Can Risk-Adapted Treatment Recommendations Replace the ‘One Size Fits All’ Approach for Early-Stage Thyroid Cancer Patients?

There is uniform agreement that initial treatment of high-risk thyroid cancer should include total thyroidectomy, compartmental neck dissection of clinically involved cervical lymph nodes, and radioactive iodine (RAI) remnant ablation. However, the optimal management of thyroid cancer patients who are at low risk for recurrence and disease-specific mortality continues to be hotly debated. In a thoughtful review in this issue, Dr. Mazzaferri concludes “the safest and most thorough surgical approach seems to be total thyroidectomy with bilateral prophylactic level VI and ipsilateral levels II and IV lymph-node compartment dissection, which must be performed by a highly experienced surgeon.” This would be recommended for all papillary thyroid cancer patients except for those very-low-risk patients with subcentimeter, unifocal, micropapillary tumors confined to the thyroid gland.

Dr. Mazzaferri argues that this approach (1) results in the highest yield of detecting microscopic lymph node metastases, (2) allows for better initial staging and a more selective use of radioactive iodine remnant ablation, and (3) can be done with minimal complications in the hands of highly experienced surgeons. Furthermore, he argues that our current clinicopathologic staging systems are designed primarily to predict disease-specific mortality and not risk of recurrence-which is in itself a considerable source of morbidity-and hence are not adequate to specifically tailor the extent of initial therapy.

Implicit in the argument for aggressive initial therapy of low-risk patients is the assumption that total thyroidectomy, prophylactic neck dissection, and RAI remnant ablation is associated with better long-term clinical outcomes than a more selective approach to initial therapy-ie, total thyroidectomy without prophylactic neck dissection or routine RAI ablation, followed by salvage therapy in the small percentage of patients initially classified as low risk who subsequently develop clinically evident recurrences. While this “one size fits all” scheme to manage thyroid cancer has been widely accepted for more than 30 years, our approach at Memorial Sloan-Kettering Cancer Center (MSKCC) differs in important respects: we attempt to calibrate the extent of initial therapy based on risk stratification, even within early-stage tumors, in order to minimize treatment-related complications.[1,2]

Risks/Benefits Reconsidered

We are particularly concerned that more widespread use of prophylactic lymph node dissection in low-risk thyroid cancer patients is likely to cause more harm than good (eg, recurrent laryngeal nerve injury, alterations in voice, hypoparathyroidism). While we agree that neck dissections can be done with minimal complications in the hands of very experienced surgeons, most thyroidectomies done in the United States are done by low-volume surgeons who are likely to have significantly higher complication rates.[3,4] Because of the lack of definitive evidence of benefit in low-risk patients and the higher rate of complications associated with more aggressive surgery, the updated American Thyroid Association thyroid cancer guidelines (which should be published this summer) will not recommend routine prophylactic central compartment neck dissection for all papillary thyroid cancer patients; however, do note that it may be appropriate for higher-risk patients (T3 and T4 tumors).

With extensive neck dissection and careful pathology review, cervical lymph node metastases can be identified at the time of diagnosis in as many as 30% to 70% of low-risk patients with micropapillary thyroid cancer (< 1 cm primary tumor).[5-7] Interestingly, the metastatic lymph nodes are found with nearly equal frequency in the central neck (level VI) and the ipsilateral neck (levels III and IV).[7-9] Despite this very high rate of micrometastatic lymph node involvement, the risk of clinically evident disease recurrence in these patients was only 5% to 10% over 20 years of follow-up in a cohort of up to 1,082 patients treated with total thyroidectomy alone (no RAI ablation),[10,11] and approximately 11% over a 30-year follow-up period in low-risk patients (< 1.5 cm, unifocal, intrathyroidal lesions) following total thyroidectomy with or without RAI ablation.[12]

