10.14639/0392-100X-N1665
Objective. The aim of this study was to investigate the relationship between differentiated thyroid carcinomas (DTCs), histopathological findings and systemic immune-inflammation index (SII) [neutrophil (N) x platelet (P) / lymphocyte (L)] values. Methods. 93 patients with DTC were included. N, P and L levels were measured, and the relationship between the SII and histopathological findings was determined. The results were compared with the values of 33 healthy controls. Results. SII values were significantly higher in the patient group than in the control group (p = 0.000). Tumour pathology diagnosis had no significant effect on SII (p = 0.90). Perineural lymphovascular and capsule invasion and extrathyroidal extension also had no significant effect on SII values. SII was significantly higher in patients with more than one tumour focus (p = 0.01). No significant relationship was determined between tumour diameter and SII.Conclusions. SII is higher in patients with DTC compared to the healthy population. High SII values may be associated with multifocality. According to the results of this study, SII does not affect the histological type, perineural, lymphovascular and capsule invasion, or extrathyroidal extension of DTC.
text/xml
1827-675X
1665
en
Arzu Bilen
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
systemic immune-inflammation index
Systemic immune inflammation index in differentiated thyroid cancers
Text.Serial.Journal
https://www.actaitalica.it/
42
Thyroid
2022-05-16
2021-05-04
2022-05-23
2022-05-23
150-154
1
Arzu Bilen
2022/05/16
10.14639/0392-100X-N1665
150
Department of Internal Medicine, Ataturk University Faculty of Medicine, Erzurum, Turkey
1827-675X
systemic immune-inflammation index
154
Systemic immune inflammation index in differentiated thyroid cancers
https://www.actaitalica.it/article/download/1665/792
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:150-154; doi: 10.14639/0392-100X-N1665




Thyroid


Systemic immune inflammation index in differentiated
thyroid cancers
L’indice infiammatorio immunitario sistemico nei carcinomi differenziati della tiroide
Ayhan Kars1, Abdulkadir Sahin2, Korhan Kılıc2, Muhammed Sedat Sakat2, Arzu Bilen3
1
 Department of Otorhinolaryngology, Head and Neck Surgery, Kastamonu University Faculty of Medicine, Kastamonu, Turkey;
2
 Department of Otorhinolaryngology, Head and Neck Surgery, Ataturk University Faculty of Medicine, Erzurum, Turkey; 3 Department
of Internal Medicine, Ataturk University Faculty of Medicine, Erzurum, Turkey


