Follow-up of differentiated thyroid cancer – what should (and what should not) be done

Thyroid cancer is the fifth most common cancer in women in the USA, and an estimated over 62 000 new cases occurred in men and women in 2015. The incidence continues to rise worldwide. Differentiated thyroid cancer is the most frequent subtype of thyroid cancer and in most patients the standard treatment (surgery followed by either radioactive iodine or observation) is effective. Patients with other, more rare subtypes of thyroid cancer-medullary and anaplastic-are ideally treated by physicians with experience managing these malignancies. Targeted treatments that are approved for differentiated and medullary thyroid cancers have prolonged progression-free survival, but these drugs are not curative and therefore are reserved for patients with progressive or symptomatic disease.

BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. To investigate the relationship between BRAF V600E mutation and PTC-related mortality. Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. Patient deaths specifically caused by PTC. Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.

The recent development and spread of ultrasonography and ultrasonography-guided fine needle aspiration biopsy (FNAB) has facilitated the detection of small papillary microcarcinomas of the thyroid measuring 1 cm or less (PMC). The marked difference in prevalence between clinical thyroid carcinoma and PMC detected on mass screening prompted us to observe PMC unless the lesion shows unfavorable features, such as location adjacent to the trachea or on the dorsal surface of the thyroid possibly invading the recurrent laryngeal nerve, clinically apparent nodal metastasis, or high-grade malignancy on FNAB findings. In the present study we report comparison of the outcomes of 340 patients with PMC who underwent observation and the prognosis of 1,055 patients who underwent immediate surgery without observation. Between 1993 and 2004, 340 patients underwent observation and 1,055 underwent surgical treatment without observation. These 1,395 patients were enrolled in the present study. Observation periods ranged from 18 to 187 months (average 74 months). The proportions of patients whose PMC showed enlargement by 3 mm or more were 6.4 and 15.9% on 5-year and 10-year follow-up, respectively. Novel nodal metastasis was detected in 1.4% at 5 years and 3.4% at 10 years. There were no factors related to patient background or clinical features linked to either tumor enlargement or the novel appearance of nodal metastasis. After observation 109 of the 340 patients underwent surgical treatment for various reasons, and none of those patients showed carcinoma recurrence. In patients who underwent immediate surgical treatment, clinically apparent lateral node metastasis (N1b) and male gender were recognized as independent prognostic factors of disease-free survival. Papillary microcarcinomas that are not associated with unfavorable features can be candidates for observation regardless of patient background and clinical features. If there are subsequent signs of progression, such as tumor enlargement and novel nodal metastasis, it would not be too late to perform surgical treatment. Even though the primary tumor is small, careful surgical treatment including therapeutic modified neck dissection is necessary for N1b PMC patients.