Predictive value of metastatic cervical lymph node ratio in papillary thyroid carcinoma recurrence

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1 ORIGINAL ARTICLE Predictive value of metastatic cervical lymph node ratio in papillary thyroid carcinoma recurrence Jonathan Yip, HBSc, 1 Steven Orlov, MD, 1 David Orlov, MD, 1 Alon Vaisman, MD, 1 Karen Gomez Hernandez, MD, 1 Daniel Etarsky, HBSc, 1 Ipshita Kak, MBBS, 1 Nikoo Parvinnejad, MD, 1 Jeremy L. Freeman, MD, FRCSC, 2 Paul G. Walfish, MD, FRCPC 1,2 * 1 Department of Medicine, Endocrine Division, University of Toronto, Toronto, Ontario, Canada, 2 Department of Otolaryngology Head and Neck Surgery, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada. Accepted 21 March 2012 Published online 22 June 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to determine whether the proportion of metastatic cervical lymph nodes resected (metastatic lymph node ratio [MLNR]) predicted papillary thyroid carcinoma (PTC) recurrence, and whether MLNR could alter the predictive ability of TNM nodal classification for recurrence in PTC. Methods. We conducted a retrospective review of patients with PTC who underwent a total or near-total thyroidectomy with at least 1 lymph node removed at our institution. Results. Of 253 patients, 35 (13.8%) developed recurrent disease. The total MLNR (ratio between total metastatic lymph nodes and total number of lymph nodes resected) independently predicted PTC recurrence (odds ratio [OR], 1.024; 95% confidence interval [CI], ; p ¼.001). In receiver operating characteristic (ROC) curve analysis, TNM nodal classification with total MLNR had greater accuracy in predicting PTC recurrence than did TNM nodal classification alone (0.726 and 0.675, respectively). Conclusion. MLNR is an independent predictor of PTC recurrence and enhances the predictive value of TNM nodal classification. VC 2012 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: thyroid carcinoma, lymph nodes, clinical predictors, nodal ratio, recurrence INTRODUCTION Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy and accounts for approximately 90% of new cases of thyroid cancer. 1 With 5- and 10-year survival rates of 95% and 90%, 2,3 the prognosis of PTC is excellent; however, recurrence develops in 15% to 30% of cases and accounts for a significant degree of morbidity due to additional treatment. 4 6 A number of clinicopathological variables have been used to predict prognosis and guide therapy in patients with PTC. 7 9 The presence of cervical lymph node metastases is considered to influence recurrence, but its impact on survival is uncertain. 2,6,10 18 Likewise, initial lymph node metastases have been shown to predict subsequent occult and distant metastases Most staging systems for PTC assign increased risk to lymph node involvement at the time of presentation. The *Corresponding author: P. G. Walfish, Mount Sinai Hospital, 600 University Ave., Room 413-7, Toronto, Ontario, Canada, M5G 1X5. pwalfish@mtsinai.on.ca This work was presented in part at the scientific program of the 93rd Annual Meeting of the Endocrine Society, Boston, Massachusetts, June 4 7, Contract grant sponsor: This study was supported in part by unrestricted educational grants from: the Da Vinci Gala Fundraiser; the George Knudson Oakdale Pro-Am Charity Golf Tournament; the Temmy Latner/Dynacare Family Foundation; the Department of Medicine Research Fund, Mount Sinai Hospital; the Mount Sinai Hospital Foundation of Toronto; and the Alex and Simona Shnaider Research Chair in Thyroid Oncology. American Joint Committee of Cancer (AJCC) pathologic TNM staging for PTC categorizes nodal status into NX (no nodes examined), N0 (no metastatic nodes), N1a (metastases to central compartment nodes), and N1b (metastases to lateral neck or superior mediastinal nodes). 7 However, existing staging systems only take into account the location and presence/absence of lymph node metastases and do not incorporate quantitative measures on the extent of lymph node involvement. Recent studies have shown that the absolute number of metastatic cervical lymph nodes is related to both recurrence and survival in PTC. 16,17,21 Unfortunately, such a parameter is dependent on the extent of lymph node dissection, which is currently not standardized. 