Observational Study Medicine ®

OPEN

Prognostic markers compared to CD3+TIL in

locally advanced nasopharyngeal carcinoma
Nasser Al-Rajhi, MDa, Shamayel F. Mohammed, MDb, Hatim A. Khoja, MDb, Mohammad Al-Dehaim, MDa,
∗
Hazem Ghebeh, PhDc,

Abstract
Locally advanced nasopharyngeal carcinoma (LA-NPC) is more prevalent in some geographic regions, including Saudi Arabia.
Typically, Tumor-Node-Metastasis (TNM) staging is used in NPC. However, it is inadequate to assess the prognosis of LA-NPC.
Therefore, we analyzed and compared several previously reported prognostic factors in LA-NPC patients, retrospectively,
including CD3+tumor-infiltrating lymphocytes (TIL) and peripheral blood hemoglobin, EBV DNA copy number, ratios of albumin-to-
alkaline phosphatase ratio (AAPR), neutrophils, or platelets-to-lymphocytes (NLR, PLR). The studied cohort was 83 LA-NPC patients
previously recruited for a randomized phase II trial with a different aim.
Univariate cox regression analysis showed no significant correlation between any of the tested variables with disease-free survival
(DFS) or overall survival (OS) with the exception of low CD3+ TIL infiltration, which correlated significantly with DFS (HR = 6.7,
P = <.001) and OS (HR = 9.1, P = .043). Similarly, in a validated multivariate cox regression analysis, only low CD3+ TIL correlated
significantly with DFS (HR = 7.0, P < .001 for TIL) and OS (HR = 9.4, P = .040).
Among tested parameters, CD3+ TIL was the only independent prognostic marker for DFS and OS in LA-NPC patients treated
with CCRT. This study supports the use of CD3+TIL, over other factors, as an independent prognostic factor in LA-NPC.
Abbreviations: AAPR = albumin-to-alkaline phosphatase ratio, HG = hemoglobin, NLR = neutrophils -to-lymphocytes ratio, NPC
= nasopharyngeal carcinoma, PLR = platelets-to-lymphocytes ratio.
Keywords: albumin-to-alkaline phosphatase, chemo-radiotherapy, EBV copy number in peripheral blood, hemoglobin,
nasopharyngeal carcinoma, neutrophils -to-lymphocytes ratio, platelets-to-lymphocytes ratio, tumor-infiltrating CD3+ Lymphocytes

