[ Chest Imaging and Pathology for Clinicians ]

A Man With Pleural Effusion and Ascites

Andrew Li, MBBS; Limei Poon, MBBS; Kay-Leong Khoo, MD, FCCP; Ju-Ee Seet, MBBCh;
Arvind Kumar Sinha, MBBS, EBNM; and Pyng Lee, MD, FCCP

A male lifelong nonsmoker aged 58 years with no prior asbestos exposure complained of
gradual worsening breathlessness over 3 months. This was associated with abdominal and leg
swelling and a 2-kg weight loss. He had no fever, night sweats, hemoptysis, joint pain, rash,
abdominal pain, chest pain, or orthopnea. The patient had no recent travel or contact with
pulmonary TB. He had stage I left-side testicular seminoma treated with left-sided radical
orchidectomy 10 years previous and recently received a diagnosis of Child’s B alcoholic liver
cirrhosis. His hepatitis B and C screen result was normal. CHEST 2015; 147(6):e208-e214

Clinical examination revealed slight pallor, reduced air was 5.8 mg/L (normal range , 15.0 mg/L), b-human
entry over the right-side hemithorax, abdominal chorionic gonadotropin level was , 2.4 IU/L (normal
distension, shifting dullness, and leg edema. There was range , 6.1 IU/L), and b2-microglobulin (B2M) level
no jaundice, finger clubbing, lymphadenopathy, or
hepatosplenomegaly. The patient’s right-side testicle
was not enlarged, and his oxygen saturation was
90% on room air, which improved to 96% on 2 L/min
supplemental oxygen administered intranasally. His
BP was 146/88 mm Hg and heart rate 92 beats/min.
There was no evidence of autoimmune disease.
The patient’s chest radiograph (Fig 1) showed a massive
right-sided pleural effusion with contralateral mediastinal
shift. Thoracocentesis revealed moderately blood-stained
exudative lymphocytic pleural effusion. Pleural fluid level
of lactate dehydrogenase exceeded 11,000 U/L (pH 7.0),
and adenosine deaminase (ADA) level was 250 U/L.
Bacterial and mycobacterial cultures of the pleural fluid
were negative. Chest, abdomen, and pelvis CT scan (Fig 2)
confirmed the presence of right-sided pleural effusion
and ascites without hepatosplenomegaly, lymphadenop- Figure 1 – Chest radiography revealed a massive right-sided pleural
athy, or left-sided lung infiltrates. a-Fetoprotein level effusion with contralateral mediastinal shift.

Manuscript received September 11, 2014; revision accepted January 12,
2015.
AFFILIATIONS: From the Division of Respiratory and Critical Care
Medicine (Drs Li, Khoo, and Lee), Department of Pathology (Dr Seet),
and Department of Diagnostic-Imaging (Dr Sinha), National Univer-
sity Hospital, Singapore; and Department of Haematology-Oncology
(Dr Poon), National University Cancer Institute of Singapore, Singapore.
CORRESPONDENCE TO: Andrew Li, MBBS, Division of Respiratory and
Critical Care Medicine, National University Hospital, NUHS Tower
Block, Level 10, 1E Kent Ridge Rd, Singapore 119228; e-mail: andrew_
yunkai_li@nuhs.edu.sg
© 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of
this article is prohibited without written permission from the American
College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.14-2237

e208 Chest Imaging and Pathology for Clinicians [ 147#6 CHEST JUNE 2015 ]
 Figure 2 – A, B, CT imaging of the
thorax, abdomen, and pelvis revealed
a massive right-sided pleural effusion
(black arrow) with contralateral
mediastinal shift and ascites (white
arrow). No hepatosplenomegaly,
lymphadenopathy, or left-sided lung
infiltrates were seen.

Figure 3 – A, Image of ascitic fluid

cytology preparation showing large
malignant lymphoid cells (Hemacolor,
original magnification 3 400).
B, CD20 immunohistochemistry
done on cell block preparation of the
same ascitic fluid sample (original
magnification 3 400).