7,20,21 Furthermore, due to the variability in surgical management of neck nodes, the discovery of positive nodes may not have equal impact on prognosis. In lieu of using the absolute number of positive metastatic nodes, metastatic lymph node ratio (MLNR; ratio between number of metastatic nodes and total number of lymph nodes harvested) has been shown to be associated with postablative stimulated thyroglobulin after prophylactic neck dissection, 22 as well as survival in PTC. 23 The MLNR has been proposed to be a more reliable and accurate means of stratifying risk than existing staging systems and is an important prognostic factor in breast, 24 colorectal, 25,26 esophageal, 27 gastric, 28,29 and bladder 30 cancers. In the setting of head and neck cancers, elevated MLNR reduces survival in well-differentiated thyroid 592 HEAD & NECK DOI /HED APRIL 2013

2 METASTATIC CERVICAL LYMPH NODE RATIO IN PTC RECURRENCE carcinoma (WDTC), 23 medullary thyroid carcinoma, 31 and oral squamous cell carcinoma. 32,33 However, in the context of PTC, it is not known whether MLNR can predict the risk of recurrence. The primary purpose of this study was to determine the predictive value of MLNR in PTC recurrence using a cohort of patients with PTC presenting for primary treatment at a single tertiary academic institution. The secondary purpose was to evaluate whether MLNR could serve a complimentary role to the AJCC TNM nodal classification in stratifying risk of recurrence. PATIENTS AND METHODS Patient selection We retrospectively analyzed the charts of patients undergoing primary treatment for PTC at Mount Sinai Hospital (Toronto, Ontario, Canada) between January 1995 and May Patients were treated according to a standard protocol by 1 of 4 surgeons and 1 endocrinologist (P.G.W.). The review aimed to identify all patients with PTC (defined as papillary thyroid carcinoma and its follicular variant) who had undergone a total or near-total thyroidectomy with at least 1 lymph node removed from the central compartment (level VI), lateral neck (levels II V), or superior mediastinum (level VII). For each patient, the total MLNR (ratio between total metastatic lymph nodes and total number of lymph nodes resected) and central MLNR (ratio between metastatic lymph nodes in level VI and number of level VI lymph nodes removed) were calculated. Patients with distant metastases at initial presentation or detectable anti thyroglobulin antibodies (anti- TgAb), measured by 2 independent methods, were excluded from this study in order to objectively evaluate the relation of nodal status to outcomes. Relevant demographic, surgical, pathologic, biochemical, treatment, clinical, and outcome data were collected. Extrathyroidal extension was classified as the presence of macroscopic or microscopic extension beyond the thyroid capsule. Extent of lymph node dissection was classified as: (1) incidental lymph nodes removed at time of thyroidectomy, (2) therapeutic central neck, (3) therapeutic unilateral 6 central neck, or (4) therapeutic bilateral 6 central neck. Recurrence was defined as any evidence of disease requiring further therapy after initial curative treatment. For each case of recurrent disease, information was also collected on the time to recurrence, site of recurrence (locoregional, distant, and unspecified), and subsequent treatment (surgery, radioactive iodine [ 131 I] therapy). The location of the recurrence was labeled as unspecified in patients with an elevated stimulated thyroglobulin level (5 lg/l) and no positive localization of disease based on clinical examination and standard imaging modalities. The study was approved by the Research Ethics Board at Mount Sinai Hospital. Surgical and postsurgical treatment protocols All patients underwent a total or near-total thyroidectomy at Mount Sinai Hospital (Toronto, Ontario, Canada). Prophylactic central compartment and lateral neck dissections are not routinely performed at our institution. A compartment-based selective neck dissection was carried out if there was clinical evidence of abnormal lymph nodes based on examination, imaging, fine-needle aspiration biopsy, or intraoperative assessment at the time of thyroidectomy. PTC and lymph node metastases were confirmed pathologically. The extent of primary disease and nodal status were classified according to the AJCC TNM staging system (6th edition). 