1. Introduction Africa. Currently, most patients have Locally advanced NPC

(LA-NPC) at the time of diagnosis, defined as stage III or IV.
Nasopharyngeal Carcinoma (NPC) is sensitive to radiation
Despite the advances in therapy, some patients relapse and die of
therapy and chemotherapy. It is a common head and neck
their disease. Biomarkers are needed to predict the response to
malignancy in Southeast Asia, the Middle East and parts of North
therapy. Tumor-Node-Metastasis (TNM) staging is currently
used to assess the prognosis of NPC. However, it is not adequate
Editor: Jorddy Neves Cruz.
to assess the prognosis of LA-NPC.
This work is supported and followed by King Faisal Specialist Hospital &
We have previously found CD3+ TIL as a robust and
Research Centre under project RAC# 2150-013.
independent prognostic factor for LA-NPC.[1] Several studies
Analyzed datasets in this study are included in this published article (or
supplementary files), otherwise available from the corresponding author upon a
tested other clinicopathological factors as prognostic factors or
reasonable request. LA-NPC, including neutrophil-to-lymphocyte ratio (NLR),[2,3]
The authors have no conflicts of interests to disclose. Platelet-to-lymphocyte ratio (PLR),[4] albumin-to-alkaline phos-
The datasets generated during and/or analyzed during the current study are
phatase ratio (AAPR),[5] baseline hemoglobin (HG)[6] and EBV
available from the corresponding author on reasonable request. DNA copy number in the peripheral blood.[7] The existence of
a
Department of Radiation Oncology, King Faisal Specialist Hospital and multiple prognostic factors highlights the importance of testing
Research Center, Riyadh, Saudi Arabia, b Deparment of Laboratory Medicine and them side-by-side to find the most appropriate markers and their
Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi relationship in a specific geographical area.
Arabia, c Stem Cell & Tissue Re-engineering Program, Research Centre, King We recently reported on the nonsignificant effect of low-dose
Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
∗ fractionated radiotherapy (LDFRT) on induction chemotherapy
Correspondence: Hazem Ghebeh, Stem Cell & Tissue Re-engineering Program,
followed by concurrent chemo-radiation in LA-NPC.[8] We
King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh
11211, (MBC 03), Riyadh, Kingdom of Saudi Arabia used this cohort of LA-NPC patients to study the correlation of
(e-mail: [email protected]). different prognostic factors with survival.
Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. In the current study, we compared side-by-side different
This is an open access article distributed under the Creative Commons prognostic markers previously reported to correlate with survival
Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and in NPC. In our studied cohort, low CD3+TIL was the only
reproduction in any medium, provided the original work is properly cited.
independent prognostic factor for LA-NPC.
How to cite this article: Al-Rajhi N, Mohammed SF, Khoja HA, Al-Dehaim M,
Ghebeh H. Prognostic markers compared to CD3+TIL in locally advanced
nasopharyngeal carcinoma. Medicine 2021;100:46(e27956).
2. Methods
Received: 6 July 2021 / Received in final form: 7 October 2021 / Accepted: 5
November 2021 This study is a retrospective, single-institution, cohort study
http://dx.doi.org/10.1097/MD.0000000000027956 testing the effect of different makers on the survival of NPC

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Al-Rajhi et al. Medicine (2021) 100:46 Medicine

