Lymph node ratio is superior to AJCC N stage for predicting recurrence in papillary thyroid carcinoma

in Endocrine Connections
Authors:
Sandeep Kumar ParvathareddyHuman Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Abdul K SirajHuman Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Zeeshan QadriHuman Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Saeeda O AhmedHuman Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Felisa DeVeraHuman Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Saif Al-SobhiDepartment of Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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Fouad Al-DayelDepartment of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

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Khawla S Al-KurayaHuman Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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https://orcid.org/0000-0002-4126-3419

Correspondence should be addressed to K S Al-Kuraya: kkuraya@kfshrc.edu.sa

*(S K Parvathareddy and A K Siraj contributed equally to this work)

Open access

Objective

Recently, lymph node ratio (LNR) has emerged as an alternative to American Joint Committee on Cancer (AJCC) N stage, with superior prognostic value. The utility of LNR in Middle Eastern papillary thyroid carcinoma (PTC) remains unknown. Therefore, we retrospectively analyzed a large cohort of 1407 PTC patients for clinicopathological associations of LNR.

Methods

Receiver operating characteristics (ROC) curve was used to determine the cut-off for LNR. We also performed multivariate logistic regression analysis to determine whether LNR or AJCC N stage was superior in predicting recurrence in PTC.

Results

Based on ROC curve analysis, a cut-off of 0.15 was chosen for LNR. High LNR was significantly associated with adverse clinicopathological characteristics such as male sex, extrathyroidal extension, lymphovascular invasion, multifocality, bilateral tumors, T4 tumors, lateral lymph node (N1b) involvement, distant metastasis, advanced tumor stage, American Thyroid Association (ATA) high-risk category and tumor recurrence. On multivariate analysis, we found that LNR was a better predictor of tumor recurrence than AJCC N stage (odds ratio: 1.96 vs 1.30; P value: 0.0184 vs 0.3831). We also found that LNR combined with TNM stage and ATA risk category improved the prediction of recurrence-free survival, compared to TNM stage or ATA risk category alone.

Conclusions

The present study suggests LNR is an independent predictor of recurrence in Middle Eastern PTC. Integration of LNR with 8th edition AJCC TNM staging system and ATA risk stratification will improve the accuracy to predict recurrence in Middle Eastern PTC and help in tailoring treatment and surveillance strategies in these patients.

Abstract

Objective

Recently, lymph node ratio (LNR) has emerged as an alternative to American Joint Committee on Cancer (AJCC) N stage, with superior prognostic value. The utility of LNR in Middle Eastern papillary thyroid carcinoma (PTC) remains unknown. Therefore, we retrospectively analyzed a large cohort of 1407 PTC patients for clinicopathological associations of LNR.

Methods

Receiver operating characteristics (ROC) curve was used to determine the cut-off for LNR. We also performed multivariate logistic regression analysis to determine whether LNR or AJCC N stage was superior in predicting recurrence in PTC.

Results

Based on ROC curve analysis, a cut-off of 0.15 was chosen for LNR. High LNR was significantly associated with adverse clinicopathological characteristics such as male sex, extrathyroidal extension, lymphovascular invasion, multifocality, bilateral tumors, T4 tumors, lateral lymph node (N1b) involvement, distant metastasis, advanced tumor stage, American Thyroid Association (ATA) high-risk category and tumor recurrence. On multivariate analysis, we found that LNR was a better predictor of tumor recurrence than AJCC N stage (odds ratio: 1.96 vs 1.30; P value: 0.0184 vs 0.3831). We also found that LNR combined with TNM stage and ATA risk category improved the prediction of recurrence-free survival, compared to TNM stage or ATA risk category alone.

Conclusions

The present study suggests LNR is an independent predictor of recurrence in Middle Eastern PTC. Integration of LNR with 8th edition AJCC TNM staging system and ATA risk stratification will improve the accuracy to predict recurrence in Middle Eastern PTC and help in tailoring treatment and surveillance strategies in these patients.

Introduction

Papillary thyroid carcinoma (PTC) is the commonest subtype of thyroid cancer, accounting for 80–90% of all thyroid cancers, and is generally associated with favorable outcome (1, 2). The incidence of PTC has increased significantly in recent years (3, 4). In Saudi Arabia, PTC is very common among females and ranks second after breast cancer (5). Although PTC has a favorable outcome, 3–10% of patients demonstrated recurrent disease within the first decade after treatment (6, 7). Accurate PTC staging is an important process to help clinicians pursue the best therapeutic options for their patients.