7 Postoperatively, patients were placed on thyroid hormone suppression therapy. Before the year 2000, the majority of patients were routinely treated with radioiodine remnant ablation at 3 to 6 months after surgery. Since the year 2000, low-risk patients received radioiodine remnant ablation based on their individual risk and in accordance with our previously published protocol. 34 A postoperative stimulated thyroglobulin was measured immediately before radioiodine remnant ablation, or at approximately 3 to 6 months after thyroidectomy. Stimulation was achieved by 1 of 3 protocols: 9-day withdrawal from triiodothyronine, 22-day withdrawal from L-thyroxine, 35 or stimulation by recombinant human thyroid stimulating hormone (Thyrogen, Genzyme Therapeutics, Cambridge, MA). 36 In addition, patients with tumors directly invading into adjacent tissues (strap muscles, trachea, esophagus, recurrent laryngeal nerve, and/or larynx) were considered for external beam radiation therapy (EBRT) to the neck on an individual basis. Patients were subsequently followed clinically and biochemically (serum thyroglobulin level) at 6- to 12-month intervals to detect disease recurrence. Patients deemed to be suspicious for recurrence underwent further investigations using 1 or more of the following tests: stimulated thyroglobulin measurement, neck ultrasound, CT, fluorodeoxyglucose-positron emission tomography, fine-needle aspiration biopsy, or a total body scan after 131 I therapy. Biochemical measurements All assays were performed in the Department of Pathology and Laboratory Medicine at Mount Sinai Hospital (Toronto, Ontario, Canada). All thyroglobulin measurements were performed in conjunction with thyrotropin and anti-tgab measurements. The serum thyroglobulin was measured by the third-generation Immulite immunochemiluminometric method (Immulite 2000; Siemens Medical Solutions Diagnostics, Los Angeles, CA) with a lower detection limit of 0.9 lg/l, or the second-generation Beckman ACCESS immunochemiluminometric method (Beckman Coulter, Fullerton, CA) with a lower detection limit of 0.1 lg/l. The serum thyrotropin was measured using a third-generation thyrotropin immunometric assay (Immulite 2000; Siemens Medical Solutions Diagnostics, Los Angeles, CA). The anti-tgab status was ascertained by 2 separate methods using a combination of the Immulite 2000 assay (detection limit of 20 kiu/l, normal values <20 kiu/l), Pharmacia TgAb EIA kit using a Personal Lab Analyzer (BioChem ImmunoSystems, Montreal, Canada; detection limit of 60 IU/L, normal values <60 IU/L), and Modular Analytics E170 assay (Roche Diagnostics, Mannheim, Germany; normal values <115 kiu/l). HEAD & NECK DOI /HED APRIL

3 YIP ET AL. TABLE 1. Patient cohort characteristics. Clinicopathologic variable Statistical analyses Value* Sex Male 64 (25.3%) Female 189 (74.7%) Age at diagnosis <45 y 115 (45.5%) 45 y 138 (54.5%) Duration of follow-up, mean (range), y 5.7 ( ) Primary tumor size <1 cm 63 (24.9%) 1 2 cm 105 (41.5%) >2 4 cm 62 (24.5%) >4 cm 20 (7.9%) Missing 3 (1.2%) Mean (range), cm 2.0 ( ) Tumor foci Unifocal 75 (29.6%) Multifocal 178 (70.4%) Extent of disease Intrathyroidal 203 (80.2%) Extrathyroidal 50 (19.8%) Nodal classification N0 163 (64.4%) N1a 47 (18.6%) N1b 43 (17.0%) Nodes resected <3 117 (46.2%) (53.8%) Adjuvant radiation Radioiodine remnant ablation 175 (69.2%) External beam therapy 11 (4.3%) None 74 (29.2%) Outcomes Recurrence 35 (13.8%) Death 1 (0.4%) Site of recurrence Locoregional 25 (71.4%) Distant 5 (14.3%) Unspecified 5 (14.3%) Median time to recurrence, median (IQR), y 1.7 ( ) Abbreviation: IQR, interquartile range. * Value represents number (%) except where otherwise stated. Data extracted was analyzed using SPSS Statistics for Macintosh 19.0 (SPSS, Chicago, IL) and SAS version 9.1 for Windows (SAS Institute, Cary, NC). Descriptive statistics for clinical and histopathologic factors were generated. Univariate analysis was used to test the association between total MLNR and PTC recurrence. Potential covariates, including sex, age at surgery, primary tumor size, tumor foci (unifocal vs multifocal), TNM nodal classification, extent of disease (intrathyroidal vs extrathyroidal extension), type of thyroidectomy (total vs near-total thyroidectomy), extent of lymph node dissection, and adjuvant radiation therapy (use of EBRT and/or radioiodine remnant ablation) were also tested for association with recurrence by univariate analyses. Multivariate logistic regression was performed on all variables that were significant on univariate analysis. In another similar analysis, the predictive value of the central MLNR was examined in patients who did not undergo lateral neck dissections. The results of the logistic regression analyses were reported as odds ratio (OR) estimates with 95% confidence intervals (CIs) and associated p values. The goodness-of-fit of each logistic regression model was assessed using the Hosmer Lemeshow test. All statistical tests were performed using 2-sided tests at the 0.05 level of significance. The number of metastatic lymph nodes was excluded from the regression models due to high collinearity with MLNR and TNM nodal classification. Receiver operating characteristic (ROC) curves with area under the curve (AUC) calculations were generated for regression models of TNM nodal classification with MLNR, TNM nodal classification, and MLNR. AUC values were compared to determine if MLNR altered the accuracy of TNM nodal classification. RESULTS Cohort characteristics Using the aforementioned selection criteria, we obtained a cohort of 268 patients with PTC. On closer examination, 15 patients were excluded because their charts contained insufficient information, leaving a final cohort of 253 patients. The clinical and histopathologic characteristics of the study population are summarized in Table 1. The female-to-male ratio was approximately 3:1, and the mean age at diagnosis was 47.3 years (SD, 13.6 years). Primary tumor sizes ranged from 0.1 cm to 8.5 cm, with a mean diameter of 2.0 cm (SD, 1.5 cm). Ninety patients (35.6%) had metastatic lymph nodes on routine pathological examination, with 47 patients (18.6%) having metastatic nodes in the central compartment only. Approximately two thirds of patients had TNM stage I disease. The mean follow-up duration was 5.7 years (SD, 4.5 years). The majority of patients underwent a total thyroidectomy (94.9%) and the remainder had a near-total thyroidectomy, depending on the surgical preferences of the operating surgeon. A total of 121 patients (48.6%) had formal neck dissections: 65 (25.6%) had a central compartment dissection, 47 (18.6%) had unilateral neck 6 central compartment dissection, and 9 (3.6%) had bilateral neck 6 central compartment dissection. The remaining 132 patients (52.2%) did not undergo formal neck dissections but had lymph nodes removed with the thyroidectomy specimen, which was noted in the pathology report and was not suspicious at the time of initial surgery. The median number of lymph nodes resected per patient was 3.0 (interquartile range [IQR], ). Thirty-five patients (13.8%) developed a recurrence. The median time to recurrence was 1.7 years (IQR, ). The extent of lymph node dissection did not influence the time to recurrence (b ¼ 0.069; p ¼.693). Recurrences were classified as locoregional (71.4%), distant (14.3%), and unspecified (14.3%). Among patients with recurrent disease, 6 (17.1%) were treated with additional surgery, 19 (54.3%) received 131 I therapy to manage their recurrence, and 10 (28.6%) were treated with both additional surgery and 131 I therapy. Ten patients (28.6%) who developed recurrences were treated with a lateral neck dissection at the time of initial 594 HEAD & NECK DOI /HED APRIL 2013