SUMMARY
Objective. The aim of this study was to investigate the relationship between differentiated
thyroid carcinomas (DTCs), histopathological findings and systemic immune-inflammation
index (SII) [neutrophil (N) x platelet (P) / lymphocyte (L)] values.
Methods. 93 patients with DTC were included. N, P and L levels were measured, and the
relationship between the SII and histopathological findings was determined. The results
were compared with the values of 33 healthy controls.
Results. SII values were significantly higher in the patient group than in the control group
(p = 0.000). Tumour pathology diagnosis had no significant effect on SII (p = 0.90). Perineu-
ral lymphovascular and capsule invasion and extrathyroidal extension also had no significant
effect on SII values. SII was significantly higher in patients with more than one tumour focus
(p = 0.01). No significant relationship was determined between tumour diameter and SII.
Conclusions. SII is higher in patients with DTC compared to the healthy population. High
SII values may be associated with multifocality. According to the results of this study, SII
does not affect the histological type, perineural, lymphovascular and capsule invasion, or
extrathyroidal extension of DTC.
KEY WORDS: differentiated thyroid cancer, histopathological findings, inflammatory
parameters, systemic immune-inflammation index
                                                                                                       Received: May 4, 2021
                                                                                                       Accepted: January 1, 2022
RIASSUNTO
Obiettivo. Lo scopo di questo studio è quello di indagare la relazione tra i carcinomi dif-
ferenziati della tiroide (DTC), i risultati istopatologici e i valori dell’indice infiammatorio        Correspondence
                                                                                                       Ayhan Kars
immunitario sistemico (SII) (neutrofili (N) x piastrine (P) / linfociti (L)).
                                                                                                       Kastamonu University Faculty of Medicine, De-
Metodi. In questo studio sono stati inclusi 93 pazienti con DTC. Sono stati misurati i livelli         partment of Otorhinolaryngology, Head and Neck
di N, P e L ed è stata determinata la relazione tra il SII e i risultati istopatologici. I risultati   Surgery, Kastamonu 37150, Turkey
sono stati confrontati con i valori di un gruppo di controllo sano di 33 membri.                       Tel. +90 5418192951
Risultati. I valori di SII erano significativamente più alti nel gruppo di pazienti rispetto al        E-mail: drakars25@hotmail.com
gruppo di controllo (p = 0.000). La patologia tumorale non ha avuto effetti significativi su
SII (p = 0.90). Anche l’invasione linfovascolare perineurale e della capsula e l’estensione
                                                                                                         How to cite this article: Kars A, Sahin A, Kılıc
extratiroidea non hanno avuto effetti significativi sui valori di SII. Il SII era significativa-
                                                                                                         K, et al. Systemic immune inflammation index
mente più alto nei pazienti con più di un focolaio tumorale (p = 0.01). Nessuna relazione
                                                                                                         in differentiated thyroid cancers. Acta Otorhi-
significativa è stata determinata tra diametro del tumore e SII.                                         nolaryngol Ital 2022;42:150-154. https://doi.
Conclusioni. SII è più alto nei pazienti con DTC rispetto alla popolazione sana. Valori ele-             org/10.14639/0392-100X-N1665
vati di SII possono essere associati alla multifocalità. Secondo i risultati di questo studio,
la SII non influenza il tipo istologico, l’invasione perineurale, linfovascolare e capsulare o         © Società Italiana di Otorinolaringoiatria
l’estensione extratiroidea del DTC.                                                                    e Chirurgia Cervico-Facciale

PAROLE CHIAVE: carcinoma differenziato della tiroide, reperti istopatologici, parametri
                                                                                                                      OPEN ACCESS
infiammatori, dell’indice infiammatorio immunitario sistemico
                                                                                                       This is an open access article distributed in accordance with
                                                                                                       the CC-BY-NC-ND (Creative Commons Attribution-Non-
Introduction                                                                                           Commercial-NoDerivatives 4.0 International) license. The
                                                                                                       article can be used by giving appropriate credit and mentio-
                                                                                                       ning the license, but only for non-commercial purposes and
Despite the rarity of thyroid cancer, it remains the most common endocrine                             only in the original version. For further information: https://
neoplasia, and the incidence is increasing 1. Differentiated thyroid carcinomas                        creativecommons.org/licenses/by-nc-nd/4.0/deed.en




