Body Cavity-Based Lymphoma in a Country with Low Human Immunodeficiency Virus Prevalence: A Series of 17 Cases from the Consortium for Improving Survival of Lymphoma.

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Cancer Res Treat. 2019;51(4):1302-1312
pISSN 1598-2998, eISSN 2005-9256
https://doi.org/10.4143/crt.2018.555
Open Access
Body Cavity–Based Lymphoma in a Country with Low Human
Immunodeficiency Virus Prevalence: A Series of 17 Cases from the
Consortium for Improving Survival of Lymphoma
Original Article
Purpose
Primary effusion lymphoma (PEL) is a type of body cavity–based lymphoma (BCBL). Most
patients with PEL are severely immunocompromised and seropositive for human immun-
odeficiency virus (HIV). We investigated the distinctive clinicopathologic characteristics of
BCBL in a country with low HIV burden.
Materials and Methods
We retrospectively collected data on the clinicopathologic characteristics, treatments, and
outcomes of 17 consecutive patients with BCBL at nine institutions in Korea.
Results
Latency-associated nuclear antigen 1 (LANA1) immunostaining indicated that six patients
had PEL, six patients had human herpesvirus 8 (HHV8)–unrelated BCBL, and five patients
had HHV8-unknown BCBL. The patients with PEL exhibited no evidence of immunodefi-
ciency except for one who was HIV positive. One (20%) and four (80%) patients with PEL
and six (100%) and zero (0%) patients with HHV8-unrelated BCBL were positive for CD20
and CD30 expression, respectively. The two patients with PEL (one HIV-positive and one
HIV-negative patient) with the lowest proliferation activity as assessed by the Ki-67 labeling
index survived for > 1 and > 4 years without chemotherapy, respectively, in contrast to the
PEL cases in the literature, which mostly showed a high proliferation index and poor survival.
Conclusion
PEL mostly occurred in ostensibly immunocompetent individuals and had a favorable out-
come in Korea. A watchful waiting approach may be applicable for managing HIV-seroneg-
ative patients with PEL with a low Ki-67 labeling index. A possible trend was detected among
LANA1, CD20, and CD30 expression in BCBL.
Key words
Body cavity-based lymphoma, Primary effusion lymphoma,
Human herpesvirus 8, Human immunodeficiency virus,
Immunophenotype
Junghoon Shin, MD1
Young Hyeh Ko, MD, PhD2
Sung Yong Oh, MD, PhD3
Dok Hyun Yoon, MD, PhD4
Jeong-Ok Lee, MD, PhD5
Jin Seok Kim, MD, PhD6
Yong Park, MD, PhD7
Ho Jin Shin, MD, PhD8
Seok Jin Kim, MD, PhD9
Jong Ho Won, MD, PhD10
Sung-Soo Yoon, MD, PhD1
Won Seog Kim, MD, PhD9
Youngil Koh, MD, PhD1
On behalf of the Consortium for Improving
Survival of Lymphoma investigators
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Correspondence: Won Seog Kim, MD, PhD
Department of Medicine, Samsung Medical
Center, 81 Irwon-ro, Gangnam-gu,
Seoul 06351, Korea
Tel: 82-2-3410-6548
Fax: 82-2-3410-1754
E-mail: wskimsmc@skku.edu
Co-correspondence: Youngil Koh, MD, PhD
Department of Internal Medicine,
Seoul National University Hospital,
101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: 82-2-2072-7217
Fax: 82-2-2072-7379
E-mail: go01@snu.ac.kr
Received October 8, 2018
Accepted January 28, 2019
Published Online February 14, 2019
*A list of author’s aliations appears at the
end of the paper.

VOLUME 51 NUMBER 4 OCTOBER 2019 1303
Introduction
Primary effusion lymphoma (PEL) is a rare subtype of non-
Hodgkin lymphoma (NHL) characterized by lymphomatous
effusions in body cavities with or without extracavitary
tumor formation [1]. Following the discovery of its universal
association with human herpesvirus 8 (HHV8) infection [2],
PEL was established as a distinct clinical entity and incorpo-
rated into the World Health Organization (WHO) classifica-
tion system for lymphoid neoplasms [3,4]. PEL mostly occurs
in patients with human immunodeficiency virus (HIV) infec-
tion [2,4]. In the four largest published series of PEL cases,
each including 11-34 patients with classic (body cavity-
based) PEL, more than 90% of the patients were young-
to-middle-aged males who had HIV risk factors such as
homosexuality or intravenous drug abuse [5-8]. Although
non-HIV–associated PEL has occasionally been observed, the
patients were either elderly ( 78 years of age) or recipients
of an organ transplant, or the disease developed in an artifi-
cial cavity related to a breast implant capsule, suggesting that
systemic or local immunocompromising conditions were
involved in the lymphomagenesis [4,9-11]. On the basis of
those observations, it is considered unusual for PEL to occur
in immunocompetent individuals.
