10.14639/0392-100X-N1089
Objective. Inflammation and nutritional status play an important role in the prognosis of cancer. Lymphocyte-to monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and prognostic nutritional index (PNI) are independent prognostic scores in numerous cancers. However, any study showed their prognostic role in low-risk differentiated thyroid carcinoma (DTC). We aimed to clarify and identify the prognostic value of inflammation indices in low-risk DTC patients. Methods. We analysed data from 116 patients, dividing the population into two groups, according to AJCC staging system (8th edition). The LMR, NLR, PLR and PNI cut-off value were determined using receiver operating characteristic (ROC) curve. Disease-free survival (DFS) was calculated with Kaplan-Meyer and Log-Rank tests and the risk of recurrence was calculated with univariate and multivariate Cox regression. Statistical significance was p &lt; 0.05. Results. We found a baseline NLR value ≥ 1.750 (75% sensitivity, 40.2% specificity) and a baseline LMR value of 3.83 (66.7% sensitivity, 48.9% specificity). Overall DFS was 74.995 ± 3.236 with a p value of 0.678. NLR showed a hazard ratio for recurrence with almost twice the risk of recurrence (Adjusted Hazard Ratio /HRA): 1.828, p-value = 0.019). Conclusions. NLR can be considered a prognostic score with twice the risk of recurrence in low-risk DTC patients with NLR &lt; 1.750.
application/xml
1827-675X
1089
en
Giovanni Docimo
https://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
prognostic nutritional index
Clinical significance of neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio and prognostic nutritional index in low-risk differentiated thyroid carcinoma
Text.Serial.Journal
https://www.actaitalica.it/
41
Thyroid
2021-03-19
2020-08-29
2021-03-19
2021-03-24
31-38
1
Giovanni Docimo
2021/03/19
10.14639/0392-100X-N1089
31
Division of Thyroid Surgery, Department of Medical and Advanced Surgical Sciences, University of Campania “Luigi Vanvitelli”, School of Medicine, Naples, Italy
1827-675X
prognostic nutritional index
38
Clinical significance of neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio and prognostic nutritional index in low-risk differentiated thyroid carcinoma
https://www.actaitalica.it/article/download/1089/522
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:31-38; doi: 10.14639/0392-100X-N1089




Thyroid


Clinical significance of neutrophil-to-lymphocyte
ratio, lymphocyte-to-monocyte ratio,
platelet-to-lymphocyte ratio and prognostic
nutritional index in low-risk differentiated thyroid
carcinoma
Significato clinico del rapporto neutrofili/linfociti, rapporto linfociti/monociti, rapporto
piastrine/linfociti e indice prognostico nutrizionale nei carcinomi differenziati
della tiroide a basso rischio
Chiara Offi, Roberto Maria Romano, Angelo Cangiano, Giancarlo Candela, Giovanni Docimo
Division of Thyroid Surgery, Department of Medical and Advanced Surgical Sciences, University of Campania “Luigi Vanvitelli”,
School of Medicine, Naples, Italy


SUMMARY
                                                                                                 Received: August 29, 2020
Objective. Inflammation and nutritional status play an important role in the prognosis of        Accepted: October 26, 2020
cancer. Lymphocyte-to monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR),
platelet-to-lymphocyte ratio (PLR) and prognostic nutritional index (PNI) are independent        Correspondence
prognostic scores in numerous cancers. However, any study showed their prognostic role           Chiara Offi
in low-risk differentiated thyroid carcinoma (DTC). We aimed to clarify and identify the         Department of Medical and Advanced Surgical
prognostic value of inflammation indices in low-risk DTC patients.                               Sciences, University of Campania “Luigi Vanvitel-
Methods. We analysed data from 116 patients, dividing the population into two groups, ac-        li”, School of Medicine, piazza Miraglia 2,
cording to AJCC staging system (8th edition). The LMR, NLR, PLR and PNI cut-off value            80138 Naples, Italy
were determined using receiver operating characteristic (ROC) curve. Disease-free survival       Tel. +39 081 5665275. Fax +39 081 5665257
(DFS) was calculated with Kaplan-Meyer and Log-Rank tests and the risk of recurrence             E-mail: chiara.o@live.com
was calculated with univariate and multivariate Cox regression. Statistical significance was
p < 0.05.                                                                                        Funding
                                                                                                 None.
Results. We found a baseline NLR value ≥ 1.750 (75% sensitivity, 40.2% specificity)
and a baseline LMR value of 3.83 (66.7% sensitivity, 48.9% specificity). Overall DFS
                                                                                                 Conflict of interest
was 74.995 ± 3.236 with a p value of 0.678. NLR showed a hazard ratio for recur-
                                                                                                 The Authors declare no conflict of interest.
rence with almost twice the risk of recurrence (Adjusted Hazard Ratio /HRA): 1.828,
p-value = 0.019).
Conclusions. NLR can be considered a prognostic score with twice the risk of recurrence            How to cite this article: Offi C, Romano RM,
in low-risk DTC patients with NLR < 1.750.                                                         Cangiano A, et al. Clinical significance of
                                                                                                   neutrophil-to-lymphocyte ratio, lymphocyte-
KEY WORDS: thyroid carcinoma, neutrophil-to-lymphocyte ratio, lymphocyte-to-                       to-monocyte ratio, platelet-to-lymphocyte ra-
monocyte ratio, platelet-to-lymphoctye ratio, prognostic nutritional index                         tio and prognostic nutritional index in low-risk
                                                                                                   differentiated thyroid carcinoma. Acta Otorhi-
                                                                                                   nolaryngol Ital 2021;41:31-38. https://doi.
RIASSUNTO                                                                                          org/10.14639/0392-100X-N1089
Oggetto. L’infiammazione e lo stato nutrizionale giocano un ruolo fondamentale nella pro-
gnosi del cancro. LMR, NLR, PLR, e PNI sono considerati fattori prognostici indipendenti         © Società Italiana di Otorinolaringoiatria
in numerosi carcinomi. Tuttavia, nessuno studio ha dimostrato il loro ruolo nella prognosi       e Chirurgia Cervico-Facciale
dei DTC-basso rischio. L’obiettivo del nostro studio è chiarire e indentificare il valore pro-
gnostico di tali valori nei pazienti con DTC-basso rischio.                                                     OPEN ACCESS
Metodi. Abbiamo analizzato 116 pazienti, dividendo la popolazione in due gruppi secondo          This is an open access article distributed in accordance with
la stadiazione AJCC. Il valore di LMR, NLR, PLR e di PNI è stato determinato con la curva        the CC-BY-NC-ND (Creative Commons Attribution-Non-
ROC. La DFS è stata calcolata con il test di Kaplan-Meyer e con il test Log-Rank, mentre il      Commercial-NoDerivatives 4.0 International) license. The
                                                                                                 article can be used by giving appropriate credit and mentio-
rischio di recidiva è stato calcolato con la regressione univariata e multivariata di Cox. La
                                                                                                 ning the license, but only for non-commercial purposes and
significatività statistica è stata considerata con valori di p-value < 0,05.                     only in the original version. For further information: https://
Risultati. Abbiamo trovato un valore di NLR ≥ 1,750 (75% sensibilità, 40,2% specificità)         creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                           31
C. Offi et al.




