Bilaterality in papillary thyroid carcinoma: does it influence prognosis?

Papillary carcinoma is the most prevalent thyroid tumor subtype, and the incidence of this variant is rising in developed countries.1 The majority of papillary thyroid cancers (PTC) are indolent, and 5-year survival among those patients receiving appropriate surgical and medical therapy is greater than 95%. Nonetheless, a subgroup of PTCs will behave aggressively, and these tumors are associated with poorer overall and disease-free survival. Identification of specific disease characteristics correlating with prognosis has therefore become an important goal, both in understanding PTC biology and in directing therapeutic intervention. Historically, prognostic variables have included age, histopathological subtype, larger tumor size, and presence of extrathyroidal extension/metastasis.1,2 Multifocality is also an important feature of PTC. Multi-focal disease is common, being identified in 38% of micropapillary carcinoma cases, and is associated with tumor recurrence. The American Thyroid Association recommends using “clinical judgment” when considering whether radioactive iodine ablation (RAI) should be used to treat multifocal PTC, especially in light of recent studies showing that, for microscopic multifocal PTC, RAI does not improve recurrence rates.2,3 In addition, significant interest has recently developed in ascertaining the relationship between PTC prognosis and the presence of mutations in BRAF, a tyrosine kinase-encoding protooncogene commonly mutated in PTC cells.4–6 In this edition of The Annals of Surgical Oncology, Wang and colleagues consider whether bilaterality should be considered a new, potentially important prognostic feature of PTC. Interestingly, though both multifocality and bilaterality in PTC are traditionally considered indications for total or near-total thyroidectomy, few data specifically examining the prognostic implications of bilateral disease have been reported.7,8 In their manuscript “Poorer prognosis and higher prevalence of BRAFV600E mutation in synchronous bilateral papillary thyroid cancer,” Wang and colleagues detail the first formal evaluation of the relationship between bilaterality and prognosis in 891 PTC patients treated with total or near-total thyroidectomy over a 9-year period who were retrospectively identified. Bilateral synchronous PTC was defined as cancer diagnosed in both thyroid lobes at the same time or within a period of 3 months following removal of the first tumor. The authors found that bilateral PTC is common, occurring in 19.9% of their cohort, and that bilaterality is associated with poorer prognosis. Increased rates of extrathyroidal extension, nodal metastasis, as well as an overall higher stage at presentation were associated with bilateral disease. Further, these findings correlated with disease-free and overall survival, both of which decreased in the context of bilateral disease. Taken together, Wang and colleagues’ findings suggest that bilaterality is an important feature of PTC biology that may improve the clinician’s ability to predict the behavior of these tumors. Because mutation of the BRAF protooncogene is now recognized as a common genetic aberrancy contributing to the pathophysiology of PTC, evaluation for BRAF mutation may also be important in assessing the prognostic relevance of disease bilaterality. As such, the authors were able to assay BRAF gene sequences obtained from 208 consecutive patients, identifying a statistically significant increase in the prevalence of BRAF protooncogene mutations in bilateral versus unilateral cases (65.7 vs. 50.4%, P = 0.038). Nonetheless, these data must be interpreted carefully, as mutation of the BRAF protooncogene in the bilateral disease cohort did not correlate with other known prognostic features of PTC, including tumor size and extrathyroidal extension. The identification of tumor features associated with poor prognosis plays an important role in defining the pathophysiology of cancer and provides insight into the clinical management of malignancy. Here, Wang and colleagues provide initial data suggesting that disease bilaterality confers poor prognosis among patients diagnosed with PTC. Although data describing the prognostic relevance of multifocal PTC have been previously reported, this study represents the first published report to examine the prognostic relevance of bilateral disease. Potentially important correlations between disease bilaterality and tumor size, BRAF protooncogene mutation, extrathyroidal extension, and metastasis are supported by the authors’ findings. Future studies should be done prospectively, should detail tumor sizes in each lobe, and should normalize the performance and extent of neck dissection, as well as the use of postoperative 131I therapy. Analysis of histopathological subtypes among PTC patients having bilateral disease, relative to unilateral cases, may also provide insight into the prognostic value of bilaterality. Although Wang and colleagues provide an interesting initial study of the significance of bilateral disease in cases of papillary thyroid carcinoma, additional data will be required to validate bilaterality as an independent predictor of disease prognosis.