World J Surg

https://doi.org/10.1007/s00268-020-05822-6

ORIGINAL SCIENTIFIC REPORT

Delta Neutrophil Index and Neutrophil-to-Lymphocyte Ratio

in the Differentiation of Thyroid Malignancy and Nodular Goiter
Mehmet Buğra Bozan1 • Fatih Mehmet Yazar1 • İlhami Taner Kale1 • Mehmet Fatih Yüzbaşıoğlu1 •
Ömer Faruk Boran2 • Ayşe Azak Bozan3

Accepted: 4 October 2020

Ó Société Internationale de Chirurgie 2020

Abstract
Background It was aimed to evaluate the relationship between delta neutrophil index (DNI) and neutrophil-to-
lymphocyte ratio (NLR) in the preoperative differentiation of nodular goiter and thyroid malignancy.
Methods Patients over the age of 18 who underwent thyroid surgery between November 2014 and November 2019
were evaluated in this retrospective cohort study. Patients were divided into two groups according to their pathology
results: malignant (Group M) and benign (Group B) thyroid disorders. White blood cell (WBC) count, neutrophil
count, lymphocyte count, IG count and DNI were measured using an automated hematological analyzer from blood
samples obtained at the preoperative period and postoperative 6th month of the follow-up. Neutrophil-to-lymphocyte
ratio (NLR) values were manually calculated. Numerical data are expressed as means ± standard deviations
(minimum–maximum values) or medians (minimum–maximum values) according to the normal distribution. Cat-
egorical values are expressed as percentages (%).
Results A total of 243 patients (190 patients in Group B and 53 patients in Group M) who met the inclusion criteria
were evaluated. The male/female ratio was 49/194. A statistically significant difference between Group M and Group
B in terms of preoperative NLR, DNI and IG count was observed (p = 0.001, \ 0.001 and \ 0.001, respectively). No
statistically significant difference was observed between the groups in terms of the control values performed in the
postoperative period in terms of the NLR, DNI and IG count (p = 0.711, 0.333 and 0.714, respectively). A significant
decrease was observed in the preoperative and postoperative DNIs, IG counts and NLRs in Group M
(p = 0.009, \ 0.001 and \ 0.001, respectively). For the diagnosis of malignant thyroid diseases, the cut-off value of
DNIs was C0.35%, and DNI sensitivity, specificity, positive predictive value (PPV) and negative predictive value
(NPV) were 79.2%, 78.9%, 79.2% and 77.9%, respectively (area under the curve [AUC]: 0.847; confidence interval
[CI]: 0.784–0.911). The cut-off value of the IG count was C25/mm3, and its sensitivity, specificity, PPV and NPV
were 83%, 72.1%, 83%, and 72.1%, respectively (AUC: 0.847; CI: 0.784–0.911).
Conclusion DNI and IG counts are cheap and easily accessible tests that can be automatically calculated from
automated systems without additional cost in differentiation of thyroid malignancies from benign disorders in the
preoperative period.

2
& Mehmet Buğra Bozan Faculty of Medicine, Department of Anesthesiology and
bbozan@yahoo.com Reanimation, Kahramanmaraş Sütçü İmam University,
Kahramanmaraş, Turkey
1
Faculty of Medicine, Department of Surgery, 3
Department of Anesthesiology and Reanimation, Necip Fazıl
Kahramanmaraş Sütçü İmam University, Kahramanmaraş, State Hospital, Kahramanmaraş, Turkey
Turkey

