The impact of metastasized cervical lymph nodes (CLN) identified on central neck dissection (CND) on the recurrence/persistence of papillary thyroid cancer (PTC) and the extent of CND needed to reduce recurrence/persistence have not been firmly established. To assess the impact of CLN metastasis and BRAF mutation on the recurrence/persistence of PTC and the potential of BRAF mutation in assisting CND. Analyses of 379 consecutive patients with PTC who underwent thyroidectomy with (n=243) or without CND (n=136) at a tertiary-care academic hospital during the period 2001–2010 for their clinicopathological outcomes and BRAF mutation status. Increasingly aggressive tumor characteristics were found as the extent of CND was advanced following conventional risk criteria from non-CND to limited CND to formal CND. Disease recurrence/persistence rate also sharply rose from 4.7% to 15.7% and 40.5% in these CND settings respectively (P<0.0001). CLN metastasis rate rose from 18.0 to 77.3% from limited CND to formal CND (P<0.0001). An increasing rate of BRAF mutation was also found from less to more extensive CND. A strong association of CLN metastasis and BRAF mutation with disease recurrence/persistence was revealed on Kaplan–Meier analysis and BRAF mutation strongly predicted CLN metastasis. CLN metastases found on CND are closely associated with disease recurrence/persistence of PTC, which are both strongly predicted by BRAF mutation. Current selection of PTC patients for CND is appropriate but higher extent of the procedure, once selected, is needed to reduce disease recurrence, which may be defined by combination use of preoperative BRAF mutation testing and conventional risk factors of PTC.
Thyroid cancer is a common endocrine malignancy with a rapidly rising incidence in recent decades (Leenhardt et al. 2004, Davies & Welch 2006, Chen et al. 2009, Howlader et al. 2011). The United States of America has seen a record of high incidence of estimated 56 460 new cases and 1780 patient deaths from this cancer for 2012 (Howlader et al. 2011). The most common type of thyroid cancer is papillary thyroid cancer (PTC), accounting for 80–90% of all thyroid malignancies (Leenhardt et al. 2004, Davies & Welch 2006, Chen et al. 2009, Howlader et al. 2011). The mainstay of treatment of thyroid cancer is thyroidectomy, with neck dissection in appropriately selected cases to remove cervical lymph nodes (CLN) suspicious for metastases (Pacini et al. 2006, Cooper et al. 2009). PTC is particularly commonly associated with CLN metastases, a major source for disease recurrence (Scheumann et al. 1994, Tisell et al. 1996, Machens et al. 2002). CLN metastases mostly involve the central neck compartment (level VI) (Gimm et al. 1998, Machens et al. 2002). Thus, therapeutic central neck dissection (CND) is generally recommended as part of the initial thyroid surgery for patients with preoperative or intraoperative findings of CLN abnormalities and selective prophylactic CND is also practiced in some settings (Pacini et al. 2006, Cooper et al. 2009, Gharib et al. 2010). However, the impact of CLN metastases and of their removal on PTC recurrence/persistence have not been uniformly established and it is often a challenge to define the right balance for CND between a conservative approach that minimizes surgical complications but potentially leave a higher risk for disease recurrence and an aggressive one that minimizes the risk for recurrence but potentially increases surgical complications.
The BRAFV600E mutation (termed as BRAF mutation hereafter) is a common genetic alteration in PTC, with an overall prevalence of around 45% (Xing 2005). It has been widely shown, in general analyses, that this mutation is associated with aggressive clinicopathological characteristics and disease recurrence/persistence of PTC (Xing 2005, 2007, Xing et al. 2005, Nikiforov & Nikiforova 2011, Kim et al. 2012). With this prognostic value, BRAF mutation has become an important factor in the risk stratification and prognostication of PTC. However, its evaluation with respect to CND and its potential in assisting CND during the initial surgery for PTC have not been well performed. We undertook this study to examine the impact of CLN metastases identified on CND as well as BRAF mutation on disease recurrence/persistence of PTC and the potential of BRAF mutation in assisting CND.