American Joint Committee on Cancer (AJCC) TNM staging system is the most commonly used staging system for thyroid cancer. AJCC nodal (N) stage in PTC is sub-divided based on the anatomical location of lymph node (LN) metastasis, being classified as central LN (N1a) or lateral LN (N1b) metastasis (8). Although it has been reported that LN involvement can impact a patient’s prognosis and increase the risk of recurrence as well as distant metastasis (9, 10, 11, 12, 13, 14), the association of N stage with clinicopathological markers and prognosis has not been fully explored in PTC from Middle Eastern ethnicity.

In addition, using N stage classification only might underestimate the significance and the extent of the burden of the disease since it is based solely on anatomical location of LN metastasis. An additional emerging prognostic factor in PTC is the lymph node ratio (LNR) (15, 16, 17, 18). The LNR, which is defined as the number of LNs showing metastatic deposits divided by the number of LN resected, is suggested to be a superior prognostic variable, better-reflecting tumor burden and recurrence prediction (19, 20, 21, 22).

Disease recurrence is the most relevant oncologic outcome in PTC since the mortality rate from PTC is very low (23, 24). To date, whether the LNR works better than the 8th AJCC N staging in predicting recurrence in Middle Eastern PTC remains unknown. In this study, we retrospectively enrolled 1407 PTC patients with clinicopathological and follow-up information and compared the effectiveness of AJCC 8th edition N staging and LNR in predicting the recurrence of PTC patients from Middle Eastern ethnicity.

Materials and methods

Patient selection

One thousand five-hundred fifteen consecutive unselected PTC patients diagnosed between 1988 and 2018 at King Faisal Specialist Hospital and Research Centre (Riyadh, Saudi Arabia) were available to be included in the study. Patients in whom regional LN could not be evaluated (Nx) were excluded from the study (n  = 108). A total of 1407 PTC cases were included for analysis. Cases were identified based on clinical history followed by fine-needle aspiration cytology for confirmation. The Institutional Review Board, King Faisal Specialist Hospital and Research Centre approved this study and the Research Advisory Council (RAC) provided waiver of consent under projects RAC #2211168 and RAC #2110031.

Clinicopathological data

Baseline clinicopathological data were collected from case records and have been summarized in Table 1. Based on the American Thyroid Association (ATA) guidelines, tall cell, hobnail, columnar cell, diffuse sclerosing and insular variants were classified as aggressive variants, whereas classical and follicular variants were classified as non-aggressive variants (25). Staging of PTC was performed using the eighth edition of the AJCC staging system. Only structural recurrence (local, regional or distant) was considered for analysis. Recurrence was defined as any newly detected tumor (local or distant) or metastatic regional LN based on ultrasound and/or imaging studies in patients who had been previously free of disease following initial treatment. Radioactive iodine (RAI) refractory disease and risk categories were defined based on 2015 ATA guidelines (25).

Table 1

Patient characteristics of the study cohort.

Overall cohort (n  = 1407)
Age at diagnosis (years)
 Median (range) 37.7 (6.0–88.0)
 <55 1160 82.4
 ≥55 247 17.6
Gender
 Male 333 23.7
 Female 1074 76.3
Histologic subtype
 Classical variant 948 67.3
 Follicular variant 239 17.0
 Tall cell variant 126 9.0
 Other variants 94 6.7
Extrathyroidal extension
 Present 621 44.1
 Absent 786 55.9
Lymphovascular invasion
 Present 298 21.2
 Absent 1109 78.8
Tumor focality
 Unifocal 709 50.4
 Multifocal 698 49.6
Tumor laterality
 Unilateral 950 67.5
 Bilateral 457 32.5
Surgical margin
 Positive 387 27.5
 Negative 1020 72.5
pT
 T1 564 40.2
 T2 452 32.2
 T3 271 19.3
 T4 117 8.3
Regional LN metastasis
 N0 661 47.0
 N1a 206 14.6
 N1b 540 38.4
pM
 M0 1332 94.7
 M1 75 5.3
TNM stage
 I 1176 83.7
 II 156 11.1
 III 22 1.6
 IV 51 3.6
BRAF mutation
 Present 768 54.6
 Absent 613 44.6
 Unknown 26 1.8
TERT mutation
 Present 181 12.9
 Absent 1124 79.9
 Unknown 102 7.2
PD-L1 IHC
 Positive 435 32.7
 Negative 896 67.3
Initial surgery
 Lobectomy 220 15.6
 Total thyroidectomy alone 374 26.5
 Total thyroidectomy with central neck dissection 813 57.9
RAI given
 Yes 1185 84.2
 No 222 15.8
RAI refractory
 Yes 244 20.6
 No 941 79.4
Recurrence
 Yes 275 19.5
 No 1132 80.5
ATA risk category
 Low 231 16.4
 Intermediate 460 32.7
 High 716 50.9

