% of patients with NHL without pleural effusions.
Primary effusion lymphoma (PEL) is a rare but interesting subgroup of lymphoma, initially observed in HIV-positive patients,3233 and characterized by lymphomatous effusions of the pleural, pericardial, or peritoneal cavity in the absence of clinically identifiable tumor masses.3435 This peculiar type of lymphomatous effusion has been recognized as a separate nosologic entity on the basis of its distinct biological features and its association with human herpesvirus 8 (HHV-8) [also termed Kaposi sarcoma-associated herpesvirus].353637 Because of its tropism for the serous cavities of the body, this type of B-cell NHL has been designated body-cavity lymphoma.38394041 Approximately half of the cases of PELs are also associated with Epstein-Barr virus (EBV) infection,3942 implicating the possible synergy of the two viruses in the pathogenesis of the disease.32 However, there have been reports of HIV-negative PELs with HHV-8 but without EBV.43 In these cases, the lymphoma is usually of the non-T, non-B, high-grade malignancy type, while in most other cases it belongs to the intermediate grade.344445 The malignant cells display an immunoblastic morphology,46 indeterminate immunophenotype, clonal immunoglobulin gene rearrangements indicating a B-cell genotype.32 Genetic analysis of the Ig heavy chain gene sequences in PEL cases revealed clonal Ig heavy chain gene rearrangements, inserted HHV-8 sequences, and in many cases inserted EBV DNA sequences.39 In addition, the chromosomal analysis of neoplastic cells showed multiple structural abnormalities.3539
PEL has an aggressive clinical course, with a median survival of only several months.41 In patients with pleural effusions, mainly in HIV-infected patients or the elderly, malignancy should be suspected even in the absence of a clinically identifiable tumor mass.
Pyothorax-associated lymphoma (PAL) is a clinicopathologic entity closely associated with EBV,4748 arising in the pleural cavity of patients with long-standing inflammatory pyothorax. Immunohistochemical procedures revealed that PAL is usually a B-cell lymphoma of diffuse large cells, or of the immunoblastic type.47 The characteristic feature of this disorder is the presence of the EBV genome in all cases of lymphoma cells. Pleural inflammation, especially with tuberculous effusion, is known to produce inflammatory cytokines such as interleukin-6, which might be implicated in lymphomagenesis.49 In another study,50 it was shown that PAL cells produce an immunosuppressive cytokine, interleukin-10, which may contribute to the development of the lymphoma by inducing locally immunosuppressive conditions. The chronic inflammatory stimuli may support the growth of EBV-infected lymphocytes, and the subsequent genetic alterations may lead to malignant transformation of the infected host cells.50 High serum titers against EBV were found in patients with PAL. These antibodies may be useful for monitoring the development of pleural lymphomas in patients with long-standing pyothorax.47 Thus, the administration of an antiviral therapy at an early stage of the disease would be one of the strategies to prevent the development of pleural lymphomas from polyclonal EBV-infected B cells.4751 Although the EBV genome is detectable in lymphoma cells of all PAL cases, HHV-8 is not an obligate pathogen in PAL, as it is not detected in all cases.52
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Castleman Disease
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Another proliferative disease of the lymphatic system, associated with pleural disease, is Castleman disease. This polyclonal lymphadenopathy is also called angiofollicular lymphoid hyperplasia (or giant lymph node hyperplasia) and features three histologic types: hyaline vascular, plasma cell, and intermediate.53 The localized Castleman disease (or type 2) is usually of the hyaline-vascular type, is located in the mediastinum in 70% of cases, and can be cured by surgical excision. Pleural effusions in this type are due to local compression.54 The multicentric Castleman disease (type 1) is usually of the plasma-cell type and may present with systemic symptoms (fever, rash, cytopenia, hypergammaglobulinemia) and extensive lymphadenopathy. This form is common in patients with AIDS. Although it is not primarily a malignancy, it may develop into NHL or in other cases have an aggressive course. HHV-8 is causally associated with the multicentric type of disease. HHV-8 is present in 95% of HIV-positive patients with Castleman disease and 27% of HIV-negative patients with Castleman disease.55 Pleural effusions have been described in multicentric Castleman disease, which in some cases are chylous.5657 The treatment of multicentric Castleman disease includes chemotherapy and corticoids. However, the multicentric form has a poor prognosis, with a mean survival of only 26 months in comparison to nearly 100% 5-year survival in localized Castleman disease.56
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Pleural Effusion in Hodgkin Disease
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Pleural effusions are common in patients with Hodgkin disease (HD). It accompanies approximately 30% of thoracic HD, and it is usually associated with obstructed lymphatic return due to enlarged hilar or mediastinal lymph nodes58 but may be due to direct pleural involvement by the tumor.15859 In HD, nodal spreading is achieved by contiguity and usually involves the superior mediastinum.1 Pulmonary parenchymal disease occurs in 38% of HD, and is invariably associated with mediastinal lymphadenopathy and often with widespread disease.1 Rarely, pleural effusion is the only manifestation of HD localized to the lateral inner thoracic wall as demonstrated by thoracic CT scan, immunohistochemistry of the pleural fluid, and closed needle biopsy.585960 In these cases, it is difficult to explain the early onset of pleural effusion. Probably, localization of HD in the pleura may interfere with pleural lymphatic drainage and lead to consequent effusion.58 Once again, pleural fluid cytology and thoracoscopy are helpful diagnostic modalities to delineate the cause in Hodgkin pleural effusions. The effusion usually responds to conventional chemotherapy.
