2021, Volume 37, Number 2, Page(s) 130-138
Relationship of Tumor-Associated Macrophage Population Detected by CD68 PG-M1, CD68 KP1, and CD163 with Latent EBV Infection and Prognosis in Classical Hodgkin Lymphoma
Hanife Seda MAVILI1, Aydýn ISISAG1, Ayca TAN1, Mine MISKIOGLU2, Lale SAKA BARAZ3, Nalan NESE1
1Department of Pathology, Manisa Celal Bayar University, Faculty of Medicine, MANISA, TURKEY
2Department of Hematology, Manisa Celal Bayar University, Faculty of Medicine, MANISA, TURKEY
3Department of Internal Medicine, Manisa Celal Bayar University, Faculty of Medicine, MANISA, TURKEY
Keywords: Classical Hodgkin Lymphoma, Macrophages, Epstein-Barr virus, CD68, CD163
To evaluate the quantity of tumor-associated macrophages (TAMs) in cases of Hodgkin Lymphoma of classical type (cHL), and to
reveal possible associations between TAM intensity and latent Epstein-Barr virus (EBV) infection, overall survival, progression-free survival,
prognostic indices, and clinicopathological parameters.
Materials and Methods: A total 46 cases of cHL with complete clinical records were selected and re-evaluated histopathologically. Staining for
CD68 (PG-M1; KP1 clones) and CD163 was evaluated and the cut-off values were defined. Also, all cases were evaluated using the chromogen in
situ hybridization (CISH) method with EBER (Epstein-Barr virus-encoded RNA) probes for the presence of possible EBV infection.
Results: It was found that high expression levels of PG-M1 and high International Prognostic Scores (IPS) were associated with shortened overall
survival (p=0.047, p=0.013). Cases with 2 or less areas of nodal region involvement were observed to have longer progression-free survival period
(p=0.043). Higher expression levels of CD68 PG-M1, CD68 KP1, and CD163 were found to show significant associations with the presence of
some clinical parameters such as the presence of B symptoms, spleen involvement, and the presence of EBV infection.
Conclusions: Our findings suggest that increase of PG-M1+ TAM is associated with shortened overall survival, while higher expressions of all
immunohistochemical markers are statistically significantly associated with the presence of EBV infection and clinical parameters mentioned
above. These findings indicate that highlighting the TAM rate via macrophage markers in cases of cHL could be helpful in determining the
prognostic risk groups and the relevant results should be mentioned in pathology reports.
Hodgkin Lymphoma (HL) makes up 0.6% of all
malignancies and 10% of lymphomas 1,
from other malignant neoplasms for not only by its
clinical presentation but also because it contains very few
neoplastic cells (Hodgkin/Reed Sternberg (HRS) cells) in
an inflammatory cell-rich background 2
. In recent years,
it has been considered that this inflammatory background
is an important factor in tumor progression and prognosis
in some hematologic malignancies such as follicular
lymphoma and Hodgkin Lymphoma of the classical type
. To highlight prognostic factors and risk
groups, many studies have been performed up to now by
different teams, such as the German Hodgkin Lymphoma
Study Group (GHSG), the European Organization for
Research and Treatment of Cancer (EORTC), the National Cancer Institute of Canada (NCIC), and the National
Comprehensive Cancer Network (NCCN). Although the
international prognostic score (IPS) still remains important
to predict the course of the disease 6,7,
novel markers are
needed to govern modern therapeutical methods in a more
exact way. It has been revealed that reactive inflammatory
cells in the microenvironment of the involved tissue
enhance the proliferative capacity and anti-apoptotic
features of HRS cells, and there has been an increase in the
number of studies on biological markers since the1980s.
First, an abundance of TAM in tumoral tissue was shown
to be associated with B symptoms and a worse prognosis
. While some of the other studies dealing with the same
issue have claimed that an increase in the number of TAM
causes a decrease in overall survival and could be used as
a new marker in evaluating risk groups 4,5,
some others found no relationship between these two parameters 9,10
. Also, there are studies showing a correlation between
TAM intensity and EBV positivity of the neoplastic cells 4,11
. There seems to be an obvious need for other studies for
these findings to take their place in routine practice. In this
study, two clones of the CD68 antibody, the most commonly
used monocyte /macrophage marker, and CD163 antibody,
a more specific marker than CD68, were used to assess
the intensity of TAM in the tumoral microenvironment.
