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139]

Original Article
Rosekeila Simões
Nomelini,
Ana Flávia
Neutrophil‑to‑lymphocyte ratio and Carrijo Chiovato,
Fernanda

platelet count as prognostic factors in Beatriz Ferreira

Abdulmassih,

ovarian malignancies
Rafael de
Carvalho da Silva,
Beatriz Martins
Tavares-Murta1,
ABSTRACT Eddie Fernando
Candido Murta
Objective: The objectives of the present study were to demonstrate the influence of neutrophils, platelets, and neutrophil–lymphocyte
ratio (NLR) in the ovarian cancer prognosis and to compare these parameters with benign ovarian neoplasms. Department of
Maternal-Child,
Materials and Methods: Records of patients underwent surgery for ovarian cysts were evaluated. There were 72 malignant neoplasms
Research Institute of
and 213 benign neoplasms. Age, parity, histologic type, tumor stage, type of surgery performed, chemotherapy, disease-free survival, Oncology (IPON)/
serum levels of tumor markers, neutrophils, lymphocytes, platelets, and NRL were recorded. The Mann-Whitney, the Chi-square Discipline of
test and multiple linear regression were used. A P-value < 0.05 was established as the significance level. Gynecology and
Obstetrics, Federal
Results: Higher values of platelets, neutrophils, and NLR were found in malignant tumors (P = 0.0132, P = 0.0208, and P < 0.0001,
University of
respectively), while lymphocytes values were higher in benign group (P < 0.0001). Preoperative platelet count 300,000/mm3 was Triângulo Mineiro,
related to less aggressive histological types (P = 0.0148). NLR <3 was related to the initial stages (P = 0.0053), and patients Minas Gerais
with disease-free survival >24 months had most often neutropenia during chemotherapy (P = 0.0482). After multivariate analysis, State, 1Department
platelets, NLR, and serum levels of CA15.3 were considered independent variables related to tumor staging (P = 0.028, P = 0.028, of Biochemistry,
Pharmacology and
and P = 0.035, respectively).
Physiology, Research
Conclusion: NLR and serum levels of platelets may represent potential prognostic factors in ovarian cancer, and they may also Institute of Oncology
serve as therapeutic targets in the future treatment strategies. (IPON)/Discipline
of Pharmacology,
Federal University of
Triângulo Mineiro,
KEY WORDS: Histological grade, neutrophil–lymphocyte ratio, ovarian neoplasms, platelets count, staging
Uberaba‑MG, Brazil

For correspondence:
INTRODUCTION neutrophils mediate a negative effect by Prof. Rosekeila Simões
Nomelini,
promoting angiogenesis and immune
Research Institute of
Ovarian cancer is currently the leading cause suppression, as well as the migration, invasion, Oncology (IPON)/
of death among gynecologic cancers. An early and metastasis of tumors.[6] Thus, the presence Discipline of
diagnosis for this cancer is difficult because of tumor‑infiltrating neutrophils, neutrophilia, Gynecology and
patients present with nonspecific symptoms in the and a high neutrophil/lymphocyte ratio (NLR) in Obstetrics, UFTM,
Av. Getúlio Guaritá,
early stages of disease.[1] Consequently, a diagnosis the blood have been associated with poor clinical 214, Bairro Abadia,
of Stage III or IV ovarian cancer is usually made. prognosis in various human cancers, including 38025‑440
Despite improvements in surgical techniques ovarian cancer.[7,8] Uberaba‑MG, Brazil.
and the advent of new chemotherapy regimens,
the rates of survival have remained relatively Other parameter associated with tumor prognosis Submitted: 28-Mar-17
unchanged.[2] is platelet count. Preoperative thrombocytosis is Revised: 18-Aug-17
a frequent finding in cases of ovarian carcinoma, Accepted: 25-Feb-18
Recent studies have demonstrated the importance and an association between advanced cancer Published: 24-Dec-19
of a patient’s inflammatory response in combination stage and high‑grade carcinomas has been
with genetic and environmental predisposition identified, thereby suggesting that platelets may Access this article online
for carcinogenesis and cancer progression. There Website: www.cancerjournal.net
This is an open access journal, and articles are distributed under the terms of the
are multiple types of cells in tumors that can Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which
DOI: 10.4103/jcrt.JCRT_304_17

contribute to tumor development.[3,4] In particular, allows others to remix, tweak, and build upon the work non‑commercially, as long as Quick Response Code:

endothelial cells, fibroblasts, and inflammatory appropriate credit is given and the new creations are licensed under the identical terms.