e di LMR di 3,83 (66,7% sensibilità, 48,9% specificità). La DFS è di 74,995 ± 3,236 con p-value di 0,678. NLR ha mostrato un Hazard Ratio
con un rischio di recidiva doppio (HRA 1,828, p-value = 0,019).
Conclusioni. NLR può essere considerato un fattore prognostico con un rischio di recidiva duplicato nei pazienti con DTC-basso rischio con
valori di NLR < 1,750.
PAROLE CHIAVE: carcinoma tiroideo, rapporto neutrofili/linfociti, rapporto linfociti/monociti, rapporto piastrine/linfociti, indice prognostico
nutrizionale



Introduction                                                             cancer, oesophagus cancer and laryngeal squamous cell
                                                                         carcinoma 5-7. Prognostic nutritional index (PNI) is a new
Papillary thyroid cancer (PTC) and follicular thyroid                    prognostic score that reflects inflammatory and nutritional
cancer (FTC) account for 85% and 12%, respectively, of                   status of patient 8. The recent literature shows that PNI is
all thyroid cancers and are defined as differentiated thy-               a predictive and prognostic index in many solid tumours,
roid carcinomas (DTC) 1. The incidence of DTC has                        such as colorectal cancer, gastric cancer, malignant pleural
doubled (28.2/100,000 new cases per year in women and                    mesothelioma, hepatocellular carcinoma, pancreatic cancer
10.1/100,000 new cases in men) in the past decade and the                and breast cancer 9-11. All these indices can be calculated on
increase is more marked than any other cancer 2. DTC is                  routine preoperative blood samples and biochemical tests,
more frequent in women, but the mortality is similar be-                 with no additional costs.
tween genders (1 death per year per 100,000 people) 3. The               NLR, LMR, PLR and PNI, to our knowledge, have never
clinical presentation of DTC varies from an indolent tu-                 been investigated in patients with low-risk DTC. Therefore,
mour with very low mortality to a very aggressive malig-                 the routine use of these inflammatory prognostic indices
nancy 3. PTC has a predominantly lymphatic spread, while                 might add prognostic stratification in low-risk DTC pa-
FTC shows haematic spreading 2. Diagnostic suspicion is                  tients.
confirmed with ultrasonography imaging and echo-guided                   According to the 2015 ATA guidelines, low-risk DTC is de-
fine needle cytology (FNC) 3. According to the American                  fined as: PTC without local or distant metastases; PTC with
Thyroid Association (ATA), the recurrence rate in low-risk               R0 after surgery; PTC without invasion of locoregional tis-
DTC is less 1-2% 3. The treatment of choice in DTCs is sur-              sues; PTC without an aggressive histology; PTC without
gery followed or not by radioactive iodine (RAI) therapy 3.              metastatic foci outside thyroid bed after RAI therapy; PTC
Pathological tumour-node-metastases (TNM) stage is the                   without vascular invasion; PTC with clinical N0 or with ≤ 5
major prognostic factor in DTC 3. The lymph node recur-                  pathological micrometastases (N1c); intrathyroidal follicu-
rence rate is variable in low-risk DTC changes according                 lar variant of PTC; intrathyroidal FTC with capsular inva-
to histotype of the neoplasm and response to surgical treat-             sion and no or < 4 foci of vascular invasion and intrathyroi-
ment and RAI therapy 1. Therefore, finding indices that can              dal papillary unifocal or multifocal microcarcinoma with
predict the presence of lymph node metastases at diagnosis               or without BRAFV600E mutations 1. We have investigated the
or the rate of lymph node recurrence in low-risk DTCs can                association between preoperative NLR, PLR, LMR, PNI
be a valid help in planning tailored treatment (thyroidec-               and the presence of lymph node metastasis and overall sur-
tomy versus hemithyroidectomy and postoperative RAI                      vival (OS) and disease-free survival (DFS) in patients with
therapy).                                                                low-risk DTC undergoing or not RAI therapy. Therefore,
The immune system is potentially able to eradicate tu-                   the aim of this study was to understand the prognostic value
mours; the inflammatory response is associated with initia-              of inflammation indices in low-risk DTC patients.
tion, progression, metastasis and prognosis 4. Neutrophils,
lymphocytes, monocytes and platelets are inflammatory
mediators. Neutrophils and platelets product pro-inflamma-               Materials and methods
tory cytokines such as endothelial growth factor (VEGF),                 We have retrospectively collected data on 208 patients who
tumour necrosis factor-α (TNF-α), interleukin-2 (IL-2),                  underwent thyroidectomy or hemithyroidectomy at the De-
interleukin-6 (IL-6) and interleukin-10 (IL-10), which con-              partment of Thyroid Surgery at the University of Campa-
tribute to tumourigenesis. Monocytes and lymphocytes, on                 nia “Luigi Vanvitelli”. All patients had an anatomopatho-
the other hand, have anti-tumoural effects 4. The literature             logical diagnosis of DTC and underwent surgery between
confirms that the neutrophil-to-lymphocyte ratio (NLR),                  March 2012 and December 2019. Clinical and pathological
platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-                    TNM staging was performed according to the American
monocyte ratio (LMR) are independent prognostic factors                  Joint Committee on Cancer (AJCC) staging system (8th edi-
in many solid cancers, including colorectal cancer, lung                 tion) 12. We enrolled 116 patients.



