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A Man With Pleural Effusion and AscitesA Man With Pleural Effusion and Ascites FREE TO VIEW

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

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 University 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


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(6):e208-e214. doi:10.1378/chest.14-2237
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Published online

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.

Figures in this Article

Clinical examination revealed slight pallor, reduced air entry over the right-side hemithorax, abdominal distension, shifting dullness, and leg edema. There was 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, lymphadenopathy, or left-sided lung infiltrates. α-Fetoprotein level was 5.8 μg/L (normal range < 15.0 μg/L), β-human chorionic gonadotropin level was < 2.4 IU/L (normal range < 6.1 IU/L), and β2-microglobulin (B2M) level 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 κ-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.

Figure Jump LinkFigure 1 –  Chest radiography revealed a massive right-sided pleural effusion with contralateral mediastinal shift.Grahic Jump Location

Figure Jump LinkFigure 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.Grahic Jump Location

Figure Jump LinkFigure 3 –  A, Image of ascitic fluid cytology preparation showing large malignant lymphoid cells (Hemacolor, original magnification × 400). B, CD20 immunohistochemistry done on cell block preparation of the same ascitic fluid sample (original magnification × 400).Grahic Jump Location

Figure Jump LinkFigure 4 –  PET/CT imaging showed 18F-fluorodeoxyglucose uptake by parietal pleura (white arrowhead) with surrounding ascites (yellow arrowhead) and pleural effusion (red arrowhead).Grahic Jump Location
What is the diagnosis?
Diagnosis: HHV8-negative primary effusion lymphoma
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 involvement 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

Table Graphic Jump Location
TABLE 1 ]  Clinical Characteristics of PEL and PAL

EBV = Epstein-Barr virus; HHV8 = human herpesvirus 8; PAL = pyothorax-associated lymphoma; PEL = pleural effusion lymphoma.

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.

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.

Table Graphic Jump Location
TABLE 2 ]  Differential Diagnosis of Pleural Effusions and Ascites

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

Table Graphic Jump Location
TABLE 3 ]  Differential Diagnosis of Raised ADA Levels

See Table 2 legend for expansion of abbreviation.

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 identified 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 from chronic infections and autoimmune diseases, chronic active hepatitis, alcoholic liver cirrhosis, and hyperthyroidism.

There is no treatment consensus for PEL, and chemotherapy 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. Pulmonary 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 understaging.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 sensitivity and specificity with PET scan for marrow 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 peritoneal 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 pleurodesis 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.

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, 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 diagnostic accuracy and remains the procedure of choice for the evaluation of patients with pleural effusions of unclear etiology.

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.

Alexandrakis MG, Passam FH, Kyriakou DS, Bouros D. Pleural effusions in hematologic malignancies. Chest. 2004;125(4):1546-1555. [CrossRef] [PubMed]
 
Vega F, Padula A, Valbuena JR, Stancu M, Jones D, Medeiros LJ. Lymphomas involving the pleura: a clinicopathologic study of 34 cases diagnosed by pleural biopsy. Arch Pathol Lab Med. 2006;130(10):1497-1502. [PubMed]
 
Steiropoulos P, Kouliatsis G, Karpathiou G, Popidou M, Froudarakis ME. Rare cases of primary pleural Hodgkin and non-Hodgkin lymphomas. Respiration. 2009;77(4):459-463. [CrossRef] [PubMed]
 
Chen YB, Rahemtullah A, Hochberg E. Primary effusion lymphoma. Oncologist. 2007;12(5):569-576. [CrossRef] [PubMed]
 
Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.4th ed. Lyon, France: International Agency for Research on Cancer; 2008:245-246, 260-261.
 
Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995;332(18):1186-1191. [CrossRef] [PubMed]
 
Gaidano G, Carbone A. Primary effusion lymphoma: a liquid phase lymphoma of fluid-filled body cavities. Adv Cancer Res. 2001;80:115-146. [PubMed]
 
Castillo JJ, Shum H, Lahijani M, Winer ES, Butera JN. Prognosis in primary effusion lymphoma is associated with the number of body cavities involved. Leuk Lymphoma. 2012;53(12):2378-2382. [CrossRef] [PubMed]
 
Saini N, Hochberg EP, Linden EA, Jha S, Grohs HK, Sohani AR. HHV8-negative primary effusion lymphoma of B-cell lineage: two cases and a comprehensive review of the literature. Case Rep Oncol Med. 2013;2013:292301. [PubMed]
 
Hooper C, Lee YCG, Maskell N; BTS Pleural Guideline Group. Investigation of a unilateral pleural effusion in adults: British Thoracic Society pleural disease guideline 2010. Thorax. 2010;65(suppl 2):ii4-ii17. [CrossRef] [PubMed]
 
Gurung P, Goldblatt M, Huggins JT, Doelken P, Nietert PJ, Sahn SA. Pleural fluid analysis and radiographic, sonographic, and echocardiographic characteristics of hepatic hydrothorax. Chest. 2011;140(2):448-453. [CrossRef] [PubMed]
 
Burgess LJ, Maritz FJ, Le Roux I, Taljaard JJ. Combined use of pleural adenosine deaminase with lymphocyte/neutrophil ratio. Increased specificity for the diagnosis of tuberculous pleuritis. Chest. 1996;109(2):414-419. [CrossRef] [PubMed]
 
Yoo C, Yoon DH, Suh C. Serum beta-2 microglobulin in malignant lymphomas: an old but powerful prognostic factor. Blood Res. 2014;49(3):148-153. [CrossRef] [PubMed]
 
Cronin CG, Swords R, Truong MT, et al. Clinical utility of PET/CT in lymphoma. AJR Am J Roentgenol. 2010;194(1):W91-W103. [CrossRef] [PubMed]
 
El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol. 2012;30(36):4508-4514. [CrossRef] [PubMed]
 
Khan AB, Barrington SF, Mikhaeel NG, et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood. 2013;122(1):61-67. [CrossRef] [PubMed]
 
Bass J, White DA. Thoracentesis in patients with hematologic malignancy: yield and safety. Chest. 2005;127(6):2101-2105. [CrossRef] [PubMed]
 
Das DK. Serous effusions in malignant lymphomas: a review. Diagn Cytopathol. 2006;34(5):335-347. [CrossRef] [PubMed]
 
Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J. 2001;18(2):402-419. [CrossRef] [PubMed]
 
Alifano M, Guggino G, Gentile M, Elia S, Vernaglia A. Management of concurrent pleural effusion in patients with lymphoma: thoracoscopy a useful tool in diagnosis and treatment. Monaldi Arch Chest Dis. 1997;52(4):330-334. [PubMed]
 
Lee P, Colt HG. Pleuroscopy in 2013. Clin Chest Med. 2013;34(1):81-91. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Chest radiography revealed a massive right-sided pleural effusion with contralateral mediastinal shift.Grahic Jump Location
Figure Jump LinkFigure 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.Grahic Jump Location
Figure Jump LinkFigure 3 –  A, Image of ascitic fluid cytology preparation showing large malignant lymphoid cells (Hemacolor, original magnification × 400). B, CD20 immunohistochemistry done on cell block preparation of the same ascitic fluid sample (original magnification × 400).Grahic Jump Location
Figure Jump LinkFigure 4 –  PET/CT imaging showed 18F-fluorodeoxyglucose uptake by parietal pleura (white arrowhead) with surrounding ascites (yellow arrowhead) and pleural effusion (red arrowhead).Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Clinical Characteristics of PEL and PAL

EBV = Epstein-Barr virus; HHV8 = human herpesvirus 8; PAL = pyothorax-associated lymphoma; PEL = pleural effusion lymphoma.

Table Graphic Jump Location
TABLE 2 ]  Differential Diagnosis of Pleural Effusions and Ascites

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

Table Graphic Jump Location
TABLE 3 ]  Differential Diagnosis of Raised ADA Levels

See Table 2 legend for expansion of abbreviation.