Figure 4 – PET/CT imaging showed 18F-fluorodeoxyglucose uptake by

parietal pleura (white arrowhead) with surrounding ascites (yellow
arrowhead) and pleural effusion (red arrowhead).

journal.publications.chestnet.org e209
was 4.9 mg/L (normal range , 1.9 mg/L). Abdominal
tap was also performed. Pleural and peritoneal fluid
cytology revealed large lymphoid cells with irregular
vesicular nuclei, coarse chromatin, and several
prominent nucleoli that stained positive for CD20
(Fig 3) and CD79A with k-restriction. PET/CT scan
showed 18F-fluorodeoxyglucose (FDG) uptake by the
parietal pleura and peritoneum (Fig 4). The bone
marrow biopsy (BMB) specimen was unremarkable.
Polymerase chain reaction tests for HIV antibody,
pleural fluid human herpesvirus 8 (HHV8), and
Epstein-Barr encoding region in situ hybridization
were negative.

What is the diagnosis?

e210 Chest Imaging and Pathology for Clinicians [ 147#6 CHEST JUNE 2015 ]

Diagnosis: HHV8-negative primary effusion
lymphoma
Discussion
Clinical Discussion
Malignant pleural effusion due to lymphoma occurs
in 20% of patients with lymphoma.1 Other thoracic
manifestations include mediastinal lymphadenopathy,
pulmonary infiltrates, consolidation, masses, pleural
thickening, and chylothorax. Primary pleural involve-
ment is rare,2 and primary effusion lymphoma (PEL)
and pyothorax-associated lymphoma (PAL) are two
well-described clinical entities (Table 1).3-5 PAL is a
differential diagnosis,4 but the lack of pyothorax and the
absence of TB in the present patient precluded PAL.
PEL is a non-Hodgkin’s lymphoma (NHL) subtype first
described in 19956 and is frequently associated with HIV
and HHV8 infections, although it occurs in 0.3% of
patients without HIV.7 PEL can involve the pericardium
and peritoneum.8 In contrast, patients with HIV/HHV8-
negative PEL are older (74 years) compared with those
with HIV/HHV8-positive PEL (44 years).9 In addition,
patients with HHV8-negative PEL tend to show a better
survival median of 11 months compared with 4 to
6 months for patients with HIV/HHV8-positive PEL.5
HHV8 is postulated to trigger oncogenic properties in
patients with HIV-positive PEL. In a case series of patients
with HIV/HHV8-negative PEL,9 no other form of
immunodeficiency apart from a patient with common
variable immunodeficiency could be identified. Epstein-
Barr virus and hepatitis C virus are plausible agents
associated with PEL.
TABLE 1 ] Clinical Characteristics of PEL and PAL
Underlying Etiology Initial Presentation
PEL
Presence of HIV Body cavity lymphoma
(AIDS-defining illness) Effusions
Immunosuppression
Presence of HHV8
Presence of EBV
Associated with hepatitis C
PAL
Pyothorax associated in Pleural thickening
patients with TB Pleural mass
Artificial pneumothorax
Presence of EBV
EBV 5 Epstein-Barr virus; HHV8 5 human herpesvirus 8; PAL 5 pyothorax-associated lymphoma; PEL 5 pleural effusion lymphoma.
journal.publications.chestnet.org
Pleural and peritoneal fluid analyses as well as radiologic
imaging are essential for diagnosis. Differentials as
elaborated in Table 2 must be considered if pleural
effusion and ascites occur together.10,11 A raised pleural
fluid level of ADA . 50 U/L has a 91% sensitivity
and 80% specificity for TB pleuritis. However, raised
ADA levels have also been observed in malignancies of
hematologic origin, bacterial infections, empyemas,
collagen vascular disease, and rheumatoid arthritis
(Table 3).12 Lymphocyte-to-neutrophil ratio (L/N) . 0.75,
when added to an ADA level . 50 U/L, improves the
specificity for TB pleuritis to 95%. L/N could be applied
to discriminate bacterial parapneumonic effusion,
empyema, and rheumatoid arthritis from TB pleuritis
because these conditions usually have an L/N , 0.75.12
Malignant pleural effusions generally have lower ADA
levels. On the other hand, effusions due to lymphomas
and leukemias could be confused with TB pleuritis
because they not only have ADA levels . 50 U/L
but also have an L/N . 0.75. This was demonstrated in
the present patient with a pleural fluid ADA level of
250 U/L and an L/N of 4.
B2M is synthesized by nucleated cells and forms the
light-chain subunit of the major histocompatibility
complex class I antigen. An elevated serum level of
B2M has been shown to be an independent predictive
and prognostic marker in patients with aggressive
lymphoma, correlating with response, duration of
remission, and overall survival. Investigators have identi-
fied a cutoff level of 3 mg/L for patients with aggressive
lymphoma13; the present patient’s serum level was
4.9 mg/L. Elevated serum B2M is also encountered in
multiple myeloma, monoclonal gammopathy, leukemia,
dialysis-related amyloidosis, secondary amyloidosis
Types and Grade of Lymphoma 5-y Overall Survival Range
Usually high-grade mature , 6 mo with poor response
B-cell lymphoma to chemotherapy
Usually high-grade mature 20%-35%; with chemotherapy,
B-cell lymphoma may improve up to 50%
e211
TABLE 2 ] Differential Diagnosis of Pleural Effusions and Ascites
Differential Diagnosis Clinical Features Pleural Fluid Features

