2021, Volume 37, Number 3, Page(s) 239-248
Prognostic and Predictive Significance of PD-L1 Expression in Non-Small Cell Lung Cancer Patients: A Single-Center Experience
Hacý ARAK1, Aydýn AYTEKIN1, Ozlem CANOZ2, Metin OZKAN3
1Department of Medical Oncology, Gaziantep University School of Medicine, GAZIANTEP, TURKEY
2Department of Pathology, Erciyes University School of Medicine, KAYSERI, TURKEY
3Department of Medical Oncology, Erciyes University School of Medicine, KAYSERI, TURKEY
Keywords: Lung, Non-small cell cancer, PD-L1, H-score
To investigate the prognostic and predictive value of PD-L1 expression in operated non-small cell lung cancer (NSCLC) patients and
to analyze its relationship with clinicopathological factors.
Material and Method: A total of 90 patients with operable NSCLC were included in this retrospective single center study. Tumor blocks of
patients were stained immunohistochemically with PD-L1 polyclonal antibody. When evaluated immunohistochemically and statistically,
patients with tumor staining percentage of ≥5%, those with +2 and +3 membranous staining intensity, and those with ≥50% H-Score were
considered positive. The relationship between PD-L1 expression status and clinicopathological features in addition to the prognostic effect of
PD-L1 on survival were statistically analyzed.
Results: The frequency of PD-L1 expression was 37%, 15% and 5% according to the staining percentage, staining intensity, and the H-Score,
respectively. There was no significant relationship between PD-L1 expression and age, gender, smoking, tumor stage and histological subtype
(p> 0.05). However, PD-L1 expression was relatively higher in patients <65 years of age, men, smokers, patients with advanced tumor stage, and
squamous cell subtype. Based on the analysis of the H-Score, no significant difference was noted regarding disease-free survival time between
PD-L1 positive and PD-L1 negative patients (median 20 [95% CI 1.2-38.7] months vs. median 27 [95% CI 17.5-36] months, p=0.208). However,
overall survival time was significantly shorter in PD-L1 positive compared to PD-L1 negative patients (median 24 months [95% CI 9.9-38] vs.
median 48 months [95% CI 33.6-62.3], p=0.049).
Conclusion: In patients with high PD-L1 expression, the biological behavior of the cancer was more aggressive, and the life expectancy was
shorter. PD-L1 expression seems to be a poor prognostic marker in NSCLC patients.
Lung cancer, accounting for 18.4% of cancer-related deaths in
the world, is the leading cause of cancer-related death in men,
and the second most common cause of cancer-related death in
. Non-small cell lung cancer (NSCLC) constitutes
80% of all lung cancers, and most patients with NSCLC are
diagnosed at an advanced stage, with a 5-year survival rate
of 19% 2
. Although the introduction of platinum-based
chemotherapies and drugs for driver mutations has enabled
a survival advantage in subgroups of patients, more effective
and general treatments are needed given the continued
progression of metastatic NSCLC disease 3
In recent years, immune system modulation has been
increasingly addressed in cancer treatment, particularly
tumor cell escape from the attack of the immune system
via inhibition of immune checkpoint molecules 4. The
best known signaling pathways of immune checkpoints are T-lymphocyte antigen-4 and programmed cell death-1 (PD-
1) / programmed cell death ligand-1 (PD-L1) 5. The coinhibitory
factor PD-1 binds to its ligands, PD-L1/PD-L2,
to transmit inhibitory signals in T cells and anti-apoptotic
signals in tumor cells. Thus, the PD-1/PD-L1 pathway is
characterized as one of the major mechanisms of tumor
immune escape. The PD-1/PD-L1 axis is also a physiological
signaling pathway that causes depletion and inactivation of
T cells to prevent the autoimmune response 6.
Immunotherapy with checkpoint inhibitors developed
for the PD-1/PD-L1 pathway has become a new method
in lung cancer treatment. Immunotherapy aims to ensure
recognition of cancer cells by the immune system, increased
sensitivity of the immune system, and reduction in immune
system inhibition. Nevertheless, the same response cannot
be obtained in all patients. PD-L1 expression level and
clinicopathological characteristics of the patients may be a
determining factor 7.