Since the establishment of PEL as a subcategory of NHL,
there have been numerous reports of HHV8-unrelated body
cavity-based lymphoma (BCBL) [12-18], a provisional entity
that does not fulfill the diagnostic criteria of PEL because of
the absence of HHV8 infection in neoplastic cells [3]. HHV8-
unrelated BCBL has a remarkable clinicopathologic similar-
ity to PEL in terms of its effusion-based growth and its large,
pleomorphic, immunoblastic-to-anaplastic cytomorphology
[17,18]; however, it differs from PEL in important aspects: (1)
it commonly affects immunocompetent individuals and
females; (2) the tumor cells often express pan-B-cell markers
including CD19, CD20, and CD79a; and (3) the combination
chemotherapy with or without rituximab shows promising
efficacy, resulting in a better prognosis compared with that
of PEL [16-18]. Therefore, it is important to differentiate
between HHV8-unrelated BCBL and PEL to ensure proper
management and prognostication of patients.
Because HIV/acquired immunodeficiency syndrome
(AIDS) confers significant morbidity and mortality due to
opportunistic infections and various malignancies, HIV-
unrelated PEL may exhibit distinctive clinical features and
have a different prognosis compared with typical HIV-
related PEL. Most, if not all, patients with PEL have been
described in North America and Europe [4-8], whereas
around 60% of patients described with HHV8-unrelated
BCBL are Japanese [16-18]. That remarkable imbalance in
case distribution is in line with the low prevalence of HIV/
AIDS, the strongest risk factor for PEL, in eastern Asia [19].
Given the rarity of HIV/AIDS in eastern Asia, studies of PEL
in patients from that area may provide novel insights into
the nature of the disease.
Here we describe the clinicopathologic characteristics and
outcomes of a series of 17 patients with BCBL in South Korea.
The aim of this study was to identify the distinctive clinico-
pathologic characteristics and outcomes of BCBL in a country
with low HIV burden. To our knowledge, this series repre-
sents the largest collection of novel cases of HIV-unrelated
PEL and the largest Asian BCBL cohort that is independent
of the existing literature.
Materials and Methods
1. Case selection
This retrospective study included all consecutive patients
diagnosed with BCBL from April 2002 to October 2016 at
nine institutions in South Korea. We defined BCBL as NHL
that (1) presented exclusively or predominantly as a malig-
nant effusion with or without extra-cavitary lesions, (2) was
confirmed either by cytological evaluation of the malignant
effusion or by tissue biopsy that revealed cytomorphology
characteristic of PEL, and (3) did not meet the diagnostic cri-
teria for any subtype of NHL other than PEL as per the cur-
rent WHO classification on the basis of the clinical history,
cytomorphology, immunophenotype, and genetic alterations
(e.g., c-myc gene rearrangement in Burkitt lymphoma). We
excluded patients diagnosed with Burkitt or Burkitt-like lym-
phoma, plasmablastic lymphoma, anaplastic large cell lym-
phoma, and pyothorax-associated lymphoma (designated as
‘diffuse large B cell lymphoma associated with chronic
inflammation’ in the 2016 WHO classification) [3].
2. Data collection
We collected the following data for each patient via med-
ical records review: demographics; sites of involved body
cavities and extra-cavitary lesions; performance status; inter-
national prognostic index score; medical histories including
hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV
infections, co-occurring malignancies (e.g., Kaposi’s sar-
coma), multicentric Castleman disease, autoimmune disease,
and iatrogenic immunosuppression such as organ transplan-
tation, immunosuppressant administration, or cytotoxic
chemotherapy; initial laboratory profiles; treatment history;
and outcome. We reviewed pathology reports for all of the
patients to confirm the diagnosis of BCBL and to obtain
Junghoon Shin, Case Series of Body Cavity–Based Lymphoma

Table 1. Clinical characteristics of 17 patients with body cavity–based lymphoma
Case Sex Age at Site of lymphoma HHV8 ECOG IPI Comorbidity Treatmenta) Response to PFS OS
No. diagnosis (yr) involvement at diagnosis PS score chemotherapy (mo) (mo)