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Postradiation Pleural Effusion
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Radiation therapy of the thorax is common in patients with lymphoma. These patients may occasionally acquire pneumonitis, pleuritis, or pericarditis after treatment.61 Pleural effusion, as a complication of radiation therapy, can be produced by two mechanisms: radiation pleuritis or lymphatic obstruction from mediastinal fibrosis.616263 Resolution of the pleural effusion may occur either with steroids or spontaneously.64 Pleural effusion secondary to radiation pleuritis is usually observed within 6 months following completion of radiotherapy, although some cases may occur after several years following intensive mediastinal radiation.5863 A late complication of thoracic irradiation is the development of chylothorax. This is caused by irradiation-induced fibrosis and occlusion of thoracic lymph vessels, and alterations in lymphatic flow that can lead to lymph leakage.6566 Postradiation pleural effusion has been reported to be successfully treated with thoracoscopic talc pleurodesis. Thoracoscopic talc pleurodesis has an overall success rate of 90% in pleural effusion (including malignant or nonmalignant causes).67 It is also effective in the treatment of chylothorax.68 When thoracoscopy is avoided, talc slurry can be administered with a slightly lower success rate (87%).67 Chemical pleurodesis is a therapeutic option not only in radiation pleuritis but also in cases of refractory or recurrent pleural effusions or in patients with contraindications (advanced age, frail clinical condition) to chemotherapy.
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Pleural Effusion in Acute Lymphocytic or Myeloid Leukemia and Hairy-Cell or Plasmacytic Leukemia
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Although pleural infiltration with malignant cells in the acute leukemias is rarely diagnosed during life, it is a common finding at autopsy.69 The presence of leukemic infiltrates in other tissues in patients with acute leukemias were found at autopsy in 10 of 15 patients who died of an unrelated cause, during complete bone marrow remission.69707172 However, isolated extramedullary sites of relapse, such as the pleura, may occur accompanying marrow involvement.6970 As the frequency of long-term survival in patients with acute leukemias is increasing, unusual sites of relapse are now being more commonly recognized.707172 The CNS and the testes have long been recognized as the most common sites of extramedullary presentation of acute leukemia.6973 Leukemic infiltration of the lungs may occur as a part of a systemic relapse or rarely as an isolated pulmonary leukemic infiltration. Most cases reported in the literature concern acute lymphocytic leukemia and very few cases of acute nonlymphocytic leukemia. Possible pathogenetic mechanisms suggested include an extramedullary proliferation of a quiescent leukemic clone with subsequent metastasis to the bone marrow or, alternatively, a subclinical marrow relapse, undetected by standard methods with consequent seeding to extramedullary sites.69 Rarely, hairy-cell leukemia and plasma-cell leukemia may present with pleural effusions with typical leukemic cells in the fluid.7475 In leukemic patients, the possibility of other causes responsible for the presence of the pleural effusion such as bacterial or viral infections, other disseminated solid tumors, or complications of chemotherapy should be excluded.767778
Immunocytologic examination of cells obtained from the pleural effusion, flow cytometry, as well as polymerase chain reaction applied to cytology specimens can contribute to the differential diagnosis. The obtained findings sometimes need to be confirmed by pleuroscopy or thoracoscopy with surgical biopsy.7879
The prognostic significance of the presence of a pleural effusion at diagnosis in patients with acute leukemia is not easy to determine. Some authors sustain that it does not affect the rate of remission and survival. Others report a worse prognosis, especially in patients with plasmacytic and hairy cell leukemia. The finding of plasmacellular exudates must be considered as a sign of a very poor prognosis, and very aggressive treatment is indicated.747580
The pleural effusion in patients with acute leukemia usually disappears after induction chemotherapy. This results in direct improvement of symptoms. However, recurrence of pleural exudates is almost inevitable if patients do not achieve remission; they may then present with respiratory failure due to massive fluid accumulation. In this circumstance, treatment or palliation of pleural disease by intrapleural chemotherapy or chemical sclerosis is impeded.7681