150
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(DTCs), developing from thyroid follicular epithelial cells,      Immune-inflammatory cell infiltration has also been de-
constitute approximately 95% of all thyroid cancers 2. Risk       scribed in thyroid cancers 1. Cells associated with inflam-
factors for DTCs include a history of radiation to the thyroid    mation (N, P and L) are obtained from peripheral blood
gland in childhood, age, female gender and family history.        and are linked to progression in various tumour types 8. SII
Papillary thyroid carcinoma (PTC) represents approximate-         is a parameter calculated using N, P and L values obtained
ly 80-85% of malignant epithelial thyroid tumours in devel-       from complete blood count, a routine, simple, and inexpen-
oped countries with sufficient dietary iodine intake, while       sive test involving blood collected from the peripheral ve-
follicular thyroid carcinoma (FTC) is more common in              nous system 6. Studies in recent years have investigated the
iodine-deficient regions and constitutes approximately 10-        novel inflammatory parameter SII in various malignancies
15% of all thyroid cancers 3. Approximately 90% of these          and have observed correlation with several cancer types 5,7.
cases exhibit good prognosis with a combination of surgi-         Geng et al. 16 described SII as an objective marker supe-
cal treatment and radioactive iodine therapy. Lobectomy-          rior to indices such as PLR, and NLR. High N and P levels
isthmusectomy or total thyroidectomy, depending on the            and low L levels produce an increase in SII, resulting in
tumour location, represent the preferred surgical treatment       an increased inflammatory response and decreased immune
in DTCs due to rates of low recurrence and high survival 4,5.     response in cancer patients. High SII levels have an adverse
Inflammation is a physiological and protective mechanism          impact on survival in several tumours 8.
that develops against tissue injury. The process is initiated     The purpose of this study was to examine the relationship be-
under the effect of various chemical signals in order to          tween DTCs and histopathological findings and SII values.
combat pathogens and repair tissue damage. It may also
become chronic, depending on the permanent nature of the          Methods
agents responsible for inflammation and the ineffectiveness
of factors responsible for eradicating it 1.                      Ninety-three patients, 19 males and 74 females, undergo-
The links between cancer and inflammation and the cel-            ing total thyroidectomy after thyroid council evaluation fol-
lular immune system are known to play a key role in the           lowing laboratory tests, imaging (thyroid ultrasonography,
inflammatory response 6. Inflammation increases the risk of       computed tomography, and scintigraphy) and ultrasound-
tumour, plays an important role in cancer progression and         guided fine-needle aspiration biopsy (FNAB) (performed
affects all tumour stages 7,8. Previous studies have investi-     by a radiologist or endocrinologist, using a 22 gauge needle
gated the powerful association between cancer and inflam-         and a 10-ml injector) and diagnosed with DTC at postopera-
mation, and inflammatory cells have been reported to af-          tive histopathological examination, between 2014 and 2019,
fect carcinogenesis 9. All stages of cancer, including onset,     were included in the study. Twelve men and 21 women, all
conversion to malignancy, genetic mutation, angiogenesis,         healthy, presenting to our hospital for routine controls were
tissue infiltration and metastasis, are affected in association   enrolled as the control group.
with the inflammatory response 7,9.                               The sample size was calculated based on SII levels, since
Relationships have been shown between chronic inflammatory        the primary aim of the study was to identify possible change
bowel diseases and colon adenocarcinoma, between chronic          in SII. The estimated difference in SII levels was calculated
hepatitis B and C and hepatic carcinoma, between Helicobac-       based on our preliminary study. With 93 patients, the sam-
ter pylori-related gastritis and gastric carcinoma, and between   ple size for the control group was calculated as 33, based
chronic oesophagitis and oesophageal carcinoma 10. Several        on a power of 99% and an alpha error of 85%, following the
studies have reported immune inflammatory cell infiltration in    Russ Lenth Piface Java module.
thyroid cancers. Inflammatory factors produced by epithelial      Histopathological findings were examined retrospectively,
cells in thyroid cancers have been shown to prevent cancer cell   and demographic characteristics such as age and sex were
apoptosis and to increase cancer resistance 1.                    recorded. N, P and L values were obtained from preopera-
Various studies have shown a relationship between tumour          tive complete blood count results, and the SII was calculat-
progression and inflammatory parameters such as the neu-          ed from these. Parameters such as the tumour histological
trophil (N)/lymphocyte (L) ratio (NLR) and the platelet           type, perineural invasion capsule invasion, lymphovascu-
(P)/L ratio (PLR) 11-14. Relationships have also been shown       lar invasion, extrathyroidal extension, number of foci and
between a high systemic immune-inflammation index (SII)           tumour diameter were determined, and their relationships
(NxP/L) and prognosis in patients with hepatocellular car-        with the SII were investigated. SII values for the age- and
cinoma, small cell lung cancer, oesophageal squamous cell         sex-matched healthy control group were calculated from
cancer (SCC), renal cell carcinoma, colorectal cancer and         complete blood counts, and these were then compared with
nasopharyngeal cancer in recent studies 15.                       patient group SII values.



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A. Kars et al.