Lymph node ratio cut-off

LNR was defined as the number of metastatic LNs divided by the number of LNs resected. To determine the cut-off value for LNR, we used the receiver operating characteristic (ROC) curve analysis. Using recurrence-free survival as the outcome, we calculated the area under curve (AUC), sensitivity, specificity and 95% CIs. We found that LNR of 0.15 was related to tumor recurrence with AUC of 0.668, sensitivity of 69% and specificity of 59% (P  < 0.001; Fig. 1). Hence, a cut-off of 0.15 was chosen for analysis of clinicopathological associations of LNR.

Figure 1
Figure 1

Receiver operating characteristic (ROC) curve for lymph node ratio (LNR). Tumors with LNR of 0.15 predicted PTC recurrence with a sensitivity of 69%, specificity of 59% and area under cover (AUC) of 0.668 (P < 0.001).

Citation: Endocrine Connections 11, 2; 10.1530/EC-21-0518

BRAF and TERT mutation analysis

BRAF and TERT mutation data was assessed in our laboratory by Sanger sequencing and has been published by us previously (26, 27).

PD-L1 immunohistochemistry

PD-L1 immunohistochemical staining and analysis were performed by us previously in PTC (26). Briefly, tissue microarray slides were processed and stained manually. Primary antibody against PD-L1 (E1L3N, 1:50 dilution, pH 9.0, Cell Signaling Technology) was used. A membranous and/or cytoplasmic staining was observed. Only the membrane staining was considered for scoring. PD-L1 was scored as described previously (28). Briefly, the proportion of positively stained cells was calculated as a percentage for each core and the scores were averaged across two tissue cores from the same tumor to yield a single percent staining score representing each cancer patient. For the purpose of statistical analysis, the scores were dichotomized. Cases showing the expression levels of ≥5% were classified as overexpression and those with less than 5% as low expression.

Follow-up and study endpoint

Patients were regularly followed by both physical examinations and imaging studies to identify tumor recurrence. The median follow-up was 9.2 years (range 1.0–30.1 years). Recurrence-free survival (RFS) was defined as the time (in months) from date of initial surgery to the occurrence of any tumor recurrence (local, regional or distant). In case of no recurrence, date of last follow-up was the study endpoint for RFS.

Statistical analysis

The associations between clinicopathological variables was performed using contingency table analysis and chi-square tests. Cut-off for LNR was determined using the ROC curve. Logistic regression was used for multivariate analysis. Two-sided tests were used for statistical analyses with a limit of significance defined as P value < 0.05. All data analyses, except ROC curve analysis, were performed using the JMP14.0 (SAS Institute, Inc., Cary, NC) software package. ROC curve analysis was performed using MedCalc software, version 10.4.7.0 for Windows (MedCalc, Ostend, Belgium).

Results

Patient and tumor characteristics

Median age of the study cohort was 37.7 years (range 6.0–88.0 years), with a male: female ratio of 1: 3.2. Classical variant PTC was the predominant histologic subtype, accounting for 67.3% (948/1407) of all cases, followed by follicular variant (17.0%; 239/1407) and tall cell variant 9.0% (126/1407). Extrathyroidal extension was noted in 44.1% (621/1407) of cases and lymphovascular invasion in 21.2% (298/1407). 49.6% (698/1407) of PTCs were multifocal and 32.5% (457/1407) were bilateral. Tumor recurrence was noted in 19.5% (275/1407) of the entire cohort (Table 1). The median time to first recurrence from initial surgery in our cohort was 2.6 years (range 0.6–19.8 years). The median number of LNs removed was 15 with the following N stage distribution: N0 (47.0%; 661/1407), N1a (14.6%; 206/1407), and N1b (38.4%; 540/1407) (Table 1). BRAF mutation was noted in 55.6% (768/1381) PTCs and TERT mutation was seen in 13.9% (181/1305). Both BRAF and TERT mutation data were available for 1299 patients in our cohort. Co-existence of BRAF and TERT mutation was noted in 10.5% (136/1299) of cases.

