Thyroid cancer accounts for only 1% of all malignancies yet is the most common form of endocrine tumor. Over the past two decades, the incidence of thyroid cancer has increased fourfold in females and threefold in males [1]. Well-differentiated thyroid cancer (WDTC), particularly papillary thyroid cancer (PTC), is the most common thyroid malignancy, comprising ~90% of new cases in iodine-sufficient areas of the world [2]. Asian women in particular were observed to have the highest incidence of WDTC, among which PTC was the most common form [3]. The prognosis of WDTC is generally excellent, with 10-year overall survival rates exceeding 90% [4]; however, higher rates of recurrence and mortality have been observed in select groups of patients [5].

Despite its clinical impact, differentiated thyroid cancer remains a difficult topic for evidence-based decision making, with most management strategies largely empirical. Due to its slow rate of progression, very large cohorts of patients followed over several decades are required to confirm significant differences in prognostic factors and treatment efficacy [6]. During the last decade, there has been a dramatic change in our understanding of the natural history of the disease resulting from the continuous evolution of diagnostic modalities and advancement in therapeutic options [7]. Over this time, follow-up paradigms have progressed considerably, and the standard of care is now focused on achieving a balance between curative therapies and minimizing overtreatment [8].

Because of the longer survival of thyroid cancer patients, description of their clinical profile and understanding of their natural history and clinical outcome are of great importance. Asian populations have been shown to exhibit higher incidence rates, further strengthening the need for location-specific data among Asian populations [3]. Filipinos in particular have consistently been reported as the ethnic group with the highest incidence of thyroid cancer in studies conducted in Hawaii [910] and Los Angeles, California [11]. A recent survey on the cancer incidence trends among Asian American populations in the United States revealed Filipino females to have the highest increase of thyroid malignancy [12]. Thyroid cancer among Filipinos was also observed to be more aggressive and recurrent in nature [13], with the risk of malignancy in Filipinos with thyroid nodules significantly higher than that of other racial ethnicities [14].

Despite the strong association between Filipinos and thyroid cancers, only a handful of case studies have been reported from the Philippines. Similarly, the most recent retrospective study of thyroid cancer in Filipino patients by De La Pena [15] in 1988 only described the incidence, diagnostic modalities, and therapeutic treatments used for these patients, with no details regarding the clinical and histologic profiles or long-term outcomes associated with WDTC in this population. Here, we performed a retrospective analysis of patients presenting with WDTC at a tertiary care hospital center in the Philippines (Philippine General Hospital).

A total of 728 patients diagnosed with WDTC by final histopathologic biopsy were included in this study. The vast majority of cases (89%) were diagnosed as PTC, with only 79 cases (11%) of follicular thyroid cancer (FTC). Females were disproportionately affected (84.9%) in both groups. The mean age at diagnosis was 44±13 years (range, 18 to 82), with a majority of cases occurring in the younger age group (<45). Thyroid cancer incidence was distributed normally across age groups, with the highest incidence seen among 41- to 50-year olds. Most patients presented with a slowly enlarging goiter, with an average duration of 6 years. These cases tended to be sporadic in nature, with only a few cases with family members with similar malignancies. None of our patients had a history of neck irradiation prior to diagnosis. Palpable lymphadenopathies at presentation were observed more often among cases of PTC, while distant metastases at presentation were more common in patients with FTC. Lungs appeared to be the most common site of distant metastasis in PTC, while bones and scalp were predominant in FTC. Concomitant lymphocytic thyroiditis and hyperthyroidism were reported in some cases of PTC, but rarely seen in FTC. Breast cancer appeared to be the most common concomitant malignancy reported (Table 1).

Fine needle aspiration biopsy (FNAB), as an initial histologic test for malignancy, exhibited low sensitivity, as 44% of PTC and 68% of FTC were initially deemed benign cases. Given the low sensitivity of this test, only 32% of FTC cases were assessed by FNAB, with the majority of patients considered to have a Bethesda score of 4, indicative of follicular neoplasm or suspicious for follicular neoplasm. Average tumor size at presentation was larger in FTC cases, while lymph node metastases, multifocality, and bilateral involvement were more common in patients with PTC. Micropapillary (18%) and follicular (15.6%) variants were among the most commonly observed PTC histologic variants (Table 2).

Calcifications, hypoechogenicity, and solid predominance were the most common sonographic findings, and most cases were multinodular and bilateral in nature. Lymph node involvement was detected by ultrasound less frequently; similarly, reported tumor size was discordant with the final histologic biopsy in most cases (Table 3).

Although a majority of both PTC (63.2%) and FTC (54.4%) presented initially as stage 1, a greater proportion (12.7%) of FTC cases presented with distant metastases. Alternatively, nodal metastases were observed more frequently among cases of PTC. Based on TNM classification scores, most tumors were between 2 and 4 cm in size. Only a small percentage of cases had a worsening of the initial cancer staging due to recurrence or persistence of the disease (Table 4).

Surgery was the treatment of choice for all patients in this study, with total thyroidectomy the most common initial surgical procedure. Nodal dissection was only performed for cases with suspected lymph node involvement. A second surgical procedure (completion thyroidectomy) was more frequent in FTC cases. Post-surgical hypoparathyroidism was seen in only a small percentage of both PTC and FTC cases. Post-surgical radioactive iodine (RAI) therapy was performed in ~75% of cases with a 6-month interval for PTC and a 12-month interval for FTC. Thyroid stimulating hormone (TSH) suppression to <0.1 mIU/L was achieved in the majority of cases. External beam radiotherapy and chemotherapy were used rarely and only offered in cases unresponsive to RAI therapy (Table 5).

