Overdiagnosis of Juvenile Thyroid Cancer: Time to Consider Self-Limiting Cancer

Overdiagnosis of thyroid cancer is now recognized as a worldwide problem. Recent data revealed that juvenile thyroid cancers grow rapidly and initially show the aggressive features; however, most of them gradually stop proliferating due to their self-limiting growth. When this selflimiting characteristic of juvenile thyroid cancer is taken into account, ultrasonography (US) screening of young generations should be avoided since early detection of thyroid cancer in the young is harmful. Furthermore, we should reconsider the desirable timing of surgery for juvenile thyroid cancer and should search for the true origin of lethal thyroid cancer. In many countries, overdiagnosis of thyroid cancer is now a serious problem, and overuse of US is recognized as one of its causes. The number of patients who might be affected by overdiagnosis depends on physicians’ attitude toward papillary thyroid microcarcinoma (PTM). For many years since the multistep carcinogenesis theory was established as the main theory on thyroid carcinogenesis, early detection and treatment have been regarded as golden rules. Thus, until recently, almost all patients with PTM detected by US were encouraged to undergo surgery. Recent studies on thyroid cancer from developed countries showed a discrepancy between an increasing incidence and stable mortality. They proved that early treatment of small thyroid cancer does not lead to decreased mortality. The concept that small and indolent thyroid tumors turn into more aggressive and lethal ones, as hypothesized in the classical concept of multistep carcinogenesis, is no longer considered true. To understand this phenomenon correctly, we should take a careful look at the natural history of thyroid cancer (Fig. 1). Thyroid cancers in children show paradoxical clinical features. They are usually recognized as large tumors with rapid growth and are often accompanied by local and distance metastases. Furthermore, their recurrence rate after surgery is much higher than in adults. However, the associated prognosis is excellent, with a life span survival rate of >95%. These features of thyroid cancers in children, which show a marked contrast to those in adults, have been puzzling clinicians for many years. Since the accident at the Fukushima Daiichi Nuclear Plant in 2011, the Fukushima Health Management Survey (FHMS), which targeted *380,000 children, has been ongoing and it has generated some surprising results that might help answer the aforementioned question. In the FHMS, >200 children have been diagnosed with thyroid cancer by US and fine needle aspiration cytology so far, confirming that papillary carcinoma is a common childhood phenomenon. The distribution of the patients’ age suggested that these cancers start growing before adolescence and grow rapidly when children are in their teens. In contrast, the tumors’ growth rate is negatively correlated with their size; thus, it is likely that they show self-limiting growth. Data from an observation study indicated that PTMs in the patients >40 years old showed limited growth and a part of them even shrank during the observation. These data suggest that thyroid cancers detected by US in children are selflimiting. Although they show rapid growth in patients in their teens or 20s, the majority of them stop proliferation after a few decades and appear as PTMs. Despite these characteristics, they are truly cancer from pathologists’ point of view, since >80% of thyroid cancers found in the FHMS showed invasion to the surrounding tissues or were accompanied by local or distant metastasis; however, they are not lethal malignancies but indolent tumors from a prognostic point of view. In summary, juvenile thyroid cancers grow rapidly and initially show the aggressive feature of invasion or metastasis; however, they are associated with an excellent prognosis because they gradually stop proliferating due to their selflimiting growth. Therefore, they can be regarded as selflimiting cancers, which are difficult to explain with the classical concept of multistep carcinogenesis whereby every indolent tumor has a risk of evolving into an aggressive one. Some researchers describe PTM as an indolent lesion of epithelial origin or innocent cancer. However, it is not appropriate to describe all juvenile PTMs using these terms. Although presented as very rare cases, some juvenile thyroid cancers cause cancer death when patients do not receive appropriate therapy. Self-limiting cancer can kill patients when showing rapid growth before growth arrest. Cases with rapid growth in childhood, or those showing a poor response to radioactive iodine therapy, may progress to cancer death regardless of the cancer’s self-limiting property. Thus, we