ORIGINAL RESEARCH

https://doi.org/10.5005/jp-journals-10002-1475
World Journal of Endocrine Surgery
Volume 16 | Issue 2 | Year 2024

Utility of Neutrophil/Lymphocyte Ratio and Platelet/Lymphocyte Ratio as an Adjunct in Predicting Malignancy in Thyroid Nodules

V Sasi Mouli¹, M Shreyamsa², Kul R Singh³, Chanchal Rana⁴ https://orcid.org/0000-0002-1783-7689, Pooja Ramakant⁵, Anand Mishra⁶

^1–6Department of Endocrine Surgery, King George’s Medical University, Lucknow, Uttar Pradesh, India

Corresponding Author: Pooja Ramakant, Department of Endocrine Surgery, King George’s Medical University, Lucknow, Uttar Pradesh, India, Phone: +91 9791507780, e-mail: poojaramakant@gmail.com

Received: 15 March 2020; Accepted: 27 December 2024; Published on: 06 March 2025

ABSTRACT

Background: Preoperative neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been associated prognostically in a few cancers. However, the role of these parameters as an adjunct with fine needle aspiration cytology (FNAC) in thyroid nodules is not determined.

Objective: To evaluate if these parameters can be used as an adjunct in determining malignancy in thyroid nodules.

Materials and methods: A retrospective study of 309 patients from July 2016 to July 2018 undergoing surgery for thyroid nodule was included. Their automated counts with NLR and PLR values were calculated. Receiver operator characteristic (ROC) curve was constructed for NLR and PLR to calculate cutoff, which was used to compare FNAC with histopathology in Bethesda category III and category IV between benign and malignant groups.

Results: A total of 309 were included, with a mean age of 38.53 years (range: 10–80 years). Female: male was 261 (84.5%): 48 (15.5%). Benign thyroid nodules (n = 247, 79.9%), of which lymphocytic thyroiditis were 39, and malignancy (n = 62, 20.1%). Median NLR was 2.03, and median PLR was 82.74, which were taken as cutoff; there was a statistically significant difference between benign and malignant nodules (p < 0.001) for both. Similarly, at these cutoff values, Bethesda category III did not show any significant difference between benign and malignancy (p = 0.24), whereas Bethesda category II and IV had statistical significance between benign and malignancy for NLR (p < 0.001 and 0.04, respectively) but not for PLR (p = 1).

Conclusion: NLR can be used as an adjunct with FNAC in suspecting malignancy in thyroid nodules.

Keywords: Fine needle aspiration cytology, Histopathology, Neutrophil:lymphocyte ratio, Platelet:lymphocyte ratio

How to cite this article: Sasi Mouli V, Shreyamsa M, Singh KR, et al. Utility of Neutrophil/Lymphocyte Ratio and Platelet/Lymphocyte Ratio as an Adjunct in Predicting Malignancy in Thyroid Nodules. World J Endoc Surg 2024;16(2):27–31.

Source of support: Nil

Conflict of interest: Dr Pooja Ramakant and Dr Anand Mishra are associated as the Editorial board members of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of these Editorial board members and their research group.

INTRODUCTION

Palpable thyroid nodules are prevalent in about 5% of females and 1% of males in iodine-sufficient areas,¹ and range from 0.4 to 7.2% in iodine-deficient areas.² On histopathology, 90% of these thyroid nodules are benign, with the rest being malignant. Among endocrine malignancies, thyroid cancer is the most common cancer.³ Most of these are differentiated thyroid cancer (DTC), and the incidence rate has been increasing in the past few decades. Clinical findings, radiological parameters, and pathology, including fine needle aspiration cytology (FNAC), are collectively used to diagnose benign or malignant thyroid nodules. The preoperative gold standard for detection of malignancy among thyroid nodules is FNAC, categorized by the Bethesda system.⁴ Sonography is observer-dependent, with a sensitivity of 91.7% and specificity of 78.94%, respectively.⁵ On FNAC, around 90% of the samples are satisfactory, with 55–74% reported as definitively benign, 2–5% definitively malignant, and the remaining classified as indeterminate cytology.¹ Molecular tests used for the indeterminate category are in clinical practice. The availability, accessibility, and cost of molecular tests are major hindrances to their wide applicability.