The mean follow-up duration of patients with PTC was 5 years, ranging from 5 months to 10 years; similar follow-up durations were seen with FTC patients, with a mean of 6 years, and a range of 5 months to 12 years. The majority of patients achieved a disease-free state following complete thyroidectomy, subsequent RAI therapy, and TSH suppressive therapy. Structural and biochemical recurrence rates for PTC and FTC were 32.7% and 29.1%, respectively. Excluding patients with distant metastases at presentation, recurrence rates for PTC and FTC were 30.1% and 18.8%, respectively. Structural or biochemical recurrence of PTC generally occurred within 30 months of the initial surgery and within 15 months of the initial post-surgical RAI therapy. Similarly, structural or biochemical recurrence of FTC frequently occurred within 49 months of the initial surgery and within 16 months of the initial post-surgical RAI therapy. Structural recurrences due to nodal metastases were commonly seen in PTC, while recurrences due to distant metastases prevailed in FTC. A majority of recurrent cases underwent repeated RAI therapy. Finally, FTC patients had a higher mortality rate (2.5%), compared with only 0.3% in PTC patients (Table 6).

PTC accounted for the vast majority of WDTC cases, consistent with previous reports [3]. The mean age at presentation of 44 years and female predominance were also consistent with findings from different international studies [161718]. In contrast, the mean duration of the goiter before initial consult of 6 years and larger mean tumor size reflect the limited access to medical care typical of most patients seen at our institution. Despite the larger mean tumor size observed here, most PTC and FTC cases were classified as stage 1 (63% and 54%, respectively), similar to the findings of other studies, which observed stage 1 tumors in 44% to 74% of patients [17192021]. This apparent discrepancy is likely due to the younger age at presentation (<45 years) seen in most cases of thyroid malignancies in our institution.

Prior neck irradiation was not seen observed in our study, since neck irradiation as a form of therapy has yet to be widely adopted in the Philippines. As expected, nodal involvement was more common in PTC cases, since it usually spreads via lymphatic drainage, as opposed to FTC which spreads hematogenously, resulting in more distant metastases at presentation [22]. Breast cancer was the most common secondary malignancy associated with thyroid cancer, consistent with the observations of Sandeep et al. [23].

The lower reliability of FNAB in establishing malignancy may be attributed to the poor sampling method, since most procedures are performed blindly. This observation is in stark contrast to that seen in other studies, in which FNAB appeared to be an excellent diagnostic tool in the initial management of thyroid nodules. However, this success was achieved only when the biopsy technique was ultrasound-guided [24], indicating that ultrasound-guided biopsy of suspected malignant nodules may be necessary to enhance its reliability as a screening test. Here, in the majority of FTC cases, a diagnosis was able to be made only after the initial surgery, with most patients undergoing a second procedure (completion thyroidectomy) due to an initial misdiagnosis by FNAB. This finding is similar to the study by Eilers et al. [25], in which there was a greater difficulty in establishing a clear diagnosis by FNAB in cases of FTC.

Ultrasound of the neck appeared to be a very useful imaging modality for most cases, providing preoperative insight of tumor size, lymph node involvement, and thyroid lobe involvement. However, sonographic features alone were not highly reliable for establishing malignancy in most cases [26]. Discordance between thyroid nodule sizes measured by ultrasound and the final biopsy result was similar to the findings of Deveci et al. [27]. Sub-centimeter nodules were also observed to have higher discordance rates compared with larger nodules on ultrasound [27].

PTC is most commonly seen in younger adults, particularly those 40 to 50 years of age, with a very high female to male ratio. The larger mean tumor size observed in this study in likely attributed to a delay in medical care, as most of our patients reported a longer duration of the goiter prior to consult. Although our data showed lower extra-thyroidal extension and comparable nodal metastases at presentation, we observed a higher degree of distant metastases at presentation and higher recurrence rate in comparison with other studies. Although this finding is consistent with data previously observed in Filipinos abroad, in whom thyroid malignancies appeared to be more recurrent and aggressive (Table 7) [132829], local factors likely delayed the initiation of medical treatment, as evidenced by the longer duration of the goiter. This difference may have contributed to the higher incidence of recurrence and metastasis seen in our institution. Timely diagnosis and treatment of thyroid cancer are therefore of the utmost importance to reduce recurrence rates. Further genetic studies might be warranted to further understand the innate aggressiveness of thyroid cancer in Filipinos.

In comparison with other international studies, Filipinos with FTC present at a younger age, with a higher female to male ratio, similar to that seen among Koreans. Larger tumor size at presentation was seen across different groups, with distant metastasis more common than nodal metastases at presentation. Higher recurrence rates were still observed among our population. Unlike PTC, patients with FTC did not significantly differ from those of other studies in terms of aggressiveness, presentation, or recurrence (Table 8) [3031].

In conclusion, PTC among Filipinos presents at a younger age, with a larger tumor size, higher degree of distant metastases at presentation, and higher recurrence rate, suggesting a more aggressive and recurrent behavior for this type of thyroid malignancy. FTC among Filipinos also presents at a young age, with high recurrence rates, but appears to behave similarly to that in other racial groups. The overall prognosis and survival rates remained excellent among Filipinos with WDTC, although a higher degree of morbidity due to disease recurrence was common.