Patients with cardiac diseases such as congestive heart                 cells/L, in the patient group than in the control group at
failure, heart valve disease, or myocardial infarction, with            395.7 ± 120.3 × 109 cells/L (p = 0.000) (Tab. I).
autoimmune diseases such as Hashimoto’s thyroiditis or                  Examination of the preoperative FNAB results revealed
Behcet’s disease, with white blood cells > 12,000/mL at                 FTC or suspicion of FTC in 56, PTC in 15, benign cytol-
complete blood count, findings suggestive of infection such             ogy in 17, and atypical findings of unknown significance
as N > 70%, with haematological disease with haemoglobin                in 5. Postoperatively, PTC was detected in 84 patients fol-
levels < 12 g/dL or > 18 g/dL, or with sickle cell anaemia,             lowing histopathological examination, and FTC in 9. Aver-
coagulopathy such as Factor 5 Leiden mutation, or distant               age SII values were 634.3 ± 247.4 × 109 cells/L in patients
metastasis were excluded from the study.                                with PTC and 671.2 ± 338 × 109 cells/L in those with FTC.
Peripheral blood specimens collected from patients in the               Pathological tumour diagnosis had no significant effect on
preoperative period and from the healthy controls were in-              SII (p = 0.70) (Tab. II).
vestigated using an automatic haematology analyser (Sysmex              Perineural invasion was positive in 2 patients with PTC,
XN-1000TM, Sysmex Europe GmbH, Japan), and complete                     lymphovascular invasion in 5, capsular invasion in 17, and
blood counts were performed. N, P and L counts were re-                 extrathyroidal extension in 5, while capsular invasion was
corded, and SII values were calculated from these values.               observed in 5 patients with FTC. Due to the insufficient
Statistical analysis was performed on SPSS 20.0 (IBM Cor-               numbers of patients with perineural invasion, lymphovas-
poration, New York, NY) software. Numerical data were ex-               cular invasion and extrathyroidal extension, statistical anal-
pressed as mean ± standard deviation. Categorical data were             ysis could not be performed. Capsular invasion was found
analysed using the chi-square test, and numerical data using            to have no significant effects on average SII (p = 0.488).
Student’s t or the Mann Whitney U tests, depending on the               Tumours were unifocal in 60 patients and multifocal in 33.
data distribution characteristics, assessed using the Shapiro-          Average SII values were 569.1 ± 280.1 × 109 cells/L in the
Wilk test. Student’s t test was applied in case of normal dis-          unifocal patients and 745 ± 372 × 109 cells/L in the multifo-
tribution, and the Mann Whitney U test in case of non-normal            cal cases. The difference between these groups was statisti-
distribution. Correlation analysis was performed using the              cally significant (p = 0.01) (Tab. II).
Pearson test. ROC analysis was also performed to estimate               The minimum tumour diameter at histopathological ex-
a cut-off point for discriminating between healthy individu-            amination was 0.1 cm and the maximum tumour diameter
als and patients with DTC. p values < 0.05 were regarded as             7 cm. Correlation analysis revealed that tumour diameter
statistically significant for all analyses.                             had no significant effect on average SII levels (p = 0.563).
                                                                        ROC analysis revealed a cut-off point for average SII of
Results                                                                 454.5 × 109 cells/L with 72% sensitivity and 68% speci-
                                                                        ficity in discriminating DTC from healthy individuals
93 patients with DTC ranging in age from 17 to 79 years                 (Tab. III, Fig. 1).
(47.5 ± 12.3) and a 33-member healthy control group rang-
ing in age between 21 and 65 years (mean 44.1 ± 10.6)
were included in the study. No significant age difference
                                                                        Discussion
was determined between groups (p = 0.13). The patient                   The present study investigated SII in DTCs, and revealed
group consisted of 19 men and 74 women, and the con-                    significantly higher mean SII values in cancer patients than
trol group of 12 men and 21 women. No significant gender                in healthy individuals.
difference was seen between groups (p = 0.06). Average                  Studies concerning average SII cut-off values have reported
SII values were significantly higher, at 638.2 ± 255.8 × 109            differing results. Hu et al. 17 investigated the effect of aver-


Table I. Demographic characteristics of the study and control groups.
                                                      Patients                    Controls                            p
                                                      (n = 93)                    (n = 33)
 Age                                                                                21-65                            0.13
                                                                                 44.1 ± 10.6
 Min-Max                                              17-79
 Mean ± SD                                         47.5 ± 12.3
 Gender (M/F)                                         19/74                         12/21                            0.06
 SII                                              638.2 ± 2 55.8                395.7 ± 120.3                       0.000*
* Statistically significant.