PD-L1 expression is a poor prognostic factor in cancers
such as stomach cancer, hepatocellular carcinoma, renal
cell carcinoma, esophageal cancer, pancreatic cancer,
ovarian cancer, and bladder cancer 8. Conversely, PDL1
expression is associated with better clinical outcomes in
breast cancer and Merkel cell carcinoma. The prognostic
value of PD-L1 expression in NSCLC, colorectal cancer,
and melanoma is controversial 9. Additionally, the
association of PD-L1 expression with clinicopathological
factors in NSCLC patients is still unclear. Therefore, this
study was designed to determine the prognostic and
predictive value of PD-L1 expression in NSCLC patients,
and to analyze the relationship between PD-L1 expression
and clinicopathological factors.
A total of 90 patients with NSCLC were included in this
retrospective single center study, conducted at a tertiary
care oncology clinic between May 2008 and September
2015. The diagnosis of an operable NSCLC, absence of a
metastasis, and availability of sufficient tumor material for
immunohistochemical analysis of PD-L1 expression were
the inclusion criteria of the study.
The study was approved by the local Ethics Committee and
was conducted in accordance with the ethical principles
stated in the most recent version of the Declaration of
Helsinki. (Institutional Ethics Committee Decision No:
Evaluation of Clinicopathologic Characteristics
Baseline characteristics of patients (age, sex, smoking
history, tumor stage, histologic type, and Eastern
Cooperative Oncology Group [ECOG] performance
status), treatment history (surgery, chemotherapy and
radiotherapy), and clinical outcomes (survival, disease
progression) were retrieved from hospital records.
Pathologic tumor stage was defined based on the American
Joint Committee on Cancer Cancer Staging Manual, 8th
edition 10. The overall survival (OS) of the patients was
calculated as the time between the date of diagnosis and
last control or death due to disease. Disease-free survival
(DFS) time was calculated as the time between the date of
diagnosis and the date of relapse or last control or death.
For immunohistochemical staining, four-micrometer-thick
histologic sections were cut from neutral buffered formalinfixed,
paraffin-embedded tissue blocks containing the sufficient tumor tissue. Before staining with PD-L1 antibody,
various dilution ratios were tested to find the appropriate
dilution ratio in a preparation and the appropriate dilution
was determined as 1/200. Four micron-sections from each
tumor block were taken on lysine glass. The sections were
kept in the oven at 60 degrees. PD-L1 primary antibody
(CD274 Polyclonal antibody, Catalog no: EAP 0528, Rabbit,
IgG, Abcam, Cambridge, United Kingdom) was applied at
1/200 dilution. Staining was done automatically using the
Ventana Benchmark XT immunohistochemistry stainer
(Roche, Mannheim, Germany) 11. The stained slides were
passed through series of alcohol with increasing ratios
(70%, 90%, and 96%) for 5 minutes each. The stained slides
were evaluated under the light microscope.
The percentage of staining in the tumor was considered
as ≤1% (negative), 1-5% (weak positive), 5-10%
(medium positive), and 10-100% (strongly positive). For
membranous staining intensity, the score was accepted as
0: negative, 1: weakly positive, 2: medium positive, and 3:
strongly positive. According to the membranous staining
intensity, PD-L1 0+ and 1+ were considered negative,
2+ and 3+ were considered positive. The H-Score was
obtained via multiplying the tumor staining percentage
and membranous staining intensity values and ranged
from 0 to 300. While evaluating statistically, patients with
a tumor staining percentage ≥ 5%, those with +2 and +3
membranous staining, and those with ≥50% H-Score were
considered positive (12). The staining percentage and
staining intensity of some patients are shown in Figure 1AD.
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|Figure 1: Percentage of staining and staining intensity with PD-L1 in NSCLC patients with various stages and histological subtypes.