1 M 70 Pleural cavity Positive 1 1 Lung cancer 1st-line CHOP PR  6  11
2 M 67 Pleural cavity, Positive 1 4 HBV 1st-line CHOP NA  6  9
bone marrow,
cervical lymph node
3 M 59 Pleural cavity Positive 1 1 HIV No chemotherapy NA  4  14
4 F 78 Pleural cavity Positive 2 4 None No chemotherapy NA 49 49
5 M 87 Pleural cavity Positive 3 NA None No chemotherapy NA  5  6
6 M 60 Pleural cavity, Positive 2 3 None 1st-line CHOP CR followed by PD 28  173
pericardial cavity, 2nd-line ICE  autoHSCT PR
peritoneal cavity
7 F 59 Vitreous body (eyeball) Negative 0 0 HCV 1st-line HD-MTX CR 66 66
8 M 80 Pleural cavity, Negative 3 5 None 1st-line R-CHOP CR  17  17
pericardial cavity
9 M 70 Pericardial cavity Negative 1 3 None 1st-line R-CHOP CR  14  14
10 M 77 Pleural cavity, Negative 2 5 None 1st-line R-CHOP CR  12  12
peritoneal cavity
11 M 83 Pleural cavity Negative 2 4 None 1st-line R-CVP NA  2  2
12 M 75 Pleural cavity, Negative 1 3 None 1st-line R-CHOP CR  46  49
pericardial cavity
13 F 76 Pleural cavity Unknown 2 2 None 1st-line CHOP CR  5  5
14 F 73 Pleural cavity, Unknown 1 4 HBV 1st-line CVP PR 10 10
peritoneal cavity
15 M 86 Pleural cavity Unknown 1 4 None 1st-line R-CVP PR  24  24
16 F 66 Pleural cavity, Unknown 1 4 None 1st-line CHOP CR  99  99
peritoneal cavity
17 F 39 Pleural cavity, Unknown 1 3 None 1st-line R-CHOP CR  123  123
lung
HHV8, human herpesvirus 8; ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, international prognostic index; PFS, progression-free sur-
vival; OS, overall survival; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; PR, partial remission; HBV, hepatitis B virus; NA, not assessed
or not available; HIV, human immunodeficiency virus; ICE, ifosfamide, carboplatin, and etoposide; autoHSCT, autologous hematopoietic stem cell transplantation;
CR, complete remission; PD, progressive disease; HCV, hepatitis C virus; HD-MTX, high-dose methotrexate; R-CHOP, rituximab plus CHOP; CVP, cyclophos-
phamide, vincristine, and prednisolone; R-CVP, rituximab plus CVP. a)Drainage was performed if clinically indicated.
1304 CANCER RESEARCH AND TREATMENT
Cancer Res Treat. 2019;51(4):1302-1312

immunophenotype information. The HHV8 infection status
of lymphoma cells was determined by immunocytochemical
staining for latency-associated nuclear antigen 1 (LANA1)
using mouse anti-HHV8 monoclonal antibodies (Cell Marq,
Hot Springs, AR) and the Ventana BenchMark XT auto-
stainer (Ventana Medical Systems, Tucson, AZ). Coinfection
with Epstein-Barr virus (EBV) was assessed by in situ hybri-
dization for EBV-encoded small RNA (EBER).
3. Statistical analysis
We divided the patients into three groups on the basis of
the LANA1 immunostaining results— those with PEL (LAN-
A1 positive), those with HHV8-unrelated BCBL (LANA1
negative), and those with HHV8-unknown BCBL (not tested
for LANA1 expression)— to describe and compare their clin-
icopathologic characteristics and prognoses. We summarized
the data as medians (ranges) for continuous variables and
numbers (%) for discrete variables. We used the International
Working Group response criteria to assess the response to
treatment [20]. We defined progression-free survival (PFS)
as the time from diagnosis to disease progression or death
from any cause, whichever occurred first. To estimate PFS,
we censored patients who were progression-free and alive at
the time of the last assessment of the disease state. We
defined overall survival (OS) as the time from diag-nosis to
death from any cause. To estimate OS, we censored patients
who were alive at the last follow-up date. We used the
Kaplan-Meier method to estimate the median PFS and OS.
No statistical test was performed because of the small num-
ber of cases.
4. Ethical statement
The Institutional Review Board at each participating insti-
tution reviewed and approved the study protocol (Seoul
National University Hospital Institutional Review Board
approval number: H-1511-051-718). Patient consent was
waived because of the retrospective nature of the study and
lack of patient interaction. We carried out all study proce-
dures including data collection and analyses in accordance
with the ethical standards of the Helsinki Declaration (revi-
sed in 2013; World Medical Association).
