Commentary

Thyroid nodular disease is a common syndrome, and its prevalence increases with age. Although the disease is predominately benign, the concern that a small proportion of nodules are cancerous necessitates thorough evaluation. Nonetheless, simple and cost-effective detection of this subgroup of cancers remains a challenge. Much effort has been made to find clinical risk factors that might provide physicians with the means to target high-risk individuals. Neck exposure to ionizing radiation during childhood is now widely known to increase both the prevalence and the aggressive nature of thyroid cancer later in life.1 Further details, such as the effect of irradiation on the natural history of thyroid nodular disease and the best means to evaluate patients, remain uncertain. The investigation by Mihailescu and Schneider2 provides important answers to some of these questions.

From a cohort of 4,296 patients exposed to head and neck radiation during childhood, the investigators studied a selected subgroup of 1,059 patients who underwent thyroidectomy as adults. The risk of cancer was assessed on both a per-nodule and a per-patient basis. Nodule size was not predictive of thyroid cancer in this cohort. In addition, the presence of multinodularity did not affect the risk of any given nodule being cancerous. The greater the number of thyroid nodules present, however, the greater the risk of thyroid cancer on a per-person basis. Mihailescu and Schneider conclude that evaluation of multiple thyroid nodules is required to adequately detect malignancy. Taken together, these data strongly support previous reports and current opinion about thyroid nodular disease.3

Other than childhood exposure to ionizing radiation, surprisingly few clinical risk factors are known to affect the risk of a nodule >1 cm in diameter being cancerous. Only young age (<25 years) and male sex seem to increase the risk, and both do so by nearly twofold. Thyroid nodule size has long been suggested as a separate factor that can influence cancer risk, although repeated analyses have disproved this assumption.3 This study supports the conclusion that nodule size does not correlate with cancer risk. In retrospect, this finding seems logical, as most thyroid cancers are papillary carcinomas (>80%), and there are no data to suggest that previously benign or precancerous lesions progress to papillary carcinoma as a function of increasing size.

Thyroid nodules should, therefore, be evaluated regardless of their size. Nodules >1 cm in diameter should undergo initial assessment of serum TSH levels, followed by ultrasound-guided fine-needle aspiration and cytologic evaluation (FNAC). Nodules smaller than 1 cm seem to pose minimal risk to patients; however, exceptions to this rule should be noted. Data from specific subgroup investigations confirm that nodules <1 cm should be considered for FNAC when detected in high-risk individuals.

Multinodularity (defined as two or more nodules, each >1 cm in diameter) occurs in 40–50% of the general population, and its prevalence increases with age. As most nodules prove to be benign and do not require intervention, a cost-effective strategy for assessing patients with multinodular thyroid glands is urgently needed. Evidence from previous studies suggests that multinodularity exerts a protective effect against thyroid cancer; however, this theory has proven to be false.3 In support of previous data, the study by Mihailescu and Schneider suggests that the risk of cancer is not fully addressed when only the largest, dominant nodule is aspirated. This statement has important implications for diagnostic evaluation: when multiple nodules are present, FNAC is required to fully exclude malignancy. The authors suggest that two or more nodules must be evaluated in such patients. Other data suggest that ultrasonographic characteristics can also be used to prioritize evaluation more effectively.

Thankfully, the potential harm associated with childhood head and neck irradiation has been recognized, and the use of such therapy is now avoided wherever possible. Although the clear association between ionizing radiation and increased cancer risk has been previously described, the study by Mihailescu and Schneider answers many remaining uncertainties. Their data suggest that multinodularity is more common (∼70%) in irradiated patients than in nonirradiated patients (∼40%), although these findings might be biased as the study was a retrospective analysis of a selected population. Furthermore, as the number of nodules increases, the prevalence of thyroid cancer also increases. These findings differ modestly, but importantly, from the findings of comparative studies, which suggested that irradiated and nonirradiated individuals have a similar rate of malignancy per person, regardless of the number of nodules. Although these differences are notable, the study also confirms the increasingly accepted view that a diligent evaluation of numerous nodules must be performed in all patients with multinodularity. Without such approach, thyroid cancer might be missed.

In summary, the data presented by Mihailescu and Schneider provide a novel insight into a unique cohort of individuals by an analysis unlikely to be reproduced again. Although these data suggest important variability in the natural history of nodular disease after radiation exposure, they also provide compelling evidence that multinodularity is not protective against cancer. Identification of potential malignancy in patients with multinodularity requires a thorough investigation of as many nodules >1 cm in diameter as possible. As the mean age of our population increases, and cross-sectional imaging techniques are increasingly used for patient examination, these conclusions are highly relevant to clinical practice. In addition, the future holds promise for improved assessment of thyroid cancer risk by other means of preoperative assessment, e.g. galectin-3 expression analysis and ultrasound elastography.6,7 While we await confirmation and validation of these advances, however, FNAC of multiple nodules remains the method of choice.