4 METASTATIC CERVICAL LYMPH NODE RATIO IN PTC RECURRENCE TABLE 2. Variable Results of univariate analysis of papillary thyroid carcinoma recurrence. All patients (n ¼ 253) Patients without lateral neck dissections (n ¼ 197) Value* p value Value* p value Sex Age at surgery Extrathyroidal disease (absent vs present) < Tumor foci (unifocal vs multifocal) Lesion size Type of thyroidectomy (total vs near-total) Adjuvant radiation therapy (EBRT and/or radioiodine remnant ablation) Extent of lymph node dissection TNM nodal classification < Total MLNR % <.001 N/A N/A Central MLNR % N/A N/A <.001 Abbreviations: PTC, papillary thyroid carcinoma; EBRT, external beam radiation therapy; MLNR, metastatic lymph node ratio; N/A, not applicable. * Value represents b value for correlation analysis or chi-square value for chi-square analysis. This variable was subjected to chi-square analysis. Analysis among 197 patients who did not undergo lateral neck (levels II V) dissections. thyroidectomy, and among this subgroup, 5 (14.3%) had further neck surgery. One patient (0.4%) died during follow-up, but it was attributed to breast carcinoma. Logistic regression to predict papillary thyroid carcinoma recurrence Elevated total MLNR, TNM nodal classification, extent of lymph node dissection, and the presence of extrathyroidal extension were all significantly correlated with disease recurrence on univariate analysis (all p <.05; Table 2). Logistic regression analysis showed that total MLNR independently predicted PTC recurrence (OR, 1.024; 95% CI, ; p ¼.001; Table 3) such that for a 10% increase in total MLNR, the odds of recurrence increased by a factor of Extrathyroidal extension, extent of lymph node dissection, and TNM nodal classification did not predict recurrence on multivariate analysis (Table 3). The model fit was considered adequate, as judged by the Hosmer Lemeshow test (chi-square ¼ 6.742; df ¼ 4; p ¼.150; data from 253 patients). In a subanalysis restricted to patients who did not undergo lateral neck dissections (n ¼ 197), elevated central MLNR, TNM nodal classification, extent of lymph node dissection, and the presence of extrathyroidal extension were significantly associated with PTC recurrence on univariate analysis (Table 2). On multivariate logistic regression, only central MLNR significantly predicted PTC recurrence (OR, 1.024; 95% CI, ; p ¼.038; Table 3). A 10% increase in central MLNR increased the odds of recurrence by a factor of However, the model of fit for this logistic regression model was poor (Hosmer Lemeshow chi-square ¼ 9.391; df ¼ 3; p ¼.037; data from 197 patients). Evaluation of nodal predictors for papillary thyroid carcinoma recurrence ROC curves for regression models using TNM nodal classification and/or total MLNR as predictors for recurrence are shown in Figure 1. The AUC was for the model with TNM nodal classification with total MLNR, for the model with TNM nodal classification alone, and for total MLNR alone. Restricting this analysis to patients without lateral neck dissections, ROC curves for regression models with TNM nodal classification and/or central MLNR as predictors TABLE 3. Results of multivariate logistic regression analysis predicting papillary thyroid carcinoma recurrence. Variable OR (95% CI) p value All patients (n ¼ 253) Extrathyroidal disease (absent vs present) ( ).070 Extent of lymph node dissection ( ).350 TNM nodal classification ( ).813 Total MLNR % ( ).001 Patients who did not undergo lateral neck dissections (n ¼ 197) Extrathyroidal disease (absent vs present) ( ).217 Extent of lymph node dissection ( ).197 TNM nodal classification ( ).674 Central MLNR % ( ).038 Abbreviations: PTC, papillary thyroid carcinoma; OR, odds ratio; CI, confidence interval; MLNR, metastatic lymph node ratio. HEAD & NECK DOI /HED APRIL