Incidence and clinicopathological associations of recurrence in PTC

Tumor recurrence was noted in 19.5% (275/1407) of PTCs during follow-up. Recurrence was significantly associated with adverse clinicopathological parameters, such as age ≥ 55 years (P  < 0.0001), male sex (P  < 0.0001), extrathyroidal extension (P  < 0.0001), bilateral tumors (P  < 0.0001), T4 tumors (P  < 0.0001), LN metastasis (P  < 0.0001), distant metastasis (P  < 0.0001), advanced tumor stage (P  < 0.0001), RAI refractory disease (P  < 0.0001) and ATA high-risk category (P  < 0.0001). On further division of N1 tumors into N1a and N1b, we found that 31.1% (168/540) of N1b tumors developed recurrence, compared to 17.0% (35/206) of N1a tumors. The difference in recurrence rate between N1a and N1b tumors was statistically significant (P  = 0.0001) (Table 2).

Table 2

Clinicopathological associations of recurrence in papillary thyroid carcinoma.

Total Recurrence present Recurrence absent P value
No. % No. % No. %
Total 1407 275 19.5 1132 80.5
Age at surgery (years)
 <55 1160 82.4 188 68.4 972 85.9 <0.0001
 ≥55 247 17.6 87 31.6 160 14.1
Gender
 Male 333 23.7 93 33.8 240 21.2 <0.0001
 Female 1074 76.3 182 66.2 892 78.8
Histologic subtype
 Classical variant 948 67.3 206 74.9 742 65.6 0.0026
 Follicular variant 239 17.0 28 10.2 211 18.6
 Tall cell variant 126 9.0 26 9.5 100 8.8
 Other variants 94 6.7 15 5.4 79 7.0
Extrathyroidal extension
 Present 621 44.1 185 67.3 436 38.5 <0.0001
 Absent 786 55.9 90 32.7 696 61.5
Lymphovascular invasion
 Present 298 21.2 57 20.7 241 21.3 0.8374
 Absent 1109 78.8 218 79.3 891 78.7
Tumor focality
 Unifocal 698 49.6 125 45.5 573 50.6 0.1242
 Multifocal 709 50.4 150 54.5 559 49.4
Tumor laterality
 Unilateral 950 67.5 154 56.0 796 70.3 <0.0001
 Bilateral 457 32.5 121 44.0 336 29.7
pT
 T1 564 40.2 99 36.1 465 41.1 <0.0001
 T2 452 32.2 63 23.0 389 34.4
 T3 271 19.3 59 21.5 212 18.8
 T4 117 8.3 53 19.4 64 5.7
pN
 N0 661 47.0 72 26.2 589 52.0 <0.0001
 N1a 206 14.6 35 12.7 171 15.1
 N1b 540 38.4 168 61.1 372 32.9
LN ratio
 ≥ 0.15 631 44.9 184 66.9 447 39.5 <0.0001
 < 0.15 776 55.1 91 33.1 685 60.5
pM
 M0 1332 94.7 225 81.8 1107 97.8 <0.0001
 M1 75 5.3 50 18.2 25 2.2
TNM Stage
 I 1176 83.7 174 63.5 1001 88.6 <0.0001
 II 156 11.1 66 24.1 90 8.0
 III 22 1.6 6 2.2 16 1.4
 IV 51 3.6 28 10.2 23 2.0
BRAF mutation
 Present 768 55.6 160 59.7 608 54.6 0.1323
 Absent 613 44.4 108 40.3 505 45.4
TERT mutation
 Present 181 13.9 85 32.7 96 9.2 <0.0001
 Absent 1124 86.1 175 67.3 949 90.8
PD-L1 IHC
 Positive 435 32.7 111 42.2 324 30.3 0.0003
 Negative 896 67.3 152 57.8 744 69.7
RAI Refractory
 Yes 244 20.6 155 58.7 89 9.7 <0.0001
 No 941 79.4 109 41.3 832 90.3
ATA risk category
 Low 231 16.4 12 4.4 219 19.3 <0.0001
 Intermediate 460 32.7 47 17.1 413 36.5
 High 716 50.9 216 78.5 500 44.2

Clinicopathological associations of LNR in PTC

Using a cut-off of 0.15, 44.8% (631/1407) of tumors had high LNR. Tumors exhibiting a high LNR were significantly associated with male sex (P  = 0.0019), extrathyroidal extension (P  < 0.0001), lymphovascular invasion (P  = 0.0034), multifocality (P  < 0.0001), bilateral tumors (P  < 0.0001), T4 tumors (P  < 0.0001), N1b (P  < 0.0001), distant metastasis (P  = 0.0006), advanced tumor stage (P  = 0.0246), RAI refractory disease (P  < 0.0001) and ATA high-risk category (P  < 0.0001). We also found a significant association with tumor recurrence (P  < 0.0001). Interestingly, high LNR was associated with BRAFmutation (P  < 0.0001) and PD-L1 expression (P  = 0.0031) (Table 3).