A) Tumor staining percentage of 25%, staining density + 3 histomorphological appearance of adenocarcinoma stage-1B case
immunostained with PD-L1 (Anti-PDL1 antibody, X20). B) Tumor staining percentage of 30%, staining density + 2 histomorphological
appearance of epidermoid cancer stage-2B case immunohistochemically stained with PD-L1 (Anti-PDL1 antibody, X10). C) Tumor
staining percentage of 20%, staining density + 2 histomorphological appearance of an epidermoid cancer stage-3B case stained with PDL1
immunohistochemically (Anti-PDL1 antibody, X20). D) Tumor staining percentage of 10%, staining density + 3 histomorphological
appearance of an epidermoid cancer stage-3A case immunohistochemically stained with PD-L1 (Anti-PDL1 antibody, X20).
Statistical analysis was performed using IBM SPSS
Statistics for Windows, version 21.0 (IBM Corp., Armonk,
NY). Categorical variables were analyzed with the Chi-
Square test and Fisher’s exact test, while Student’s t test
was used to analyze parametric variables. DFS and OS were
calculated with the Kaplan-Meier method and the Log-
Rank test. First, DFS and OS were compared according
to age, gender, disease stage, smoking status, history of
adjuvant chemotherapy and/or adjuvant radiation therapy,
type of surgery, histological subtype, ECOG performance
score, and membranous staining intensity by univariate
cox regression analysis, and then multivariate analysis
was performed. Data were expressed as “mean (standard
deviation; SD)”, minimum-maximum, 95% confidence
interval (CI) and percent (%) where appropriate. P<0.05
was considered statistically significant.
The age, gender, smoking status, histological subtype, stage
of the disease, developing metastasis, and median survival
times of the patients are summarized in Table I
ECOG performance scale (PS) assessment revealed that 49
(54%) of the patients were PS-0, 39 (43%) were PS-1 and 2.
Overall, 52 (57%) patients had lobectomy, 36 (40%) had
pneumonectomy, and 2 patients had segmentectomy.
Eighteen patients received radiotherapy and 66 patients
received adjuvant chemotherapy.
Expression of PD-L1 and its Relationship with the
PD-L1 was positive (tumor staining ≥ 5%) in 34 (37.0%)
patients. Based on membranous staining intensity, PDL1
was negative in 56 patients, 1+ in 20 patients, 2+ in 11
patients, and 3+ in 3 patients. According to the membranous staining scores 14 (15.0%) patients were considered to be
Based on H-Score analysis, 5 (5%) patients were considered
to be positive (H-scores ≥ 50%).
No significant difference was noted between PD-L1
negative and PD-L1 positive patients in terms of age (Mean
age 58 ± 8.3 vs. 55 ± 8.5 years, p=0.149).
In all these assessment methods, both DFS and OS were
shorter in PD-L1 positive patients. PD-L1 expression
frequency and DFS and OS times according to various
criteria are summarized in Table II.
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|Table II: Prevalence of PD-L1 by various criteria and its effect on survival
There was no statistically significant association between
PD-L1 expression and clinicopathological features such
as the patient’s age, gender, smoking status, tumor stage
and histological subtype. When the relationship between
clinicopathological features and PD-L1 expression was
examined, the intensity of membranous staining was taken
as basis. These findings are summarized in Table III.
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|Table III: Evaluation of clinicopathological features of the patients with PD-L1 expression
While patients were operable and had no metastasis at the
time of diagnosis; various distant metastases developed in
some patients during follow-up, including lymph node
metastasis in 29 (32%), bone metastasis in 15 (17%),
contralateral lung metastasis in 13 (14%), brain metastasis
in 13 (14%), liver metastasis in 9 (10%), pleural metastasis
in 7, and adrenal gland metastasis in 3 patients. There was no statistically significant association between PD-L1
expression, and the metastasis status of the patient.