5 YIP ET AL. FIGURE 1. Receiver operating characteristic (ROC) curves for papillary thyroid carcinoma (PTC) recurrence by lymph node variables (TNM nodal classification and/or total metastatic lymph node ratio (MLNR) in the 253 patients. The curve representing the regression model including both TNM nodal classification and total MLNR is depicted by the dotted line, and its area under the curve (AUC; 0.726) was the greater compared to models of TNM nodal classification (0.675) and total MLNR (0.720). are shown in Figure 2. The AUC was for the model with TNM nodal classification with central MLNR, for the model with TNM nodal classification alone, and for central MLNR alone. DISCUSSION In patients diagnosed with PTC and treated with primary surgical therapy, total MLNR was an independent predictor of recurrent disease on a mean follow-up of 5.7 years. Given that the total MLNR does not assign additional risk to the location of lymph node metastases, and it may be artificially decreased in the setting of lateral neck dissections, we also explored the predictive value of a central MLNR in patients who did not undergo lateral neck dissections. This analysis revealed that central MLNR independently predicted PTC recurrence in this subset of patients. Our results are consistent with those from a recent study, which found higher postablative stimulated thyroglobulin values among those with higher central MLNR. 22 Extrathyroidal extension, extent of lymph node dissection, and TNM nodal classification were all associated with PTC recurrence but did not reach significance on multivariate analyses with total or central MLNR. It is somewhat surprising that extrathyroidal extension is not a significant predictor of PTC recurrence on multivariate analysis, as it is well established to be an important adverse prognostic factor in PTC. 5,10 Our classification of extrathyroidal extension, however, did not distinguish between macroscopic and microscopic extrathyroidal extension, of which the latter has been shown to have no impact on PTC recurrence. 37 As a result, it is possible that our observation was due to a sizable portion of our cohort having microscopic extrathyroidal extension. The present study also demonstrated that age at diagnosis, primary tumor size, tumor focality, adjuvant radiation therapy (EBRT and/or radioiodine remnant ablation), and extent of thyroidectomy (total vs near-total thyroidectomy) had no impact on PTC recurrence. Patient age and primary tumor size are established prognostic factors for cancer-specific survival in WDTC 10,20 ; however, our center has previously shown that they are not reliable predictors of residual/recurrent disease. 13 With regard to adjuvant radiation therapy, our findings are concordant with those of other studies that have questioned the impact of EBRT 7 and radioiodine remnant ablation 38,39 on recurrence and mortality. Two recent systematic analyses suggested that radioiodine remnant ablation administration may not decrease recurrence in low-risk patients with WDTC. 40, I therapy is also less efficacious in lymph node metastases in PTC. 42,43 Secondary analyses examined whether MLNR could serve a complimentary role to the TNM nodal classification in stratifying for risk of recurrent disease. In comparing AUC calculations, the regression model including both TNM nodal classification and total MLNR was more accurate in predicting PTC recurrence compared with a model with TNM nodal classification alone (Figure 1). Restricting this analysis to patients who did not undergo lateral neck dissections, a model including both TNM nodal classification and central MLNR had better performance characteristics than a model with TNM nodal classification alone (Figure 2). Our findings suggest that the performance characteristics of TNM nodal classification in predicting recurrent PTC are improved by the addition of MLNR, which is a measure of the extent of lymph node metastases. A recent study by Ebrahimi et al 44 has also found that MLNR provides additional prognostication information that can assist the AJCC TNM nodal classification in risk stratification for oral squamous cell carcinoma. In addition, ROC analyses showed that total MLNR (Figure 1) and central MLNR (Figure 2) were more accurate in predicting PTC recurrence compared with TNM nodal classification. This is in keeping with other studies that have found TNM nodal classification in PTC to be inadequate for prognostication, and they have proposed FIGURE 2. Receiver operating characteristic (ROC) curves for papillary thyroid carcinoma (PTC) recurrence by lymph node variables (TNM nodal classification and/or central metastatic lymph node ratio (MLNR) in the 197 patients without lateral neck dissections (levels II V). The curve representing the regression model including both TNM nodal classification and central MLNR is depicted by the dotted line, and its area under the curve (AUC; 0.684) was the greater compared to models of TNM nodal classification (0.669) and central MLNR (0.683). 596 HEAD & NECK DOI /HED APRIL 2013