32
                                                                      Clinical significance of NLR, LMR, PLR and PNI in low-risk DTC




We included patients aged over 18 years and not pregnant       dimension, capsular invasion, vascular invasion, laterality,
with: single or multiple thyroid nodule with cytological di-   unifocality, multifocality and stage were obtained from ar-
agnosis of TIR1c, TIR3a, TIR3b, TIR4 and TIR5 to FNC;          chive files. Laboratory data on white blood cells, neutro-
characteristic of low-risk DTC, according to 2015 ATA          phils, lymphocytes, monocytes, eosinophils, basophils and
guidelines; complete medical history and complete preop-       platelets were obtained from archive data. NLR, LMR and
erative blood tests. We excluded patients with: presence of    PLR were obtained from the simple relationship between
single or multiple thyroid nodule with cytological diagnosis   the two values; PNI was obtained using the following for-
of TIR1 or TIR2; other histopathological thyroid cancer as     mula: [10 x albumin (g/dL) + (0.005 x total lymphocytes
medullary thyroid cancer (MTC) or anaplastic thyroid can-      count (103/µL)]. All surgical procedures were performed
cer (ATC); autoimmune thyroid disease (Hashimoto’s thy-        by two surgeons. The surgical treatments performed were
roiditis or Basedow’s disease); neck surgery within 5 years;   total thyroidectomy (TT), near total thyroidectomy (NTT)
neck radiation therapy; previous thyroid tumour; previous      or hemithyroidectomy (HT). TT is the surgical treatment
tumour of the head-neck district; chronic inflammation due     of choice in the treatment of thyroid diseases that requires
to HBV, HCV, chronic gastritis, nephritis or gout; immune      extracapsular removal of the gland in its entirety. NTT
or haematological disease; history of chronic anticoagulant    involves the extracapsular removal of the gland leaving a
drugs use and proliferative haemopoietic disorders. The        small thyroid residue at the level of the recurrent laryngeal
flow chart (Fig. 1) shows the patients enrolled according to   nerve or at the level of the nerve entrance at the laryngeal
the inclusion and exclusion criteria.                          level where total removal is associated with a sacrifice of
We divided the population into two groups based on age:        the nerve itself. HT involves the removal of the thyroid lobe
≤ 55 years and > 55 years, according to the AJCC thyroid       associated with the removal of the isthmus. These surgical
staging system (8th edition). All patients underwent blood     treatments are foreseen in the treatment of DTC by the ATA
and biochemical analyses, FNC, thyroid and laterocervical      guidelines 1.
lymph node ultrasound and fibreoptic-laryngoscopy in the       During follow-up we assessed postoperative RAI therapy
30 days prior to surgery. Clinical and demographic data as     I131, the rate of lymph node recurrence and DFS. After pri-
age and sex were obtained from the archive files. Anato-       mary surgery, a follow-up programme was carried out for
mopathological findings suchas histopathological type,         all patients. During the first years, physical examination,
                                                               serum thyroglobulin (Tg) and neck ultrasound were per-
                                                               formed every 3 months and every 6 months from the second
                                                               year. In our population we had a follow-up ranging from 3
                                                               to 93 months. Recurrence was defined by increased serum
                                                               Tg (≥ 20 μg/L) and the appearance of suspicious lymph
                                                               node metastases on neck ultrasound, and then confirmed
                                                               with FNC and Tg measurement in FNC eluates. DFS was
                                                               defined as the interval between primary surgery and lymph
                                                               node recurrence.
                                                               This study was approved by the Ethics Committee of the Uni-
                                                               versity of Campania “Luigi Vanvitelli” (AOU4588/2020).
                                                               Written informed consent was obtained from all partici-
                                                               pants. All procedures performed were in according to Hel-
                                                               sinki Declaration.