PD-L1 Expression and Survival Outcomes
Based on the analysis of membrane staining intensity of
PD-L1 expression, the median DFS time was 20 months
(95% CI 4.54-35.45), 27 months (95% CI 20.35-33.68) and 25 months (95% CI 17.85-32.14) in PD-L1 positive, PDL1
negative, and total patients, respectively. PD-L1 status
had no significant impact on DFS (p=0.340). OS was
also similar between PD-L1 positive and PD-L1 negative
patients according to membranous staining intensity 24
months (95% CI 2.2-68) vs. 46 months (95% CI 39-52),
respectively (p=0.707). Kaplan-Meier plots showing the
DFS and OS times of PD-L1 positive and negative patients
according to membranous staining intensity are shown in
Click Here to Zoom
|Figure 2: Kaplan Meier plots showing the Disease-Free Survival (DFS) and Overall Survival (OS) times of Programmed death-ligand 1
(PD-L1) positive and negative patients by membranous staining intensity. A) DFS curves in PD-L1 positive and negative NSCLC patients.
B) OS curves in PD-L1 positive and negative NSCLC patients.
Based on the analysis of the H-Score, no significant
difference was noted in DFS between PD-L1 positive
and PD-L1 negative patients (median 20 [95% CI 1.2- 38.7] months vs. median 27 [95% CI 17.5-36] months,
respectively (p=0.208)), whereas OS time was significantly
shorter in PD-L1 positive vs. PD-L1 negative patients
(median 24 months [95% CI 9.9-38] vs. 48 months [95% CI
Cox regression analysis findings on potential factors
that can affect DFS (age, gender, membranous staining
intensity of PD-L1, disease stage, smoking status, adjuvant
chemotherapy status, adjuvant radiotherapy status, type of
surgery, histological subtype, and patient performance) are
summarized in Table IV.
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|Table IV: Univariate and multivariate analysis of factors affecting disease-free survival
When the parameters affecting the OS were examined
with univariate analysis, the stage of the disease, the PD-L1 positivity according to the H-score, the adjuvant
RT status, the type of surgery performed, and the patient’s
performance status were found to be significantly
associated with OS. In multivariate analysis, the stage of the
disease and the patient’s performance status were found as
independent parameters affecting OS (Table V).
Click Here to Zoom
|Table V: Univariate and multivariate analysis of factors affecting overall survival
In this study, we investigated the prevalence of PD-L1
expression in NSCLC patients and its relationship with
clinicopathological features along with its predictive and
In previous studies, cases with a tumor staining percentage
of ≥5% or membranous staining intensity of 2+ and 3+,
or an H-Score of ≥50% were considered positive for PDL1
12. In our study, the prevalence of PD-L1 in NSCLC
patients was determined to be 37%, 15% and 5% based on
tumor staining percentage, membranous staining intensity
and H-score, respectively. The H-score from all patient
samples was used as the cut-off value to standardize PDL1
positivity. Given the use of various threshold limits for
PD-L1 positivity, its prevalence has varied among different
studies 13,14, ranging from 5-57%, depending on the
method, scoring system, or antibody used, as well as the differences in race, histological subtype and disease stage
15. The significant efficacy of atezolizumab developed
for PD-L1 targeting therapy was demonstrated in the
group of NSCLC patients with high PD-L1 expression
16. Therefore, the presence of PD-L1 expression in the
NSCLC patient group is an important marker in predicting
treatment efficacy in PD-L1 targeting therapy.
Although there are many studies on PD-L1 expression in
NSCLC patients, its relation to clinicopathological features
remains unclear. In our study, no statistically significant
relationship was found between PD-L1 expression and
patients’ age, gender, or smoking status. However, PDL1
expression was relatively higher among men, patients
that are <65 years, patients with early stage disease, and
squamous cell cancer. In previous studies, in general, PDL1
protein expression was not significantly associated with
clinicopathological features of NSCLC, including gender,
age, and smoking status 17. However, in one study 18,
PD-L1 expression was reported to be associated with
smoking status in NSCLC patients. In another study, PDL1
expression was found to be high in non-smokers and
women in the Japanese population 19. This difference may
be due to the fact that the rate of women and non-smokers
in the study conducted in the Japanese population was
significantly higher than the rates in our study. In a study
by Cooper et al., PD-L1 expression was found to be high
in the young patient group 14. In this case, it is thought
that tumor tissue in young patients expresses PD-L1 in
response to the strong immune system. The relationship
between PD-L1 and clinicopathological features in NSCLC
patients is not as clear as the relationship between driver
mutations and clinicopathological features.
