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Implications of extra nodal extension in differentiated thyroid cancer

Roh et al, from Asan Medical Center in Korea reviewed their experience of 2071 patients undergoing thyroidectomy. Forty-seven percent of these patients had positive nodes, while microscopic extranodal extension was noted in 13% and macroscopic extranodal extension was noted in 3.4% (70 patients). They noticed post treatment recurrence of 5.5%. In their multivariate analysis, the number of positive nodes, lymph node ratio, extranodal extension, and ATA risk groups were independent variables affecting recurrence. Extrathyroidal extension of the primary tumor (T4) and extranodal extension were independent variables associated with shorter overall survival. Macroscopic extranodal extension was significantly associated with gross extrathyroidal extension of the primary tumor. In patients will squamous cell carcinoma in head and neck the extranodal extension is an important prognostic factor with considerable impact on long-term survival and need for adjuvant therapy. However, this has not been studied very well in thyroid carcinoma.We recognize the minimal impact of nodal metastasis in thyroid cancer, however, bulky nodal disease, older age, aggressive histology, and major extranodal extension does have direct implication in future recurrences. Byers et al, initially did not notice any major impact of extranodal extension. However, Sugitani et al, from Japan, considered extranodal extension and bulky nodal metastasis as an important prognostic factor and grouped these patients in the high risk. Although the impact of many predictive factors on outcome has long been agreed in differentiated thyroid cancer (DTC), this cannot be said of regional metastasis. Initially, nodal disease in papillary thyroid cancer (PTC) was thought of as a factor which was associated with improved disease specific survival. However, nodal disease is more common in younger patients and this protective effect was later disproven as large datasets became available for multivariate analysis. Although not protective, the impact of nodal disease on survival is minimal. Many patients presenting with regional metastases are young and survival outcomes therefore seem unaffected. However, closer scrutiny demonstrates that in contrast to young patients, where nodal disease did not predict cause specific mortality, in older patients it is associated with distant metastasis, further recurrences and therefore worse survival. The position has always been made more difficult to interpret due to the different therapeutic approaches adopted by disease management teams internationally. Those groups who favor prophylactic neck dissection in PTC identify high rates of occult low-volume disease which is of minimal significance in terms of survival. In contrast, those groups who do not practice prophylactic neck dissection and only perform lymphadenectomy in the therapeutic setting encounter less disease which is of greater size and of more significance in terms of prognostication. Over recent years, an improved understanding has been reached about the impact of nodal disease on outcome and features of nodal disease which are of particular importance. The site of nodal disease is an important factor predicting outcome, particularly in older patients. Central neck disease is thought to represent the first echelon of metastasis whereas involved nodes in the lateral neck represents more advanced disease and is associated with higher rates of distant metastasis, and therefore, compromised survival. Nodal size is also critical. Small volume, microscopic central neck disease is of no relevance in terms of survival. In contrast, large volume nodal deposits are of greater clinical importance and are related to both increased recurrence andworse survival. The number of involved nodes is also critical to outcome.With a high number of involved nodes (>5) being associated with poor outcome. In addition to site, size, and number of nodes, the presence of extra nodal extension (ENE) has been shown to be associated with higher rates of recurrence and in some instances worse survival as shown by the recent paper by Roh et al. The vast majority of DTC cases remain encapsulated within metastatic nodal deposits, but those that demonstrate ENE have an aggressive biology with corresponding clinical behavior. Patients with extranodal extension are at higher risk for further recurrences and the resection may be more complicated with soft tissue involvement. These high risk patients may require external radiation therapy in selected cases. Similar findings have led to the incorporation of nodal site in the AJCC 8th edition or N1a central versus N1b lateral disease. However, at present only the ATA recognizes ENE as amongst the highest risk category alongside pT4a disease and widely invasive follicular thyroid cancer. The ATA system is designed to predict recurrence, not survival and in this system ENE is thought to be associated with recurrence rates of around 40%. In contrast, the AJCC has not yet incorporated ENE in to its recently revised system, due to a lack of evidence of the negative impact on survival. This improved understanding of the biology of neck disease underpins recent advances in the approach to managing the neck in cases of PTC. Previously, recognition of high rates of occult small