                                                               Statistical analysis
                                                               Continuous variables were described as mean and standard
                                                               deviation (SD), while categorical variables were described
                                                               as number of cases and percentage. Independent t-tests
                                                               were performed to compare continuous variables (month
                                                               of recurrences, maximum diameter of neoplasm and all
                                                               haematological values with their relatives score), and a test
                                                               of proportions was applied to categorical variables (number
                                                               of patients, FNC, RAI, lymph node recurrences and micro-
Figure 1. Flow chart of eligible patients.                     carcinoma). The LMR, NLR, PLR and PNI cut-off values



                                                                                                                                33
C. Offi et al.




were determined using a receiver operating characteristic                                     and anatomopathological report are shown in Table I. The
(ROC) curve. Moreover, Fisher’s exact test was used to                                        study cohort included 80 (68.9%) patients ≤ 55 years and
analyse gender, surgical treatment, laterality of neoplasm                                    36 (31.1%) patients > 55 years; the mean age was 43.1
and histopathological reports. DFS was calculated with                                        years in the group ≤ 55 years and 63.8 years in the group
the Kaplan-Meyer method and Log-Rank test was used to                                         > 55 years. Female patients were 85.3% without no sig-
compare recurrences. The risk of recurrence (Hazard Ratio,                                    nificant difference (p-value 0.26) between groups. There
HR) was calculated using univariate and multivariate Cox’s                                    was no TIR1c in our population. TIR3a, TIR3b, TIR4 and
regression. Statistical significance was considered in case                                   TIR5 in the ≤ 55 year group were 3.75%, 40%, 18.75% and
of p value < 0.05. Statistical analysis was performed with                                    37.5%, respectively, and 8.34%, 25%, 30.55% and 36.11%,
SPSS version 23 (SPSS©, Chicago, IL, USA).                                                    respectively, in the > 55 year group with no significant dif-
                                                                                              ference. The principal surgical procedures applied were
                                                                                              TT/NTT, and HT was performed in only 5.2% of the co-
Results                                                                                       hort (p = 0.08). Tumours were present in 41.4% in the right
We retrospectively enrolled 116 consecutive patients who                                      lobe and in 58.6% in the left lobe (p = 0.06). We analysed
underwent surgery for a low-risk DTC in our department                                        only low-risk DTC and recorded 106 cases (91.4%) of PTC
from March 2012 and December 2019. According to AJCC                                          and 10 cases (8.6%) of FTC (p = 0.49). We found a micro-
stage, patients were divided in two groups: low-risk DTC                                      carcinoma in 50% of the cohort (p = 0.99). In the entire
≤ 55 years and low-risk DTC ≤ 55 years. Baseline demo-                                        population, we recorded a maximum diameter of neoplasia
graphic characteristics, cytology details, surgical treatment                                 of 1.37 cm (p = 0.403). In the ≤ 55 year group, 100% of


Table I. Baseline characteristics of patients.
 Characteristic                                           Population                     ≤ 55 years                                 > 55 years                          p-value
                                                                                  (according to AJCC stage)                  (according to AJCC stage)
 Patients (%)                                               116                             80 (68.9)                                  36 (31.1)                        < 0.001
 Mean age in years (SD)                                49.2 (± 12.45)                     43.1 (± 8.45)                              63.8 (± 8.58)                      < 0.001
 Sex (%)
 Male                                                      17 (14.7)                         14 (17.5)                                   3 (8.4)                          0.26
 Female                                                    99 (85.3)                         66 (82.5)                                  33 (91.6)
 FNC (%)
 TIR1c                                                       0 (0)                             0 (0)                                      0 (0)                           0.99
 TIR3a                                                      6 (5.2)                          3 (3.75)                                   3 (8.34)                          0.56
 TIR3b                                                     41 (35.3)                         32 (40)                                     9 (25)                           0.17
 TIR4                                                      26 (22.4)                        15 (18.75)                                 11 (30.55)                         0.24
 TIR5                                                      43 (37.1)                        30 (37.5)                                  13 (36.11)                         0.72
 Surgery (%)
 TT/NTT                                                   110 (94.8)                         78 (97.5)                                  32 (88.9)                         0.08
 HT                                                        6 (5.2)                            2 (2.5)                                   4 (11.1)
 Laterality of tumour (%)
 Right                                                     48 (41.4)                          29 (35)                                   19 (52.8)                         0.06
 Left                                                      68 (58.6)                          53 (65)                                   15 (47.2)
 Anatomopathological reports (%)
 PTC                                                     106 (91.4)                         74 (92.5)                                  32 (88.9)                          0.49
 FTC                                                       10 (8.6)                           6 (7.5)                                   4 (11.1)
 Mean maximum diameter in cm (SD)                       1.37 (± 1.89)                      1.47 (± 2.2)                               1.15 (± 0.8)                       0.403
 Stage (%)
 I                                                        111 (95.7)                         80 (100)                                   31 (86.1)                        0.002
 II                                                        5 (4.3)                            0 (0)                                     5 (13.9)
 Microcarcinoma (%)                                        58 (50)                           40 (50)                                     18 (50)                          0.99
SD: standard deviation; PTC: papillary thyroid carcinoma; FTC: follicular thyroid carcinoma; TT: total thyroidectomy; NTT: near total thyroidectomy; HT: hemithyroidectomy.