An attempt was then made to statistically determine the
possible associations between TAM intensity and prognosis
and latent EBV infection. It was also aimed to determine
whether there are significant associations between TAM
intensity and IPS, EORTC score, and clinicopathologic
Forty-six cHL patients, who had been regularly followedup
between 2008 and 2016 at the Hematology Department
of Manisa Celal Bayar University Hospital, and whose
slides and paraffin blocks were extracted from the archives
of the Department of Pathology, were evaluated in the
study. The study was approved by the institutional ethics
committee (Date: 25.02.2016, Reference No: 20478486-51)
Among these, 24 were nodular sclerosing (NS), 20 were
mixed cellularity (MS), 1 was lymphocyte rich (LR), and 1
was the lymphocyte depleted (LD) type. Course of disease,
clinical features, laboratory findings, presence or absence
of B symptoms, presence or absence of bulky (R ≥ 10 cm)
lesion(s), presence or absence of mediastinal mass, stage of
the disease according to the modified Ann Arbour System,
and presence or absence of recurrence(s) and progression
were noted from the patients’ files and pathology reports.
Risk groups were determined according to IP score and
EORTC score. As the number of cases is not high, both
scoring systems were applied for all patients at any stage.
Patients were divided into two categories according to
IP scores; low-risk group (IPS≤ 3) and high-risk group
(IPS≥4). Another categorization was also performed
according to the EORTC score; low-risk group (not bearing
any of the above-mentioned risk factors) and high-risk
group (bearing at least one risk factor).
From the patients’ files, it was determined that various
treatment protocols had been administered depending
on the stage of the disease and the performance of the
patients. Forty-four of the cases underwent a conventional
adriamycin, bleomycin, vinblastine, dacarbazine (ABVD)
treatment regimen, and in addition to this, radiotherapy was applied to the tumor-associated area in some of the
cases. Because the performance status of the remaining
two cases was low, no chemotherapy was administered
and they died 2 months and 8 months after the initial
diagnosis. One of these patients had the LD and the other
had the MS type of cHL, respectively. In 9 out of 18 cases
showing recurrence or progression after the initial therapy,
additional chemotherapy regimens were also administered.
Immunohistochemistry and chromogenic in situ
For immunohistochemistry, 4μ-thick sections obtained
from formalin-fixed/paraffin-embedded tissues were
placed on positive-charged electrostatic slides (Isotherm
Technical Laboratory Glass Materials). All sections were
then placed on a fully automated immunohistochemical
staining machine (Ventana, Benchmark, XT IHC/ISH).
UltraView Universal DAB Detection Kit compatible with
the device was used for IHC staining. Monoclonal mouse
primary antibodies CD163 (clone MRQ-26, prediluted,
VENTANA, Cat. No: 760-4437) and CD68 (clone KP-
1, prediluted, VENTANA, Cat. No: 790-2931and clone
PG-M1, prediluted, DAKO, Code: IS613, prediluted, Cat.
No: 760-4437) were applied and staining was completed
according to the standard procedures. To detect EBV-RNA
with an EBER (Epstein-Barr virus-encoded RNA) probe
via the CISH method, 4μ-thick tissue sections placed on
positive-charged electrostatic slides were also used. All
tests were performed with a fully automated ISH machine
(Ventana, Benchmark XT, IHC/ISH), by using EBER 1
DNP Probe (Regulatory status: ASR; Cat. No: 760-1209),
compatible with the machine, and the Ultraview AP Red
ISH Kit for EBV RNA signaling, and staining was completed
according to the standard procedures.
Evaluation of immunohistochemical and ISH staining
For immunohistochemical studies, the rate of staining
macrophages was determined via consensus of two
observers (A. I. and H. S. M.) by standard research
microscope. To assess the rate of staining macrophages,
microscopic fields that were rich in HRS cells were chosen
and almost the same fields were used to evaluate all three
antibodies. Assessment was made in 5 neighboring highpower
fields in each case in a quantitative manner, by
counting the number of staining macrophages and all other
non-neoplastic cells, and recording the rate of staining
macrophages in multiples of 5%. To assess a case as EBER
(+), it has been stated that almost all neoplastic cells have
to be stained with EBER-ISH technique (12). So, cases with
nuclear staining of nearly all neoplastic cells were assessed
to be positive with EBER.
As the highest expression levels were obtained with CD163
followed by CD68 PG-M1 and CD68 KP1 expressions in a
decreasing manner, the rates of 50%, 40% and 30%, which
were close to the median values were considered as primary
cut-off values, respectively. Furthermore, the rate of 30%
for CD163 and 10% for CD68 PG-M1 and CD68 KP1
were determined as secondary cut-off values in order to
investigate whether lower expressions were significant. In
survival analysis, overall survival was defined as the period
from diagnosis to death of the patient for any reason or to
last recorded follow-up date while progression-free survival
was defined as the period from diagnosis to progression or
recurrence of the disease or to last recorded follow-up date.