Table 3

Clinicopathological associations of lymph node ratio (LNR) in papillary thyroid carcinoma.

Total LNR ≥0.15 LNR <0.15 P value
No. % No. % No. %
Total 1407 631 44.8 776 55.2
Age at surgery (years)
 <55 1160 82.4 527 83.5 633 81.6 0.3391
 ≥55 247 17.6 104 16.5 143 18.4
Gender
 Male 333 23.7 174 27.6 159 20.5 0.0019
 Female 1074 76.3 457 72.4 617 79.5
Histologic subtype
 Classical variant 948 67.3 483 76.6 465 59.9 <0.0001
 Follicular variant 239 17.0 48 7.6 191 24.6
 Tall cell variant 126 9.0 60 9.5 66 8.5
 Other variants 94 6.7 40 6.3 54 7.0
Extrathyroidal extension
 Present 621 44.1 379 60.1 242 31.2 <0.0001
 Absent 786 55.9 252 39.9 534 68.8
Lymphovascular invasion
 Present 298 21.2 156 24.7 142 18.3 0.0034
 Absent 1109 78.8 475 75.3 634 81.7
Tumor focality
 Unifocal 698 49.6 272 43.1 426 54.9 <0.0001
 Multifocal 709 50.4 359 56.9 350 45.1
Tumor laterality
 Unilateral 950 67.5 370 58.6 580 74.7 <0.0001
 Bilateral 457 32.5 261 41.4 196 25.3
pT
 T1 564 40.2 219 34.8 345 44.6 <0.0001
 T2 452 32.2 209 33.2 243 31.4
 T3 271 19.3 131 20.8 140 18.1
 T4 117 8.3 71 11.3 46 5.9
pN
 N0 661 47.0 0 0.0 661 85.2 <0.0001
 N1a 206 14.6 174 27.6 32 4.1
 N1b 540 38.4 457 72.4 83 10.7
pM
 M0 1332 94.7 583 92.4 749 96.5 0.0006
 M1 75 5.3 48 7.6 27 3.5
TNM stage
 I 1176 83.7 506 80.4 670 86.3 0.0246
 II 156 11.1 86 13.7 70 9.0
 III 22 1.6 12 1.9 10 1.3
 IV 51 3.6 25 4.0 26 3.4
BRAF mutation
 Present 768 55.6 388 62.7 380 49.9 <0.0001
 Absent 613 44.4 231 37.3 382 50.1
TERT mutation
 Present 181 13.9 92 15.7 89 12.4 0.0934
 Absent 1124 86.1 496 84.3 628 87.6
PD-L1 IHC
 Positive 435 32.7 222 36.9 213 29.2 0.0031
 Negative 896 67.3 380 63.1 516 70.8
RAI refractory
 Yes 244 20.6 155 27.2 89 14.5 <0.0001
 No 941 79.4 414 72.8 527 85.5
Recurrence
 Yes 275 19.6 184 29.2 91 11.7 <0.0001
 No 1132 80.4 447 70.8 685 88.3
ATA risk category
 Low 231 16.4 1 0.2 230 29.6 <0.0001
 Intermediate 460 32.7 226 35.8 234 30.2
 High 716 50.9 404 64.0 312 40.2

LNR is a better predictor of tumor recurrence than AJCC N stage

Since high LNR was associated with tumor recurrence, we sought to determine whether it could be used as an independent predictor of recurrence. Using multivariate logistic regression analysis, we found high LNR to be an independent predictor of recurrence (odds ratio = 1.96; 95% CI = 1.12–3.43; P  = 0.0184), whereas LN stage was not an independent predictor of recurrence (Odds ratio = 1.30; 95% CI = 0.72–2.35; P  = 0.3831) (Table 4).

Table 4

Multivariate logistic regression analysis for predictors of recurrence in papillary thyroid cancer.