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Pleural Effusion in Chronic Leukemias
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In chronic lymphocytic leukemia (CLL), apart from mediastinal adenopathy, involvement of the thorax is uncommon, consisting of pulmonary infiltrates and pleural effusion.82 The presence of pulmonary infiltrates may predispose to the transformation to a more aggressive lymphoid neoplasm such as Richter syndrome or prolymphocytic transformation.83 When the effusion is the result of leukemic pleural infiltration, the fluid may be hemorrhagic and contains numerous lymphocytes identical to those in the blood and bone marrow.84 Once again, the differential diagnosis of a pleural effusion in a patient with CLL includes infection, primary pleural involvement, central lymphatic obstruction, pleural infiltration by other neoplasias, and changes induced by previous irradiation or chemotherapy.8485 There are several cytologic, histologic, and immunologic methods that can be used to determine the etiology of the pleural effusion.828586 In pleural effusions due to infiltration of CLL, the lymphocytes are predominantly B cells, while in pleural effusions due to other causes, such as tuberculosis and pulmonary emboli, the lymphocytes are predominantly T cells.8485 In most reactive pleural effusions, T cells predominate and a small proportion of polyclonal B cells may be found.82 A high proportion of T cells, with monoclonal T-cell receptor rearrangements, may be found in T-cell neoplasms.86 The study of clonality and immunocytochemistry can help provide a definite diagnosis especially in cases of B-cell CLL with a predominance of reactive T lymphocytes in the pleural effusion, which may be complicated by tuberculosis, lung cancer, and central lymphatic obstruction due to mediastinal lymphadenopathy.8687
Patients with pleural involvement by CLL usually have a long-standing diagnosis of CLL before the pleural effusion develops.84 If malignancy or tuberculosis is suspected in a patient with CLL and a pleural effusion, pleural biopsy or thoracoscopy should be the main diagnostic procedures in order to differentiate tuberculosis from a neoplastic lymphocytic pleural infiltration.8487
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Pleural Effusion in Chronic Myelocytic Leukemia
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Serous effusions due to disease infiltration in myeloproliferative disorders, such as chronic myelocytic leukemia (CML), have been reported in various case reports throughout the literature.8889 In these cases, the predominant cells in the pleural fluid are mature and immature granulocytes, monocytes, and variable numbers of blasts.88 The fluid is usually hemorrhagic. Pleural infiltration in CML sometimes appears shortly before transformation to acute leukemia, and in theses cases the pleural fluid contains a greater proportion of blast cells.8890 Leukocyte alkaline phosphatase (LAP) activity, known to be low in CML granulocytes of peripheral blood, has been reported to be normal in the granulocytes of the pleural effusion. LAP-negative circulating granulocytes of these patients with CML were incubated with the pleural liquid, and after 40 to 70 h almost all were intensely LAP positive. This finding suggests that a low LAP activity score in resting CML neutrophils is attributable to the absence of the appropriate stimuli rather than incapacity to synthesize the enzyme.91 Additionally, in Philadelphia chromosome-positive cases, the Philadelphia chromosome is detected in the pleural granulocytic cells by conventional cytogenetic methods.8889
Another cause of pleural effusion in CML is extramedullary hemopoiesis, although the pleura are rarely a site in these patients.8890 Possible obstruction of pleural capillaries or infiltration of interstitial tissue by leukemic cells during uncontrolled leukocytosis and increased capillary permeability due to cytokine production may be other responsible mechanisms for the development of pleural effusions in these patients.92
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Pleural Effusion in Other Chronic Myeloproliferative Diseases