To assess possible relations between the above-defined cutoff
values and the clinicopathologic parameters, laboratory
findings, and the presence of EBV, Fisher’s exact test was
used. Significant variables obtained in univariate analysis
were then evaluated for multivariate analysis by using the
logistic regression model. The Kaplan-Meier procedure
was used for survival analysis and the log-rank test was
applied to compare survival curves. Pearson and Spearman
correlation tests were utilized to evaluate the correlation
between expressions of the three immunohistochemical markers. P values smaller than 0.05 were considered as
statistically significant while p values equal or greater
than 0.05 but smaller than 0.1 were considered as having
borderline significance. All tests were performed by using
SPSS (Statistical Package for Social Sciences), version 20.0.
|Age, gender, and clinicopathologic findings
Age, gender and clinicopathologic findings of all cases are
shown in Table I. A total of 5 patients died at 2, 6, 8, 40 and
50 months after the initial diagnosis, respectively.
Evaluation of light microscopy, CD163 and CD68
expressions and CISH studies
Examples of abundant and scant HRS cell population in
the non-neoplastic background in H&E stained slides of
two different cases are shown in Figure 1A, B, respectively.
In these cases, EBER ISH was positive in the first (Figure
1C) and negative in the second (Figure 1D). When TAM
intensity was evaluated in all three markers, it was seen that
the highest levels of expression were observed with CD163
and lower levels were detected with CD68 clone KP1.
Examples of high and low expression levels of CD163, CD68
PG-M1, and CD68 KP1 of the above cases are presented
in Figure 2A-C and Figure 2D-F, respectively. However, expression levels of all three markers were correlated
statistically (p<0.001; Pearson and Spearman correlation
tests). It was also observed that staining with histiocytic
markers was more intense in the areas where neoplastic
cells were abundant, especially with CD163.
Click Here to Zoom
|Figure 1: A) Abundant
HRS cells in case #42
B) Scant HRS cells in
case #18 (H&E; x400).
C) EBER ISH positive
HRS cells in case #42
D) EBER ISH negative
HRS cells in case #18
Click Here to Zoom
|Figure 2: A) 70% CD163 expression in case #42(IHC; x200). B) 65% CD68 PG-M1 expression in case #42 (IHC; x200). C) 45% CD68
KP1 expression in case #42 (IHC; x200). D) 10% CD163 expression in case #18 (IHC; x200). E) 10% CD68 PG-M1 expression in case #18
(IHC; x200). F) 5% CD68 KP1 expression in case #18 (IHC; x200).
Relationship of CD163 and CD68 expression, EBV
infection, age, gender and clinicopathologic parameters
Statistical data obtained to assess relationship of survival
with CD163 and CD68 PG-M1 and CD68 KP1 expressions
according to two different cut-off points, EBV infection,
age, gender and clinicopathologic parameters are shown
in Table I. It was stated that overall survival was decreased
with higher CD68 PG-M1 expression levels (according to
the 40% cut-off point) and higher IP scores (p=0.047 and
p=0.013, respectively). There was a significant relationship between a long duration of progression-free survival and
the number of involved nodal regions below 3 (p=0.043),
while there was a borderline statistically significant
difference with the presence of EBV infection (p=0.062).
No significant differences were found between survival and
types of cHL (i. e. NS or MS types; LR and LD types were
Click Here to Zoom
|Table I: Age, gender, clinicopathologic findings of the cases and relationship of survival with clinicopathologic parameters and
expression levels of histiocytic markers according to two different cut-off points.
Relationship of CD163 and CD68 expression with EBV
infection and clinicopathologic parameters
Statistical data obtained to assess relationship of CD163,
CD68 PG-M1, and CD68 KP1 expressions with EBV
infection and clinicopathologic parameters are shown in
Table II. Increased staining intensity for all three histiocytic
markers was found to be correlated with the presence of B
symptoms, splenic involvement, presence of EBV infection,
and high-risk group according to EORTC. Multivariate analyses revealed that significant relationships between all
three markers and EBV infection and B symptoms were
retained. This was also the same for increased CD163 and
CD68 PG-M1 expressions and splenic involvement.
Click Here to Zoom
|Table II: Significant (bold) and borderline significant (red) results obtained between clinicopathologic parameters and expression levels of CD68 PG-M1 according to 40%
and 10% cut-off points, CD68 KP1 according to 30% and 10% cut-off points, and CD163according to 50% and 30% cut-off points.