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                                                                                                                                                    SII in differentiated thyroid cancers




Table II. Effect of histopathological diagnosis and multifocality on SII levels.
                                                                                                                                              SII                               p
    Histopathological diagnosis                                                            PTC (n = 84)                                  634.3 ± 247.4                      0.702
                                                                                            FTC (n = 9)                                   671.2 ± 338
    Multifocality                                                                        Unifocal (n = 60)                               569.1 ± 280.1                      0.012*
                                                                                         Multifocal (n = 33)                               745 ± 372
*
    Statistically significant. PTC: papillary thyroid carcinoma; FTC: follicular thyroid carcinoma; SII: Systemic inflammation index.


Table III. ROC analysis.
 Risk factor                                  AUC (95%)                       Cut-off                  p                    Sensitivity (%)                     Specifity (%)
    SII                                         0.804                          454.5                0.000                         72.7                               67.9
                                            (0.715-0.892)


                                                                                                    determined a cut-off value for average SII of 715.739 × 109
                                                                                                    cells/L, and described SII as a valuable diagnostic and prog-
                                                                                                    nostic marker. In the present study, the average SII cut-off
                                                                                                    value for DTC patients was 454.5 × 109 cells/L (72% sensitiv-
                                                                                                    ity and 68% specificity), and we concluded that values higher
                                                                                                    than this figure were significant to discriminate between pa-
                                                                                                    tients with DTC and healthy individuals.
                                                                                                    Oztürk et al. 13 investigated early stage SCC of the tongue
                                                                                                    and showed that high average SII values adversely affected
                                                                                                    both local recurrence and survival. In their study of SCC
                                                                                                    of the tongue, Deveci and Sürmeli 15 reported that perineu-
                                                                                                    ral and lymphovascular invasion, an event of importance
                                                                                                    in cancer prognosis, was more common in patients with
                                                                                                    high average SII values, and that average SII was correlated
                                                                                                    with the extent of poor differentiation in these patients. In
                                                                                                    contrast, SII values had no effect on perineural, lympho-
                                                                                                    vascular, capsular invasion, or extrathyroidal extension in
                                                                                                    patients with papillary and follicular thyroid cancer in the
                                                                                                    present research. Li et al. 6 described average SII as a pow-
                                                                                                    erful marker of tumour proliferation and one-year survival
                                                                                                    in elderly patients with a newly diagnosed with solid tu-
Figure 1. ROC analysis for discrimination between differentiated thyroid car-                       mour. Those authors reported poor tumour differentiation
cinomas and healthy individuals. The cut-off value was calculated as 454.5,                         and poor prognosis in patients with high average SII values
with 72.7% sensitivity and 67.9% specificity.                                                       compared to those with low values. The meta-analysis by
                                                                                                    Zhong et al. 8 also showed that average SII is a powerful
age SII on prognosis in HCC and determined a cut-off value                                          marker of poor prognosis in patients with a solid tumour.
of 330 × 109 cells/L, reporting that SII ≥ 330 × 109 cells/L                                        The principal limitation of the present study is the low
may be associated with poor prognosis. Chen et al. 18 inves-                                        number of patients exhibiting perineural invasion, capsular
tigated the usefulness of mean SII in predicting prognosis in                                       invasion, lymphovascular invasion and extrathyroidal ex-
patients with colorectal cancer, determined a cut-off value of                                      tension. This represented a disadvantage in terms of statisti-
340 × 109 cells/L (85.7% sensitivity and 52.4% specificity),                                        cal analysis of the relationship between average SII and these
and described SII as the best predictor of long-term survival                                       histopathological findings, and thus of its effect on progno-
and recurrence. In another study, Li et al. 19 identified aver-                                     sis. In addition, since postoperative follow-ups were not re-
age SII as an independent prognostic factor in patients with                                        corded, we were unable to draw any conclusions regarding
laryngeal SCC. Those authors determined a cut-off value of                                          preoperative average SII and disease prognosis. However,
517.64 × 109 cells/L (66.2% sensitivity and 74.7% specific-                                         the principal aim of this study was to investigate whether
ity). In their study of nasopharyngeal carcinoma, Zeng et al. 20                                    average SII is a practicable marker in the diagnosis of DTC.