34
                                                                                                            Clinical significance of NLR, LMR, PLR and PNI in low-risk DTC




Table II. Baseline haematological values.
 Blood values                                              Population                      ≤ 55 years                                  > 55 years                           p-value
                                                                                    (according to AJCC stage)                   (according to AJCC stage)
    Mean albumin (SD)                                    4.49 (± 0.31)                      4.51 (± 0.26)                               4.45 (± 0.40)                        0.356
    Mean white blood cells (SD)                          6.82 (± 2.17)                      7.03 (± 2.18)                               6.53 (± 2.09)                        0.116
    Mean neutrophils (SD)                                4.37 (± 1.67)                      4.61 (± 1.74)                               3.84 (± 1.38)                         0.21
    Mean lymphocytes (SD)                                2.45 (± 4.29)                      2.65 (± 5.15)                               2.02 (± 0.73)                        0.467
    Mean monocytes (SD)                                  0.42 (± 0.14)                      0.43 (± 0.14)                               0.39 (± 0.13)                        0.157
    Mean eosinophils (SD)                                0.16 (± 0.10)                      0.16 (± 0.10)                               0.17 (± 0.09)                        0.549
    Mean basophils (SD)                                  0.04 (± 0.03)                      0.04 (± 0.03)                               0.03 (± 0.01)                         0.06
    Mean platelets (SD)                                 259.8 (± 52.05)                   266.08 (± 51.10)                            245.69 (± 52.09)                       0.051
    Mean LMR (SD)                                        6.20 (± 8.29)                      6.37 (± 9.61)                               5.48 (± 4.12)                        0.751
    Mean NLR (SD)                                        2.41 (± 1.09)                      2.59 (± 1.20)                               2.01 (± 0.66)                        0.001
    Mean PLR (SD)                                       145.05 (± 48.8)                   151.14 (± 51.8)                              131.5 (± 38.8)                        0.045
    Median PNI (SD)                                     44.94 (± 3.17)                     45.13 (± 2.69)                              44.53 (± 4.06)                        0.354
SD: standard deviation; LMR: lymphocyte-to-monocyte ratio; NLR: neutrophil-to-lymphocyte ratio; PLR: platelet-to-lymphocyte ratio; PNI: prognostic nutritional index.



Table III. RAI, recurrences and lymph nodes recurrence frequency.
                                                Population                                 ≤ 55 years                                  > 55 years                           p-value
                                                                                    (according to AJCC stage)                   (according to AJCC stage)
    RAI therapy (%)                                       59 (50.86)                          47 (58.8)                                   12 (33.3)                           0.01
    Lymph node recurrences (%)                            24 (20.68)                          18 (22.5)                                    6 (16.7)                           0.63
    Mean months of recurrence (SD)                      22.45 (± 21.71)                    26.44 (± 23.81)                              10.50 (± 3.50)                        0.13
SD: standard deviation; RAI: radioactive iodine.



patients were in TNM stage I, while in the > 55 year group                                       Table III shows data from patients who underwent RAI
13.9% of patients were in TMN stage II, with a significant                                       therapy, lymph node recurrence and DFS in months. The
difference between groups (p = 0.002). This difference is                                        percentage of lymph node recurrence and DFS in months
due to staging of the malignancy. The patients in stage II                                       showed no significant differences between groups. In all,
had a T3a, and therefore neoplasm size and age determinate                                       47 patients underwent RAI therapy (58.8%) in the ≤ 55
the stage [15].                                                                                  year group and 12 patients (33.3%) in the > 55 year group
Table II shows baseline haematological values. Only two                                          with a significant difference between groups (p = 0.01).
values, mean NLR and mean PLR, showed a significant dif-                                         Our data showed that the indication to RAI was common
ference between groups. Mean NLR was 2.41 (SD ± 1.09)                                            in young patients.
in entire population, 2.59 (SD ± 1.20) in the ≤ 55 year group                                    Table IV shows prognostic scores to evaluate recurrence
and 2.01 (SD ± 0.66) in the > 55 year group (p = 0.001).                                         risk factors; in particular, adjusted NLR showed a HR of
Mean PLR was 145.05 (SD ± 48.8) in the entire popula-                                            1.828 (p = 0.019). Other haematological values showed no
tion, 151.14 (SD ± 51.8) in the ≤ 55 year group and 131.5                                        significant differences in the HR.
(SD ± 38.8) in the > 55 year group (p = 0.045).                                                  We calculated the receiver operating characteristic


Table IV. Univariate and multivariate analysis evaluating risk factors affecting recurrences.
                                            Unadjusted HR (95% CI)                     p-value                                Adjusted HRa (95% CI)                         p-value
    PNI                                                1.110 (0.985-1.252)                          0.088                       1.088 (0.966-1.225)                          0.162
    NLR                                                1.240 (0.873-1.760)                          0.229                       1.828 (1.103-3.029)                          0.019
    LMR                                                1.008 (0.961-1.057)                          0.739                       1.011 (0.958-1.066)                          0.696
    PLR                                                0.997 (0.998-1.005)                           0.47                       0.988 (0.975-1.001)                          0.079
a
 Adjusted for age, full blood count values, procedure and dimension of lesion. HR: hazard ratio; CI: confidential interval; PNI: prognostic nutritional index; NLR: neutrophil-to-
lymphocyte ratio; LMR: lymphocyte-to-monocyte ratio; PLR: platelet-to-lymphocyte ratio.




                                                                                                                                                                                      35
C. Offi et al.




Figure 2. ROC curve of LMR with a cut-off value of 4.635 (AUC 0.540 ± 0.066,           Figure 4. DFS functions distinguished between patients ≤ 55 years and
66.7% sensitivity, 48.9% specificity) and PNI (AUC 0.417 ± 0.079). (LMR:               > 55 years. DFS was 74.995 ± 3.236; DFS was 72.249 ± 3.689 in patients
lymphocyte-to-monocyte ratio; PNI: prognostic nutritional index; AUC: area un-         ≤ 55 and DFS was 77.514 ± 5.717 in patients >55 years. Log-rank test was
der curve).                                                                            used to compare recurrences (p = 0.678). (DFS: disease-free survival).