Materials and methods
Patients and clinicopathological data
The study was approved by our institutional review board and informed consents were obtained where required. We reviewed records of 379 consecutive cases of PTC who underwent total or near-total thyroidectomy with or without CLN dissection at the Johns Hopkins Hospital (Baltimore, MD, USA) during the period 2001–2010 (Table 1). These included 266 (70.2%) conventional PTC, 94 (24.8%) follicular variant PTC, 15 (4%) tall cell variant PTC, and four (1.1%) other types of PTC. There were 277 (73.1%) female and 102 (26.9%) male patients with a median age of 44 years (range, 12–85). Clinicopathological characteristics were obtained from the electronic pathological and medical records of our hospital and are presented in Table 1. After the initial thyroid surgery, 290 patients returned for follow-up and managements at our institution, including radioiodine-131 (RAI) remnant ablation in 247 (85.2%) patients within 1–2 months of thyroidectomy with a median dose of 100 mCi (3700 MBq) (range, 20–155 mCi (740–5735 MBq)). Among these 290 patients, 274 continued follow-up for >6 months and 16 were followed <6 months at our institution. The remaining 89 patients did not return for any follow-up at our institution.
Comparison of clinicopathological characteristics of papillary thyroid cancer in patients with central neck dissection (CND) with those without
|CND (any form) (N=243)||Non-CND (N=136)|
|Clinicopathological characteristics||n/N||%||n/N||%||P value|
|Age (years) median (range)||42.0 (12–79)||48.5 (18–85)||0.001|
|Tumor size (cm) median (range)||1.8 (0.2–9.0)||1.9 (0.2–10.0)||0.52|
|III and IV||51/243||21.0||15/135||11.1||0.02|
Central neck dissection
We used the currently American Thyroid Association (ATA) consensus-recommended terminology and classification of CND (Carty et al. 2009). Indications for CND were conventional high-risk factors, particularly clinically or radiographically abnormal CLN, found preoperatively or intraoperatively. CND included formal CND defined as ipsilateral or bilateral removal of prelaryngeal, pretracheal, and paratracheal CLN or limited CND defined as removal of limited number of CLN (one to six lymph nodes). There were 243 patients who underwent CND, including 110 cases with formal CND (33 ipsilateral and 77 bilateral) and 133 cases with limited CND. The non-CND group of 136 cases did not have any form of CLN removal. Ipsilateral level II and III neck dissections in 21 cases and bilateral level II and III neck dissections in 11 cases were also performed along with their CND.
Follow-up for disease recurrence/persistence of PTC
Patients with follow-up <6 months were excluded from the persistence/recurrence analysis as the effect of initial treatments, especially RAI, may not have been complete and serum thyroglobulin (Tg) may linger behind for months after the initial treatments. There were 274 patients who had follow-up of ≥6 months after the initial treatments with a median follow-up period of 35 months (interquartile range 15–81). These patients were included in the analysis of disease recurrence/persistence. Disease recurrence referred to reappearance of PTC following a period of being disease-free after the initial treatments while disease persistence referred to continuous existence of disease since their initial treatments. Recurrent/persistent disease was considered to be present in patients with TSH-stimulated or -unstimulated serum Tg ≥2 ng/ml, positive radioiodine body scan, or cytologically or pathologically confirmed recurrent thyroid cancer lesions. Some patients did not have thyroid remnant radioiodine ablation. These patients usually fell into the category of non-CND or limited CND and were not subjected to radioiodine diagnostic testing or stimulated Tg testing during follow-up. Patients in this group were considered to be disease recurrence/persistence free when serum Tg was undetectable (<0.1 ng/ml) under standard thyroxine therapy with no clinical and radiographical evidence for disease existence. For these patients, recurrent/persistent disease was considered to be present when serum Tg was detectable (≥0.1 ng/ml).
Genomic DNA prepared from primary PTC was analyzed for BRAF mutation by sequencing exon 15 of the BRAF gene as described previously and part of the BRAF mutation data was from our earlier studies (Xing et al. 2005, 2009). BRAF mutation data were available for 281 cases in this study.
