Papillary Thyroid Microcarcinoma

Prevalence: Autopsy Series and Incidental Finding at the Time of Thyroid Surgery

The high prevalence of papillary microcarcinoma has been appreciated from autopsy studies done before the emergence of high-resolution ultrasonography. In the United States, these studies have shown up to a 13% prevalence of micropapillary cancer, whereas in other parts of the world, substantially higher prevalence rates have been noted. For example, in Finland the prevalence in one study was 36%, leading the authors of that study to conclude that the “smallest forms of occult papillary carcinoma of the thyroid are so common in Finland that they can be regarded as a normal finding.” The prevalence of micropapillary carcinoma in pathologic specimens is also highly dependent on how carefully one looks for it. In one Spanish study, the initial prevalence based on grossly visible lesions was 5.3%, but when each thyroid was cut into blocks and carefully examined histologically, the prevalence increased to 22%. The prevalence of micropapillary carcinoma in some series was independent of age. For example, in Sweden the prevalence was approximately 7% for patients under age 50 or over age 80, and in Wisconsin, in the United States, the prevalence was 3% in an autopsy study of young adults. Micropapillary carcinoma is frequently an incidental finding at the time of thyroid surgery and has been reported in 2% to 50% of surgical specimens.

Clinical Incidence and Prevalence

The Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute in the United States provides data that help define the present and predict the future prevalence of papillary microcarcinoma. In 2018, the estimated incidence of new thyroid cancers was 53,990 per year and the measured prevalence of thyroid cancer (all thyroid cancers, not just papillary microcarcinoma) in 2015 was 765,547. Yet if we apply a conservative estimated figure of 6% for the prevalence of papillary carcinoma based on autopsy studies in the United States, the prevalence should be in excess of 18 million individuals. The annual incidence of thyroid cancer in the United States has been increasing, with the 2015 incidence from the SEER database of 15.03 per 100,000, compared with only 4.85 per 100,000 in 1975. In contrast, mortality from thyroid cancer has remained constant: 0.5 and 0.5 per 100,000 in 1975 and 2015, respectively. Although there is controversy as to whether the true incidence of thyroid cancer is increasing in the United States, it is widely accepted that a major component of the increased thyroid cancer incidence is due to ascertainment bias from improved imaging, allowing us to more readily detect both papillary microcarcinomas as well as larger thyroid cancers. This is illustrated by the data from South Korea, where women were offered inexpensive ultrasonographic screening of their thyroid glands coincident with their annual mammograms, resulting in a 14-fold increase in the incidence of thyroid cancer over several years. If indeed there are 18 million individuals with papillary cancer in the United States, we presently have detected about 4.3% of these cancers. With continued improvement in imaging and aggressive use of ultrasound-guided fine-needle aspiration (FNA) biopsy, it should not be a surprise that the annual incidence of thyroid cancer detection has increased by more than threefold since 1975. However, presumably due to guidelines which have recently focused on avoiding overdiagnosis and overtreatment, the annual increase in the rate of thyroid cancer detection peaked at 6.9% in the decade ending in 2009 and has recently fallen to 2.2% per year.

Pathologic data from hospitals also demonstrate that a substantial portion of the increasing incidence of thyroid cancer is due to the detection of papillary microcarcinoma. At the Queen Elizabeth Hospital in Hong Kong, the percentage of papillary microcarcinomas in operative pathology specimens increased from 5.1% in the period from 1960 to 1980 to 21.7% in the period from 1991 to 2000. Publications in 2006 from the University of Wisconsin in the United States and at the University of Ferrara in Italy reported that papillary microcarcinoma represented 43% and surgically excised thyroid cancers represented 40%, respectively.

Therefore when reviewing data on the natural history of papillary microcarcinoma, it is important to understand that published series are reporting only on the 4.3% of cancers that have come to clinical attention for one reason or another, and that more recent publications are including higher percentages of incidental cancers that would have gone undetected previously.

Clinical Series of Patients with Micropapillary Cancer

There have been many published series of patients with papillary microcarcinoma from single institutions. The Mayo Clinic updated its series in 2008, which includes 900 patients with an average follow-up of 17.2 years (range of 6 to 89 years). Twenty-three percent of the tumors were multifocal, 17% bilateral, 2% extrathyroidal, 30% had nodal involvement, and 0.3% had distant metastatic disease. Less than 25% were under 5 mm and more than a third were 9 to 10 mm. The 40-year cause-specific mortality was 0.7%—all three patients who died presented with lymphadenopathy, one had massive lymphadenopathy, and one had pulmonary metastases upon presentation. Recurrences occurred in 8% of patients, most in cervical nodes, but 1.5% occurred in the thyroid bed. Nodal recurrences occurred in 16% of patients with positive nodes at presentation and only 0.8% of patients without nodes at presentation. Recurrences occurred in 11% of patients with multifocal disease and 4% of patients with unifocal disease.

The Noguchi Thyroid Clinic in Japan also updated its series in 2008, which included 2070 patients with an average follow-up of 15 years. Recurrences occurred in 3.5% of patients at a mean of 10.3 years. Distant metastases occurred in only 0.2% of patients. Recurrence was more likely in patients with larger tumors (greater than 5 mm), more nodes, and invasion (e.g., into the recurrent laryngeal nerve or esophagus), and less likely in patients with coexistent thyroid autoimmunity.

The series of 203 patients from the Queen Elizabeth Hospital in Hong Kong reports a 4.9% rate of nodal recurrence and a 1% rate of local recurrences. Two patients developed pulmonary metastases (1%), and two patients died. The risk of nodal recurrence was increased 6.2-fold when nodes were present at presentation and 5.6-fold when the tumor was multifocal. The researchers did not find higher recurrence rates in tumors greater than 5 mm, but the larger papillary microcarcinomas were more likely to have extrathyroidal extension. Comparing papillary microcarcinomas with larger papillary cancers, there were similar rates of multifocality, but the larger papillary cancers were associated with higher rates of nodal metastases and nodal, local, and distant recurrences.

Recurrence occurred in 4.8% of 293 patients reported from South Korea after a median follow-up of 65 months; cervical nodes at presentation were associated with an increased risk of recurrence. Recurrence occurred in 3.1% of 287 patients from Rome, Italy, and included two patients (0.7%) with distant metastases; multifocal disease, extrathyroidal extension, and a higher number of cervical nodes at presentation were risk factors for recurrence.

Data from several series demonstrate multifocality in 20% to 40% of patients, bilateral disease in 10% to 19% of patients, extrathyroidal invasion in 2% to 38% of patients, cervical nodal involvement in 17% to 43% of patients, and distant metastases in 0% to 3% of patients ( Table 20.1 ). In one series of 671 patients from Seoul, Korea, 24% had central nodal involvement and 3.7% had lateral nodal involvement.

In a meta-analysis of 17 studies that included 854 patients with incidentally discovered papillary microcarcinoma with 2669 nonincidental cases, the recurrence rates were 0.5% and 6.5%, respectively.