                                                                                       We also calculated a ROC Curve for NLR and PLR (Fig. 3).
                                                                                       NLR cut-off values was 1.750 with 75% sensitivity, 40.2%
                                                                                       specificity and an AUC of 0.564 ± 0.065. As for the PNI
                                                                                       cut-off value, we found no cut-off value for PLR. All PLR
                                                                                       values were below the ROC curve reference line with an
                                                                                       AUC of 0.484 ± 0.075.
                                                                                       Figure 4 shows DFS curves in the two groups. Over-
                                                                                       all DFS was 74.995 ± 3.236; DFS in the ≤ 55 year group
                                                                                       was 72.249 ± 3.689 and in the > 55 year group was
                                                                                       77.514 ± 5.717 (p = 0.678). There was no significant dif-
                                                                                       ference between recurrences based on age, as shown above.

                                                                                       Discussion
                                                                                       Herein, we tried to find a correlation between haematologi-
                                                                                       cal inflammation indexes and prognosis and risk of recur-
                                                                                       rence. This is the first study that has examined correlations
Figure 3. ROC curve of NLR with a cut-off value of 1.750 (AUC 0.564 ± 0.065,           between LMR, NLR, PLR, PNI and the risk of recurrence
75% sensitivity, 40.2% specificity) and PLR and (AUC 0.484 ± 0.075). (NLR: neutro-     in patients with low-risk DTC. The 2015 ATA guidelines
phil-to-lymphocyte ratio; PLR: platelet-to-lymphocyte ratio; AUC: area under curve).   suggest undergoing HT in low-risk DTC patients and to
                                                                                       undergo NTT/TT in case of expected postoperative RAI
(ROC) curves for LMR and PNI values (Fig. 2). We                                       therapy, follow-up based on increased serum Tg and pa-
found 4.635 as best cut-off value for LMR with 66.7%                                   tient preference 1. Various studies have documented a re-
sensitivity, 48.9% specificity and an area under the curve                             currence rate of 1-2% in patients who underwent thyroid
(AUC) of 0.540 ± 0.066. We did not find a cut-off value                                surgery without postoperative RAI therapy over a follow-
for PNI. All PNI values entered in the ROC curve were                                  up of 5-10 years 13,14. Indeed, with a low risk of recurrence,
below the reference line with an area under the curve of                               the risk stratification changes during follow-up 1. The aim
0.417 ± 0.079.                                                                         of our study was to find an instrument that can identify, at



36
                                                                          Clinical significance of NLR, LMR, PLR and PNI in low-risk DTC




the time of diagnosis, patients at higher risk of recurrence       them as independent risk factors. In our population, we
which would allow improving the follow-up protocols and            found an NLR cut-off value of 1.750 with 75% sensitivity
plan tailored treatment.                                           and 40.2% specificity. This suggests that we have a good
Blood inflammatory cells play an important role in initia-         chance of finding unwell patients with NLR values ≥ 1.750,
tion, progression, metastasis and prognosis in oncological         but a poor chance of finding healthy patients. Therefore,
patients. Inflammatory blood mediators include neutro-             only NLR showed a valid HR for recurrence, and indeed it
phils, lymphocytes, monocytes and platelets. Monocytes             is associated with almost twice the risk of recurrence (Ad-
and lymphocytes play an important role as anti-tumoural            justed HR 1.828, p = 0.019), while patient age showed no
mediators. Low levels of lymphocytes and monocytes has             significant difference in terms of risk of recurrence. Even
been observed in advanced stage neoplasms and are asso-            if patients with > 55 years had higher DFS, there was no
ciated with a poor prognosis 15. Monocytes penetrate the           significant difference between groups (p = 0.678). This can
tumour mass, reduce angiogenesis and induce apoptosis of           be explained by the fact that in our cohort there were more
cancerous cells, thus reducing cancer invasion and progres-        patients ≥ 55 years undergoing RAI therapy.
sion 15,16. In the literature, low LMR has been associated         According to the most recent studies, there are few correla-
with poor prognosis in numerous solid cancers and is an in-        tions between PLR and prognosis of patients with DTC.
dependent prognostic factor. This alteration of the immune         Ceylan et al. found no correlation between clinicopatho-
system promotes angiogenesis, progression and tumour               logic features of PTC and PLR 23. Ozmen et al. reported
invasion 17,18. In thyroid carcinoma the low LMR value is          that PLR and NLR are more successful indexes for diag-
associated with worse prognosis, a high risk of recurrence         nosis and recurrence of DTC than C-reactive protein (they
of ATC and high-risk DTC 19,20. At the moment no study             included FTC, PTC and microcarcinoma). They found
has examined whether a low LMR value in low-risk DTCs              that high NLR and PLR are associated with high levels of
can be an indicator of worse prognosis and increased risk of       thyroglobulin and worse prognosis, but their study did not
lymph node recurrence. In our study, the LMR cut-off val-          evaluate cut-off values of these indexes 25. In our study, we
ue was 4.635 with 66.7% sensitivity and 48.9% specificity.         did not find a cut-off value for PLR because the PLR AUC
In the literature, various studies have reported that NLR          was 0.484 ± 0.075 and all values were under reference line.
is an independent prognostic factor in numerous solid tu-          Therefore, further studies are necessary to correlate PLR
mours 5,21. However, there are few in DTC. A high ratio            with multiple variables.
is due to an increased neutrophil count compared to lym-           PNI is a score that assesses the patient’s nutritional sta-
phocyte count. As mentioned above, neutrophils produce             tus and immune status based on evaluation of lymphocyte
VEGF and inhibit TNF-α, facilitating tumour progression            counts and albumin. PNI is a prognostic independent score
and invasion, and a decreased lymphocyte and monocyte              in most solid cancers, including colorectal cancer, gastric
count is associated with reduction in antineoplastic activ-        cancer, malignant pleural mesothelioma, hepatocellular
ity 4,15,16. Moreover, neutrophils promote the secretion of        carcinoma, pancreatic cancer and breast cancer. Studies
IL-2, IL-6 and IL-8, contributing to tumourigenesis 4. De-         show that a low PNI value is associated with worse progno-
spite this, the exact correlation between NLR and cancer           sis due to the deficiency in the nutritional state and deficits
prognosis still is not entirely clear. Chen et al. suggested       of the immune system 9-11. In our study, we did not found
that a low NLR (≤ 1.6) is associated with a high risk of PTC       a cut-off value for PNI. Our hypothesis was that we se-
recurrence, but with a follow-up of 12.2 ± 3.8 months it is        lected a population without concomitant pathologies and
not possible to have an estimate of DFS and OS at 5 or 10          with low-risk DTC, a type of indolent tumour with good
years 22. Ceylan et al. suggested an NLR cut-off value of          prognosis.
1.92 and a correlation between a high NLR, large tumour            This study showed that only NLR was a prognostic score,
size and positivity of extra-thyroidal spread 23. Seretis et al.   but further studies are necessary to clarify and validate its
reported that an elevated preoperative mean NLR is present         specific role.
in patients with microcarcinoma and in DTC, and found
that elevated mean NLR does not show any significant dif-
ference between patients with multifocal or unifocal micro-
                                                                   Conclusions
carcinoma. They did not evaluate an NLR cut-off, but only          The correlation between inflammatory indexes and OS and
the NLR preoperative mean 24. In the literature there are no       DFS has been established in numerous solid tumours. In
univocal and concordant data, and thus further studies are         our study, NLR emerged as a prognostic factor. Obviously,
needed to find possible correlations between inflammatory          additional studies are needed to demonstrate this correla-
indexes and risk of DTC lymph node recurrence to validate          tion and cannot yet be used to stage and stratify patients