The Statistical Program for Social Sciences (SPSS) version 19 software was used for the data analysis in this study. Numerical data were expressed as medians and ranges while categorical data were expressed as numbers and percentages. The nonparametric Wilcoxon Rank Sum test was used to compare numerical parameters and χ2 and Fisher exact tests were used to compare categorical values. Kaplan–Meier survival curves and log-rank test were used to analyze the effects of CND and BRAF mutation on PTC recurrence/persistence over time. Univariate and multivariate logistic regression analyses were used to calculate the odds ratios for the clinicopathological characteristics of PTC in association with positive CLN metastasis found on CND. All reported P values were two sided and P<0.05 was considered to be significant.
PTC displayed more aggressive pathological characteristics and disease recurrence/persistence in patients with CND than those without
As shown in Table 1, PTC patients who underwent any form of CND displayed more aggressive tumor characteristics than patients who did not have any form of CND, except for tumor size that was similar in the two groups. Specifically, extrathyroidal invasion, vascular invasion, tumor multifocality, and advanced American Joint Committee on Cancer (AJCC) stages III and IV were seen in 21.4 vs 9.0% (P=0.003), 25.7 vs 9.7% (P<0.0001), 49.8 vs 38.5% (P=0.045), and 21.0 vs 11.1% (P=0.02), in patients with CND vs non-CND respectively. The BRAF mutation, which is known to be associated with aggressiveness of PTC (Xing 2005, 2007, Xing et al. 2005, Nikiforov & Nikiforova 2011, Kim et al. 2012), showed a higher prevalence in patients with CND than those without. However, this did not reach statistical significance, perhaps reflecting the relatively small number of patients in the non-CND group (Table 1). Disease recurrence/persistence was also significantly higher in patients with CND, with 28.1% in these patients vs only 4.7% in patients without CND (P<0.0001).
CLN metastasis and tumor recurrence/persistence of PTC with different extents of CND
With the relatively high rate of disease recurrence/persistence in the overall analysis on patients with CND above, we further examined this issue in different settings of CND. As CLN metastasis is the most common source of recurrence/persistence of PTC (Mazzaferri & Jhiang 1994, Scheumann et al. 1994, Roh et al. 2007, Hughes & Doherty 2011), we also looked at CLN metastasis with various extents of CND, including limited CND, formal ipsilateral CND, and formal bilateral CND. As shown in Table 2, CLN metastasis became increasingly positive as CND became more extensive. Specifically, CLN metastasis was found in 24/133 (18.0%), 24/33 (72.7%), 61/77 (79.2%), and 85/110 (77.2%) cases for limited CND, formal ipsilateral CND, formal bilateral CND, and combined formal CND (either ipsilateral or bilateral) respectively. When specifically comparing the CLN metastasis rate in combined formal CND patients (85/110 (77.2%)) with patients with limited CND (24/133 (18%)), the difference was strongly significant (P<0.0001). Strikingly, the disease recurrence/persistence rate was also remarkably and sharply increasing from less extensive to more extensive CND. Specifically, disease recurrence/persistence was found in 5/107 (4.7%), 13/83 (15.7%), 9/26 (34.6%), 25/58 (43.1%), and 34/84 (40.5%) cases for non-CND, limited CND, formal ipsilateral CND, formal bilateral CND, and combined formal CND (either ipsilateral or bilateral) respectively. Within patients who underwent any CND, disease recurrence/persistence rate was strikingly higher in those who had formal CND (either ipsilateral or bilateral) (34/84 (40.5%)) than those who had limited CND (13/83 (15.7%)) (P=0.001). BRAF mutation occurrence in primary tumors was also generally more common in patients who underwent formal CND (ipsilateral or bilateral) (39/81 (48.1%)) than those with limited CND (29/99 (29.3%)) and patients without any CND (28/101 (27.2%)) (Table 2).