patients. The study was a secondary analysis of a randomized 2.5. Statistical analysis
controlled trial made for a different aim.[8] The correlation between proposed risk factors and survival
This study was conducted according to the declaration of outcomes was evaluated using Cox proportional hazard model.
Helsinki and guidelines of the Institutional Review Boards (IRBs) The model was further validated by forward selection using the
of King Faisal Specialist Hospital and Research Centre (Research Bayesian information criterion (BIC) validation method. Survival
Ethics Committee, REC, and Basic Research Committee BRC) plots were generated using Kaplan–Meier methods, while
who approved the work under RAC# 2150-013. The need for survival curves were compared using the log-rank test. Time
consent has been waived as the study was retrospective and was censored for patients who were alive or disease-free at the last
patients were not individually identifiable. follow-up. All analysis was performed using JMP statistical
software (Cary NC, USA), and a P value of .05 was the threshold
2.1. Patient selection for significance.
All enrollments were among NPC patients recruited to test the
effect of low-dose fractionated radiation with induction neo- 3. Results
adjuvant chemotherapy followed by concurrent chemoradio-
3.1. Patient characteristics
therapy (CCRT) trial[8] (registered in clinicaltrials.gov:
NCT03890185). Among 108 patients enrolled, tissue blocks The majority of patients were males with large tumors (T3 and
were only available for 83 patients (42 in the control arm and 41 T4), advanced lymph node involvement (N), which is consistent
patients in the experimental arm). According to the 2018 with LA-NPC. Tumors were predominantly non-keratinizing
American Joint Committee on Cancer (AJCC 8th edition) staging undifferentiated carcinoma, that is WHO type III histological
system, all patients were manually restaged and designated as subtype (Table 1).
stage III or IV. The treatment arm “Trial Arm” was part of the LA-NPC patients were followed up for a median time of 4.7
multivariate analysis. Patients were followed up regularly in the years from the time of diagnosis, of which 20 (24%) relapsed,
clinics or by phone. including 5 patients with local or loco-regional and another 16
(25%) with systemic relapse. From all the LA patients, eventually,
7 (8%) died of the disease.
2.2. Neutrophils -to-lymphocytes ratio, platelets-to-
lymphocytes ratio, hemoglobin EBV DNA in peripheral
blood 3.2. Correlation between the different clinicopathological
markers
Data on NLR, PLR, HG within 2 weeks of diagnosis and before
initiation of treatment was available in patients’ medical files. Age correlated with CD3+TIL as older patients had lower TIL
Similarly, EBV DNA status in peripheral blood was available as scores (P = .011). Patients with anemia were mostly young
routine care for NPC patients. Data were missing on EBV DNA
status for eight patients. The used cutoff was based on what was
used in previous reports (NLR, HG, EBV DNA) or the median Table 1
(AAPR and PLR). Patients characteristics.
Features Categories # Patients
2.3. Immunohistochemistry ∗
Age <40 yr 32 (39)
Formalin-fixed paraffin-embedded (FFPE) NPC tissue blocks, Range 18–72 Median 45 ≥ 40 yr 51 (61)
obtained at the time of diagnosis, were used for this study. Gender Female 21 (25)
Male 62 (75)
Immunostaining was performed as previously described in
WHO Type I 0 (0)
detail.[1] Briefly, immunohistochemistry was performed on 4 m
II 5 (6)
m sections using a fully automated Ventana Benchmark Ultra III 78 (94)
(Ventana/Roche) system. The CD3 antibody was a ready-to-use T stage T1 26 (31)
primary antibody from Ventana. Antibody binding was detected T2 2 (2)
using the ultraView DAB detection kit available from Ventana. T3 30 (36)
T4 25 (30)
N stage N0 5 (6)
2.4. Pathological scoring N1 12 (15)
As adapted from Salgado et al,[9] scoring of lymphocyte N2 24 (29)
infiltration was done in a semi-quantitative estimation giving a N3 42 (51)
TNM staging III 24 (29)
4-tier scale score as previously described in detail.[1] The score
IV 59 (71)
depended on the percentage of CD3+ TIL occupying the field.
Relapse No 63 (76)
Score 1 was given for TIL occupying <10% of the field, while Yes 20 (24)
scores 2, 3, and 4 were given for TIL occupying 10 to 40, 40 to 70, Type of relapse None 63 (77)
and >70% of the field, respectively. Two independent anatomi- Local 3 (4)
cal pathologists (HK & SM), blinded to the treatment outcome, Locoregional 3 (2)
scored and interpreted the histological tumor sections. A Systemic 14 (16)
consensus was reached in case of discrepancy. Scores were Survival Alive 76 (92)
further dichotomized into low CD+3 TIL (scores 1 and 2) or high Dead 7 (8)
CD3+ TIL (scores 3 and 4). ∗
Percentage of cases.

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Table 2
Univariate Cox proportional hazard regression analysis of the different clinicopathological features and biomarkers with disease-free
survival and overall survival in 83 patients with LA-NPC.
Relapse DFS Death OS
∗ ∗