Results
1. Clinical characteristics
We identified a total of 17 BCBL cases. LANA1 immunos-
taining results were available for 12 patients, of which six
were positive for LANA1 (indicating PEL) and six were neg-
ative for LANA1 (indicating HHV8-unrelated BCBL). The
demographic and clinical characteristics of the patients are
described in Table 1 and summarized for the entire cohort
and for subgroups based on HHV8 positivity in Table 2. All
of the patients were native Koreans of the Asian race. Diag-
nosis of BCBL was made by cytological evaluation of lym-
phomatous effusion in 12 patients (70.6%) and by tissue
biopsy in the remaining five patients (29.4%)— pleural biopsy
in four patients and cervical lymph node biopsy in one pati-
ent. At the time of diagnosis, four patients with PEL and one
patient with HHV8-unrelated BCBL had B symptoms (fever,
weight loss, or night sweats). The male-to-female ratio was
5:1 in both the PEL cohort and the HHV8-unrelated BCBL
cohort and 1:4 in the HHV8-unknown BCBL cohort. Except
in two patients (one with PEL who had cervical lymph node
and bone marrow lesions and one with HHV8-unknown
BCBL who had a lung lesion, all of which were pathologi-
cally confirmed), BCBL presented exclusively as malignant
effusions involving one or multiple body cavities (Tables 1
and 2). The pleural space was the most frequently involved
body cavity in all three categories of BCBL. Interestingly, one
case of HHV8-unrelated BCBL exclusively involved the vit-
reous body of the eye (case 7) (Table 1).
Only one of the 17 patients with BCBL had HIV infection
(case 3) (Table 1). Except for that patient, no patient had any
apparent history of immunocompromising conditions or
iatrogenic immunosuppression. One patient with PEL and
one patient with HHV8-unknown BCBL were positive for
HBV surface antigen. One patient with HHV8-unrelated
BCBL was positive for anti-HCV antibody; however, a reverse
transcription-polymerase chain reaction assay did not detect
HCV RNA, indicating that the HCV infection was resolved.
None of the patients had any history of Kaposi’s sarcoma,
multicentric Castleman disease, or autoimmune disease.
Blood cell counts were unremarkable for most patients; one
patient who had HBV-related liver cirrhosis showed moder-
ate thrombocytopenia with a platelet count of 66,000/µL at
the time of PEL diagnosis (Table 2).
2. Immunophenotype and EBV status
A representative case of PEL with a characteristic cytomor-
phology and immunohistochemical staining pattern for
LANA1 is shown in Fig. 1. The results of immunophenotypic
VOLUME 51 NUMBER 4 OCTOBER 2019 1305
Junghoon Shin, Case Series of Body Cavity–Based Lymphoma

analysis and in situ hybridization for EBER are shown in
Fig. 2. All six patients with PEL had diffuse and strong pos-
itivity for LANA1. Three of the six patients (50%) with PEL
were positive for EBER, whereas all but one of the patients
(83.3%) with HHV8-unrelated BCBL were negative for EBER.
Of the five patients with PEL who were tested for CD20
expression, one was weakly positive (20%); that patient also
displayed CD79a expression with focal positivity (case 3). In
contrast, all six patients with HHV8-unrelated BCBL were
positive for CD20 expression. In the reports in the literature,
lymphocyte activation markers CD30 and CD38, pan-leuko-
cyte marker CD45, and plasma cell differentiation marker
CD138 are all commonly expressed in patients with PEL [16].
Results for CD30, CD38, CD45, and CD138 were positive in
four of five (80%), two of two (100%), one of three (33.3%),
and four of five (80%) patients with PEL who were tested for
those markers in our study, respectively. In contrast, results
for CD30 and CD138 were negative in three of three (100%)
Table 2. Patient characteristics of the entire cohort and subgroups based on HHV8 positivitya)
Characteristic Entire PEL HHV8-unrelated HHV8-unknown
cohort (n=17) (n=6) BCBL (n=6) BCBL (n=5)
Age at diagnosis (yr) 73 (39-87) 68.5 (59-87) 76 (59-83) 73 (39-86)
Sex
Male 11/17 (64.7) 5/6 (83.3) 5/6 (83.3) 1/5 (20.0)
Female 6/17 (35.3) 1/6 (16.7) 1/6 (16.7) 4/5 (80.0)
Site of lymphoma involvement