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Introduction
Thyroid surgery is the most common surgical procedure
among endocrine surgeries. It is performed in patients with
suspected malignancy, patients diagnosed with malig-
nancy, and patients with toxic nodular goiter [1]. Ultra-
sonographic findings can be helpful for the evaluation of
malignancies (solid composition, hypoechogenicity, irreg-
ular or infiltrative margins, microcalcifications), and sus-
picious lesions can be referred for fine-needle aspiration
biopsy (FNAB) [2]. FNAB is used as a daily technique in
preoperative evaluation to differentiate malignant and
benign nodules. However, complications including hema-
toma formation, tumor transplantation along the needle
trace, thyroid nodule infarction and vascular proliferation
can be seen even in this minimally invasive procedure [3].
Therefore, the differentiation of benign and malignant
groups using noninvasive methods before surgery has
become important.
Cancer-related inflammation, including papillary thyroid
carcinoma, is involved in carcinogenesis and the progres-
sion of neoplastic disease [4, 5]. Neutrophils induced by
the tumor can accelerate tumor metastasis [4]. Lympho-
cytes, as the cornerstone of the adaptive immune system,
inhibit tumor cell proliferation and migration and destroy
metastases [4]. Previous studies have shown that increased
lymphocyte count has a positive effect on survival in
patients with advanced cancer [6]. Furthermore, Kupffer
cells, also known as liver macrophages, destroy circulating
cancer cells and help to prevent the distribution of tumor
cells via the circulation. Therefore, routine blood test
parameters have been investigated as predictive or prog-
nostic factors for carcinomas since blood parameters in
these tests show whether there is inflammation. The neu-
trophil count, lymphocyte count, neutrophil-to-lymphocyte
ratio (NLR), lymphocyte-to-monocyte ratio (LMR), mean
platelet volume (MPV) and platelet distribution width
(PDW) have been studied in terms of numerous malig-
nancies [4].
Tumor-related inflammation is the activated bone mar-
row and inflammation induced by malignancies. Inflam-
matory activity that is poorly controlled or uncontrollable
may be responsible for malignant transformation [7]. To
this point, the NLR has previously been shown to be useful
in the differentiation of thyroid malignancies and benign
thyroid diseases [8]. The delta neutrophil index (DNI) and
an increased immature granulocytes (IG) count represent
active bone marrow. The delta neutrophil index, which is
manifested by IG formation in inflammatory and infectious
events, shows changes in the white blood cell count [9].
This study aimed to evaluate the relation between the
automatically calculated DNI/IG count and the manually
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calculated NLR from the complete blood (CB) count
parameters in the preoperative period and their ability to be
used as cost-effective, noninvasive indicators of the
malignant inflammatory response in the differentiation of
nodular goiter and thyroid malignancy.
Materials and methods
Patients over the age of 18 who underwent thyroid surgery
(bilateral total thyroidectomy, unilateral total thyroidec-
tomy, bilateral subtotal thyroidectomy, unilateral subtotal
thyroidectomy, bilateral near-total thyroidectomy for
nodular goiter and thyroid malignancy, complementary
thyroidectomy for recurrent cases) between November
2014 and November 2019 in the tertiary surgical clinic of
Kahramanmaraş Sütçü İmam University were evaluated in
this retrospective cohort study. Patients were divided into
two groups according to their pathology results: malignant
(Group M) and benign (Group B) thyroid disorders.
All procedures performed in studies involving human
participants were in accordance with the ethical standards
of the institutional and/or national research committee and
with the 1964 Declaration of Helsinki and its later
amendments or comparable ethical standards. The study
was approved by the Bioethics Committee of the Medical
Faculty of Kahramanmaraş Sütçü İmam University (Date:
27.11.2019; Session Number: 2019/22; Decision No: 6)
(Clinical trials ID: NCT04425512).
Preoperative biopsy results of patients undergoing
FNAB in the preoperative period were investigated
according to the Bethesda Classification System [10].
White blood cell (WBC) count, neutrophil count, lym-
phocyte count, IG count and DNI (IG percentage) were
measured using an automated hematological analyzer (XN
3000; Sysmex Corp., Kobe, Japan) from blood samples
obtained at the preoperative previous week of selective
surgery as preoperative samples and postoperative 6th
month of the follow-up period as postoperative samples.
Neutrophil-to-lymphocyte ratio (NLR) values were manu-
ally calculated. The IG fraction included promyelocytes,
myelocytes and metamyelocytes but not band neutrophils
or myeloblasts [11]. Moreover, the DNI (IG percentage)
was the ratio of the IG count to the white blood cell count.
Patient data were obtained from patient epicrisis forms
and preoperative and postoperative laboratory and pathol-
ogy results recorded in the computer system.
Inclusion Criteria: Operated patients for benign or
malignant thyroid diseases.
Exclusion criteria: Patients undergoing emergency sur-