Clinicopathological variables Recurrence
Univariate Multivariate
Odds ratio 95% CI P-value Odds ratio 95% CI P-value
Age
 ≥ 55 years (vs < 55 years) 2.81 2.07–3.81 <0.0001 2.56 1.74–3.77 <0.0001
Sex
 Male (vs female) 1.90 1.42–2.53 <0.0001 1.52 1.11–2.09 0.0094
Histology
 Aggressive variants (vs non-aggressive variants 0.93 0.65–1.35 0.7114
Tumor laterality
 Bilateral (vs unilateral) 1.86 1.42–2.44 <0.0001 1.29 0.95–1.74 0.1012
Tumor focality
 Multifocal (vs Unifocal) 1.23 0.94–1.60 0.1248
Extrathyroidal extension
 Present (vs Absent) 3.28 2.48–4.34 <0.0001 1.89 1.38–2.59 <0.0001
Lymphovascular invasion
 Present (vs Absent) 0.97 0.70–1.34 0.8378
pT
 T3-4 (vs T1-2) 2.14 1.62–2.82 <0.0001 1.48 1.08–2.02 0.0154
Distant metastasis
 Present (vs absent) 9.84 5.96–16.24 <0.0001 7.49 4.02–13.94 <0.0001
TNM stage
 III–IV (vs I–II) 3.96 2.45–6.41 <0.0001 0.41 0.20–0.85 0.0170
LN metastasis
 Present (vs absent) 3.05 2.28–4.10 <0.0001 1.30 0.72–2.35 0.3831
LN ratio
 ≥ 0.15 (vs <0.15) 3.09 2.35–4.09 <0.0001 1.96 1.12–3.43 0.0184

LNR combined with TNM stage and ATA risk category as a predictor of recurrence-free survival

We next sought to analyze whether LNR combined with TNM stage and ATA risk category could better predict RFS, compared to either of them alone. On multivariate Cox proportional hazards model, we found that compared to TNM stage alone, the hazard ratios of corresponding stage combined with LNR was higher (Table 5). Similarly, the hazard ratios of ATA risk category combined with LNR was higher, compared to the corresponding ATA risk category alone (Table 6). This suggests that combining LNR with TNM stage or ATA risk category was a better predictor of RFS compared to either of them alone.

Table 5

Univariate and multivariate analyses of baseline variables for recurrence-free survival with the TNM staging system.

Univariate Multivariate
HR (95% CI) P value HR (95% CI) P value
8th TNM
 I Reference Reference
 II 3.985 (2.997–5.300) <0.0001 4.250 (2.613–6.912) <0.0001
 III 3.030 (1.342–6.843) 0.0080 3.103 (1.180–8.165) 0.0220
 IV 7.923 (5.286–11.873) <0.0001 7.320 (3.759–14.252) <0.0001
8-h TNM with LNR
 I with low LNR Reference Reference
 I with high LNR 3.628 (2.602–5.060) <0.0001 2.958 (2.090–4.187) <0.0001
 II with low LNR 7.219 (4.499–11.581) <0.0001 7.630 (3.812–15.273) <0.0001
 II with high LNR 9.423 (6.170–14.392) <0.0001 8.857 (4.941–15.877) <0.0001
 III with low LNR 2.117 (0.292–15.344) 0.4580 2.220 (0.282–17.453) 0.4480
 III with high LNR 10.646 (4.233–26.779) <0.0001 9.516 (3.202–28.281) <0.0001
 IV with low LNR 18.018 (10.062–32.266) <0.0001 17.423 (7.681–39.522) <0.0001
 IV with high LNR 15.309 (8.257–28.382) <0.0001 12.560 (5.337–29.556) <0.0001
Table 6

Univariate and multivariate analyses of baseline variables for recurrence-free survival with ATA risk stratification.

Univariate Multivariate
HR (95% CI) P value HR (95% CI) P value
2015 ATA risk category
 Low Reference Reference
 Intermediate 2.172 (1.152–4.097) 0.0170 2.195 (1.159–4.157) 0.0160
 High 6.610 (3.696–11.822) <0.0001 4.666 (2.502–8.704) <0.0001
2015 ATA risk category with LNR
 Low with low LNR Reference Reference
 Intermediate with low LNR 0.700 (0.286–1.714) 0.7000 0.750 (0.306–1.839) 0.5300
 Intermediate with high LNR 3.807 (1.992–7.275) <0.0001 3.811 (1.981–7.330) <0.0001
 High with low LNR 4.964 (2.692–9.154) <0.0001 3.793 (1.989–7.235) <0.0001
 High with high LNR 7.892 (4.380–14.220) <0.0001 6.081 (3.230–11.447) <0.0001

Discussion

Cancer recurrence remains a major challenge for PTC patients. It is clinically important to identify markers that can accurately predict recurrence. Predicting tumor recurrence is needed to tailor the initial treatment and follow-up intensity. In this study, we first determined the tumor recurrence rate to be 19.5% (275/1407) in Middle Eastern PTC. This recurrence rate is relatively high (29, 30, 31) and highlights the urgent need to establish an accurate model to predict recurrence in PTC patients from Middle Eastern ethnicity. Interestingly, our cohort also presented with more aggressive disease, as evidenced by a high rate of aggressive variants (15.7%), multifocality (49.6%), extrathyroidal extension (44.1%) and a lower age at presentation (median, 38 years). This probably reflects the inherent aggressive nature of PTC in this ethnicity, as evidenced by other studies from this region, which also found a relatively high rate of aggressive variants (32, 33), multifocality (34, 35), extrathyroidal extension (32, 36) and a low median age at diagnosis (37, 38). However, it could also be partially attributed to the fact that ours is the foremost tertiary care center in the region and most advanced diseases are referred to our hospital from all over Saudi Arabia.