Pleural cavity 15/17 (88.2) 6/6 (100) 4/6 (66.7) 5/5 (100)
Pericardial cavity 4/17 (23.5) 1/6 (16.7) 3/6 (50.0) 0/5 (0)
Peritoneal cavity 4/17 (23.5) 1/6 (16.7) 1/6 (16.7) 2/5 (40.0)
Extra-cavitary lesionb) 2/17 (11.8) 1/6 (16.7) 0/6 (0) 1/5 (20.0)
ECOG PS at diagnosis
0-1 10/17 (58.8) 3/6 (50.0) 3/6 (50.0) 4/5 (80.0)
2-4 7/17 (41.2) 3/6 (50.0) 3/6 (50.0) 1/5 (20.0)
IPI risk group
Low (0-1) 3/16 (18.8) 2/5 (40.0) 1/6 (16.7) 0/5 (0)
Low-intermediate (2) 1/16 (6.2) 0/5 (0) 0/6 (0) 1/5 (20.0)
High-intermediate (3) 4/16 (25.0) 1/5 (20.0) 2/6 (33.3) 1/5 (20.0)
High (4-5) 8/16 (50.0) 2/5 (40.0) 3/6 (50.0) 3/5 (60.0)
Comorbidity
HIV 1/17 (5.9) 1/6 (16.7) 0/6 (0) 0/5 (0)
HBV 2/17 (11.8) 1/6 (16.7) 0/6 (0) 1/5 (20.0)
HCV 1/17 (5.9) 0/6 (0) 1/6 (16.7) 0/5 (0)
Co-occurring malignancy 1/17 (5.9)c) 1/6 (16.7)c) 0/6 (0) 0/5 (0)
Laboratory profile at diagnosis
WBC  10,000/µL 3/17 (17.6) 1/6 (16.7) 0/6 (0) 2/5 (40.0)
Hemoglobin < 10 g/dL 4/17 (23.5) 1/6 (16.7) 2/6 (33.3) 1/5 (20.0)
Platelet < (130103)/µL 1/17 (5.9) 1/6 (16.7) 0/6 (0) 0/5 (0)
Serum albumin < 3.5 g/dL 12/17 (70.6) 5/6 (83.3) 5/6 (83.3) 2/5 (40.0)
Serum creatinine  1.5 mg/dL 3/17 (17.6) 1/6 (16.7) 1/6 (16.7) 1/5 (20.0)
LDH above normal 13/16 (81.2) 4/6 (66.7) 4/5 (80.0) 5/5 (100)
2-microglobulin  3.5 mg/dL 5/10 (50.0) 2/4 (50.0) 2/5 (40.0) 1/1 (100)
C-reactive protein  0.8 mg/dL 17/17 (100) 6/6 (100) 6/6 (100) 5/5 (100)
Values are presented as median (range) or number (%). HHV8, human herpesvirus 8; PEL, primary effusion lymphoma;
BCBL, body cavity-based lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, international
prognostic index; HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; WBC, white blood
cell; LDH, lactate dehydrogenase. a)The proportions are calculated as the frequency divided by the total number of evaluable
patients for each characteristic, b)Extra-cavitary lesions were present in one patient with PEL who had both bone-marrow
and cervical lymph-node lesions and one patient with HHV8-unknown BCBL who had a lung lesion, c)Lung cancer.
1306 CANCER RESEARCH AND TREATMENT
Cancer Res Treat. 2019;51(4):1302-1312

and two of two (100%) patients with HHV8-unrelated BCBL
who were tested for those markers, respectively. Results for
multiple myeloma oncogene 1/interferon regulatory factor
4 were positive in six of seven patients tested (85.7%), includ-
ing two patients with PEL, three patients with HHV8-unre-
lated BCBL, and one patient with HHV8-unknown BCBL.
Results for immunoglobulin  and  light chains were nega-
tive in all seven of the patients tested. Among the five pati-
ents with PEL and four patients with HHV8-unrelated BCBL
who were tested for the fraction of Ki-67–positive tumor cells
(Ki-67 labeling index), three with PEL had a Ki-67 labeling
index  40% (cases 3 and 4, 30%; case 1, 40%), indicating a
Fig. 2. Immunophenotypic analysis and in situ hybridization for Epstein-Barr virus–encoded small RNA (EBER). The cases
are presented in the same order as in Table 1. Latency-associated nuclear antigen 1 (LANA1) and EBER are shown in the
first and second columns, respectively, while the remaining markers are arranged in descending order of the number of
cases in which they were analyzed. All markers that were stained in at least one case are shown. Blank tiles indicate that
assays were not performed or data were not available. MUM1, multiple myeloma oncogene 1; IRF4, interferon regulatory
factor 4; , immunoglobulin  light chain; , immunoglobulin  light chain.
Positive
Negative
Marker expression
100
90
80
70
60
50
40
30
Ki-67 labeling index (%)
Case number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
LANA1
EBER
CD20
CD3
CD30
CD45
CD138
MUM1/IRF4
κ
λ
CD79a
Bcl-2
Bcl-6
CD56
Pax5
CD38
c-Myc
CD2
CD19
ki-67
Fig. 1. Lymphoma cells with positive nuclear staining for latency-associated nuclear antigen 1 in the ascitic fluid of a repre-
sentative primary effusion lymphoma patient. (A) Ascites smear exhibits individually scattered tumor cells with an
immunoblastic or plasmablastic cytomorphology. (B) Immunohistochemistry using an antihuman herpesvirus 8 antibody
shows dark brown nuclear staining of tumor cells.