gery, patients with concomitant rheumatological disease,
pathologically diagnosed patients with any type of thy-
roiditis (e.g., Hashimoto thyroiditis, subacute thyroiditis),
World J Surg
patients with concomitant thyroidectomy for parathyroid
disease, patients with thyroid malignancies with metastasis
(nodal or distant organ metastasis) and patients whose data
were not available or whose data were missing.
Statistical analysis
The power analysis of the study was conducted with the
G-Power 3.0.10 programming system. In the estimation of
power analysis and sample size, for a power of 0.8 and an
effect size of 0.1 in the evaluation of two groups for two
repeated measures, a total of 102 patients were required.
Statistical analysis was performed using Social Package
for the Social Sciences (SPSS) version 20 software. In the
evaluation of independent groups, Kolmogorov–Smirnov
and Shapiro–Wilk tests were used to determine whether the
distribution of variables was normal. Student’s t-test or the
Mann–Whitney U-test was used to evaluate the numerical
data between groups. The chi-squared test or Fischer’s
exact test was used to evaluate categorical data. For the
related samples, the Wilcoxon rank test was used to eval-
uate the differences between the preoperative numerical
values and the postoperative numerical values. Sensitivity
and specificity values and cut-off values were obtained via
the receiver operating characteristic (ROC) curve analysis
to evaluate the effectiveness of the NLR, IG count and
DNI.
Numerical data are expressed as means ± standard
deviations (minimum–maximum values) or medians
(minimum–maximum values) according to the normal
distribution. Categorical values are expressed as percent-
ages (%).
Results
The data of 302 patients who underwent thyroid surgery
between November 2014 and November 2019 in the
Kahramanmaraş Sütçü İmam University Department of
General Surgery were evaluated, retrospectively. A total of
243 patients (190 patients in Group B and 53 patients in
Group M) who met the inclusion criteria were evaluated
(Fig. 1).
When the patients were examined in terms of sex, the
male/female ratio was 49/194. The mean age of male and
female patients was 53 (27—81) years and 46 (19—76)
years, respectively (p = 0.286). Demographic data and
FNAB distributions of the patients are presented in Table 1.
A statistically significant difference between Group M
and Group B in terms of preoperative NLR, DNI and IG
count was observed (p = 0.001, \ 0.001 and \ 0.001,
respectively) (Table 2). No statistically significant differ-
ence was observed between the groups in terms of the
control values performed in the postoperative period in
terms of the NLR, DNI and IG count (p = 0.711, 0.333 and
0.714, respectively) (Table 3).
In the present study, a significant decrease was observed
in the preoperative and postoperative DNIs, IG counts and
NLRs in Group M (p values: 0.009, \ 0.001 and \ 0.001,
respectively).
ROC curve analysis of preoperative NLRs, DNIs and IG
counts in the diagnosis of malignant thyroid diseases: For
the diagnosis of malignant thyroid diseases, the cut-off
value of DNIs was C 0.35%, and DNI sensitivity, speci-
ficity, positive predictive value (PPV) and negative pre-
dictive value (NPV) were 79.2%, 78.9%, 79.2% and
77.9%, respectively (area under the curve [AUC]: 0.847;
confidence interval [CI]: 0.784–0.911). The cut-off value
of the IG count was C 25/mm3, and its sensitivity, speci-
ficity, PPV and NPV were 83%, 72.1%, 83% and 72.1%,
respectively (AUC: 0.847; CI: 0.784–0.911). These values
were higher than the NLR for both parameters in Group M
preoperatively (Fig. 2 and Table 4).
Pathologic Results: Our pathological results are similar
with the literatural view, and papillary thyroid carcinoma
was the most seen malignant thyroid pathology (Table 5).
Discussion
Thyroid nodules are one of the clinically and radiologically
common pathologies. The most common type among the
malignant nodules is differentiated thyroid cancer, and its
incidence has been increasing throughout the world
[12, 13]. It is important to differentiate benign and malig-
nant thyroid nodules in 7–15% of thyroid nodules [14].
In the preoperative evaluation, ultrasonography shows
the characteristics of thyroid disorders. These characteris-
tics are used to differentiate malignant and benign thyroid
disorders. Solid and hypoechoic nodules, a partial solid
component in a cystic lesion, microcalcifications (repre-
senting fine stippled psammomatous calcifications), and
irregular margins of a hypoechoic halo are associated with
thyroid malignancies [15, 16].
Nodule size is a nonspecific finding; however, larger
nodules demonstrate increased rates of malignancy on
biopsy. The relationship between size and malignancy rates
is not linear, and the approximate threshold for increased
malignancy is 2 cm, beyond which cancer rates do not
increase [15]. In our study, the nodule size was higher in
benign thyroid disorders. This difference was thought to be
the result of operative criteria for benign thyroid disorder
patients. In our clinic, we are more likely to operate on
giant nodular goiter patients with compression symptoms
such as respiratory distress and forced ventilation.
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Patients with hyperthrophic nodules (with complaints as