Inflammation is believed to play a critical role in various stages of malignancy, such as initiation, progression, invasion, and metastasis.⁶^,⁷ Total leukocyte count (TLC), neutrophils, lymphocytes, C-reactive protein (CRP), and albumin denote systemic inflammatory markers. Leukocytes participate actively in the inflammatory process. Simple surrogate markers of immune responsiveness include routine hematological parameters, such as total and differential leukocyte count (TLC, DLC), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR), as these are readily available tests, relatively inexpensive, and are done as part of routine blood investigations. Though these parameters are not diagnostic in any particular disease pathology, they correlate with the amount of inflammation, and Kim et al. have found these parameters to be of prognostic significance.⁸^,⁹ In esophageal, gastric, colonic, pancreatic, lung, and renal malignancies, inflammatory markers like CRP, NLR, and interleukin-6 (IL-6) have been found to be of prognostic importance.⁶ However, little is known about NLR, PLR, and their relationship with thyroid disorders.³ This study is conducted to investigate the utility of NLR and PLR in predicting the nature of thyroid pathologies, that is, benign and malignant, and to evaluate if these parameters can be used as an adjunct in determining malignancy in thyroid nodules.

MATERIALS AND METHODS

This is a retrospective study of our patients who underwent surgery for thyroid nodules from 1^st July 2016, to 31 July 2018. Data such as age, gender, TLC, DLC, platelet count, thyroid stimulating hormone (TSH), and tumor size were collected from a prospectively maintained departmental database. As per our departmental policy, blood samples were obtained in the morning between 9 and 11 AM, and within one week before surgery. Blood counts were obtained from our institutional laboratory using an automated analyzer—Swelab Alpha. NLR and PLR were calculated using the automated count reports. Thyroid stimulating hormone was estimated by Architect Plus CI4000 (Abbott Limited) using the chemiluminescence method. FNAC was graded according to the Bethesda system for reporting thyroid cytopathology.⁴ Bethesda category II (B-II) comprises benign lesions, Bethesda category III (B-III) comprises atypia of unknown significance (AUS) and follicular lesion of unknown significance (FLUS), Bethesda category IV (B-IV) is follicular neoplasm (FN), Bethesda category V (B-V) is suspicious of malignancy (SoM), and Bethesda category VI is malignant. FNAC and histopathology examination were performed by one of the three dedicated endocrine pathology consultants at our institute, and the largest tumor size on pathology was considered for analysis, which was either benign or malignant based on the final histopathology report. The age-group was divided into <55 years and >55 years, based on the 8th American Joint Commission on Cancer (AJCC) classification. The largest tumor size was divided into <4 cm and >4 cm. We divided NLR into group A and group B based on the median NLR, and similarly into group C and group D based on the median PLR. On the basis of histopathology, groups were divided as group I containing benign thyroid nodules, group II containing patients with benign pathology and lymphocytic thyroiditis (LT), and group III containing patients with differentiated thyroid cancer (DTC). Statistical analysis was performed on the basis of various parameters among the three groups.

We excluded patients undergoing completion surgeries, those with infectious diseases, systemic diseases such as diabetes, known asthmatics on steroid use, patients diagnosed with malignancies other than papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), and patients with leukocyte count values above or below our laboratory range.

Statistical Analysis

Data analysis was done using Statistical Package for the Social Sciences (SPSS) version 23 (SPSS Inc., Chicago, Illinois, United States) statistical software. Categorical variables were evaluated with the Chi-squared test. Normality was tested by the Kolmogorov–Smirnov test. Quantitative variables were evaluated by independent t-test and analysis of variance (ANOVA) for normal data. For nonnormal quantitative data, nonparametric tests were applied, namely the Mann–Whitney U test and Kruskal–Wallis test. A p-value of <0.05 was considered significant. Receiver operating characteristic (ROC) curve was plotted for NLR and PLR values for all included patients. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for four values of NLR and PLR each.