                                                                                                                                    37
C. Offi et al.




with low-risk DTC. The limitation of our study is its ret-                    11
                                                                                   Wang Y, Battseren B, Yin W, et al. Predictive and prognostic value of
rospective nature. Follow-up should be extended to 10                              prognostic nutritional index for locally advanced breast cancer. Gland
                                                                                   Surg 2019;8:618-26. https://doi.org/10.21037/gs.2019.10.08
years to better assess the risk of long-term recurrence and                   12
                                                                                   Zanoni DK, Patel SG, Shah JP. Changes in the 8th edition of the
a larger population should be examined. Our hope is that                           American Joint Committee on Cancer (AJCC) staging of head and
in the future these scores can be used to predict the risk of                      neck cancer: rationale and implications. Curr Oncol Rep 2019;21:52.
recurrence and to identify patients with low-risk DTC to be                        https://doi.org/10.1007/s11912-019-0799-x
submitted to RAI therapy to avoid delays in treatment and
                                                                              13
                                                                                   Vaisman F, Shaha A, Fish S, et al. Initial therapy with either thyroid
                                                                                   lobectomy or total thyroidectomy without radioactive iodine remnant
to avoid overtreatment by implementing tailored therapy.                           ablation is associated with very low rates of structural disease recur-
                                                                                   rence in properly selected patients with differentiated thyroid cancer.
                                                                                   Clin Endocrinol (Oxf) 2011;75:112-9. https://doi.org/10.1111/j.1365-
Acknowledgements                                                                   2265.2011.04002.x
The ethical committee of University of Campania “Luigi                        14
                                                                                   Durante C, Montesano T, Attard M, et al. Long-term surveillance of
                                                                                   papillary thyroid cancer patients who do not undergo postoperative
Vanvitelli” approved the study protocol: AOU4588/2020.                             radioiodine remnant ablation: is there a role for serum thyroglobulin
The datasets used and/or analysed during the current study                         measurement? J Clin Endocrinol Metab 2012;97:2748-53. https://doi.
are available from the corresponding author on reasonable                          org/ 10.1210/jc.2012-1123
request.                                                                      15
                                                                                   Chanmee T, Ontong P, Konno K, et al. Tumor-associated macrophag-
                                                                                   es as major players in the tumor microenvironment. Cancers (Basel)
                                                                                   2014;6:1670-90. https://doi.org/10.3390/cancers6031670
References                                                                    16
                                                                                   Goswami KK, Ghosh T, Ghosh S, et al. Tumor promoting role of
                                                                                   anti-tumor macrophages in tumor microenvironment. Cell Immunol
1
     Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid
                                                                                   2017;316:1-10. https://doi.org/10.1016/j.cellimm.2017.04.005
     Association Management Guidelines for adult patients with thyroid
     nodules and differentiated thyroid cancer: the American Thyroid As-      17
                                                                                   Pan YC, Jia ZF, Cao DH, et al. Preoperative lymphocyte-to-monocyte
     sociation Guidelines Task Force on thyroid nodules and differenti-            ratio (LMR) could independently predict overall survival of resect-
     ated thyroid cancer. Thyroid 2016;26:1-133. https://doi.org/10.1089/          able gastric cancer patients. Medicine (Baltimore) 2018;97:13896.
     thy.2015.0020                                                                 https://doi.org/10.1097/MD.0000000000013896
2
     Gambardella C, Patrone R, Di Capua F, et al. The role of pro-            18
                                                                                   Sun Y, Zhang L. The clinical use of pretreatment NLR, PLR, and