shortness of breath, asthma, chronic obstructive lung diseases),
thyrotoxiosis (Tachicardia, anger, pitosis), mass in the neck
n: 343

Applied diagnostic tests

Ultrasonography
Thyroid function tests
Complete Blood Cell Count

Excluded from the study

Toxic goiter: 37
Malignancies with lymph node metastasis in
ultrasonography: 4

Thyroid Biopsy for suspicios lesions for malignancies in ultrasonography

(microcalcifications, solid hypoechoic nodules, irregular margins) and >1
cm larger nodules
n: 267
Operation without biopsy nodules with a diameter greater than 4 cm
n: 35

Thyroid Surgery Patients

n: 302

Excluded from the study

Thyroiditis in pathologic findings: 26
Malignancies with lymph node metastasis in pathologic
results: 5
Patients with concomitant other organ malignancies: 4
Patients operated for concomitant parathyroid diseases: 8
Patients with missing data: 10

Patients included to the study

n: 243

BenignNodular Goiter (Group B) Thyroid Malignancies (Group M)

n: 190 n: 53

Fig. 1 Flowchart of case distribution of the study

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Systemic inflammatory responses in malignancies may
be due to hematopoietic changes, endocrine hormones and
nonspecific neuroendocrine metabolism caused by tumor
hypoxia, necrosis or local tissue damage [17]. The tumor
microenvironment and inflammatory response have an
important role in stimulating tumor cell proliferation, sur-
vival, angiogenesis, invasion and metastasis. This stimu-
lation is achieved through the stimulation of T lymphocytes
and chemokines and through the activation of cytokines,
interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF
alpha) and C-reactive protein (CRP) [18–20]. Cancer cells
secrete myeloid growth factors (granulocyte colonizing
factor, IL-1, IL-6 and TNF alpha), leading to tumor-related
leukocytosis and neutrophilia [17].
The NLR is an indicator of both inflammatory burden
(neutrophil count) and regulatory mechanisms (lymphocyte
count) in inflammatory diseases [21]. The increase in NLR
values in the preoperative period has been reported to be a
sign of poor prognosis in some types of cancer (lung,
gastric, pancreatic, cholangiocarcinoma, colorectal and
ovarian cancers) [17]. Accordingly, the NLR is an indicator
of the stimulation of cancer progression and the microen-
vironment by factors that stimulate tumor growth, such as
vascular endothelial growth factor, hepatocyte growth
factor, matrix metalloproteinases and elastases [17, 22, 23].
In a study by Seretis et al. [24] involving patients with
papillary carcinoma, an elevated NLR was reported to be
highly associated with carcinoma. Additionally, PLR is a
new type of hemotologic parameter that worked for dif-
ferent types of malignancies as a prognostic factor in
gastric, ovarian, colorectal, and pancreatic cancer and
cholangiocarcinoma [25]. In a study conducted by Yildiz
et al., PLR was evaluated for differentiating nodular goiter
and papillary thyroid cancer in 90 patients and PLR can be
a helpful marker for distinguishing these two pathologies