Cervical lymph node (CLN) metastases, disease recurrence, and BRAF mutation status of papillary thyroid cancer in different settings of central neck dissection (CND)
|Types of CND||Total number of cases||Cases with positive CLN metastasis N (%)||Recurrence/persistence n/N (%)||BRAF mutation-positive cases n/N (%)|
|Non-CND||136||–||5/107 (4.7)||28/101 (27.7)|
|Limited CND||133||24 (18)||13/83 (15.7)||29/99 (29.3)|
|Formal ipsilateral CND||33||24 (72.7)||9/26 (34.6)||17/25 (68.0)|
|Formal bilateral CND||77||61 (79.2)||25/58 (43.1)||22/56 (39.3)|
|Combined formal CND||110||85 (77.2%)||34/84 (40.5%)||39/81 (48.1%)|
|Overall||379||109/243 (44.9)||52/274 (19)||96/281 (34.2)|
Kaplan–Meier analysis of the disease recurrence/persistence-free probability presented in Fig. 1 more clearly shows the recurrence/persistence patterns in different settings of CND, with a higher prevalence associated with more extensive CND. Specifically, comparing patients who did not undergo any form of CND with those who did undergo CND showed that the recurrence/persistence-free survival was strikingly better in the former (log rank test, P<0.0001) (Fig. 1A). There was also a significant worsening in the persistence/recurrence-free probability from patients with no CND to patients with limited CND and to patients with formal CND (log rank test, P<0.0001) (Fig. 1B). Consistent with previous reports, BRAF mutation was significantly associated with several high-risk characteristics and disease recurrence of PTC on the overall analysis of all the cases (Table 3). We also examined this relationship within the patients who underwent any form of CND. Even with a much smaller number of cases in this group, we still found that CLN metastasis and extrathyroidal invasion rates were significantly higher in BRAF mutation-positive patients than BRAF mutation-negative patients, with a strong trend of higher recurrence/persistence rate in the former (Table 3). The association of BRAF mutation with disease recurrence/persistence in patients who underwent CND is more clearly illustrated in Fig. 2A on Kaplan–Meier analysis of disease recurrence-free survival (log rank test, P=0.03).
Association of BRAF mutation with clinicopathological characteristics of papillary thyroid cancer
|All patients (with or without CND)||Patients with CND|
|BRAF positive (N=96)||BRAF negative (N=185)||BRAF positive (N=68)||BRAF negative (N=112)|
|Clinicopathological characteristics||n/N||%||n/N||%||P value||n/N||%||n/N||%||P value|
|Age (years) median (range)||46.5 (23–85)||44.0 (12–81)||0.48||41.5 (24–73)||42.0 (12–79)||0.38|
|Tumor size (cm) median (range)||2.0 (0.5–9.0)||2.0 (0.2–10.0)||0.53||2.0 (0.5–9.0)||2.0 (0.3–6.0)||0.40|
|Lymph node metastases||37/68||54.4||38/112||33.9||0.01||37/68||54.4||38/112||33.9||0.01|
|III and IV||24/96||25.0||25/185||13.9||0.025||18/68||26.5||18/112||16.1||0.13|
Importance of CLN metastasis in the recurrence/persistence of PTC in patients after CND and their predictive factors
We next further investigated the importance of CLN metastasis for disease recurrence/persistence of PTC exclusively in patients who underwent CND. We found that in these patients, disease recurrence/persistence was also significantly associated with CLN metastasis. Specifically, 38/84 (45.2%) cases with CLN metastases had disease recurrence/persistence while only 9/83 cases (10.8%) without CLN metastases had disease recurrence/persistence, representing a striking difference (P<0.0001). Kaplan–Meier analysis in Fig. 2B more clearly shows this strong association of PTC recurrence/persistence with CLN metastasis in patients with CND; those patients with only negative CLN without metastasis found on CND had a very low rate of disease recurrence/persistence (log rank test P<0.0001).
