To our knowledge, the current data set is the largest and most detailed to date of patients with malignant hot thyroid nodule. In that regard, this study complements the informative and excellent 2012 review by Pazaitou-Panayiotou and colleagues examining the association of thyroid carcinoma with a broader spectrum of hyperthyroid states, including Graves’ disease and toxic multinodular goiter in addition to hyperfunctioning thyroid nodule [81
]. Of note, although it was not the focus of the Pazaitou-Panayiotou et al. review to perform a detailed analysis of the historical and clinical features of malignant hot nodule cases, as we did here, Pazaitou-Panayiotou and colleagues did include an evaluation of thyroid carcinoma prevalence. The reported percentages of thyroid carcinoma in their collected case series of patients with hot nodules, which overlapped but did not mirror exactly those case series evaluated here and which also included some cases of thyroid carcinoma occurring in extranodular thyroid tissue, ranged between 2.5 – 12.0%. This corresponds to a weighted average of 6.9% and thus is similar to the 3.1% prevalence estimated here. In its discussion of thyroid carcinoma in patients with hyperfunctioning nodules, the Pazaitou-Panayiotou et al. review also included several other important commentaries. For instance, they draw attention to two studies suggestive of a higher prevalence of thyroid carcinoma in hot nodules occurring in children [82
], though the latter study included children from an iodine-deficient region. In addition, they discuss several reports in which activating mutations of the TSH receptor gene were identified within malignant hot nodules [81
There are several noteworthy discussion points and implications to the findings presented here. The first relates to the prevalence of malignancy within solitary hot nodules. As mentioned, in the available surgical case series that addressed this topic, a varied prevalence was noted, ranging from 0 – 12.5%, with a weighted average of 3.1%. Only a minority of the patients who underwent surgery in those series did so because of concerning findings from FNA, and as such, we do not believe that the data set is biased towards cases in which a post-operative diagnosis of malignancy was expected. We realize that this collection of case series includes only a small fraction of the total number of solitary hot nodules that have occurred, and also that the vast majority of malignant hot nodules likely have gone unreported. Furthermore, it is likely that malignancy goes undiagnosed in many cases of hot nodules treated with radioiodine, especially those harboring microcarcinomas. Despite these limitations, we do believe there are sufficient numbers of cases included among the collected 14 surgical case series of subjects to cite the 3.1% figure as being a fair and representative estimate of malignancy prevalence amongst solitary hyperfunctioning nodules. While this 3.1% prevalence figure is low – and in fact is lower than the estimated 5 - 15% prevalence of malignancy among all thyroid nodules [6
] – it is not trivial. Thus, the possibility of malignancy within a hot nodule must not be overlooked by a managing clinician, particularly if management other than surgical resection is chosen.
Another important discussion point regards the limitations resulting from the retrospective nature of this analysis, including incomplete data and differing methodology used in many of the collected case reports and case series of malignant hot nodule. While some of the primary sources were meticulous in their case descriptions, others included less-thorough descriptions. For example, tumor size was frequently not reported, and thus it was unclear if a PTC tumor was simply an incidental microcarcinoma embedded within a larger hot nodule or a large, follicular variant of PTC comprising the entirety of the nodule. While we have included some cases in which the malignancy was a microcarcinoma and thus of uncertain clinical significance [84
], these cases are clearly in the minority (only 8 of the 77 reported tumors were less than one centimeter in size). Other factors affecting the data set are the evolution of technology and our understanding of risk factors for thyroid carcinoma. For instance, thyroid ultrasound began clinical use in the late 1960s, and prior to this, nodule size was estimated by palpation. Earlier reports would not have commented on some of the suspicious sonographic features recognized today. Additionally, the radioimmunoassays used to measure TSH have undergone many generations of refinement over the past several decades, and thus the presence and degree of hyperthyroidism may have been underestimated in earlier studies.
Also worth discussing are the differential prevalences of thyroid carcinoma histologic subtype found in hot nodules as compared to nodules as a group. As mentioned, there was a much higher prevalence of both FTC and Hurthle cell carcinoma in hot nodules (36.4% and 7.8%, respectively) as compared to in all nodules (10% and nearly 3%, respectively). Additionally, a substantial percentage of the PTC cases found in hot nodules were the follicular variant. This may have bearing on the current algorithm for evaluation of patients with thyroid nodules as recommended in the 2009 thyroid nodule and thyroid carcinoma management guidelines [6
]. In particular, for those nodules found by biopsy to have follicular neoplasm by histology, the guidelines recommend consideration be made for performing an 123
I thyroid scan, if not already done, especially if the serum TSH is in the low-normal range; if the nodule is found to be hyperfunctioning, it can then be followed [6
]. However, the high prevalence of both FTC and FVPTC reported for malignant hot nodules suggests that a biopsy diagnosis of follicular neoplasm within a hot nodule may not be as reassuring as previously thought. Also of interest, in a 2009 study, Sundaraiya and colleagues reported a case of metastatic FTC occurring in the setting of thyrotoxicosis, in which high-grade extrathyroidal uptake of technetium-99m-pertechnetate was observed; in a literature search, they found 74 other cases of thyrotoxicosis resulting from well-differentiated thyroid cancer metastatic lesions, most of which demonstrated histologic evidence of FTC [85
As a final point of discussion, since none of the historical, biochemical or radiologic characteristics that were assessed seems to predict malignancy in the collected cases of hot nodules, one might ask if there is any utility in biopsying hot nodules. Such would be a shift from the current thyroid nodule management guidelines which views an increased nodular radiotracer uptake pattern as a reassuring characteristic from a cancer perspective [6
]. Given the estimated 3.1% prevalence of malignancy within hot nodules, and also taking into account the difficulty in predicting whether a particular hot nodule is malignant, we recommend that hot nodules that are not treated surgically (as is an option to manage the hyperthyroidism) be considered for biopsy if high-risk historical and/or suspicious sonographic features are present or if these nodules grow over time, just as is currently recommended for nodules that are not hyperfunctioning [6
]. This should also include previously hyperfunctioning nodules treated with radioiodine, although the known occurrence of dystrophic calcification and cystic degeneration as sequelae of radioiodine ablation should be taken into account when assessing their sonographic features [86
]. Future prospective studies could help determine if biopsying at the time of diagnosis all hot nodules with suspicious sonographic characteristics and/or associated high-risk historical features versus biopsying hot nodules only if the initial sonographic characteristics worsen over time would result in better outcomes.