[26]. Ari and Gunver have reported that PLR and NLR
levels are higher in patients with papillary carcinoma than
in healthy individuals [25]. In contrast to these studies, in a
meta-analysis conducted by Liu et al. [27], it has been
reported that this parameter cannot be used to differentiate
patients with goiter and patients with differentiated thyroid
carcinoma. In the present study, elevated NLR values were
found to be significantly higher in thyroid malignancies
than in benign thyroid disorders. However, our results
showed low specificity and sensitivity for the NLR.
Immature granulocytes are indicative of increased
myeloid cell production. The number of immature granu-
locytes increases in the presence of inflammatory and
infectious conditions. The DNI is a new inflammatory
marker that indicates circulating IG fractions. Since it can
be measured with automated devices, the DNI can be
analyzed rapidly and simultaneously with the complete
blood count [28]. In previous studies, it was shown that the
DNI was used in the analysis of different types of infec-
tions (sepsis, acute appendicitis, acute pancreatitis, pneu-
monia, etc.) and noninfectious inflammatory responses
(cardiac mortality risk) [29–31]. In the present study, the
increase in DNIs was more pronounced in patients with
thyroid malignancies than in patients with nodular colloidal
goiter, and this difference was statistically significant. In

Table 1 Demographic parameters, preoperative ultrasonographic diameter results of the lesions and preopreative FNA evaluation rates of groups
[11]
Group B Group M p values
(n = 190) (n = 53)

Age (years) [median (min–max)] 47 (19 – 76) 47 (27 – 81)

Gender [n (%)] Male 18.4% (35/190) 26.4% (14/53) 0.2
Female 81.6% (155/ 73.6% (39/53)
190)
Preoperative ultrasonographic diameter of the lesion (mm) 30 (5 – 100) 18 (2 – 90) 0.002*
Preoperative FNAB Nondiagnostic or Unsatisfactory 15.8% (30/190) 3.8% (2/53)
results Benign 60.5% (115/ 17% (9/53)
190)
Atypia of undetermined significance or follicular lesion of 8.4% (16/190) 18.9% (10/53)
undetermined significance
Follicular neoplasm or suspicious for a follicular neoplasm 1.6% (3/190) 13.2% (7/53)
Suspicious for malignancy 1.1% (2/190) 18.9% (10/53)
Malignant 0.5% (1/190) 17% (9/53)
Preoperative FNAB not applied 12.1% (23/190) 11.3% (6/53)
*
p \ 0.05
(Group B: benign thyroid disorders; Group M: malignant thyroid disorders; FNAB: fine-needle aspiration biopsy)

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Table 2 Preoperative NLR, DNI and IG count between Group M and Group B
Group B Group M p -value
Med Mean ± SD Min–Max Med Mean ± SD Min–Max

NLR 1.71 1.88 ± 0.86 0.08 – 5.92 2.09 2.29 ± 1.02 1.1 – 6.5 0.012*
DNI (%) 0.3 0.27 ± 0.11 0 – 0.5 0.5 0.6 ± 0.48 0.2 – 3.2 \ 0.001*
IG (/mm3) 20 20.47 ± 10.3 0 – 60 40 55.47 ± 59.3 10 – 430 \ 0.001*
*
p \ 0.05
NLR Neutrophil/Lymphocyte ratio, IG immature granulocyte count, DNI delta neutrophil index/immature granulocyte percentage, Med Median,
SD standard deviation, Group M malignant thyroid disorders, Group B benign thyroid disorders