TB Chronic cough, hemoptysis, weight loss, ADA . 70 U/L

night sweats
History of TB exposure
Subphrenic, hepatic, or splenic Fever, abdominal pain radiating to the
abscess shoulder tip, chills, cough, dyspnea
Pancreatitis Fever, epigastric pain radiating to the
back, vomiting
Pleural effusion with pancreatitis, which
denotes more-severe disease and an
increased likelihood of pseudocyst
formation
Asbestos/mesothelioma Usually asymptomatic
May have pleuritic chest pain, dyspnea,
cough, weight loss
History of asbestos exposure with prolonged
latency . 15 y
Lymphoma, ie, PEL Lymphadenopathy and hepatosplenomegaly
May present incidentally or with weight loss,
breathlessness, easy bruising, recurrent
infections
Meig syndrome Triad of pleural effusion, ascites, and benign
ovarian cancer
Chylothorax Possible causes include chylous ascites,
lymphangioleiomyomatosis, lymphoma
Congestive heart failure with Exertional dyspnea, orthopnea, PND,
frusemide lower-limb swelling
Hepatic hydrothorax and ascites History of liver cirrhosis
May present with ascites and exertional
dyspnea
Systemic lupus erythematosus Can present with pleuritis (involving both
peritoneum and pleura) with pleural
effusion and ascites
Usually pleural effusions are small and
bilateral
Lymphocytic, exudative
Lymphocyte:neutrophil . 0.75 if ADA
40-50 U/L
Neutrophilic, exudative
Positive fluid culture
Exudative
Pleural fluid/serum amylase . 1
Elevation of pancreatic amylase
isoenzyme
Exudative with nonspecific high cell
counts (may be monocyte
predominant) and LDH
Pleural fluid cytology sensitivity low
Thoracoscopy is the best method for
diagnosis
Lymphocyte or monocyte predominant,
exudative
Positive pleural fluid cytology
ADA level usually , 36 U/L
May present with chylothorax
Usually transudative, but can be
exudative
May have reactive mesothelial cells
Negative cytology
Milky, turbid fluid with . 50%
lymphocytes
Triglyceride levels . 1.24 mmol/L with
chylomicrons, absent cholesterol
crystals, and low cholesterol levels
Usually transudative but can appear
exudative due to frusemide
Can be reclassified if serum-effusion
albumin gradient . 1.2 g/dL
NT-proBNP . 1,500 pg/mL
Transudative with alkaline pH and
normal glucose levels
Despite diuretics, rarely will convert
into protein-discordant exudative
effusion
Even with spontaneous bacterial
pleuritis, may still remain
transudative; a high ANC is the
early indicator of spontaneous
bacterial pleuritis
Chest radiograph usually shows
unilateral right-sided pleural
effusion
Elevated pleural fluid ANA level
Increased pleural fluid/serum ANA
ratio (may also be seen in MPE)

ADA 5 adenosine deaminase; ANA 5 antinuclear antibody; ANC 5 absolute neutrophil count; LDH 5 lactate dehydrogenase; MPE 5 malignant pleural
effusion; NT-proBNP 5 N-terminal pro-brain natriuretic peptide; PND 5 paroxysmal nocturnal dyspnea. See Table 1 legend for expansion of other
abbreviation.