A B
VOLUME 51 NUMBER 4 OCTOBER 2019 1307
Junghoon Shin, Case Series of Body Cavity–Based Lymphoma

low proliferative activity and indolent disease, whereas all
four with HHV8-unrelated BCBL had a Ki-67 labeling index
 50% (case 8, 95%; cases 10 and 11, 90%; case 12, 50%).
Immunophenotype data were limited for the patients with
HHV8-unknown BCBL; CD20 and CD45 were expressed in
all two (100%) and three (100%) of the patients with HHV8-
unknown BCBL who were tested, respectively.
3. Treatment and response
Fourteen patients were treated with cytotoxic chemother-
apy. Three of the patients with PEL did not receive any che-
motherapy because of old age (cases 4 and 5) or an unknown
reason (case 3). The first-line treatments are summarized in
Table 3. Most patients received combination chemotherapy
of cyclophosphamide, doxorubicin, vincristine, and predni-
solone (CHOP) with (n=5) or without (n=5) rituximab. All
three patients with PEL who were treated with chemother-
apy were negative for CD20 and received CHOP alone as a
first-line treatment. All but one of the patients with HHV8-
unrelated BCBL (all positive for CD20) received rituximab-
containing regimens such as rituximab plus CHOP (R-CHOP,
n=4) or rituximab plus cyclophosphamide, vincristine, and
prednisolone (R-CVP, n=1). The remaining patient with
HHV8-unrelated BCBL, who presented with a malignant
effusion involving only the vitreous cavity of the eye, was
treated with high-dose methotrexate, which resulted in com-
plete remission (CR). The first-line regimens were more het-
erogeneous in the HHV8-unknown BCBL cohort (Table 3).
We had response information for 12 of the 14 patients that
received cytotoxic chemotherapy. Overall, nine patients
(75%) achieved CR and three patients (25%) achieved partial
remission (PR) after the first-line treatment. R-CHOP resul-
ted in CR in all five of the patients who received it (four with
HHV8-unrelated BCBL and one with HHV8-unknown
BCBL). CHOP alone resulted in one PR and one CR in the
PEL cohort and two CRs in the HHV8-unknown BCBL
cohort. Two patients with HHV8-unknown BCBL who were
treated with cyclophosphamide, vincristine, and predniso-
lone (CVP)-based regimens achieved PR (cases 14 and 15).
One patient with PEL who received CHOP and achieved CR
experienced relapse of the lymphoma at 28 months after ini-
Table 3. First-line chemotherapy regimens
Regimen Entire PEL HHV8-unrelated HHV8-unknown
cohort (n=17) (n=6) BCBL (n=6) BCBL (n=5)
CHOP 5 (29.4) 3 (50.0) 0 ( 2 (40.0)
R-CHOP 5 (29.4) 0 ( 4 (66.7) 1 (20.0)
CVP 1 (5.9) 0 ( 0 ( 1 (20.0)
R-CVP 2 (11.8) 0 ( 1 (16.7) 1 (20.0)
HD-MTX 1 (5.9) 0 ( 1 (16.7) 0 (
No chemotherapy 3 (17.6) 3 (50.0) 0 ( 0 (
Values are presented as number (%). PEL, primary effusion lymphoma; HHV8, human herpesvirus 8; BCBL, body cavity-
based lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; R-CHOP, rituximab plus CHOP;
CVP, cyclophosphamide, vincristine, and prednisolone; R-CVP, rituximab plus CVP; HD-MTX, high-dose methotrexate.
Table 4. Comparison of clinical characteristics and outcome of classic PEL cases between the historical controlsa) and the
present cohort
Characteristic Nador Boulanger Simonelli Boulanger Guillet Present
et al. [4] et al. [5] et al. [6] et al. [7] et al. [8] cohort
No. of cases 15 12 11 28 34 6
Male-to-female ratio 15:0 12:0 10:1 27:1 31:3 5:1
Age, median (range, yr) 44 (31-85) 43.5 (33-66) 41 (26-58) 44 (33-78) 45 (40-54) 68.5 (59-87)
HIV positivity rate (%) 87 100 100 100 100 17
Median survival 5 mo 5.6 mo 6 mo 6.2 mo 10.2 mo 4.1 yr
PEL, primary effusion lymphoma; HIV, human immunodeficiency virus. a)The five largest case series of PEL reported thus
far (to our knowledge) were used for comparison.
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Cancer Res Treat. 2019;51(4):1302-1312

tial diagnosis and was subsequently treated with ifosfamide,
carboplatin, and etoposide (ICE) combination chemotherapy
followed by autologous hematopoietic stem cell transplan-
tation (autoHSCT), which resulted in PR (case 6).
4. Survival
The PFS and OS of each patient are described in Table 1.