Table 3 Postoperative NLR, DNI and IG count between the Group M and Group B
Group B Group M p-value
Med Mean ± SD Min–Max Med Mean ± SD Min–Max

NLR 1.89 2.09 ± 0.98 0.81 – 6.95 1.84 1.92 ± 0.62 0.97 – 3.44 0.784
DNI (%) 0.3 0.30 ± 0.11 0.1 – 0.8 0.3 0.35 ± 0.23 0 – 1.5 0.522
IG (/mm3) 20 24.36 ± 13.45 10 – 90 20 28.14 ± 22.70 0 – 130 0.745
*
p \ 0.05
NLR Neutrophil/Lymphocyte ratio, IG immature granulocyte count, DNI delta neutrophil index/immature granulocyte percentage, Med median,
SD standard deviation, Group M malignant thyroid disorders, Group B benign thyroid disorders, Group C control group

Fig. 2 ROC of the NLRs, DNIs

and IG counts for malignant
thyroid disorders

the postoperative period, these values decreased signifi- Group M and Group B. Since there is no study in the
cantly in the malignant group compared to the preoperative literature on this subject, no literature comparison could
period, and no significant difference was observed between have been made. As stated by Yuen et al. in their

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Table 4 The receiver operating characteristic (ROC) analysis of preoperative NLR, DNI and IG count for malignant thyroid disorders
Parameters ARUC Asymptotic 95% confidence p-value Sensitivity (%) Spesivity (%) Cut-off value PPV (%) NPV (%)
interval
Lower bound Upper bound

NLR 0.613 0.535 0.690 0.009* 62.3 49.6 C 1.77 62.3 54.7
DNI (%) 0.847 0.784 0.911 \ 0.001* 79.2 78.9 C 0.35 79.2 77.9
IG Count (/mm3) 0.869 0.809 0.929 \ 0.001* 83 72.1 C 25 83 72.1
*
p \ 0.05
NLR Neutrophil/Lymphocyte ratio, IG immature granulocyte count, DNI delta neutrophil index/immature granulocyte percentage, ARUC area
under curve, CI confidence interval, PPV positive predictive value, NPV negative predictive value

In conclusion, the DNI and IG count, which are among

Table 5 Pathologic results of Group M
the complete blood count parameters, are inexpensive and
Pathology Count (n%) easily accessible tests that can be examined using auto-
Follicular thyroid carcinoma 5 (9.4)
mated systems in the differentiation of benign nodular
goiter and thyroid malignancies in the preoperative period.
Medullary thyroid carcinoma 2 (3.8)
The effectiveness of this study, which can be considered a
Papillary thyroid carcinoma 46 (86.8)
preliminary study, can be improved with large, prospective
Total 53 (100)
and multicenter studies involving a larger number of
patients with malignancies.

hypotheses, an increase in the inflammatory response in Fundings

patients with malignancy without septic inflammation
suggests that it may be associated with inflammation. None
Therefore, DNIs and IG counts appear to be important
markers with high specificity and sensitivity rates in dif- Compliance with ethical standards
ferentiating between thyroid malignancy and nodular goi-
Conflict of Interest The authors declare that they have no conflicts
ter. However, it must be kept in mind that local infections of interest.
can affect the neutrophil and immature granulocyte count.
For this reason, retrospective results can be affected by Ethical approval The Bioethics Committee of the Medical Faculty
these conditions and prospective studies can diminish this of Kahramanmaras Sütçü Imam University (Date: 27.11.2019; Ses-
sion Number: 2019/22; Decision No: 6)
problem.

Limitations
References
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measurement of the DNI and IG count can be used to
differentiate thyroid cancers from nodular colloidal goiter,
as far as we know, in the literature. This feature is an
important advantage of our study.
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