Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults.

The ret/PTC rearrangements (PTC-1, PTC-2, and PTC-3) are characteristic of papillary thyroid cancer (PTC). In adults, PTC-1 is common and may be associated with an aggressive clinical course. The incidence and significance of ret/PTC mutations are less well understood in children. We examined spontaneous PTC from 33 patients (23 females and 10 males) with a median age of 18 yr (range, 6-21 yr) and a median follow-up of 3.5 yr (range, 0-13.4 yr). The ret/PTC mutations were identified in 15 tumors (45%), including 8 PTC-1 (8 of 15, 53%), 2 PTC-2 (2 of 15, 13%), 2 PTC-3 (2 of 15, 13%), and 3 (3 of 15, 20%) combined PTC mutations (PTC-1 and PTC-2). This distribution is significantly different (P = 0.001, by chi2 analysis) from that reported for children with radiation-induced PTC. There was no correlation between the presence or type of ret/PTC mutation and patient age, tumor size, focality, extent of disease at diagnosis, or recurrence. We conclude that ret/PTC mutations are 1) common in sporadic childhood PTC, 2) predominantly PTC-1, 3) frequently multiple, and 4) of different distribution than that reported for children with radiation-induced PTC.

Infiltration of differentiated thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival for children and young adults.

An immune response directed against thyroid cancer might be important in preventing metastasis and recurrence. This idea is supported by previous observations showing that adults with autoimmune thyroiditis or lymphocytic infiltration surrounding papillary thyroid carcinoma (PTC) have improved disease-free survival. The long-term outcome for differentiated thyroid cancer is even more favorable for children and young adults. If the immune response is important, we hypothesized that tumor-associated lymphocytes with a high proliferation index would be found in thyroid cancers from children and young adults and would be associated with improved disease-free survival. Using immunohistochemistry, we examined 39 childhood PTC, 9 follicular thyroid carcinomas, 2 medullary thyroid carcinomas, 11 benign thyroid lesions, and 2 normal thyroid glands for the presence of lymphocytes (leukocyte common antigen) and lymphocyte proliferation (proliferating cell nuclear antigen, Ki-67). The majority of PTC (65%) and follicular thyroid carcinomas (75%) from children and young adults contained lymphocytes in the immediate vicinity of thyroid cancers, but only 7 (18%) patients with PTC also had a diagnosis of autoimmune thyroiditis. Disease-free survival did not correlate with the presence or number of lymphocytes per high power field. In contrast, disease-free survival was significantly improved (P = 0.01) for thyroid cancers with the greatest number of Ki-67-positive lymphocytes per high power field. The number of lymphocytes per high powered field was greater for multifocal PTC (P: = 0.023), and the number of proliferating lymphocytes was greatest for PTC with regional lymph node involvement (30.5 +/- 12.3 vs. 6.8 +/- 5.0; P = 0.047). We conclude that proliferation of tumor-associated lymphocytes is associated with improved disease-free survival for children and young adults with thyroid cancer.

Tyrosine kinase expression is increased in papillary thyroid carcinoma of children and young adults.

Tyrosine kinases (TKs) are important candidate genes for malignant transformation and at least 21 different TKs have been identified in the thyroid gland. We hypothesized that the collective activity of these TKs might be increased in thyroid carcinoma and have association with the clinical behavior of individual tumors. To test this, we determined TK expression by immunohistochemistry in 74 archival thyroid tissue blocks (48 papillary thyroid carcinoma, PTC; 9 follicular thyroid carcinoma, FTC; 17 benign thyroid diseases) from children and young adults. Mean TK expression was greater for PTC (2.1 +/- 0.11) than benign lesions (1.6 +/- 0.2, p = 0.027), and also tended to be greater in FTC (2.1 +/- 0.25, p = 0.12). Recurrence risk was three-fold greater for PTC with intense TK expression (4/15, 27%) than for PTC with minimal - moderate TK expression (3/33, 9.0%). However, this was not statistically significant (p = 0.10). In PTC, TK expression correlated with expression of the receptor for hepatocyte growth factor / scatter factor (cMET, r = 0.31, p = 0.044). In FTC, TK expression did not correlate with cMET, but tended to be greater in young patients (r = -0.59, p = 0.09). We conclude that TK expression is increased in PTC and possibly associated with an increased recurrence risk.

Extensive surgery improves recurrence-free survival for children and young patients with class I papillary thyroid carcinoma.