During a median follow-up period of 1.4 years (range, 0.2 to
14.4 years), one patient with PEL (5.9% overall) experienced
disease progression, and three patients (17.6% overall) died,
one each with PEL (case 4), HHV8-unrelated BCBL (case 7),
and HHV8-unknown BCBL (case 14). The cause of death was
unknown for the patient with PEL and pneumonia for the
other two patients.
The patient with PEL that showed the lowest tumor cell
growth fraction (case 4) survived for > 4 years without any
chemotherapy. Another patient with PEL who had HIV
infection (case 3) survived for > 1 year without chemother-
apy. The patient with PEL that relapsed 28 months after CR
lived for > 12 years thereafter with salvage ICE chemother-
apy and autoHSCT (case 6). In the PEL, HHV8-unrelated
BCBL, and HHV8-unknown BCBL cohorts, the median PFS
was 3.2 years, 5.5 years, and not reached, respectively, and
the median OS was 4.1 years, 5.5 years, and not reached, res-
pectively.
Discussion
We described 17 patients with BCBL diagnosed in South
Korea with a focus on clinicopathologic characteristics and
outcomes. We divided the patients into three categories
based on the results of immunocytochemical staining for
LANA1, which is currently the standard assay to detect
HHV8 infection in lymphoma cells, an essential requirement
for a diagnosis of PEL [1]. We found a remarkable lack of
association between immunocompromising conditions and
PEL. Only one of six patients with PEL was HIV seropositive,
and no other patient had a prior history of organ transplan-
tation, immunosuppressant treatment, or cytotoxic chemo-
therapy. Therefore, five of the six patients with PEL in our
series were ostensibly immunocompetent. By contrast, more
than 90% of patients with PEL described in the literature are
HIV seropositive, mostly with severely decreased circulating
CD4-positive T cell counts (Table 4) [4-8]. That remarkable
difference in the rate of HIV seropositivity among patients
with PEL between our series and the patients described in
the literature— most of whom are Caucasians from regions
with moderate-to-high HIV prevalence— is in line with the
fact that South Korea has one of the lowest HIV burdens
worldwide, with an HIV seroprevalence of only 0.003%-
0.01% [21].
Patients with PEL in our study had a favorable prognosis
with a median OS of 4.1 years, whereas those in previous
studies consistently had poor outcomes, with a median OS
of around 6 months (Table 4) [4-8]. Most patients in the liter-
ature with PEL and HIV infection had severe immunodefi-
ciency at the time of PEL diagnosis, with more than 60%
having a prior history of AIDS-related illness and a CD4-pos-
itive T cell count of < 200/µL [4-8]. Four out of eight deaths
in a previous series of patients with HIV infection and PEL
were due to causes unrelated to PEL, such as sepsis or hemo-
ptysis [5]. In addition, there have been several reports in
which patients with HIV infection and PEL were successfully
treated with antiretroviral therapy alone [6,22,23]. In the
present cohort, two patients with the lowest Ki-67 labeling
index (30%) survived for 14 and 49 months each without hav-
ing had chemotherapy at the end of follow-up, which is in
contrast to the PEL patients in the literature who mostly
demonstrated a high proliferation index [24]. Taken together,
our findings suggest that the poor outcomes observed in his-
torical PEL cases are largely due to HIV-related complica-
tions, such as opportunistic infections and malignancies,
rather than to PEL. In that case, watchful waiting with only
supportive measures such as drainage of the effusion would
be appropriate for the management of chemotherapy-intol-
erant, HIV-seronegative patients with PEL. In particular, PEL
with low proliferation activity might represent an indolent
subset that patients can survive for a long time, suggesting
the potential value of Ki-67 immunostaining for the prognos-
tic stratification of PEL. Given the small size and the retro-
spective nature of our case series, future prospective studies
are needed to confirm those hypotheses.
Although the detection of HHV8 infection in neoplastic
cells is essential to make a diagnosis of PEL as per the WHO
criteria [3], we found that five out of 17 patients with BCBL
were not tested for HHV8 positivity, and the majority of pati-
ents with HHV8-unrelated or HHV8-unknown BCBL were
mislabeled as having PEL in their medical records or pathol-
ogy reports (data not shown). The frequent misdiagnosis of
HHV8-unrelated BCBL as PEL is due in part to the lack of a
specific subcategory describing HHV8-unrelated BCBL in the
current NHL classification despite its unique clinical features
[17]. For that reason, there are many different terms for
HHV8-unrelated BCBL in the literature, such as HHV8-
unrelated PEL-like lymphoma [15,18], HHV8-negative
malignant effusion lymphoma [14], and HHV8-negative
effusion-based lymphoma [17], causing difficulties in clari-
fying their clinical entity. Discrimination between PEL and
HHV8-unrelated BCBL is crucial, because patients with
HHV8-unrelated BCBL have a high expression rate (> 80%)
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Junghoon Shin, Case Series of Body Cavity–Based Lymphoma

of pan-B-cell markers including CD20, whereas those with
PEL do not [16-18], which means that rituximab should have
therapeutic value for HHV8-unrelated BCBL but not for PEL.