cells have key roles.[5] Among inflammatory cells, For reprints contact: reprints@medknow.com

Cite this article as: Nomelini RS, Carrijo Chiovato AF, Abdulmassih FB, da Silva RC, Tavares-Murta BM, Murta EF. Neutrophil-
to-lymphocyte ratio and platelet count as prognostic factors in ovarian malignancies. J Can Res Ther 2019;15:1226-30.

1226 © 2018 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow
[Downloaded free from http://www.cancerjournal.net on Tuesday, December 7, 2021, IP: 182.2.75.139]
Nomelini, et al.: NLR and platelets in ovarian cancer
E‑mail: rosekeila@terra.com.br, rosekeila.nomelini@pesquisador.cnpq.br
play a role in tumor growth and progression.[9,10] A shorter
disease‑free survival period has also been observed in
patients with epithelial ovarian cancer and preoperative
thrombocytosis.[9]
The identification of new markers and methods for an early
diagnosis of ovarian cancer, as well as new prognostic factors,
are needed. Therefore, the aims of the present study were to
assess and compare the platelet count and NLR in the peripheral
blood of patients with benign versus malignant ovarian tumors
before surgery, identify possible associations between NLR
and preoperative platelet count with clinical, laboratory, and
pathological prognostic factors in cases of malignant ovarian
cancer, and verify whether chemotherapy‑induced neutropenia
during treatment is related to disease‑free survival.
MATERIALS AND METHODS
This retrospective study was approved by the Research
Ethics Committee of the University. Patients who were
treated at the Pelvic Mass Clinic and underwent surgery
for an ovarian cyst were evaluated. Each cyst received a
confirmed pathological diagnosis of malignant (n = 72) or
benign (n = 213). The criteria for surgical treatment were
anechoic cysts with a maximum diameter of <7 cm, with
persistence of alteration for more than 6 months and normal
tumor markers; altered tumor markers; anechoic cysts with
a maximum diameter ≥7 cm; ovarian masses with solid
contents, presence of intracystic vegetation, thick septa, 2 or
more fine septa; bilaterality; presence of ascites; and Doppler
color with resistance index ≤0.4.[11,12] Laparotomy was the
approach of choice except for anechoic and small cysts. Patients
who needed chemotherapy used platinum‑based regimens.
The inclusion criterion was the histological diagnosis of ovarian
neoplasia. Exclusion criteria were torsion of the adnexal
pedicle, secondary malignant ovarian neoplasia (metastasis),
previous antineoplastic treatment; immunosuppressive
diseases; and relapse.
Regarding histological grade, malignant neoplasms were
classified as well differentiated (Grade 1), moderately
differentiated (Grade 2), and poorly differentiated (Grade 3).
Well‑differentiated tumors and Stages I and II (FIGO) were
considered tumors of better prognosis than moderate and
poorly differentiated tumors and Stages III and IV.
For each patient, age, parity, histologic type, tumor stage, type
of surgery performed, chemotherapy, disease‑free survival,
and serum levels of tumor markers, neutrophils, lymphocytes,
and platelets were recorded. NLR was evaluated during
chemotherapy and was also recorded.
Journal of Cancer Research and Therapeutics - Volume 15 - Issue 6 - October-December 2019
Data were analyzed with GraphPad Prism software 6 (La
Jolla, CA, USA) and SPSS software (Version 22.0. Armonk, NY:
IBM Corp). Mann–Whitney test was used to compare benign
and malignant groups, and Chi‑square test was used to assess
prognostic factors. Subsequently, a multivariate analysis
was performed (multiple linear regression). A P < 0.05 was
established as the significance level.
RESULTS
Platelet counts, absolute number of neutrophils, and NLR were
higher in malignant ovarian tumors group compared with
benign ovarian tumors group (P = 0.0132, P = 0.0208, and
P < 0.0001, respectively). In contrast, absolute lymphocyte
counts were lower in the malignant tumor patients compared
with the benign tumor patients (P < 0.0001) [Table 1].