+ HR 95% CI P
+ HR 95% CI P
Age
<40 yr 27 (84)† 5 (16) 1 30 (94) 2 (6) 1
≥40 yr 36 (71) 15 (29) 1.98 0.7–5.5 .183 46 (90) 5 (10) 1.5 0.3–8.0 .601
Gender
Females 18 (86) 3 (14) 1 20 (95) 1 (5) 1
Males 45 (73) 17 (27) 2.2 0.7–7.7 .197 56 (90) 6 (10) 2.1 0.3–17.8 .472
WHO Type
III 61 (78) 17 (22) 1 71 (91) 7 (9) 1
II 2 (40) 3 (60) 3.2 0.9–11.0 .068 5 (100) 0 (0) 0.0001 2.6x10^-105–7.2x10^96 .940
Trial Armx
Control arm 34 (81) 8 (19) 1 39 (93) 3 (7) 1
LDXRT 29 (71) 12 (29) 1.7 0.7–4.1 .253 37 (90) 4 (10) 1.5 0.3–6.7 .592
UICC Stage
III 17 (71) 7 (29) 1 20 (83) 4 (17) 1
IV 46 (78) 13 (22) 1.4 0.6–3.5 .478 56 (95) 3 (5) 0.3 0.1–1.2 .090
CD3+TIL
High 43 (91) 4 (9) 1 46 (98) 1 (2) 1
Low 20 (56) 16 (44) 6.7 2.2–20.2 < .001 30 (83) 6 (17) 9.1 1.1–76.1 .042
AAPR
>0.58 34 (85) 6 (15) 1 36 (90) 4 (10) 1
<0.58 29 (67) 14 (33) 2.4 0.9–6.3 .076 40 (93) 3 (7) 0.7 0.2–3.2 .671
NLR
<3 47 (78) 13 (22) 1 57 (95) 3 (5) 1
>3 16 (70) 7 (30) 1.6 0.6–3.9 .341 19 (83) 4 (17) 7.6 0.8–17.0 .083
PLR
<172 36 (80) 9 (20) 1 44 (98) 1 (2) 1
> 172 27 (71) 11 (29) 1.5 0.6–3.7 .334 32 (84) 6 (16) 1.8 0.8–86.1 .074
HG
Low (<110 g/L) 20 (87) 3 (13) 1 22 (96) 1 (4) 1
Normal (≥110 g/L) 43 (72) 17 (28) 2.4 0.7–8.2 .160 54 (90) 6 (10) 2.4 0.3–19.8 .421
EBV DNA copies‡
Negative (< 1500 copies/mL) 46 (75) 15 (25) 1 55 (90) 6 (10) 1
Positive (≥1500 copies/mL) 10 (71) 4 (29) 1.2 0.4–3.5 .773 13 (93) 1 (7) 0.7 0.1–6.0 .761
(+ and -) are numbers patients.
∗
P values in bold represent significant data.
†
Numbers between brackets are the percentages of patients.
‡
Eight samples had unknown EBV DNA copies status.
x
Trial arm in a previous trial (NCT03890185) that is not related to this study where Control arm = No irradiation during neoadjuvant chemotherapy while LDXRT = Lose dose of irradiation during the neoadjuvant
chemotherapy.
AAPR = albumin-to-alkaline phosphatase ratio, NLR = neutrophils-to-lymphocyte ratio, PLR = platelets-to-lymphocytes ratio.

(P = .047) and females (P < .001). There was a correlation with worse OS (HR = 9.1, P.043), while there was a trend of
between EBV copies >1500 copies/mL and clinical-stage 4A correlation between worse OS and higher NLR (>3) or PLR
(P = .015). On the other hand, AAPR, NLR, and PLR did not (>172) with only a borderline significance.
correlate significantly with any other tested factor (data not Kaplan–Meier survival curves showed statistically significant
shown). separation between DFS of low and high CD3+ TIL groups of
patients (Fig. 1, log-rank P < .001). On the other hand, the
significance of the difference in DFS between low and high AAPR
3.3. Correlation of clinicopathological and other
was borderline. Similarly, Kaplan-Meier survival curves showed
biomarkers with survival
statistically significant separation between OS of low and high
We then looked at the correlation of different clinicopathological CD3+ TIL groups of patients (log-rank P .015, Fig. 2). Similarly,
markers, including CD3+ TIL, AAPR, NLR, PLR, HG, and EBV there was a significant separation between OS of patients with
DNA copies, with the disease outcome. Univariate Cox high and low PLR (log-rank, P .036).
regression analysis showed that among tested makers, only Multivariate Cox regression analysis was performed to
low CD3+TIL correlated significantly with worse DFS (HR = 6.7, determine independent factors that correlate with the survival
P < .001) while there was a trend of correlation with only of LA-NPC in our patients. While both CD3+TIL and AAPR
borderline significance between worse DFS and WHO type II as correlated significantly with DFS (P = .004 and P = .017 respec-
well as worse DFS and lower AAPR (Table 2). On the other hand, tively), the significance of the correlation remained only with
low CD3+ TIL was the only makers that significantly correlated CD3+TIL and DFS upon validation (HR = 5.9, P < .001)

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Figure 1. Effect of various Biomarkers on the disease-free survival (DFS) of LA-NPC patients (n = 83). Kaplan–Meier survival curves showing disease-free survival
(DFS) of patients in relation to their Tumor CD3+TIL infiltration or peripheral blood’s NLR (Neutrophil-to-Lymphocytes Ratio), PLR (Platelet-to-Lymphocytes Ratio),
(Albumin-to- Alkaline Phosphatase Ratio) AAPR, hemoglobin, or EBV DNA copies. Statistical significance was calculated using the log-rank test.

