Progress Towards Improving Initial Risk Stratification for Patients With Papillary Thyroid Cancer

Donald S. A. McLeod


Clin Endocrinol. 2020;92(4):282-283. 

Risk stratification has become an indispensable part of thyroid cancer management. It assists clinicians and patients in decision-making about the need for and extent of planned treatment; in assessing prognosis; and in determining the intensity of follow-up. Thyroid cancer guidelines recommend performing risk stratification at all stages of thyroid cancer care.[1–4]

Multiple risk stratification tools are available to clinicians. The three most commonly used are as follows: tumour-node-metastasis (TNM) staging systems (the most recent being American Joint Committee on Cancer 8th edition staging);[5] the American Thyroid Association's (ATA) initial risk stratification system;[1] and dynamic risk stratification.[6] Each strategy is designed for different purposes and use at varying times post-diagnosis. TNM staging predicts risk of thyroid cancer death at diagnosis/first staging. ATA initial risk stratification predicts risk of residual and recurrent disease after initial treatment. Dynamic risk stratification may be used continuously to predict the risk of recurrent disease based on biochemical or imaging findings during follow-up.

The 2015 ATA initial risk stratification system with proposed modifications continues to have a prominent role in the risk stratification milieu. The key outcome to predict for many differentiated thyroid cancer patients is persistent/recurrent disease (most have low risk for thyroid cancer death), and optimal local management can reduce this risk. ATA initial risk stratification is often used to assess the required extent of surgery and potential usefulness of post-operative radioactive iodine administration. Evidence strongly supports the use of ATA initial risk stratification; however, significant gaps in knowledge must be bridged through further research. Firstly, the majority of validation studies have been performed in cohorts treated with both total thyroidectomy and radioactive iodine; fewer studies have examined people treated with lobectomy alone. This is important because lobectomy is likely to have increased in popularity as clinicians apply current thyroid cancer guidelines that endorse lobectomy as a treatment option for many papillary thyroid cancers of diameter <4 cm,[1–4] after previous Western guidelines recommended total thyroidectomy for all tumours >1 cm diameter.[7–9] Secondly, the 2015 proposed modifications to the ATA initial risk system require further assessment. A prominent change to the ATA system was to differentiate risk based on the number and size of involved nodes, rather than a simple presence or absence of nodal metastases. While noted as a possible prognostic factor, the presence or absence of extranodal extension was not included in the system, pending further evidence. Another controversial component was to continue classifying tumours with minimal/microscopic extrathyroidal extension as intermediate risk, despite mounting evidence that it plays a little independent role in determining chance of recurrence.[10–12] Thirdly, the 2015 ATA initial risk system is more complex than previous versions; researchers and clinicians should continuously consider the balance between completeness and ease of use.

In this setting, Song et al report an important study in Clinical Endocrinology.[13] The authors retrospectively reviewed 571 patients treated with lobectomy alone for 1–4 cm diameter papillary thyroid cancers at Asan Medical Center, Korea, from 1996 to 2009. They analysed the risk of persistent/recurrent disease based on either the full 2015 ATA initial risk system or on ATA-defined nodal risk status in the central neck (patients with lateral nodal metastases were not included in the study). In post hoc analysis, the authors reanalysed prognosis using modified ATA-defined nodal risk levels, after removing clinically apparent nodes from the intermediate risk group and including extranodal extension as a higher risk nodal feature. They conclude that a simplified classification system based only on nodal status better predicted disease persistence/recurrence in patients undergoing lobectomy than the full ATA initial risk system.

The analysis of Song et al is careful and the conclusions reasonable; the authors should be congratulated on their high-quality work. Several other conclusions can be made from this study. Firstly, lobectomy appears to have an excellent safety profile for many patients with 1–4 cm papillary thyroid cancers and no lateral cervical nodal metastases. Secondly, ATA intermediate risk patients had a very high disease-free survival; their intermediate risk status was most commonly due to the presence of microscopic extrathyroidal extension. This study adds further weight to previous evidence suggesting that microscopic extrathyroidal extension is not an important risk factor for recurrent disease. Lastly, the presence or absence of extranodal extension of tumour appears to be highly predictive of the risk for recurrent disease.

Would and should the ATA abandon the general structure of its current initial risk system for a simplified approach based on nodal status for patients treated with lobectomy? The answers are no and no. Only a small number of patients in this study were labelled as ATA intermediate risk based on features other than microscopic extrathyroidal extension. Song et al's study has inadequate power to conclude that patients with vascular invasion (n = 5) or with aggressive histologic variants (n = 3) are not intermediate risk. Likewise, power is inadequate to suggest down classifying cN1 (clinically apparent nodal metastases; n = 19) patients in the ATA system. Song et al's multivariate models indicate a 37% worse disease-free survival compared with N0 although because of very small numbers the confidence intervals are wide (and cross the line of unity). In addition, cN1 status might be important in classifying recurrence risk in patients with lateral node metastases, who were excluded from this study. It is unlikely that the ATA would want to adopt separate criteria for initial risk stratification systems for lobectomy patients versus those treated with total thyroidectomy.

However, the ATA would do well to consider the data of Song et al in considering future iterations of initial risk criteria. Downstaging of microscopic extrathyroidal extension may accurately reflect the excellent prognosis for most patients with this histologic feature. The ATA should be less cautious to include extranodal extension as a high-risk feature next time, and further work could be considered to define optimal risk groupings for patients currently classified as ATA intermediate risk based on nodal metastasis characteristics; these patients are a heterogenous group with many appearing to have an excellent prognosis. The data from Song et al strongly suggest that some patients with papillary thyroid cancer (eg patients with tumours <4 cm and no lateral lymph node metastases) that could be treated more conservatively than current standards derived from the ATA risk stratification system, but other patients (eg those with extranodal extension) might benefit from more aggressive therapy.