A NLR <3 was associated with Stages I and II ovarian
tumors (P = 0.0053), thereby suggesting a better prognosis.
However, there were no statistically significant associations
identified between NLR and tumor grade, histological type, or
lymph node status. Regarding histological grade, platelet serum
levels <350,000/mm3 were found to be related to histological
Table 1: Neutrophil‑lymphocyte ratio, absolute number of
neutrophils, lymphocytes and platelets in the peripheral
blood in benign and malignant groups
Benign Malignant
NLR 1.9 (1.3‑2.7) 2.6* (1.9‑4.5)
Neutrophils ×103/mm3 4.3 (3.4‑5.6) 5.0+ (3.7‑6.8)
Lymphocytes ×103/mm3 2.2 (1.9‑2.8) 1.8* (1.2‑2.1)
Platelets ×103/mm3 250 (211‑300) 275+ (236‑333)
*P<0.0001, P<0.05 compared with the benign
+
group (Mann‑Whitney). Values are medians (25‑75 percentiles).
NLR=Neutrophil‑lymphocyte ratio
Figure 1: (a) Association between neutrophil–lymphocyte ratio and
tumor staging (P = 0.0053). (b) Association between platelet counts
and histological grade (P = 0.02). (c) Association between neutropenia
during chemotherapy and disease‑free survival (P = 0.0482)
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Nomelini, et al.: NLR and platelets in ovarian cancer
Table 2: Multivariate analysis considering staging,
histological grade, and lower neutrophil value during
chemotherapy treatment
Variable P surgeries, respectively.[24] For patients with ovarian cancer, high
Staging Histological grade
Age 0.359 0.859
Platelets 0.028 0.141
NLR 0.028 0.568
CA‑125 0.322 0.951
CA‑15.3 0.035 0.241
CA‑19.9 0.274 0.305
Multivariate analysis (multiple linear regression). NLR=Neutrophil‑lymphocyte
ratio
Grade 1 (P = 0.02). An analysis of the absolute number of
neutrophils present in patients undergoing chemotherapy
demonstrated that the incidence of neutropenia during
treatment was related to disease‑free survival. In particular,
patients with a disease‑free survival period longer than
24 months more frequently developed neutropenia (a neutrophil
count <1200/mm3) during chemotherapy (P = 0.0482) [Figure 1].
Subsequently, multivariate analysis (multiple linear regression)
was performed. Platelets, NLR, and serum levels of CA15.3
were considered independent variables related to tumor
staging (P = 0.028, P = 0.028, and P = 0.035, respectively).
Regarding the histological grade, no significant association
was found [Table 2].
DISCUSSION
An inflammatory response can lead to an increase in
neutrophil levels and a reduction in lymphocyte levels.[13] For
ovarian tumors, platelet count may be higher in malignant
tumors compared with benign tumors.[14‑16] In a study that
evaluated the association between preoperative NLR and
histopathologically diagnosed adnexal tumors, higher
NLR values predicted ovarian cancer with a cutoff value
of 3.35 (sensitivity 55% and specificity 81%).[17] The NLR,
platelet–lymphocyte ratio, and neutrophil, CA‑125, and platelet
values were higher in the malignant neoplasms compared with
the benign tumors, whereas lymphocyte values were lower in
cases of ovarian cancer.[18] One study demonstrated that the
association of thrombocytosis with CA‑125 levels improves
specificity and positive predictive value in the diagnosis of
malignant adnexal tumors.[16] In the present study, NLR and
absolute neutrophil counts were higher, while the absolute
number of lymphocytes was lower, in the cases of ovarian
cancer that were examined. There is visible strong need of
more numerous study groups for analyzes the role of NLR in
the differentiation between benign and malignant neoplasms.
Blood count parameters have been linked to the prognosis
for both malignant and borderline ovarian tumors.[19‑23] For
tumor‑infiltrating neutrophils, elevated blood neutrophils
and a high NLR have been associated with a worse prognosis
for several types of malignancies. In addition, less effective
1228 Journal of Cancer Research and Therapeutics - Volume 15 - Issue 6 - October-December 2019
therapeutic results have been achieved when neutrophil counts