Tumor recurrence was significantly associated with advanced T stage (P  < 0.0001). Surprisingly 17.6% (99/564) of pT1 tumors exhibited tumor recurrence, which is relatively higher in comparison to other studies where the recurrence rate in T1 is rare (39, 40, 41). Comparing within AJCC N stage subgroups, tumor recurrence was found to be significantly more common in patients with N1b stage (31.1%, 168/540) as against patients with N1a (17.0%, 35/206) and N0 (10.9%, 72/661), as expected.

Although the 8th edition of AJCC TNM staging is commonly used to predict the patient’s outcome, it has some limitations. Patients with PTC and LN metastasis are staged according to the presence or absence of LN metastasis in anatomic compartments. The extent of the disease is not considered in this staging system. There is growing evidence showing the value of considering the extent of LN metastasis in PTC prognosis (14, 42, 43, 44). The American Thyroid Association (ATA) risk stratification system now considers the size and number of LN metastasis as an important factor in risk stratification (25).

Recently, more tailored risk stratification using LNR was proposed as a more reliable prognosticator of recurrence in PTC. Recent investigations of LNR in PTC have suggested that it has prognostic significance in both the central as well as lateral LN metastasis and maybe superior to conventional AJCC staging (17, 45, 46). Others have suggested the integration of LNR to the current staging system to improve the prediction of recurrence in patients with PTC (18). For Middle Eastern PTC, the use of LNR as a predictive tool for recurrence has not previously been analyzed. In this study, using a cut-off of 0.15 for LNR, we were able to identify a subset of Middle Eastern PTC patients at high risk of tumor recurrence and that LNR was positively associated with adverse clinicopathological characteristics, such as male gender, multifocality, larger tumor size, extrathyroidal extension, bilateral tumors and RAI-refractiveness. We also noted a positive correlation between LNR and BRAF mutations as well as PD-L1 protein overexpression, which we previously have shown to have negative impact on Middle Eastern PTC (26, 47).

Interestingly, LNR of more than 0.15 was a strong independent predictor of tumor recurrence (odds ratio = 1.96; 95% CI = 1.12–3.43; P  = 0.0184). Patients with LNR more than 0.15 exhibited a two-fold higher risk of recurrence, while the patient with N1 (using AJCC N staging) showed a 1.3-fold high risk of recurrence, suggesting that LNR was a better predictor of recurrence than the AJCC N stage. The fact that higher LNR increased the HR of the same stage tumor especially for TNM stage I (Table 5), is a strong indication of LNR predictive power of recurrence even in the early stage. Also, patients with high-risk ATA with LNR ≥0.15 had a much higher HR compared to the high-risk ATA category alone (6.08 vs 4.67; Table 6), further strengthening the importance of LNR as a predictor of recurrence. This is clinically very important since it indicates that LNR is the most suitable and valuable predictor for recurrence in PTC patients of Middle Eastern ethnicity and suggests that adding LNR to the 8th AJCC TNM staging and ATA risk stratification system should be considered by clinicians to increase the accuracy of predicting PTC recurrence in this population.

Our study included a large sample size from the Middle Eastern population allowing for adequate multivariable adjustment for patient and treatment characteristics. Also, this study is from a single institute, which helped in providing accurate and homogenous information such as gene mutations, type of therapy and length of follow-up. Despite the strength of this study, it is limited by its retrospective nature which could cause selection bias. Also, this study was conducted on PTC from a specific ethnicity and therefore further larger multicenter studies from other ethnicities are encouraged to make generalizable conclusions.

In conclusion, the present study suggests LNR is an independent predictor of recurrence in Middle Eastern PTC. Integration of LNR with 8th edition AJCC TNM staging system and ATA risk stratification will improve the accuracy to predict recurrence in Middle Eastern PTC and help in tailoring treatment and surveillance strategies in these patients.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

Study concept and design: K S A, S K P, A K S. Executed the study: S K P, A K S, Z Q, S O A, F D, S A, F A D. Statistical analysis: Z Q. Drafting the article: K S A, A K S, S K P. Critical revision of the article for important intellectual content, writing of the article, and approval of the final version: K S A, S K P, A K S, Z Q, S O A, F D, S A, F A D.