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Other chronic malignant conditions of the hemopoietic system may be associated with pleural effusions. Such conditions include systemic mastocytosis, chronic eosinophilic leukemia, myelofibrosis, and polycythemia vera. The effusions in these patients are due to infiltration of the pleura at the stage of leukemic transformation or are reactive with the presence of macrophages, mesothelial cells, and T lymphocytes.909394
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Pleural Effusion in Myelodysplastic Syndromes
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The presence of a pleural effusion in myelodysplastic syndromes (MDS) is rare and, as in other hemopoietic diseases, is usually a consequence of infection. A pleural effusion, secondary to leukemic infiltration, is a rare initial manifestation in patients with MDS.9596 The presence of extramedullary disease in MDS has been well documented only in cases of chronic myelomonocytic leukemia with disease progression, in which leukemic infiltration can occur in any organ.96 In patients with chronic myelomonocytic leukemia, pleural effusion, and lymphadenopathy, cytologic examination of the pleural fluid and lymph node biopsy usually show leukemic infiltration.9697
Previous reports have described hematologic improvement and effective resolution of pleural effusions in patients with MDS following conventional doses of steroids9298 or a combination of steroids and chemotherapy.99 In another study,100 a case of refractory anemia with pericardial and pleural effusions responded to steroid treatment. Immunologic abnormalities are frequently seen during the clinical course of MDS.101 They are attributed to defective B-, T-, and natural killer-cell function. Increased or decreased levels of Igs and monoclonal gammopathy may be found in patients with MDS.102103 Pulmonary disorders such as vasculitis or eosinophilic infiltration complicated by pleural effusion may present another cause of morbidity and mortality in these patients.979899
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Pleural Effusions in Multiple Myeloma
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Multiple myeloma (MM) is a malignant proliferation of plasma cells that usually invades the bone marrow, but may involve other areas as well. Involvement of the thorax may occur, producing thoracic skeletal lesions, plasmacytomas (both intramedullary and extramedullary), pulmonary infiltrates, and pleural effusions (myelomatous and nonmyelomatous).104105
Pleural effusions occur in approximately 6% of patients with myeloma. The etiology is multifactorial, and effusions due to pleural myelomatous involvement are rare, occurring in < 1% of cases.106 Furthermore, a pleural effusion in MM may be due to nephrotic syndrome, pulmonary embolism, congestive heart failure secondary to amyloidosis, secondary neoplasms and infiltration by myeloma cells from adjacent skeletal or parenchymal locations, direct implantation of plasma cells on the pleura, and mediastinal lymph node infiltration with lymphatic obstruction.104105107
In the literature, 80% of myelomatous pleural effusions are due to the IgA type perhaps as a result of its major tendency to invade extraosseus structures.105106 Diagnostic criteria to confirm the myelomatous etiology are the demonstration of the monoclonal protein in pleural fluid electrophoresis (which is identical to that identified in the serum of the patients), detection of typical plasma cells in pleural fluid cytology, and histologic confirmation using a pleural biopsy specimen.105108109 Extramedullary plasmacytoma is a rare type of tumor, comprising approximately 4 to 6% of plasma-cell malignancies.104110 Few cases have been described arising from the mediastinum.110 The mediastinal location of extramedullary plasmacytoma and the extension to pleural spaces may be a cause of a pleural effusion. A case report111 described a case of extramedullary plasmacytoma of the lung with metastasis to the other lung and pleural effusion.
A well-recognized complication of MM is amyloidosis. In rare cases where amyloidosis involves the pleura, effusions with transudative or exudative features may develop. The diagnosis of pleural amyloidosis by biopsy is important because it is usually refractory to conventional treatment and may necessitate pleurodesis.112 A substantial number of patients with pulmonary amyloidosis associated with systemic amyloidosis also have MM. In a retrospective study113 with biopsy-proven pulmonary amyloidosis in 35 patients with systemic amyloidosis, 5 (14%) were found to have associated MM.
