Thyroid nodule size predictive of risk for follicular carcinoma

The recent retrospective study by Kamran et al clarifies several controversial issues in the management of patients with thyroid nodules. The authors carefully examined their experience with a very large cohort of patients. In fact, this study represents one of the largest published series in this field. The results reveal that there is an increased risk for malignancy in nodules measuring more than 2 cm compared with those less than this threshold. Further, the risk for cancer does not progressively rise with increasing nodule size. This is a powerful piece of information for a clinician when deciding which nodules require FNA. This study suggests that, in patients with multiple nodules, preferential attention may be required for those lesions measuring more than 2 cm over smaller ones to enhance the likelihood of identifying malignancy. At the same time, it upholds our current practice of selecting nodules to aspirate based on ultrasound features concerning for malignancy, rather than size alone, since the likelihood of malignancy is not higher in a 4 cm nodule than in a 2 cm nodule. 

Additionally, the authors found that there does not appear to be an increased risk for false negative FNA results in larger nodules. For years, many clinicians have argued in favor of removal of benign nodules measuring larger than 4 cm based on concerns for missing a diagnosis of malignancy. This study found that the rates of false negative FNAs were extremely low in nodules of all sizes, ranging from 0.7% to 1.5%. The decision to proceed to surgery in patients with such large nodules may instead be based on cosmetic or compressive concerns rather than a fear of missing malignancy.

It is important to note some limitations to the study. These results are based on the experience of one academic center with a very high level of expertise in the management of patients with thyroid nodules. The clinicians, radiologists and pathologists at this center are among the best in this field and their collective interpretive skills with ultrasonography and FNA may not translate to all centers seeing these patients. A further limitation of this study is the retrospective design. Finally, the authors concede that the majority of benign nodules did not undergo repeat FNA or surgical resection and that this is a potential limitation of the study. While this is, in fact, a limitation of the study, it is also considered the standard of care to simply observe cytologically benign nodules. Repeat aspiration is reserved for nodules with suspicious features or growth. Likewise, surgical removal of a benign nodule is generally only pursued in the event of patient preference or mass effect. In spite of the above limitations, this is a powerful study that will certainly impact patient care and advances our understanding of thyroid nodule biology.

The indeterminate thyroid nodule FNA cytology result continues to present challenges for optimal clinical management recommendations, even in the era of molecular diagnostics. Thyroid nodule ultrasound characteristics provide useful features to help predict malignancy risk, but at the end of the day they do not trump cytologic diagnosis and as the authors state, are subject to significant inter-observer variability. This study demonstrates that the easily identifiable and reproducible size criteria of nodules have a direct correlation predictive of follicular and Hurthle cell carcinomas, though the absolute difference in risk between nodules <2 cm and >2 cm is relatively small. 

This manuscript highlights two other clinically relevant aspects of thyroid nodule management. It supports the American Thyroid Association thyroid nodule guideline regarding the preferential aspiration of nodules with sonographically suspicious features, but in the absence of distinct suspicious features of nodules within a MNG, to aspirate the largest nodules (and based on this manuscript, perhaps a cut-off of 2 cm would be appropriate — ATA Revised guidelines, Thyroid 2009).  Additionally, this study supports the growing evidence that larger nodules do not have a greater false negative cytology rate than smaller nodules and size criteria alone, in the absence of other clinical indications, should not primarily direct a surgical referral.