Acknowledgement

The authors would like to thank Padmanaban Annaiyappanaidu and Nabil Siraj for their technical assistance.

References

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    Figure 1

    Receiver operating characteristic (ROC) curve for lymph node ratio (LNR). Tumors with LNR of 0.15 predicted PTC recurrence with a sensitivity of 69%, specificity of 59% and area under cover (AUC) of 0.668 (P < 0.001).

  • 1

    Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA: A Cancer Journal for Clinicians 2021 71 733. (https://doi.org/10.3322/caac.21654)

    • Search Google Scholar
    • Export Citation
  • 2

    Shi X, Liu R, Basolo F, Giannini R, Shen X, Teng D, Guan H, Shan Z, Teng W & Musholt TJ et al.Differential clinicopathological risk and prognosis of major papillary thyroid cancer variants. Journal of Clinical Endocrinology and Metabolism 2016 101 264274. (https://doi.org/10.1210/jc.2015-2917)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Pereira M, Williams VL, Hallanger Johnson J, Valderrabano P. Thyroid cancer incidence trends in the United States: association with changes in professional guideline recommendations. Thyroid 2020 30 11321140. (https://doi.org/10.1089/thy.2019.0415)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nature Reviews: Endocrinology 2016 12 646653. (https://doi.org/10.1038/nrendo.2016.110)

    • Search Google Scholar
    • Export Citation
  • 5

    Alrawaji A, Alshahrani Z, Alzahrani W, Alomran F, Almadouj A, Alshehri S, Alzahrani A, Bazarbashi S, Alhashmi H, Almutlaq H, et al. Cancer Incidence Report Saudi Arabia 2015. In Saudi Cancer Registry. Riyadh, Saudi Arabia: SH Council, 2018.

    • Search Google Scholar
    • Export Citation
  • 6

    Park S, Kim WG, Song E, Oh HS, Kim M, Kwon H, Jeon MJ, Kim TY, Shong YK, Kim WB. Dynamic risk stratification for predicting recurrence in patients with differentiated thyroid cancer treated without radioactive iodine remnant ablation therapy. Thyroid 2017 27 524530. (https://doi.org/10.1089/thy.2016.0477)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Leboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM, Bidart JM, Travagli JP, Schlumberger M. Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis. Journal of Clinical Endocrinology and Metabolism 2005 90 57235729. (https://doi.org/10.1210/jc.2005-0285)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR, Winchester DP. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more ‘personalized’ approach to cancer staging. CA: A Cancer Journal for Clinicians 2017 67 9399. (https://doi.org/10.3322/caac.21388)

    • Search Google Scholar
    • Export Citation
  • 9

    Adam MA, Pura J, Goffredo P, Dinan MA, Reed SD, Scheri RP, Hyslop T, Roman SA, Sosa JA. Presence and number of lymph node metastases are associated with compromised survival for patients younger than age 45 years with papillary thyroid cancer. Journal of Clinical Oncology 2015 33 23702375. (https://doi.org/10.1200/JCO.2014.59.8391)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Nixon IJ, Wang LY, Palmer FL, Tuttle RM, Shaha AR, Shah JP, Patel SG, Ganly I. The impact of nodal status on outcome in older patients with papillary thyroid cancer. Surgery 2014 156 137146. (https://doi.org/10.1016/j.surg.2014.03.027)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Rubinstein JC, Dinauer C, Herrick-Reynolds K, Morotti R, Callender GG, Christison-Lagay ER. Lymph node ratio predicts recurrence in pediatric papillary thyroid cancer. Journal of Pediatric Surgery 2019 54 129132. (https://doi.org/10.1016/j.jpedsurg.2018.10.010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Chen L, Zhu Y, Zheng K, Zhang H, Guo H, Zhang L, Wu K, Kong L, Ruan W & Hu J et al.The presence of cancerous nodules in lymph nodes is a novel indicator of distant metastasis and poor survival in patients with papillary thyroid carcinoma. Journal of Cancer Research and Clinical Oncology 2017 143 10351042. (https://doi.org/10.1007/s00432-017-2345-2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Zaydfudim V, Feurer ID, Griffin MR, Phay JE. The impact of lymph node involvement on survival in patients with papillary and follicular thyroid carcinoma. Surgery 2008 144 10701077; discussion 1077. (https://doi.org/10.1016/j.surg.2008.08.034)

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