e212 Chest Imaging and Pathology for Clinicians [ 147#6 CHEST JUNE 2015 ]
TABLE 3 ] Differential Diagnosis of Raised ADA Levels
Infective Rheumatology Malignancy
TB Rheumatoid pleuritis Mesothelioma
Legionella Systemic lupus Chronic lymphatic
erythematosus leukemia
Empyema Lymphoma
Brucellosis/
Q fever
See Table 2 legend for expansion of abbreviation.
from chronic infections and autoimmune diseases,
chronic active hepatitis, alcoholic liver cirrhosis, and
hyperthyroidism.
There is no treatment consensus for PEL, and chemo-
therapy comprising cyclophosphamide, doxorubicin,
vincristine, and prednisolone is the mainstay of
therapy.9 Novel approaches such as antiviral therapy
and targeted cellular therapies are still under clinical
evaluation.4
Radiologic Discussion
Enlarged mediastinal lymph nodes are typical CT scan
findings of lymphoma, which can extend to the surrounding
lung parenchyma, mediastinum, and chest wall. Pulmo-
nary nodules, consolidation, and pleural masses and
effusion can be associated with lymphadenopathy.14 PEL,
on the other hand, is a unique entity that manifests only
as serositis.8
PET/CT imaging identifies areas of increased FDG
uptake from lymphomatous involvement that are not
evident on CT scan alone.14 The present patient’s
PET/CT scan revealed enhancement of the pleura and
peritoneum without lymph node involvement, which
further supports the diagnosis of PEL. Other differentials
for FDG uptake by both peritoneum and pleura include
TB pleurisy and mesothelioma with peritoneal spread.
PET/CT imaging is emerging as a staging modality for
lymphomas because of its high sensitivity in detecting
extranodal involvement. It can also aid in disease
prognostication and assessment of treatment response.14
BMB is an invasive procedure required for staging,
especially for low-grade indolent lymphomas. However,
patchy bone marrow involvement can be observed in
NHL, which may lead to sampling error and understag-
ing.15 Khan et al16 reported 40% sensitivity and 100%
specificity with BMB for NHL, and other studies explored
the feasibility of replacing BMB with PET/CT imaging.
A number of studies have demonstrated high sensi-
tivity and specificity with PET scan for marrow
journal.publications.chestnet.org
infiltration by diffuse large B-cell lymphoma.15
Although PET/CT imaging may potentially replace
BMB in the future for some subtypes of lymphoma, large
prospective validation trials are eagerly awaited.
Pathologic Discussion
HHV8-negative PEL express B-cell antigens (CD20,
CD79A, CD22, PAX5/BSAP), surface and cytoplasmic
immunoglobins, but absent CD138.9 Pleural and perito-
neal fluid in the present patient showed large mature
B cells that bore similar morphology to diffuse large
B-cell lymphoma and expressed CD20 and CD79A
without CD138.
Because pleural fluid specimens harbor degenerate
lymphoid cells or cells indistinguishable from reactive
lymphocytes, diagnostic yield from pleural fluid is low
at 30%.17,18 Immunocytochemistry and phenotyping
have helped to further increase the yield by 8% to
16%,18 and novel techniques such as morphometry and
chromosomal analysis have reported diagnostic yields
of 80% but would require clinical validation. Closed
pleural biopsy has a poor yield at 40% that markedly
increases to 75% when guided by imaging.18,19
The role of thoracoscopy in lymphoma was studied by
Alifano et al20 in 17 patients suspected of lymphomatous
pleural effusions. Diagnostic accuracy conferred by
thoracoscopic pleural biopsy specimens was 82%,
which is superior to other methods described. Because
thoracoscopy can be performed safely under conscious
sedation and local anesthesia,21 it not only expedites the
evaluation of patients with pleural effusions of unclear
etiology with high accuracy but also offers symptom
relief and palliation by fluid drainage and talc pleurode-
sis in patients with advanced thoracic malignancies.
Thoracoscopy was not performed in the present patient
because the diagnosis was made based on pleural and
peritoneal fluid cytology. The chest drain insertion
relieved the patient’s symptoms.
Clinical Course and Outcome
After one cycle of cyclophosphamide, doxorubicin, and
vincristine and a dose of pegylated granulocyte colony-
stimulating factor, acute liver failure developed in the
patient. He died 1 month later.
Conclusions
HIV/HHV8-negative PEL is rare and uniquely presents
as serositis without lymphadenopathy. Diagnosis depends
on the recognition of B cells that express CD20, CD79A,
e213
CD22, and absent CD138. PET/CT scan may be a useful
imaging modality to aid clinicians in the selection of
appropriate sites of the pleura or peritoneum for biopsy
as well as in staging. Thoracoscopy confers high diag-
nostic accuracy and remains the procedure of choice for
the evaluation of patients with pleural effusions of
unclear etiology.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to
CHEST that no potential conflicts of interest exist with any companies/
organizations whose products or services may be discussed in this
article.
Other contributions: CHEST worked with the authors to ensure that
the Journal policies on patient consent to report information were
met.
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[ 147#6 CHEST JUNE 2015 ]