Our findings related to the membrane staining intensity
revealed 14 patients to have positive PD-L1 expression,
including 10 (71%), 3 (22%), and 1 (7%) patient with
squamous cell carcinoma, adenocarcinoma and large cell
carcinoma, respectively. In accordance with the majority of
the previous studies, there was no statistically significant
association between PD-L1 expression and histological
subtypes in our study. However, the positivity of PD-L1
expression was relatively higher in squamous cell carcinoma
according to the staining density. PD-L1 expression was
reported to be higher in adenocarcinoma in a study by Mu
et al. 20, whereas it was reported to be associated with
squamous cell carcinoma in a study by Velcheti et al. 21.
However, in a meta-analysis of 1550 patients by Pan et
al., the authors reported no relationship between PD-L1
expression and histological subtypes 17. This may be due
to the fact that studies are conducted with patient groups with different stages and different clinicopathological
characteristics. Squamous cell lung cancer benefited less
from drugs developed against driver mutations. Therefore,
high PD-L1 expression and benefit from immunotherapy
are important in this subgroup of patients.
The relationship between PD-L1 expression and the stage
of the disease in some cancers has been previously studied
22. In our study, there was no significant relationship
between PD-L1 expression and disease stage when stage-1
and 2 were considered as early stage and stage-3 as localadvanced
stage. However, numerically higher PD-L1
expression was observed in early stage patients. Perhaps
in the early stage of the disease, PD-L1 expression of
tumor cells increases as a response to the strong immune
system. In previous studies, no significant relationship was
reported between PD-L1 expression and disease stage 20.
The findings of the current study were also compatible with
the literature. In addition, the high PD-L1 expression in the
early stage in our study may be related to the shorter DFS
time in the PD-L1 positive group.
There is a hypothesis that when PD-L1 is positive, the
tumor can hide itself from the immune system and spread
in a shorter time and the disease may become metastatic
23. Therefore, in our study, PD-L1 expression and distant
metastasis status were investigated to determine whether
the high PD-L1 expression is related to the recurrence of the
disease or the increased risk of distant metastasis. Although
our patients were operable at the time of study enrollment,
various cases developed metastasis during the follow-up.
The distant organ metastasis involved bone, brain and liver
metastasis, supporting the literature 24. Our findings
revealed no significant association between the metastasis
status of the patients and PD-L1 expression. The high
expression of PD-L1 suggests an increase in the spread of
the disease. In a past study, a higher rate of lymph node
metastasis was found in the patient group with high PD-L1
expression 25. In addition, a high expression of PD-L1
was considered to indicate the aggressiveness of the tumor
and to be an independent risk factor for postoperative
recurrence 26. When NSCLC is PD-L1 positive, it is not
clear which organ metastases increase significantly. This
was difficult to detect in our study population.
In previous studies, the effect of PD-L1 expression on
DFS and OS in NSCLC patients was investigated 27. In
most studies, increased PD-L1 expression was found to be
associated with a short life span. On the other hand, it was
not significantly associated with survival in some studies
and reported to be a good prognostic factor in others 23.
In our study, according to the membrane staining intensity, the median DFS was 20 months (95% CI 4.5-35.4) in PDL1
positive patients, while it was 27 months (95% CI20.3-
33.6) in PD-L1 negative patients, with no statistically
significant difference between the two groups. OS was 24
months (95% CI 2.4-68) in patients with positive PD-L1
expression and 46 months (95% CI 39-52) in patients with
negative PD-L1 expression, and no statistically significant
difference was noted in OS time between the two groups.