Waldenström macroglobulinemia is a rare lymphoproliferative disorder of insidious onset associated with a monoclonal increase in the serum level of IgM. Pulmonary involvement in Waldenström macroglobulinemia is relatively rare and occurs in 3 to 5% of the cases,114 but may present with pulmonary masses, nodules, diffuse infiltrates, or pleural effusions. In rare cases of pleural involvement, lymphoid and plasmatocytoid cells are found in the effusion and monoclonal IgM in the cell-free fluid.115
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Pleural Effusion in Bone Marrow Transplantation
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Pleural effusions and other noninfectious pulmonary complications have been reported in 10 to 39% of patients following transplantation,116117118 but most studies have not identified the cause of these effusions. Pleural effusion may accompany various serious and potentially life-threatening complications occurring in approximately one third of all patients after bone marrow transplantation (BMT).119 It may result from an infectious process,116120 veno-occlusive disease,117 granulocyte/macrophage colony-stimulating factor toxicity,121 acute and/or chronic graft-vs-host disease (GVHD),117118 and recurrence of the initial disease.117 In these latter cases, CD8+/human leukocyte antigen-DR–positive lymphocytes with CD57 expression predominate in the fluid.120 Other authors122123 observed a high incidence of pleural effusions after conditioning with a conventional dose of cyclophosphamide and total-body irradiation. In patients with extensive chronic GVHD, isolated effusions have been reported.124 In these cases, the term serositis has been used to describe sterile pleural and pericardial effusions in patients with extensive untreated chronic GVHD.120124
A distinguishable entity called posttransplantation lymphoproliferative disorder (PTLD) has been associated with the reactivation of EBV or cytomegalovirus infection. This disorder develops early after BMT and behaves as a rapidly progressive disease.120 PTLD includes a spectrum of lymphoid proliferations, ranging from a benign reactive lymphoid hyperplasia to a high-grade NHL.120125 The majority of these disorders are of the B-cell phenotype. PTLDs with a T or null phenotype have been reported occasionally.126127128 It is a serious and sometimes fatal complication in these patients, and probably results from early deficiency in EBV or cytomegalovirus-specific cytotoxic T cells.129130
In addition to GVHD and infections, a capillary leak syndrome occurs frequently in BMT patients.131 The underlying pathophysiology is poorly understood, but the clinical manifestations of excessive weight gain, ascites, pleural effusion, fever, rash, hypotension, and edema associated with kidney and liver abnormalities suggest a common injury to multiple organs.131132 The onset of the syndrome occurs in the first weeks after transplantation. The generalized endothelial damage is initiated by the chemo/radiotherapy conditioning regimens and occurs in both allogeneic and autologous transplant recipients. This disorder is enhanced by mediators derived from leukocytes and endothelial cells.131133134
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Conclusion
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Patients with hematologic malignancies may occasionally acquire pleural effusions. This is most frequent in patients with lymphomas, as the thorax is a common site of primary disease involvement. Pleural fluid cytology or pleural biopsy provides the diagnosis in approximately half of these patients. In the cases of lymphomatous exudates, cytometry and immunophenotyping of the pleural fluid categorizes the lymphoproliferative disease, if present, and helps differentiate them from reactive or tuberculosis-associated effusions. Thoracoscopy (medical or video-assisted thoracoscopic surgery) is a useful diagnostic modality for difficult cases and for the definite diagnosis of a lymphoma, due to the ability to biopsy. EBV is implicated in the pathogenesis of pyothorax-associated lymphoma, whereas HHV-8 is associated with the development of primary effusion lymphoma and Castleman disease. Acute and chronic leukemias are occasionally accompanied by pleural effusions due to infiltration of the pleura by leukemic cells. However, patients with a known hematologic malignancy may acquire a pleural effusion due to lymphatic obstruction, disease extension, infections, or other malignancies. Treatment-associated toxicities may result in pleural effusions such as antineoplastic drugs, radiation, and BMT. Treatment of the primary disease usually improves the pleural effusion; however, in refractory cases pleurodesis may be considered.
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Footnotes
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Abbreviations: BMT = bone marrow transplantation; CLL = chronic lymphocytic leukemia; CML = chronic myelocytic leukemia; EBV = Epstein-Barr virus; GVHD = graft-vs-host disease; HD = Hodgkin disease; HHV-8 = human herpesvirus 8; LAP = leukocyte alkaline phosphatase; MDS = myelodysplastic syndromes; MM = multiple myeloma; NHL = non-Hodgkin lymphoma; PAL = pyothorax-associated lymphoma; PEL = primary effusion lymphoma; PTLD = posttransplantation lymphoproliferative disorder
Received for publication January 10, 2003.
Accepted for publication June 27, 2003.
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Abstract
Introduction