In these studies, a level VI neck dissection at the time of total thyroidectomy may have influenced the recurrence rate in the central neck, but would have had little impact on the 50% of low-risk patients who may also harbor clinically unsuspected (and therefore, untreated) micrometastatic disease in the lateral neck. These data suggest that even without specific therapy (neck dissection or RAI ablation), the majority of these subclinical, micrometastatic cervical lymph nodes do not become clinically evident during 20 to 30 years of follow-up. The lack of disease progression in most micrometastatic lymph nodes is consistent with the observation that following tumor initiation or metastatic seeding, cancer cells can enter a state of senescence and lie dormant for many years, or even indefinitely.[13] Therefore, the simple presence of microscopic thyroid cancer in small cervical lymph nodes may not justify more aggressive therapy.

Recent data suggest that the risk of recurrence in patients with cervical lymph node metastases can be estimated based on the size, number, and histologic characteristics of the involved nodes. For example, the risk of recurrence was not significantly different when patients with micrometastatic cervical lymph node involvement (2-mm foci of metastatic disease within cervical lymph nodes) were compared with control patients without clinically evident lymph node metastasis at diagnosis (5% vs 6%).[14] Furthermore involvement of fewer than five small cervical lymph nodes without extranodal extension is associated with a similarly low risk of clinically evident recurrence (7%).[15] Conversely, patients who had 10 or more involved nodes, nodes larger than 3 cm, or extranodal extension of the tumor demonstrated significantly higher rates of cervical nodal recurrence (18% to 31%).[15,16]

Because of these considerations, we continue to recommend therapeutic, compartment-oriented neck dissections for clinically evident metastatic lymph nodes. However, we do not routinely recommend prophylactic neck dissections in low-risk patients who are likely to respond very well to our initial interventions (thyroid surgery, thyroid hormone suppressive therapy, with or without RAI ablation). Our primary concern is that the surgical risks outweigh any potential benefit in these patients. Furthermore, the overall disease-specific survival is greater than 99% in low-risk patients, despite a local recurrence rate of 5% to 10%. Although not rigorously proven, this argues that salvage therapy (surgery and/or radioactive iodine) at the time of recurrence is effective in most patients.

Risk Stratification

We agree with Dr. Mazzaferri that standard initial risk stratification schemes (such as AJCC/TNM, MACIS) do not adequately segregate patients at risk of developing clinically significant disease recurrence. We have proposed a risk stratification paradigm that begins with an initial assessment based on age, size of the primary tumor, completeness of resection, tumor histology, lymph node status, and postoperative serum thyroglobulin. We follow this with ongoing reassessments based on response to therapy to help gauge the risk for developing recurrences.[2,17] This ongoing restratification scheme incorporates variables that monitor response to therapy (serum thyroglobulin, neck ultrasound), which are used to “reclassify” patients during postoperative surveillance.

It is now also timely to incorporate molecular markers into the risk stratification of thyroid cancers at presentation. Activating mutations of BRAF are found in > 40% of papillary thyroid cancers[18] and are associated with higher frequency of extrathyroidal invasion, lymph node metastases, advanced stage at presentation,[19] and refractoriness to RAI treatment.[20] This and other somatic oncogene mutations can be determined in preoperative fine-needle aspiration samples, and can refine diagnosis and perhaps help inform the initial approach to therapy.[21] Although this genetic information has not yet been used prospectively in clinical studies, the evidence for its significance is now quite compelling.[22]

Conclusions

In summary, a risk-adapted approach to the initial management of thyroid cancer allows identification of patients at high risk for either recurrence or disease-specific mortality that are likely to benefit from total thyroidectomy, therapeutic neck dissection, and RAI ablation. More importantly, risk stratification can also identify a significant proportion of thyroid cancer patients at low risk for recurrence and death, in whom total thyroidectomy without cervical lymph node dissection or RAI remnant ablation can be expected to result in excellent clinical outcomes. We propose that with judicious use of serum thyroglobulin and neck ultrasonography, the vast majority of the 5% to 10% of low-risk patients who develop local recurrences can be readily detected and subsequently treated with little impact on their overall survival.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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