Some parameters did not reach statistical significance in our
study due to small sample size and insufficient follow-up
time. However, when evaluated according to the H-Score,
OS time was significantly shorter in PD-L1 positive vs. PDL1
negative patients (24 months [95% CI 9.9-38] vs. 48
months [95% CI 33.6-62.3], p=0.049). DFS time was also
shorter in the PD-L1 positive vs. negative group, although
it was not statistically significant.
OS time was significantly shorter in the PD-L1 positive group
according to the percentage of staining, staining intensity,
and H-score. In this case, the positive PD-L1 in operated
NSCLC patients may require a closer follow-up regarding
recurrence. Therefore, in our study, PD-L1 positivity was
accepted as a poor prognostic factor for NSCLC patients,
similar to previous studies 7. Atezolizumab, avelumab
and durvalumab were developed for treatment against this
marker, which normally has poor prognostic value, and
this was turned into an opportunity. The predictive value
of PD-L1 expression has been used in drug efficacy studies
of anti-PD-L1 drugs 28.
In the univariate analysis, the factors significantly affecting
DFS were the stage of the disease, adjuvant chemotherapy,
adjuvant RT, the performance status of the patients, and
the type of surgery performed. In the multivariate analysis,
the stage of the disease, adjuvant chemotherapy, and
the performance status of the patients were significant
predictors of DFS. In univariate analysis, factors affecting
OS were stage of disease, PD-L1 positivity according to
H-score, adjuvant radiotherapy, type of surgery, and
patient performance. The factors affecting OS in the
multivariable analysis were the stage of the disease and the
patient’s performance status. These findings of our study
were consistent with previous studies 29-31.
Limitations associated with this study were related to its
retrospective design and relatively small sample size. In
addition, there was a possibility of cross-reactivity since
polyclonal antibodies were used in our study. However, the
results of our study should contribute to new prospective
studies on the predictive and prognostic role of PDL1
expression in patients with NSCLC, as assessed by immunohistochemistry. It will be more appropriate to
conduct studies with standard methods and antibodies in
large cohorts and homogeneous patient groups.
In conclusion, our findings revealed that the prevalence
of PD-L1 expression in NSCLC patients changes
depending on the evaluation methods and there is no wellestablished
relationship between PD-L1 expression and
clinicopathological features. When PD-L1 expression is
evaluated using standard methods, it may have predictive
value for anti-PD-L1 treatment modalities. PD-L1 positivity
is associated with shorter DFS and OS in operated NSCLC
patients. PD-L1 expression in operated NSCLC patients
may require closer follow-up due to the risk of early
recurrence. Accordingly, our findings seem to indicate PDL1
expression as a poor prognostic marker for NSCLC.
This study was carried out with the financial support of
Erciyes University Scientific Research Projects unit (Project
CONFLICT of INTEREST
The authors do not have any conflict of interest or financial
disclosures to declare.
Concept: HA, Design: HA, ÖC, MÖ, Data collection or
processing: HA, Analysis or Interpretation: HA, AA, ÖC,
Literature search: HA, Writing: HA, AA, Approval: HA,
1) Bade BC, Dela Cruz CS. Lung Cancer 2020: Epidemiology,
Etiology, and Prevention. Clin Chest Med. 2020;41:1-24.
2) Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer
J Clin. 2020;70:7-30.
3) Giaccone G. Epidermal growth factor receptor inhibitors in
the treatment of non-small-cell lung cancer. J Clin Oncol.
4) Pardoll DM. The blockade of immune checkpoints in cancer
immunotherapy. Nat Rev Cancer. 2012;12:252-64.
5) Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights
into cancer immunoediting and its three component phases-
-elimination, equilibrium and escape. Curr Opin Immunol.
6) Dong Y, Sun Q, Zhang X. PD-1 and its ligands are important
immune checkpoints in cancer. Oncotarget. 2017;8:2171-86.
7) Pawelczyk K, Piotrowska A, Ciesielska U, Jablonska K, Gletzel-
Plucinska N, Grzegrzolka J, Podhorska-Okolow M, Dziegiel
P, Nowinska K. Role of PD-L1 expression in non-small cell
lung cancer and their prognostic significance according to
clinicopathological factors and diagnostic markers. Int J Mol Sci.