References

Alexandrakis MG, Passam FH, Kyriakou DS, Bouros D. Pleural effusions in hematologic malignancies. Chest. 2004;125(4):1546-1555. [CrossRef] [PubMed]
 
Vega F, Padula A, Valbuena JR, Stancu M, Jones D, Medeiros LJ. Lymphomas involving the pleura: a clinicopathologic study of 34 cases diagnosed by pleural biopsy. Arch Pathol Lab Med. 2006;130(10):1497-1502. [PubMed]
 
Steiropoulos P, Kouliatsis G, Karpathiou G, Popidou M, Froudarakis ME. Rare cases of primary pleural Hodgkin and non-Hodgkin lymphomas. Respiration. 2009;77(4):459-463. [CrossRef] [PubMed]
 
Chen YB, Rahemtullah A, Hochberg E. Primary effusion lymphoma. Oncologist. 2007;12(5):569-576. [CrossRef] [PubMed]
 
Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.4th ed. Lyon, France: International Agency for Research on Cancer; 2008:245-246, 260-261.
 
Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995;332(18):1186-1191. [CrossRef] [PubMed]
 
Gaidano G, Carbone A. Primary effusion lymphoma: a liquid phase lymphoma of fluid-filled body cavities. Adv Cancer Res. 2001;80:115-146. [PubMed]
 
Castillo JJ, Shum H, Lahijani M, Winer ES, Butera JN. Prognosis in primary effusion lymphoma is associated with the number of body cavities involved. Leuk Lymphoma. 2012;53(12):2378-2382. [CrossRef] [PubMed]
 
Saini N, Hochberg EP, Linden EA, Jha S, Grohs HK, Sohani AR. HHV8-negative primary effusion lymphoma of B-cell lineage: two cases and a comprehensive review of the literature. Case Rep Oncol Med. 2013;2013:292301. [PubMed]
 
Hooper C, Lee YCG, Maskell N; BTS Pleural Guideline Group. Investigation of a unilateral pleural effusion in adults: British Thoracic Society pleural disease guideline 2010. Thorax. 2010;65(suppl 2):ii4-ii17. [CrossRef] [PubMed]
 
Gurung P, Goldblatt M, Huggins JT, Doelken P, Nietert PJ, Sahn SA. Pleural fluid analysis and radiographic, sonographic, and echocardiographic characteristics of hepatic hydrothorax. Chest. 2011;140(2):448-453. [CrossRef] [PubMed]
 
Burgess LJ, Maritz FJ, Le Roux I, Taljaard JJ. Combined use of pleural adenosine deaminase with lymphocyte/neutrophil ratio. Increased specificity for the diagnosis of tuberculous pleuritis. Chest. 1996;109(2):414-419. [CrossRef] [PubMed]
 
Yoo C, Yoon DH, Suh C. Serum beta-2 microglobulin in malignant lymphomas: an old but powerful prognostic factor. Blood Res. 2014;49(3):148-153. [CrossRef] [PubMed]
 
Cronin CG, Swords R, Truong MT, et al. Clinical utility of PET/CT in lymphoma. AJR Am J Roentgenol. 2010;194(1):W91-W103. [CrossRef] [PubMed]
 
El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol. 2012;30(36):4508-4514. [CrossRef] [PubMed]
 
Khan AB, Barrington SF, Mikhaeel NG, et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood. 2013;122(1):61-67. [CrossRef] [PubMed]
 
Bass J, White DA. Thoracentesis in patients with hematologic malignancy: yield and safety. Chest. 2005;127(6):2101-2105. [CrossRef] [PubMed]
 
Das DK. Serous effusions in malignant lymphomas: a review. Diagn Cytopathol. 2006;34(5):335-347. [CrossRef] [PubMed]
 
Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J. 2001;18(2):402-419. [CrossRef] [PubMed]
 
Alifano M, Guggino G, Gentile M, Elia S, Vernaglia A. Management of concurrent pleural effusion in patients with lymphoma: thoracoscopy a useful tool in diagnosis and treatment. Monaldi Arch Chest Dis. 1997;52(4):330-334. [PubMed]
 
Lee P, Colt HG. Pleuroscopy in 2013. Clin Chest Med. 2013;34(1):81-91. [CrossRef] [PubMed]
 
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