6 METASTATIC CERVICAL LYMPH NODE RATIO IN PTC RECURRENCE novel staging systems incorporating other quantitative measures of extent of lymph node metastases, including the number of metastatic lymph nodes (>10) 21 and large nodal metastases (>3 cm). 16 A limitation to the MLNR is that it does not assign additional risk to the number of metastatic lymph nodes. It is unclear whether the prognostic value of 1 of 2 lymph nodes positive for PTC is the same as that of 5 of 10 lymph nodes. In the present study, the number of metastatic lymph nodes could not be included in the logistic regression models because it was highly collinear with MLNR, as indicated by a high variance inflation factor (data not shown). Given that our center does not routinely perform prophylactic neck dissections, the nodal yield was generally low and the number of patients classified as node negative may be overestimated due to the possibility that some microscopic lymph node metastases were not detected. Although the importance of a minimal acceptable nodal yield has been established in other solid cancer sites, we are unaware of any literature that recommends such a standard in PTC. Also, the prognostic significance of nodal yield in WDTC has not been shown to follow conventional wisdom, as Beal et al 23 showed that increasing nodal yield was associated with poorer survival in their entire cohort and in nodenegative patients, but it had no impact on node-positive patients. Similarly, we observed that the number of lymph nodes resected was positively associated with recurrent disease in our cohort. However, this was not the case in nodenegative patients (data not shown). These observations also suggest that nodal understaging (identifying no/less nodal involvement in those with lower number of lymph nodes resected) may have a limited influence on the risk for PTC recurrence. Furthermore, a recent review has concluded that, although the incidence of microscopic lymph node involvement is high in PTC, recurrence rates are much lower than those with macroscopic lymph node involvement, regardless of whether a prophylactic central neck dissection was performed. 37 Another limitation to the current study is the inability to distinguish recurrent from persistent disease when using the definition of "recurrence" outlined in the Methods section. However, to our knowledge, there is no consensus on an objective definition to distinguish these 2 clinical entities. 21,47 As such, we recognize that some cases of "recurrent" disease may in fact represent persistent disease after incomplete initial surgery. Finally, the present study was limited by the extent of pathologic review on surgical specimens. The number of lymph nodes examined is not only dependent on the extent of surgery performed, but also the extent to which a specimen is subjected to pathologic examination. 32,33 At our center, dedicated head and neck pathologists with extensive experience analyze all surgical specimens. Although an elevated MLNR likely reflects a higher degree of tumor burden in the neck, it is also influenced by individual surgical practices and the extent of lymph node examination by individual pathologists. CONCLUSION Our findings suggest that MLNR independently predicts risk of PTC recurrence, and can serve a complimentary role to the AJCC TNM nodal classification by providing additional prognostic information to assist in risk stratification. Acknowledgements We thank the following individuals for their assistance in this study: Akanksha Ganguly, Cindy Hu, Davis Tam, and Tenzin Zingshuk. REFERENCES 1. Hall FT, Beasley NJ, Eski SJ, Witterick IJ, Walfish PG, Freeman JL. 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