RESULTS

Of 372 patients undergoing surgery, 63 were excluded, including those with thyroid abscess (n = 1), parathyroid carcinoma (n = 1), completion thyroidectomy (n = 2), eosinophilia (n = 2), comorbidities (n = 18), TLC above normal range (n = 21), and thyroid malignancies other than DTC (n = 18). A total of 309 patients were included in this study. The mean age was 38.53 ± 13.81 years (range: 10–80 years). Females were 261 (84.5%) compared to males (n = 48, 15.5%). The number of patients with benign thyroid nodules was 247 (79.9%), and malignant were 62 (20.1%). Of the 247 benign cases, 39 (12.62%) had histopathology associated with lymphocytic thyroiditis.

The majority of the patients were younger, with age < 55 years [n = 260 (84.1%)]. Data based on tumor size cutoffs included 151 (48.9%) patients with tumor size <4 cm and 158 (51.1%) patients with tumor size >4 cm. The mean TSH was 1.80 µIU/L ± 2.07 (range: 0.01–8.8). There was no statistical significance in terms of age and gender between benign and malignant groups, with p-values of 0.988 and 1.00, respectively. On FNAC, the number of patients with Bethesda categories II, III, IV, V, and VI were 249, 12, 26, 1, and 21, respectively, with categories V and VI being malignant on final histopathology.

Figure 1 shows the ROC curves for NLR and PLR plotted for all the patients, showing sensitivity and 1-specificity. Table 1 shows four values of NLR and PLR with sensitivity, specificity, and negative and positive predictive values. The mean NLR with standard deviation (SD) was 2.26 ± 0.97, and the median NLR was 2.03 (range: 0.94–8.8). The mean PLR with SD was 92.11 ± 39.76, and the median PLR was 82.74 (range: 33.99–361.11).

**Table 1:** Values of NLR and PLR with their respective sensitivity, specificity, positive and negative predictive values, and accuracy
	Sensitivity	Specificity	PPV	NPV	Accuracy
NLR
1.64	90	26	23	91.2	38.8
2.03	81	60	33	92.5	63.4
2.22	67	67	33.67	89	87.2
2.74	50	90	55.5	97.29	82
PLR
64.45	90	27	23.5	59.6	39.6
82.74	73	56	29.3	89.2	74
90.74	67	67	33.67	88	87
125.07	43.5	90	52.1	84	80.7

NLR and PLR values taken respectively at sensitivity and specificity of 90%, sensitivity equal to specificity, and at median values, respectively

Fig. 1: Receiver operating characteristic (ROC) curve for NLR and PLR. Area under the curve (AUC) for NLR is 0.764 and for PLR is 0.730

Comparison of benign, benign with lymphocytic thyroiditis, and malignant groups (i.e., groups I, II, III) is shown in Table 2. Figure 2 shows a significant difference in TLC, neutrophils, lymphocytes, platelets, NLR, and PLR. When median NLR and PLR were taken as cutoffs at 2.03 and 82.74, respectively, there was statistical significance between the benign and malignant nodules, with p-values of <0.001 for both. Analysis of benign (Bethesda-category II), AUS and FLUS (Bethesda-category III), and follicular neoplasm (Bethesda-category IV) lesions on FNAC and their final histopathology reports is shown in Table 3, when median NLR and median PLR values are taken as cutoffs.

**Table 2:** Comparison of benign, benign with lymphocytic thyroiditis, differentiated thyroid cancer
Parameters	Benign n = 208 (group I)	Benign with LT n = 39 (group II)	DTC n = 62 (group III)	p-value
Age (in years)	38.17 ± 13.54	39.58 ± 14.52	39.22 ± 14.40	0.803
Gender F/M	175/33	36/3	50/12	0.75
TLC (per μL)	7697 ± 1600^a	7839 ± 1838	8444 ± 1787	0.006^a
Neutrophils (per μL)	4782 ± 1150^b	5386 ± 1374	5929 ± 1841	<0.001^b
Lymphocytes (per μL)	2557 ± 621^b	2106 ± 542	2064 ± 564	<0.001^b
Platelets (10⁶/μL)	2.00 ± 0.6	1.94 ± 0.48	2.32 ± 0.68^c	0.01^c
NLR	1.93 ± 0.52	2.60 ± 0.55	3.16 ± 1.54	<0.001^d
PLR	82.18 ± 29.80	97.01 ± 30.47	122.37 ± 55.74^c	<0.001^c
TSH (μIU/mL)	1.77 ± 1.53	2.29 ± 1.97	1.59 ± 1.07	0.074
Largest size of tumor (cm)	4.6 ± 2.08	3.83 ± 1.84	4.15 ± 2.17	0.063