Macrophages are usually found in the microenvironment
of solid tumors and hematologic malignancies 13
has been increasing experimental evidence supporting the
notion that macrophages promote tumor progression and
facilitate cancer development 14-16
. The relationship of
TAM with B symptoms and a worse prognosis in cHL have
been stated many years ago 8
and these findings were then
supported by gene expression profiling studies. In their first
gene expression profile study, Steidl et. al. have reported
a decrease in progression-free survival when TAMs are
more than 5%, by using CD68 immunohistochemistry
. In a study conducted by Sanchez and colleagues with
advanced-stage cHL patients from Spain and Houston, a
significant correlation was found between high levels of
CD68 expression (PG-M1 ve KP1 clones) and shortened
duration of disease-specific survival in Spanish patients but
no significant association was found with the patient group
from Houston and with CD163 11
. This finding suggests
that socio-demographic factors may also be effective in
attaining different results in different studies. Similar to
the above-mentioned studies, there are many other studies
emphasizing that increased number of TAMs is associated
with shortened overall survival, progression-free survival,
and disease-free survival 4,17-27
. While CD163 has been
used either with CD68 PG-M1 18,
or CD68 KP1 4,20,21,23
in some of these studies, only a single clone of CD68
has been utilized in others 17,19,22,24
<-r27>. A significant
relationship was found between survival and both CD163
and CD68 expressions 4,20,21,23,
or expression of either
one of these markers 17-19,22,24-27
. However, there are
other studies which have found no relationship between
survival and expression of either of these three markers 9,10
. In our study, only increased expression of CD68 PGM1
with the 40% cut-off point was found to be correlated
with shortened overall survival. Also, there are many other
studies stating a significant relationship between increased
numbers of TAMs and clinicopathologic/laboratory
parameters. These parameters include advanced (>45
years) age, male gender, presence of B symptoms, high
IP score (>4 or>2), and advanced stage disease 4,5,17,20
. In our study, increased numbers of TAM was found to
be significantly related with the presence of B symptoms,
splenic involvement, and high EORTC score. Like survival
analyses, there are studies with opposite results in this 9
. In our study, it was seen that CD163 positivity
was higher than both clones of CD68 as in the literature
. However, there are publications reporting the
. Correlation of the intensity of staining of
all three markers found in other studies 20
and in this
study suggests that using any marker while searching for
TAM intensity may suffice, but the conflicting results in
terms of significance suggest that it may be better to use
CD163 and CD68 together. It is also unclear which clone
of CD68 is more suitable for use. Since KP1 clone was
used in most of the studies, significant results related to
survival were obtained mostly with this clone 4,5,17-23
This fact reveals the need for other comparative studies.
In assessing intensity of TAM with histiocytic markers in
cHL, another issue is finding out the precise cut-off points.
Different cut-off values have been used in other studies.
While some have used the median value of expression rate
(25%, 50%) of macrophage markers 17,18,
preferred cut-off points determined in earlier studies (<5%,
5%-25%, 25%-50%, >50%) 9,11
. As the expression levels
obtained with CD163, CD68 PG-M1, and CD68 KP1 were
sorted in a decreasing manner, the rates 50%, 40% and 30%,
which were around the median values, were preferred as the
primary cut-off values, respectively. To see the significance
of lower levels of expression, rates of 30% for CD163 and
10% for CD68 PG-M1 and CD68 KP1 were determined as
secondary cut-off values. EBV infection has been shown
to alter the microenvironment of tumoral tissue in cHL
but it is controversial whether this infection
has a prognostic role. Studies suggesting a shortened
are more common than others claiming
that the survival period is not affected 4
. No significant
relationship between EBER positivity and overall survival
was found in this study, although a borderline significance
was obtained between with progression-free survival. Similar
to some other reports, it was also found that TAM intensity
determined by all three histiocytic markers was higher in
EBER+ patients than in EBER– cases 4,9,11
. This finding
suggests that the presence of EBV may play an effective
role in immune response and macrophage activation and
polarization. Although this study was conducted with a
relatively small group of patients and studies involving
larger series with longer follow-up periods are needed, it
was concluded that routinely examining TAM intensity in
cHL patients and recording the results in pathology reports
may not only provide additional prognostic information
but may also contribute to future investigations.
CONFLICT of INTEREST
The authors declare no conflict of interest.
This work was supported by the Scientific Research Project
Office of Manisa Celal Bayar University. Project Number:
Concept: AÝ, HSM, Design: HSM, AÝ, Data collection
or processing: HSM, LSB, MM, AÝ, NN, Analysis or
Interpretation: HSM, AÝ, AT, Literature search: HSM,
Writing: HSM, Approval: HSM
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