8) Wang A, Wang HY, Liu Y, Zhao MC, Zhang HJ, Lu ZY, Fang YC,
Chen XF, Liu GT. The prognostic value of PD-L1 expression for
non-small cell lung cancer patients: A meta-analysis. Eur J Surg
9) Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human
cancers and its association with clinical outcomes. Onco Targets
10) Hwang JK, Page BJ, Flynn D, Passmore L, McCaul E, Brady J,
Yang IA, Marshall H, Windsor M, Bowman RV, Naidoo R, Guan
T, Philpot S, Blake ME, Fong KM. Validation of the eighth edition
tnm lung cancer staging system. J Thorac Oncol. 2020;15:649-54.
11) Lantuejoul S, Sound-Tsao M, Cooper WA, Girard N, Hirsch
FR, Roden AC, Lopez-Rios F, Jain D, Chou TY, Motoi N, Kerr
KM, Yatabe Y, Brambilla E, Longshore J, Papotti M, Sholl LM,
Thunnissen E, Rekhtman N, Borczuk A, Bubendorf L, Minami
Y, Beasley MB, Botling J, Chen G, Chung JH, Dacic S, Hwang D,
Lin D, Moreira A, Nicholson AG, Noguchi M, Pelosi G, Poleri C,
Travis W, Yoshida A, Daigneault JB, Wistuba, II, Mino-Kenudson
M. PD-L1 Testing for Lung Cancer in 2019: Perspective from the
IASLC Pathology Committee. J Thorac Oncol. 2020;15:499-519.
12) D’Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno
A, Landi L, Tibaldi C, Minuti G, Salvini J, Coppi E, Chella A,
Fontanini G, Filice ME, Tornillo L, Incensati RM, Sani S, Crinò
L, Terracciano L, Cappuzzo F. PD-1 and PD-L1 expression in
molecularly selected non-small-cell lung cancer patients. Br J
13) Lin C, Chen X, Li M, Liu J, Qi X, Yang W, Zhang H, Cai Z, Dai
Y, Ouyang X. Programmed death-ligand 1 expression predicts
tyrosine kinase inhibitor response and better prognosis in
a cohort of patients with epidermal growth factor receptor
mutation-positive lung adenocarcinoma. Clin Lung Cancer.
14) Cooper WA, Tran T, Vilain RE, Madore J, Selinger CI, Kohonen-
Corish M, Yip P, Yu B, O’Toole SA, McCaughan BC, Yearley
JH, Horvath LG, Kao S, Boyer M, Scolyer RA. PD-L1 expression
is a favorable prognostic factor in early stage non-small cell
carcinoma. Lung Cancer. 2015;89:181-8.
15) Chen YB, Mu CY, Huang JA. Clinical significance of programmed
death-1 ligand-1 expression in patients with non-small cell lung
cancer: A 5-year-follow-up study. Tumori. 2012;98:751-5.
16) Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre
A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroðlu
M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y,
Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR.
Atezolizumab for first-line treatment of PD-L1-selected patients
with NSCLC. N Engl J Med. 2020;383:1328-39.
17) Pan ZK, Ye F, Wu X, An HX, Wu JX. Clinicopathological and
prognostic significance of programmed cell death ligand1 (PDL1)
expression in patients with non-small cell lung cancer: A
meta-analysis. J Thorac Dis. 2015;7:462-70.
18) Chen YY, Wang LB, Zhu HL, Li XY, Zhu YP, Yin YL, Lü FZ,
Wang ZL, Qu JM. Relationship between programmed deathligand
1 and clinicopathological characteristics in non-small cell
lung cancer patients. Chin Med Sci J. 2013;28:147-51.
19) Azuma K, Ota K, Kawahara A, Hattori S, Iwama E, Harada T,
Matsumoto K, Takayama K, Takamori S, Kage M, Hoshino T,
Nakanishi Y, Okamoto I. Association of PD-L1 overexpression
with activating EGFR mutations in surgically resected nonsmallcell
lung cancer. Ann Oncol. 2014;25:1935-40.
20) Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression
of PD-L1 in lung cancer may contribute to poor prognosis
and tumor cells immune escape through suppressing tumor
infiltrating dendritic cells maturation. Med Oncol. 2011;28:682-8.
21) Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos
KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL.
Programmed death ligand-1 expression in non-small cell lung
cancer. Lab Invest. 2014;94:107-16.
22) Kawahara T, Ishiguro Y, Ohtake S, Kato I, Ito Y, Ito H, Makiyama
K, Kondo K, Miyoshi Y, Yumura Y, Hayashi N, Hasumi H,
Osaka K, Muraoka K, Izumi K, Teranishi JI, Uemura H, Yao M,
Nakaigawa N. PD-1 and PD-L1 are more highly expressed in
high-grade bladder cancer than in low-grade cases: PD-L1 might
function as a mediator of stage progression in bladder cancer.
BMC Urol. 2018;18:97.
23) Brody R, Zhang Y, Ballas M, Siddiqui MK, Gupta P, Barker C,
Midha A, Walker J. PD-L1 expression in advanced NSCLC:
Insights into risk stratification and treatment selection from a
systematic literature review. Lung Cancer. 2017;112:200-15.
24) Tamura T, Kurishima K, Nakazawa K, Kagohashi K, Ishikawa
H, Satoh H, Hizawa N. Specific organ metastases and survival
in metastatic non-small-cell lung cancer. Mol Clin Oncol.
25) Li H, Xu Y, Wan B, Song Y, Zhan P, Hu Y, Zhang Q, Zhang
F, Liu H, Li T, Sugimura H, Cappuzzo F, Lin D, Lv T. The
clinicopathological and prognostic significance of PD-L1
expression assessed by immunohistochemistry in lung cancer:
A meta-analysis of 50 studies with 11,383 patients. Transl Lung
Cancer Res. 2019;8:429-49.
26) Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y,
Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J. Overexpression
of PD-L1 significantly associates with tumor aggressiveness and
postoperative recurrence in human hepatocellular carcinoma.
Clin Cancer Res. 2009;15:971-9.
27) Sun JM, Zhou W, Choi YL, Choi SJ, Kim SE, Wang Z, Dolled-
Filhart M, Emancipator K, Wu D, Weiner R, Frisman D, Kim
HK, Choi YS, Shim YM, Kim J. Prognostic significance of PD-L1
in patients with non-small cell lung cancer: A large cohort study
of surgically resected cases. J Thorac Oncol. 2016;11:1003-11.
28) Schildhaus HU. Predictive value of PD-L1 diagnostics. Pathologe.
29) Zhang H, Zhang DX, Ju T, Zhou J. The effect of postoperative
radiotherapy on the survival of patients with resectable stage
III-N2 non-small-cell lung cancer: A systematic review and
meta-analysis. Neoplasma. 2019;66:717-726.
30) Burdett S, Pignon JP, Tierney J, Tribodet H, Stewart L, Le Pechoux
C, Aupérin A, Le Chevalier T, Stephens RJ, Arriagada R, Higgins
JP, Johnson DH, Van Meerbeeck J, Parmar MK, Souhami RL,
Bergman B, Douillard JY, Dunant A, Endo C, Girling D, Kato
H, Keller SM, Kimura H, Knuuttila A, Kodama K, Komaki R,
Kris MG, Lad T, Mineo T, Piantadosi S, Rosell R, Scagliotti G,
Seymour LK, Shepherd FA, Sylvester R, Tada H, Tanaka F, Torri
V, Waller D, Liang Y. Adjuvant chemotherapy for resected earlystage
non-small cell lung cancer. Cochrane Database Syst Rev.
31) O’Mahony S, Nathan S, Mohajer R, Bonomi P, Batus M, Fidler
MJ, Wells K, Kern N, Sims S, Amin D. survival prediction in
ambulatory patients with stage III/IV non-small cell lung cancer
using the palliative performance scale, ECOG, and Lung cancer
symptom scale. Am J Hosp Palliat Care. 2016;33:374-80.