(Table 3). On the other hand, there was no significant correlation addition, several tumor-released cytokines like TNF-a and IL-6
between any of the tested factors and OS. However, upon can module albumin levels; thus, it reflects indirectly on the
validation, low CD3+TIL significantly correlated with shorter patient’s tumor status. On the other hand, alkaline phosphatase is
DFS (HR = 7.0, P < .001) and OS (HR = 9.4, P < .001), and there commonly released into the bloodstream upon bone metasta-
was borderline significance between higher PLR and shorter OS sis.[11] Therefore, AAPR has been recently used as a prognostic
(Table 4). Altogether, CD3+ TIL was the only independent marker in several malignancies, including NPC.[5,12] In our
prognostic factor that correlated significantly with DFS and OS in cohort of LA-NPC, there was a trend for a correlation between
validated multivariate analysis. AAPR and RFS; however, it did not reach statistical significance.
Neutrophils and lymphocytes constitute a large portion of
circulating white blood cells. The general state of a cancer patient
4. Discussion
can affect the expansion, activation status, or distribution of
Despite the importance of TNM staging in cancer, it is less helpful peripheral blood cells’ various components, especially neutro-
in LA-NPC, an advanced form of the disease that is common in phils and lymphocytes. Stress hormones like glucocorticoids and
some geographical regions like Saudi Arabia. We have previously catecholamine have an important complex impact on the
shown that among several immunological markers, CD3+ TIL distribution of leukocytes and their subtypes between blood,
was the most promising as a robust and practical marker to bone marrow, and tissues (Reviewed by Ince et al [13]).
estimate the prognosis of LA-NPC in our patients. In this work, Glucocorticoids can induce apoptosis of lymphocytes,[14] while
we have compared CD3+TIL with other clinicopathological adrenaline can increase lymphocyte number.[13] Although the
factors commonly associated with LA-NPC or NPC’s survival in relationship is complex, higher neutrophils in tumors in many
general. Although there was a trend for correlation between cases can reflect a failed immune response as they promote tumor
AAPR, NLR or PLR and survival, CD3+TIL was the only growth and metastasis, while they can have an antitumor effect in
significant and independent prognostic factor for LA-NPC in other situations/cancers.[15] NLR is associated with a worse
multivariate analysis. prognosis in many cancers, including breast,[16] esophageal,[17]
Albumin is the most abundant protein in the blood, and its ovarian,[18] and lung[19] cancers, as well as Hodgkin’s lympho-
level correlates with the nutritional status of patients.[10] In ma.[20] Similarly, higher NLR has been associated with a poorer

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Figure 2. Effect of various Biomarkers on the overall survival (OS) of LA-NPC patients (n = 83). Kaplan–Meier survival curves showing disease-free survival (DFS) of
patients in relation to their Tumor CD3+TIL infiltration or peripheral blood’s NLR (Neutrophil-to-Lymphocytes Ratio), PLR (Platelet-to-Lymphocytes Ratio), (Albumin-
to- Alkaline Phosphatase Ratio) AAPR, hemoglobin, or EBV DNA copies. Statistical significance was calculated using the log-rank test.