     phylactic central compartment lymph node dissection in el-                    LMR in patients with esophageal squamous cell carcinoma: evidence
     derly patients with differentiated thyroid cancer: a multicentric             from a meta-analysis. Cancer Manag Res 2018;10:6167-79. https://
     study. BMC Surg 2018;18(Suppl 1):110. https://doi.org/10.1186/                doi.org/10.2147/CMAR.S171035
     s12893-018-0433-0                                                        19
                                                                                   Yokota M, Katoh H, Nishimiya H, et al. Lymphocyte-monocyte ratio
3
     Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet                 significantly predicts recurrence in papillary thyroid cancer. J Surg
     2016;388:2783-95. https://doi.org/10.1016/S0140-6736(16)30172-6               Res 2020;246:535-43. https://doi.org/10.1016/j.jss.2019.09.034
4
     Dupré A, Malik HZ. Inflammation and cancer: what a surgical on-          20
                                                                                   Ahn J, Song E, Oh HS et al. Low lymphocyte-to-monocyte ratios
     cologist should know. Eur J Surg Oncol 2918;44:566-70. https://doi.           are associated with poor overall survival in anaplastic thyroid car-
     org/10.1016/j.ejso.2018.02.209                                                cinoma patients. Thyroid 2019;29:824-9. https://doi.org/10.1089/
5
     Mercier J, Voutsadakis IA. Comparison of hematologic and other                thy.2018.0684
     prognostic markers in metastatic colorectal cancer. J Gastrointest       21
                                                                                   Szkandera J, Gerger A, Liegl-Atzwanger B, et al. The derived neutro-
     Cancer 2019;50:493-506. https://doi.org/10.1007/s12029-018-0108-1             phil/lymphocyte ratio predicts poor clinical outcome in soft tissue sar-
6
     Liu D, Jin J, Zhang L, et al. The neutrophil to lymphocyte ratio may          coma patients. Am J Surg 2014;210:111-6. https://doi.org/10.1016/j.
     predict benefit from chemotherapy in lung cancer. Cell Physiol Bio-           amjsurg.2014.10.021
     chem 2018;46:1595-605. https://doi.org/10.1159/000489207                 22
                                                                                   Chen W, Wei T, Li Z, et al. Association of the preoperative inflamma-
7
     Feng JF, Huang Y, Chen QX. Preoperative platelet lymphocyte ratio             tion-based scores with TNM stage and recurrence in patients with pap-
     (PLR) is superior to neutrophil lymphocyte ratio (NLR) as a predictive        illary thyroid carcinoma: a retrospective, multicenter analysis. Cancer
     factor in patients with esophageal squamous cell carcinoma. World J           Manag Res 2020;12:1809-18. https://doi.org/10.2147/CMAR.S239296
     Surg Oncol 2014;12:58. https://doi.org/10.1186/1477-7819-12-58           23
                                                                                   Ceylan Y, Kumanlıoğlu K, Oral A, et al. The correlation of clinico-
8
     Sun G, Li Y, Peng Y, et al. Impact of the preoperative prognostic nu-         pathological findings and neutrophil-to-lymphocyte and platelet-
     tritional index on postoperative and survival outcomes in colorectal          to-lymphocyte ratios in papillary thyroid carcinoma. Mol Imaging
     cancer patients who underwent primary tumor resection: a systematic           Radionucl Ther 2019;28:15-20. https://doi.org/10.4274/mirt.gale-
     review and meta-analysis. Int J Colorectal Dis 2019;34:681-9. https://        nos.2018.60490
     doi.org/10.1007/s00384-019-03241-1                                       24
                                                                                   Seretis C, Gourgiotis S, Gemenetzis G, et al. The significance of
9
     Migita K, Takayama T, Saeki K, et al. The prognostic nutritional in-          neutrophil/lymphocyte ratio as a possible marker of underlying papil-
     dex predicts long-term outcomes of gastric cancer patients independ-          lary microcarcinomas in thyroidal goiters: a pilot study. Am J Surg
     ent of tumor stage. Ann Surg Oncol 2013;20:2647-54. https://doi.              2013;205:691-6. https://doi.org/10.1016/j.amjsurg.2012.08.006
     org/10.1245/s10434-013-2926-5                                            25
                                                                                   Ozmen S, Timur O, Calik I, et al. Neutrophil-lymphocyte ratio (NLR)
10
     Pinato DJ, North BV, Sharma R. A novel, externally validated inflam-          and platelet-lymphocyte ratio (PLR) may be superior to C-reactive
     mation-based prognostic algorithm in hepatocellular carcinoma: the            protein (CRP) for predicting the occurrence of differentiated thyroid
     prognostic nutritional index (PNI). Br J Cancer 2012;106:1439-45.             cancer. Endocr Regul 2017;51:131-6. https://doi.org/10.1515/enr-
     https://doi.org/10.1038/bjc.2012.92                                           2017-0013




38