BACKGROUND: Children with papillary thyroid cancer (PTC) rarely die of their disease, but are at high risk for recurrence, particularly with multifocal tumors (which occur in 42% of children with PTC). It is not clear if more extensive surgery, with an increased risk of complications, lessens the risk for recurrence. The authors hypothesized that patients with disease presumed to be confined to the thyroid gland (class I PTC) could have multifocal disease, involving the contralateral lobe, of which the surgeon is unaware. Treatment with less than subtotal thyroidectomy might be associated with a higher risk of recurrence. METHODS: The charts of 37 patients with Class I PTC diagnosed at < or =21 years of age between 1953 and 1996 were reviewed. The incidence of surgical complications and the risk of recurrence based on the extent of initial surgery ([1] lobectomy with or without isthmusectomy, [2] subtotal, or [3] total thyroidectomy) and adjunctive therapy with thyroid hormone or radioactive iodine (RAI) were examined. RESULTS: Eight patients had recurrent PTC. Patients treated with lobectomy with or without isthmusectomy were more likely to have recurrence than patients treated with subtotal or total thyroidectomy (Odds ratio, 8.7; 95% CI 1.4 to 54). Although the incidence of complications was statistically similar among the 3 surgical groups, 3 patients, all treated with more extensive surgery, had permanent hypoparathyroidism. There were too few patients to determine whether treatment with thyroid hormone or RAI offered additional benefit. CONCLUSIONS: In children with Class I PTC, more extensive surgery is associated with a lower risk of recurrence. This finding must be weighed against the risk of complications when determining the optimal treatment for individual patients.

Ras mutations are uncommon in sporadic thyroid cancer in children and young adults.

Mutations in the ras genes (H-ras, K-ras, and N-ras) occur in 10-15% of all human cancers, and commonly arise from single base substitutions at codons 12, 13, or 61. Although ras mutations have been found in adult thyroid cancers, they were absent from the two studies which examined childhood thyroid cancers. Both studies included only children with radiation induced thyroid cancer, and it remains unclear if ras mutations occur in children without radiation exposure. To answer this question, we examined archival tissue blocks from 31 children with papillary thyroid cancer (PTC) 4 with follicular thyroid cancer (FTC), 2 with medullary thyroid cancer (MTC), and 1 with lymphoma (LYM). Only 1 patient with PTC had previous radiation exposure. Genomic DNA was extracted and used for PCR amplification of the ras genes. The PCR products were analyzed by oligospecific hybridization for mutations at codons 12, 13, and 61. Two of the PTCs (6.5%) contained ras mutations. Both patients had class II disease and no history of previous radiation exposure. One patient subsequently developed bone and lung metastases. The patient with lymphoma also had a ras mutation (N-61), but ras mutations were absent from all FTC and MTC. These results suggest that ras mutations are uncommon in spontaneous childhood thyroid cancer, but occur with a frequency similar to that found in previous reports of adult differentiated thyroid cancers. The number of subjects was too small to determine if ras mutations are more common in patients with aggressive papillary thyroid cancer.

Clinical features associated with metastasis and recurrence of differentiated thyroid cancer in children, adolescents and young adults.

OBJECTIVE: Differentiated thyroid cancer (DTC), including papillary (PTC) and follicular (FTC) variants, is unusual in children and accounts for only 10% of all cases. For that reason, knowledge of the clinical features which predict recurrence is limited. We reviewed 170 cases of childhood DTC to determine if specific clinical or pathological findings were associated with increased risk of recurrence. DESIGN: This was a retrospective study of children and adolescents with DTC registered in the Department of Defense Automated Centralized Tumor Registry. PATIENTS: We reviewed 137 cases of PTC and 33 cases of FTC diagnosed between 1953 and 1996 at < or = 21 years of age. RESULTS: In the PTC group (median follow-up 6.6 years, range 2 month-39.5 years), only one patient died, but 21 developed local and 6 developed distant recurrence. By univariate analysis, recurrence was more common in patients with multifocal (odds ratio 7.5) or large tumours (odds ratio 4.1), and in those with palpable cervical lymphadenopathy (odds ratio 3.0) or metastasis at diagnosis (odds ratio 2.8). By multivariate analysis focality was the best predictor of recurrence (P = 0.0019). In the FTC group (median follow-up 5 years, range 6 month-38.1 years), no patient died of disease, but 5 developed recurrence. As with PTC, recurrence was more likely in patients with multifocal tumours (odds ratio 22.0). CONCLUSIONS: Differentiated thyroid cancer in children and adolescents has low mortality, but a high risk of recurrence. Young patients with large, multifocal tumours that are already metastatic at diagnosis have the greatest risk of recurrence.