prognosis in NPC.[2,3] However, many of these reports were Platelets in the blood can facilitate tumor cell metastasis
meta-analyses that pooled data from several studies to increase through multiple mechanisms (Reviewed by Schlesinger et al [21]).
sample size and show the trend and its significance. In the current Platelets can encase tumor cells in the bloodstream and protect
study, we also found a trend of lower OS of LA-NPC patients them from natural killer cells. Furthermore, platelets can attract
with higher NLR while the significance was borderline (Fig. 2). It granulocytes to facilitate tumor cells’ extravasation from the
is possible that in larger cohorts, the statistical significance would bloodstream to form a metastatic colony. The platelet-to-
be reached. lymphocyte ratio (PLR) is an inflammatory marker applied for

Table 3
Multivariate Cox proportional hazard survival analysis for clinicopathological features and other biomarkers as disease-free survival and
overall survival in 83 patients with LA-NPC.
DFS OS
∗
HR 95% CI P HR 95% CI P
AGE .422 .736
GENDER .638 .738
WHO TYPE .201 .922
Trial Arm .509 .927
UICC Stage .207 .236
CD3+TIL 6.0 1.7–21.0 .005 8.2 0.7–97.0 .095
AAPR 3.2 1.1–10.0 .040 .651
NLR .908 .446
PLR .122 .184
HG .546 .917
EBV DNA copies .400 .444
∗
P values in bold represent significant data of the multivariate analysis before validation.

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Table 4
Validated Multivariate Cox proportional hazard survival analysis for clinicopathological features and other biomarkers as disease-free
survival and overall survival in 83 patients with LA-NPC.
DFS OS
HR 95% CI nP HR 95% CI nP
AGE 1.000 1.000
GENDER 1.000 1.000
WHO TYPE 1.000 1.000
Trial Arm 1.000 1.000
UICC Stage 1.000 1.000
CD3+TIL 6.9 2.3–21.1 <0.001 9.6 1.1–81.3 0.038
AAPR 1.000 1.000
NLR 1.000 1.000
PLR 1.000 6.8 0.81–56.1 0.077
HG 1.000 1.000
EBV DNA copies 1.000 1.000
nP represents the significant data after validation using forward selection and the Bayesian information criterion (BIC) validation method.

many diseases, including cancer. PLR is associated with a worse Acknowledgments

prognosis of many cancers.[22] Similarly, meta-analyses from a We would like to thank King Abdulaziz City for Science and
pool of several studies have shown that PLR is associated with Technology (KACST) for supporting this work financially under
poor prognosis in NPC.[4,23] In the current study, higher PLR was the national science and technology NSTP project #12-
associated with shorter OS (P = .036, Fig. 2); however, the MED2423-20 (Nasser Al-Rajhi).
association was not statistically significant in multivariate
analysis.
Generally, lower baseline hemoglobin (<110 g/L) is associated Author contributions
with a worse status of patients in NPC;[6] however, there was no Conceptualization: Nasser Al-Rajhi, Hazem Ghebeh.
significant correlation of baseline hemoglobin with the survival of Data curation: Nasser Al-Rajhi, Shamayel F. Mohammed, Hatim
NPC patients in this study. As expected, lower baseline A. Khoja, Mohammad Al-Dehaim, Hazem Ghebeh.
hemoglobin was associated with young and female patients, Formal analysis: Hazem Ghebeh.
factors that tend to be associated with better survival making the Funding acquisition: Nasser Al-Rajhi.
association between hemoglobin and NPC complicated in Investigation: Hazem Ghebeh.
countries with relatively young patients like Saudi Arabia. Methodology: Hazem Ghebeh.
The EBV DNA copy number in blood post-treatment is Project administration: Hazem Ghebeh.
associated with a worse prognosis in NPC;[7] however, there was Software: Hazem Ghebeh.
no correlation between EBV DNA copy and survival in our study. Supervision: Hazem Ghebeh.
One of our study’s limitations was the missing EBV DNA copy Writing – original draft: Hazem Ghebeh.
status in 8 samples, likely affecting the correlation results. This is Writing – review & editing: Nasser Al-Rajhi, Hazem Ghebeh.
in addition to other limitations including, being a secondary
analysis for a trial that was done for a different aim, limitation in
factors that could be analyzed and an experimental treatment References
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