p-value calculated by ANOVA test; ^agroup I is different from group III; ^bgroup I different from groups II and III; ^cgroup III different from group I to II; ^dgroup I different from groups II and III, group II different from I and III

**Table 3:** Comparison of Bethesda (B) category—II, III, IV thyroid nodules on FNAC with final HPR in determining benign and malignancy taking median NLR and PLR as cutoff
Parameter		NLR <2.03	NLR ≥2.03	p-value	PLR <82.74	PLR ≥82.74	p-value
B-II (n = 249)	Benign	129	101	<0.001	127	103	0.014
B-II (n = 249)	Malignant	1	18	<0.001	5	14	0.014
B-III (n = 12)	Benign	4	2	0.24	4	2	0.24
B-III (n = 12)	Malignant	1	5	0.24	1	5	0.24
B-IV (n = 26)	Benign	8	3	0.04	6	5	1
B-IV (n = 26)	Malignant	4	11	0.04	7	8	1

Figs 2A and B: (A) Mean NLR levels with three histopathology groups, namely benign, lymphocytic thyroiditis (LT), and differentiated thyroid cancer (DTC). Statistical significance was found when comparing benign with LT (p < 0.001), benign with DTC (p < 0.001), and LT with DTC (p = 0.04); (B) mean PLR levels with three histopathology groups, namely benign, lymphocytic thyroiditis (LT), and differentiated thyroid cancer (DTC). Statistical significance was found when comparing benign with DTC (p < 0.001) and LT with DTC (p = 0.02). There was no statistical significance between benign and LT (p = 0.062)

DISCUSSION

In 1863, Rudolf Virchow, a German pathologist, first suggested the association of chronic inflammation with cancer.⁷^,¹⁰ Dailey et al. in 1955 proposed a positive association between chronic thyroiditis and cancer.¹¹

Studies have shown an association between systemic responses by the host, such as inflammatory markers, and the microenvironment of the tumor. Host response in cancers may be attributed to neutrophilia and a relative lymphopenia, which favor a pro-tumor inflammatory response, with a resultant elevation in NLR and PLR in various cancers.¹²^,¹⁵

Higher values of NLR can be due to increased neutrophil count and/or a reduced lymphocyte count. NLR can be interpreted as two immune pathways. The first includes neutrophils, which are responsible for inflammation, and the second includes lymphocytes, which are responsible for the regulatory pathway.³ Neutrophilia in cancers may be either due to tissue destruction, resulting in cytokine release, which in turn sets off a systemic inflammatory response by the host, or as a paraneoplastic syndrome, where there may be ectopic production of myeloid growth factors.¹⁶ The alteration in cell population, resulting in augmented expression of genes involving immune response, may result in increased lymphocytes in the tumor in contrast to normal tissue.¹⁷ Cellular models showed upregulation of pro-inflammatory markers in thyrocytes in cases of RET (rearranged during transfection) proto-oncogene activation that leads to malignancy.¹⁸ At the molecular level, the association between chronic thyroiditis and cancer can be seen with upregulation of RAS, BRAF, and ERK MAP Kinase pathways.¹⁹

In this study, we evaluated the possible application of a simple, relatively inexpensive, automated hemogram with NLR and PLR as an indirect marker for DTC in patients with thyroid nodules. The results of this study show significantly higher neutrophils, NLR, and PLR, with low levels of lymphocytes in DTC (group III) and LT (group II) compared to the benign group (group I). The increase in NLR and PLR in LT (group II) and DTC (group III) shows that there is a key role of inflammatory markers such as neutrophils and lymphocytes. Our study shows a significantly high NLR and PLR, which were associated with DTC compared to the benign group.