We also examined the relationship of various clinicopathological factors with CLN metastasis to identify those factors that were predictive for CLN metastasis in patients who underwent CND. These included male gender, patient age, tumor size, extrathyroidal invasion, vascular invasion, tumor multifocality, advanced AJCC stages, and BRAF mutation. As shown in Table 4, except for patient age and tumor multifocality, all these factors showed a significant predictive value in terms of odds ratios, to various levels, for CLN metastasis. Among them, extrathyroidal invasion, vascular invasion, and AJCC stages III and IV showed the highest predictive power (it needs to be noted that the lymph node metastasis status is factored into the calculation of AJCC stages). The predictive power of BRAF mutation for CLN metastasis was also high, albeit apparently less prominent than some of these pathological factors. This is an underestimate of the importance of BRAF mutation, as the type of CLN metastasis associated with BRAF mutation is qualitatively different and, unlike these pathological characteristics, BRAF mutation, as a unique prognostic factor, can be known preoperatively as will be discussed in Discussion section.
Predictive power of clinicopathological factors for cervical lymph node metastasis of papillary thyroid cancer in patients with central neck dissection
|Clinicopathological characteristics||Odds ratio||95% CI||P value||Odds ratio||95% CI||P value|
Adjusted for male, tumor size, extrathyroidal invasion, vascular invasion, AJCC stage III/IV disease, and BRAF mutation.
Although therapeutic CND and, in selected cases, prophylactic CND in accompany of thyroidectomy for PTC are advocated in some settings (Cooper et al. 2009), whether CND is needed in the treatment of PTC in a patient and to what extent it should be performed are often not a straightforward decision to make in practice. The reason is twofold: i) the impact of CLN metastases and CND to remove them on the clinical outcomes of PTC has not been uniformly established, and ii) there are potentially serious complications associated with CND, such as hypoparathyroidism and recurrent laryngeal nerve injuries (Sywak et al. 2006, Roh et al. 2007, Mazzaferri et al. 2009, Rosenbaum & McHenry 2009). It is thus not surprising that current performance of CND in patients with PTC varies. This study examined CLN metastases with respect to CND and their impact on disease recurrence/persistence of PTC and similarly the impact of BRAF mutation and hence its potential role in assisting the decision of CND.
Our study found a very low recurrence/persistence rate of PTC in the patients who did not undergo any form of CND, suggesting that the current selection of such patients following standard criteria for not pursuing CND is optimally practiced. Interestingly, in patients with CND, more aggressive clinicopathological characteristics of PTC were found as the extent of CND was advanced. This may not be surprising as CND is usually prompted by the preoperative or intraoperative findings of high-risk features of PTC. An interesting finding, however, was also the sharply increasing disease recurrence/persistence as the extent of CND was advanced; in patients with formal CND, the recurrence/persistence rate was up to 40 vs 16% in patients with limited CND and only 5% in patients without CND (Table 2). A high rate of PTC recurrence/persistence in patients who underwent CND was also often reported in other studies from academic tertiary centers (Kouvaraki et al. 2004, Davidson et al. 2008). These results reflect the fact that patients selected for extensive CND prompted by routine clinical criteria likely had more aggressive diseases, such as CLN metastases. CLN metastasis is the known most common source of disease recurrence/persistence of PTC (Mazzaferri & Jhiang 1994, Scheumann et al. 1994, Roh et al. 2007, Hughes & Doherty 2011). Indeed, this study found a high CLN metastasis rate in patients with CND, up to nearly 80% in patients who underwent formal CND (Table 2).
Clinically or radiologically detectable abnormal lymph nodes are often accompanied by microscopic ones (Arturi et al. 1997, Pereira et al. 2005, Roh et al. 2011). Some investigators suggested that a more aggressive surgical approach with more comprehensive dissection might offer long-term benefits. For example, by showing the association of more CLN removal with a lower rate of PTC recurrence/persistence, Davidson et al. (2008) suggested that more comprehensive neck dissection might offer patients the best chance of remission. Also, as exemplified by the study of Kouvaraki et al. (2004), reoperation of recurrent PTC, which is associated with increased surgical risk, could be avoided in many patients by more comprehensive initial CLN dissection. The results on disease recurrence/persistence of PTC in this study demonstrate further the importance of CLN metastases in the recurrence/persistence of PTC and emphasize the need to more thoroughly remove them at the initial treatment.