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Further studies are needed to examine the effect of these his-            4
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Conflict of interest statement
                                                                               S0140-6736(00)04046-0
The authors declare no conflict of interest.                              11
                                                                               Ong HS, Gokavarapu S, Wang LZ, et al. Low pretreatment lym-
                                                                               phocyte-monocyte ratio and high platelet-lymphocyte ratio ındicate
Funding                                                                        poor cancer outcome in early tongue cancer. J Oral Maxillofac Surg
This research did not receive any specific grant from fund-                    2017;75:1762-1774. https://doi.org/10.1016/j.joms.2016.12.023
                                                                          12
                                                                               Huang SH, Waldron JN, Milosevic M, et al. Prognostic value of pre-
ing agencies in the public, commercial, or not-for-profit
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sectors.                                                                       oropharyngeal cancer stratified by human papillomavirus status. Can-
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Authors’ contributions                                                    13
                                                                               Ozturk K, Akyildiz NS, Uslu M, et al. The effect of preoperative
Conceptualisation: AK and AS. Data curation: AS, MSS,                          neutrophil, platelet and lymphocyte counts on local recurrence and
                                                                               survival in early-stage tongue cancer. Eur Arch Otorhinolaryngol
and AB. Formal analysis: AK and KK. Methodology: all                           2016;273:4425-4429. https://doi.org/10.1007/s00405-016-4098-y
authors. Project administration: AK, MSS, and AB. Visu-                   14
                                                                               Grimm M, Rieth J, Hoefert S, et al. Standardized pretreatment inflam-
alisation: all authors. Writing – original draft: AK, AS, and                  matory laboratory markers and calculated ratios in patients with oral
KK. Writing – review editing: all authors.                                     squamous cell carcinoma. Eur Arch Otorhinolaryngol 2016;273:3371-
                                                                               3384. https://doi.org/10.1007/s00405-016-3950-4
                                                                          15
                                                                               Deveci I, Sürmeli M. Correlation of systemic immune-inflammation
Ethical consideration                                                          index and neutrophil-to-lymphocyte ratio with histopathological
Approval for this retrospective study was granted by the                       findings in patients with tongue cancer. Haydarpasa Numune Med J
Ataturk University Medical Faculty Clinical Research Eth-                      2018;58:122-127. https://doi.org/10.14744/hnhj.2018.96268
ical Committee (No. B.30.2.ATA.0.01.00/247).
                                                                          16
                                                                               Geng Y, Shao Y, Zhu D, et al. Systemic ımmune ınflammation index
                                                                               predicts prognosis of patients with esophageal squamous cell carci-
The research was conducted ethically, with all study proce-                    noma: a propensity score-matched analysis. Sci Rep 2016;6:39482.
dures being performed in accordance with the requirements                      https://doi.org/10.1038/srep39482
of the World Medical Association’s Declaration of Helsinki.               17
                                                                               Hu B, Yang XR, Xu Y, et al. Systemic immune-inflammation index
Written informed consent was obtained from each partici-                       predicts prognosis of patients after curative resection for hepatocel-
                                                                               lular carcinoma. Clin Cancer Res 2014;20:6212-6222. https://doi.
pant/patient for study participation and data publication.                     org/10.1158/1078-0432.CCR-14-0442
                                                                          18
                                                                               Chen JH, Zhai ET, Yuan YJ, et al. Systemic immune-inflammation
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