As PTC is relatively indolent in nature²⁰ among thyroid cancers, the amount of systemic inflammatory response may be less compared to anaplastic thyroid carcinoma (ATC). This can be attributed to a relatively higher value of NLR and PLR in ATC (excluded from the study) than in DTC. We also found that patients diagnosed as Bethesda category II, III, or IV on FNAC, but who had malignant thyroid nodules in final HPR, had significantly higher neutrophils and NLR compared to benign cases. Median NLR cutoff values showed statistical significance in Bethesda categories II and IV in determining malignancy, whereas in Bethesda category III, it was not found to be statistically significant. Hence, the clinician could have a high suspicion of malignancy when FNAC is benign with high NLR values. The statistical significance in Bethesda category II may be explained by the fact that the overall number of patients was maximum in this category.

In our study, DTC had relatively lower NLR values compared to values of other solid tumor NLR. A systematic review and meta-analysis by Templeton et al.²¹ evaluating NLR association with the prognosis of various solid tumors (head and neck, breast, pulmonary, gastrointestinal, urological, and gynecological malignancies) stated median values of NLR up to 7.7. According to a few studies, NLR values greater than 5 were considered a poor prognostic factor.²⁰ Our study showed a mean NLR of 2.26 ± 0.97, and a median of 2.03 (0.94–8.8), with an NLR >5 in only 12 patients (all belonging to the carcinoma group).

The study by Seretis et al.²² showed that NLR was significantly higher in patients who had incidental papillary microcarcinoma as well as thyroid cancers. Various clinicopathological parameters have been shown to have a positive association with NLR, such as age, tumor size, bilaterality, multifocality, lymph node metastasis, extrathyroidal invasion, TNM stage, recurrence risk, and prognosis,⁶^,²³^,²⁸ indicating aggressive behavior of the tumor in more advanced stages of disease. Studies to date using NLR in DTC have been heterogeneous in methodology and statistical analysis, and sample size, hence producing varied and inconsistent results.

Turkmen et al.²⁹ proved PLR to be a better predictor of inflammation in patients with end-stage renal disease. Ozmen et al.⁹ showed that values of both NLR and PLR are increased in malignant thyroid lesions, with NLR being a better predictor than PLR. Similar results were seen in this study, where ROC curve analysis for NLR and PLR had AUCs of 0.764 and 0.730, respectively.

Various studies show increased mortality and/or recurrence rates with higher NLR in various solid organ cancers, namely colorectal, stomach, hepatocellular, lung, renal cell carcinoma, pancreatic, and cholangiocarcinoma.²⁰

Also, the diagnostic value of these parameters in the category of AUS/FLUS did not show any significance, which can be attributed to a small number of patients belonging to this group. This corresponds with the study by Bayir et al.,³⁰ though their study had no statistical significance for preoperative NLR in benign and malignant thyroid nodules.

This study has a few limitations. Being retrospective in nature, it could not include data regarding the extent of lymphocytic infiltration in these benign and malignant thyroid nodules and compare the same with hematological parameters. Also, comparison in the preoperative and postoperative periods to observe the normalization of these parameters was not available. Since differentiated thyroid cancers have a relatively better prognosis compared to other malignancies, a larger number of patients with long-term follow-up is necessary to obtain sufficient power regarding recurrence, disease-free survival, and/or overall survival rates. Although sonography could have been complementary, USG findings were not included in this study, as they are more observer-dependent.

CONCLUSION

Since NLR and PLR lack specificity, and histopathology is the gold standard for diagnosis, these parameters alone cannot be considered for diagnosing malignancy. However, these parameters may be complementary. Hence, these parameters can be used as an adjunct with FNAC and USG in suspecting malignancy in thyroid nodules. Thyroid cancer, its microenvironment, and systemic inflammation need further detailed molecular studies to confirm interactions and possible relationships.

ORCID

Chanchal Rana https://orcid.org/0000-0002-1783-7689

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