A major challenge in defining CND is to determine the existence of CLN metastasis, given the fact that preoperative ultrasonography can miss central CLN metastasis in up to 50% of cases (Kouvaraki et al. 2003, Stulak et al. 2006, Ahn et al. 2008, Vergez et al. 2010) and manual intraoperative detection of CLN metastases also lacks sensitivity (Vergez et al. 2010). This study demonstrates that several clinicopathological characteristics, such as extrathyroidal invasion, vascular invasion, and advanced stages, were highly associated with CLN metastases on CND. These, when found intraoperatively, should promote more comprehensive CND. However, their information is often not available until after the surgery. Consistent with many previous studies (Xing et al. 2005, Kebebew et al. 2007, Elisei et al. 2008, Yip et al. 2009, Howell et al. 2011), this study demonstrates a strong association of BRAF mutation with multiple high-risk clinicopathological characteristics of PTC, including CLN metastasis, as well as disease recurrence/persistence. This was uniquely shown also within the group of patients who underwent CND, which represents the first analysis exclusively focused on patients who underwent CND for such a role of BRAF mutation. It is important to note that CLN metastases of PTC associated with BRAF mutation often have lost the expression of thyroid iodide-handling genes and hence lost radioiodine avidity (Xing 2007, Xing et al. 2009). Recurrent PTC in such patients resists radioiodine treatments. Thus, the quality of CLN metastases differ in the presence and absence of BRAF mutation and complete surgical removal of metastasized CLN through comprehensive CND in the initial thyroid surgery is essential in preventing disease recurrent/persistent disease of BRAF mutation-positive PTC. BRAF mutation as such a unique prognostic marker is also valuable because it can be readily and reliably tested for on preoperative thyroid fine-needle aspiration biopsy specimens, which, in fact, has been shown to preoperatively strongly predict high-risk clinicopathological characteristics of PTC, including CLN metastases and disease recurrence/persistence (Xing et al. 2009).
Recent studies suggested the possibility of intratumor heterogeneity for BRAF mutation in PTC and higher percentage of BRAF mutation, on quantitative analysis, was associated with more aggressive of PTC (Guerra et al. 2012a,b). It would be interesting to see whether quantitative analysis of BRAF mutation would predict any unique patterns of clinicopathological outcomes of PTC with respect to different types of CND. Our results are consistent with many previous studies, including meta analyses, on the strong association between BRAF mutation and more aggressive clinicopathological outcomes of PTC (Xing 2005, 2009, Xing et al. 2005, Kebebew et al. 2007, Elisei et al. 2008, Yip et al. 2009, Howell et al. 2011, 2012, Guerra et al. 2012a, Joo et al. 2012, Kim et al. 2012, Li et al. 2012, Tufano et al. 2012). These clinical results are supported by many in vitro and in vivo studies demonstrating the biological impact of BRAF mutation on cellular and molecular processes and microenvironments that promote cancer cell proliferation, invasion, and metastasis (Hu et al. 2006, Xing 2007, Nucera et al. 2010).
In summary, this study demonstrates the important role of CLN metastases in disease recurrence/persistence of PTC and their prediction by BRAF mutation, supporting the importance of appropriate CND to thoroughly remove CLN metastases. Specifically, if based on the current standard risk criteria, it is determined that CND is necessary, then it seems prudent to perform a thorough and effective CND procedure to maximally remove lymph nodes given the currently high recurrence rate in PTC patients who receive CND. In this group of patients, a positive BRAF mutation test should particularly favor the effort to pursue more thorough CND. Obviously, this approach needs to be balanced by the potentially increased risk of complications associated with aggressive CND. In these patients, use of preoperative testing of BRAF mutation on thyroid needle biopsy specimens in combination with other conventional risk factors to determine the aggressive level of CND may be a reasonable approach.
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.
This study is supported by the US National Institute of Health R01 CA134225 to M Xing.
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