Pleural Effusions in Hematologic

Malignancies
Michael G. Alexandrakis, MD; Freda H. Passam, MD; Despina S. Kyriakou, MD;
and Demosthenes Bouros, MD, FCCP

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.
(CHEST 2004; 125:1546 1555)
Key words: leukemia; lymphoma; pleural fluid; pleural infiltration
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

everyday practice, physicians dealing with

D uring
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.
*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.
Manuscript received January 10, 2003; revision accepted June 27,
2003.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
permissions@chestnet.org).
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@med.duth.gr
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Pleural Effusions in Non-Hodgkin

Lymphoma
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).5,6 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.8,9
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The fluid may appear serous or serosanguineous.

Pleural effusions in lymphomas are usually exudates.10 12 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.14 16 In 12% of the cases of
pleural effusions in NHL, the fluid may be chylous.1,7
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.18,19
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).2,10,21,22
In the cases of reactive pleural effusions, the lymphocytes are small, mature, polyclonal, and predominantly of the T-cell subset.10,23,24 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.9,17
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.9,11,25
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.5,6,26
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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.7,28 30
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,32,33 and characterized by
lymphomatous effusions of the pleural, pericardial,
or peritoneal cavity in the absence of clinically
identifiable tumor masses.34,35 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].3537 Because of its tropism for the serous cavities of the body, this type of
B-cell NHL has been designated body-cavity lymphoma.38 41 Approximately half of the cases of PELs
are also associated with Epstein-Barr virus (EBV)
infection,39,42 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.34,44,45 The
malignant cells display an immunoblastic morphology,46 indeterminate immunophenotype, clonal immunoglobulin gene rearrangements indicating a Bcell 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.35,39
PEL has an aggressive clinical course, with a
median survival of only several months.41 In patients
with pleural effusions, mainly in HIV-infected paCHEST / 125 / 4 / APRIL, 2004

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tients 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,47,48
arising in the pleural cavity of patients with longstanding 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.47,51 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

Castleman Disease
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
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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.56,57 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

Pleural Effusion in Hodgkin Disease

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.1,58,59
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.58 60 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.

Postradiation Pleural Effusion

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.61-63 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 intenReviews

sive mediastinal radiation.58,63 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.65,66
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.

Pleural Effusion in Acute Lymphocytic or

Myeloid Leukemia and Hairy-Cell or
Plasmacytic Leukemia
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.69 72 However,
isolated extramedullary sites of relapse, such as the
pleura, may occur accompanying marrow involvement.69,70 As the frequency of long-term survival in
patients with acute leukemias is increasing, unusual
sites of relapse are now being more commonly
recognized.70 72 The CNS and the testes have long
been recognized as the most common sites of extramedullary presentation of acute leukemia.69,73
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.74,75 In leukemic
patients, the possibility of other causes responsible
for the presence of the pleural effusion such as
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bacterial or viral infections, other disseminated solid

tumors, or complications of chemotherapy should be
excluded.76 78
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.78,79
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.74,75,80
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.76,81

Pleural Effusion in Chronic Leukemias

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.84,85 There
are several cytologic, histologic, and immunologic
methods that can be used to determine the etiology
of the pleural effusion.82,85,86 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.84,85 In
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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.86,87
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.84,87

Pleural Effusion in Chronic Myelocytic

Leukemia
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.88,89 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.88,90 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.88,89
Another cause of pleural effusion in CML is
extramedullary hemopoiesis, although the pleura are
rarely a site in these patients.88,90 Possible obstruction of pleural capillaries or infiltration of interstitial
tissue by leukemic cells during uncontrolled leukocytosis and increased capillary permeability due to
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cytokine production may be other responsible mechanisms for the development of pleural effusions in
these patients.92
Pleural Effusion in Other Chronic
Myeloproliferative Diseases
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.90,93,94
Pleural Effusion in Myelodysplastic
Syndromes
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.95,96 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.96,97
Previous reports have described hematologic improvement and effective resolution of pleural effusions in patients with MDS following conventional
doses of steroids92,98 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.102,103 Pulmonary disorders such as vasculitis or eosinophilic
infiltration complicated by pleural effusion may
present another cause of morbidity and mortality in
these patients.9799
Pleural Effusions in Multiple Myeloma
Multiple myeloma (MM) is a malignant proliferation of plasma cells that usually invades the bone
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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).104,105
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.104,105,107
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.105,106 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.105,108,109 Extramedullary
plasmacytoma is a rare type of tumor, comprising
approximately 4 to 6% of plasma-cell malignancies.104,110 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.
Waldenstro m macroglobulinemia is a rare lymphoproliferative disorder of insidious onset associated with a monoclonal increase in the serum level of
IgM. Pulmonary involvement in Waldenstro m 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 effuwww.chestjournal.org

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sions. In rare cases of pleural involvement, lymphoid

and plasmatocytoid cells are found in the effusion
and monoclonal IgM in the cell-free fluid.115

Pleural Effusion in Bone Marrow

Transplantation
Pleural effusions and other noninfectious pulmonary complications have been reported in 10 to 39%
of patients following transplantation,116 118 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,116,120 veno-occlusive disease,117 granulocyte/macrophage colonystimulating factor toxicity,121 acute and/or chronic
graft-vs-host disease (GVHD),117,118 and recurrence
of the initial disease.117 In these latter cases, CD8/
human leukocyte antigen-DRpositive lymphocytes
with CD57 expression predominate in the fluid.120
Other authors122,123 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.120,124
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.120,125 The majority of
these disorders are of the B-cell phenotype. PTLDs
with a T or null phenotype have been reported
occasionally.126 128 It is a serious and sometimes fatal
complication in these patients, and probably results
from early deficiency in EBV or cytomegalovirusspecific cytotoxic T cells.129,130
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.131,132 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
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1551

both allogeneic and autologous transplant recipients.

This disorder is enhanced by mediators derived from
leukocytes and endothelial cells.131,133,134
Conclusion
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 tuberculosisassociated 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 pyothoraxassociated 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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