Indeed, in our study, all four patients with HHV8-unrelated
BCBL who were treated with R-CHOP achieved CR.
In our study as well as in the literature, patients with PEL,
but not those with HHV8-unrelated BCBL, were frequently
positive for CD30 expression [7,8,16]. The high rate of CD30
expression in PEL is reminiscent of other CD30-expressing
lymphomas such as anaplastic large cell lymphoma, Hodg-
kin lymphoma, and a subset of diffuse large B-cell lym-
phoma, for which brentuximab vedotin, an anti-CD30 anti-
body conjugated to the anti-microtubule agent monomethyl
auristatin E, has shown antitumor activity [25-28]. In a recent
preclinical study, brentuximab vedotin demonstrated a pro-
mising antitumor effect on PEL cell lines and xenograft mice,
urging further investigation in clinical trials [29]. The find-
ings of our study suggest that physicians should give more
attention to precise discrimination between HHV8-unrelated
BCBL and PEL for optimal management and clinical trial
design.
Our study has several limitations. First, the small number
of cases and the incompleteness of the data preclude drawing
firm conclusions in many aspects. For instance, we could not
determine whether the tumor cell immunophenotype of PEL
differed between immunocompetent patients and immuno-
compromised patients. Although our results suggest that
PEL may have more favorable outcomes in patients without
HIV infection than in those with HIV infection, we did not
test that hypothesis explicitly, which will require a prospec-
tive study with a larger cohort. Second, as this study is a
medical record-based retrospective study with no central
pathology review conducted, the determination of LANA1
immunostaining positivity was not standardized across par-
ticipating institutions. Third, most of our analyses were des-
criptive in nature, with no formal statistical testing. None-
theless, PEL is so rare that, even worldwide, the largest con-
secutive series of classic PEL cases included only 34 patients,
and that of HHV8-unrelated BCBL cases is even smaller
[8,17]. To our knowledge, our series represents the largest
collection of consecutive Asian patients with PEL or HHV8-
unrelated or HHV8-unknown BCBL.
In conclusion, in a consecutive series of patients with BCBL
in a country with low HIV burden, most patients with PEL
were HIV seronegative and immunocompetent. Those pati-
ents, especially those with low proliferation activity of neo-
plastic cells, had an indolent disease course and long survival
even with supportive care only. Our findings raise a testable
hypothesis that watchful waiting is a reasonable approach
when managing HIV-seronegative patients with PEL who
may not tolerate chemotherapy or whose neoplastic cells
show low proliferative activity. The Ki-67 labeling index
might serve as a marker for the prognostic stratification of
PEL. HHV8-unrelated BCBL was successfully treated with
rituximab-containing chemotherapy, which corroborates the
findings of previous studies [14-18]. We also found that
physicians often fail to distinguish between HHV8-unrelated
BCBL and PEL despite the important therapeutic implica-
tions. The upcoming revisions of the WHO classification of
lymphoid neoplasms should be based on a thorough discus-
sion of the most proper categorization of HHV8-unrelated
BCBL. Several emerging hypotheses generated from the
present study should be confirmed in future prospective
studies based on larger cohorts.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Acknowledgments
This work was supported by a grant from the National Research
Foundation of Korea for the Cellular Heterogeneity Research Center
(NRF-2016R1A5A1011974), funded by the Ministry of Science, ICT &
Future planning, Republic of Korea. The authors thank the Consor-
tium for Improving Survival of Lymphoma for their efforts in coor-
dinating the study. This manuscript has been edited by native
English-speaking experts associated with BioScience Writers LLC,
Houston, TX, USA.
Author Details
1Department of Internal Medicine, Seoul National University Hos-
pital, Seoul, 2Department of Pathology, Samsung Medical Center,
Seoul, 3Department of Internal Medicine, Dong-A University Col-
lege of Medicine, Busan, 4Department of Oncology, Asan Medical
Center, Seoul, 5Department of Internal Medicine, Seoul National
University Bundang Hospital, Seongnam, 6Department of Internal
Medicine, Yonsei University College of Medicine, Seoul, 7Depart-
ment of Internal Medicine, Korea University Anam Hospital, Seoul,
8Department of Internal Medicine, Pusan National University Hos-
pital, Busan, 9Department of Medicine, Samsung Medical Center,
Seoul, 10Department of Internal Medicine, Soonchunhyang Univer-
sity Seoul Hospital, Seoul, Korea
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