are high.[7] High preoperative and postoperative NLRs have also
been associated with advanced stage tumors and suboptimal
preoperative values of NRL have been associated with a worse
response to platinum‑based, first‑line chemotherapy, and poor
clinical outcome.[25] NRL has also been related to advanced FIGO
stage, higher CA‑125 serum levels, more extensive ascites, less
chemotherapeutic response,[26] and shorter overall survival
and disease‑free survival.[8] CA‑125 positively correlates with
neutrophil count and inversely correlates with lymphocyte
count, thereby suggesting that tumors secrete CA‑125 and
neutrophilic growth factors.[27] These data are in agreement
with our study, in which NLR <3 was associated with Stages
I and II ovarian tumors. Multivariate analysis demonstrated
that NLR is directly related to staging.
One of the parameters associated with tumor prognosis is
platelet count and preoperative thrombocytosis frequently
presents in cases of ovarian carcinoma. For patients with
advanced epithelial ovarian cancer, an association between
advanced tumor stage and poor prognostic factors of survival
have been observed.[9,15,28] A high platelet count at the time of
debulking surgery has also been associated with suboptimal
resection and a shorter overall survival period.[29] This can
be explained by the direct proliferative effect of platelets on
cancer cells that have been observed both in vivo and in vitro,
thereby suggesting that patients with ovarian cancer and
thrombocytosis have high rates of tumor proliferation compared
with patients with normal platelet counts.[30] In the present
study, circulating platelet levels <3,50,000 platelets/mm3 were
associated with well‑differentiated tumors, and this would
suggest a better prognosis. In multivariate analysis, absolute
platelet value was directly related to staging.
Conventionally, neutropenia is considered a side effect
of chemotherapy that should be avoided. Moreover,
chemotherapy‑induced neutropenia has been associated with
prognosis in various types of cancer.[31‑35] In a meta‑analysis,
chemotherapy‑induced neutropenia or leukopenia was found
to be related to improved survival in patients with advanced
cancer or hematological malignancies.[36] However, in another
study, no relationship between chemotherapy‑induced
neutropenia and prognosis in ovarian cancer was observed.[37]
In the present study, patients with a disease‑free survival
period longer than 24 months more frequently developed
neutropenia during chemotherapy.
The discovery of new prognostic factors in ovarian cancer
may lead to better treatment. Thus, more aggressive
adjuvant treatments may be performed in patients with
worse prognostic factors. In addition, the blood count is an
inexpensive and affordable test.
The main limitation of the study is the small amount of patients.
Further studies with a larger sample are needed to better
[Downloaded free from http://www.cancerjournal.net on Tuesday, December 7, 2021, IP: 182.2.75.139]
Nomelini, et al.: NLR and platelets in ovarian cancer
elucidate the role of platelets and NLR in ovarian cancer. Our data
demonstrate that these blood count parameters may represent
potential prognostic factors in ovarian cancer, and they may also
serve as therapeutic targets in the future treatment strategies.
Acknowledgment
The authors wish to acknowledge the funding received from
the   CNPq (National Council for Scientific and Technological
Development), FUNEPU (Foundation for Teaching and Research
in Uberaba), and the FAPEMIG (Foundation for Research
Support of Minas Gerais state).
Financial support and sponsorship
This study was financially supported by CNPq (National
Council for Scientific and Technological Development), FUNEPU
(Foundation for Teaching and Research in Uberaba), and the
FAPEMIG (Foundation for Research Support of Minas Gerais
state).
Conflicts of interest
There are no conflicts of interest.
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