1. Janice Kang

2. Asymptomatic 5 yo F w/ family history of MEN 2A  Mother, brother w/ prophylactic thyroidectomy at age 8. Maternal grandfather died of complications of cancer (unknown type).  Exon 11 RET mutation  Calcitonin 45 pg/mL  T4, T3, TSH, and PTH wnl  Urine metanephrines negative CASE PRESENTATION

3. Preoperative ultrasound

4. Operation  Total thyroidectomy and parathyroidectomy  Cystic lesion at left inferior pole sent for frozen section= hemorrhagic parathyroid tissue  2 superior parathyroid glands identified, bilateral RLNs identified  No node dissection

5. Familial Medullary Thyroid Cancer  Medullary thyroid cancer (~100% penetrance)  Pheochromocytoma  Hyperparathyroidism MEN 2A  Medullary thyroid cancer only (~100% penetrance)

6. MEN 2B  Medullary thyroid cancer (~100% penetrance)  Tumor develops at earlier age, more aggressive  Pheochromocytoma  Marfanoid habitus (w/o Marfan's syndrome), mucosal neuromas, intestinal ganglioneuromas

7. RET protein  Tyrosine kinase receptor that transduces growth and differentiation signals  Found in C cells of the thyroid gland, adrenal medulla, neuron, and other derivatives of neural crest cells.  Ligand binding  dimerization  signal transduction  Mutation = GAIN of function: ligand-independent dimerization and activation

8. When to operate with a known gene mutation? ATA risk stratification is dependent on RET genotype A Exons 13,14,15 mutations May delay operation >5 yo B Exon 10 mutation Operate < 5 yo C Exon 11 mutation Operate < 5 yo D Codon 918 mutation-MEN 2B Operate < 1 yo (youngest age at diagnosis = 9 mo)

9. Prognostic Factors of Disease-Free Survival after Thyroidectomy in 170 Young Patients with a RET Germline Mutation: A Multicenter Study of the Groupe Francais d’Etude des Tumeurs Endocrines  1977-2006 Retrospective analysis 170 pts <21 yo from hereditary MTC families  Total thyroidectomy [+ central or central+bilateral LND in 75% of pts]  Class, Tumor size, node status, preoperative basal CT, and age No patients with a preoperative basal CT <30 pg/mL had persistent or recurrent disease.

10. Tumor size >10 mm, node status (N1), A Exons 13,14,15 mutations DFS: 100% 3.7 yrs B Exon 10 mutation DFS: 95.5% 6.1 yrs C Exon 11 mutation DFS: 86.3% 7.7 yrs D Codon 918 mutation-MEN 2B DFS: 5.6% 8.8 yrs class, preoperative basal CT > 30, and age >10 yo Disease free survival

11. Inclusion criteria: RET mutation carrier with no evidence of disease (including medullary thyroid cancer, pheochromocytoma, or hyperparathyroidism) Primary objective: determine risk of waiting to perform thyroidectomy and central lymph node dissection until stimulated calcitonin levels are elevated. Secondary objective: Identify serum calcitonin level at which metastatic disease is likely to be found Rosella, et al. The Timing of Total Thyroidectomy in RET Gene Mutation Carriers Could Be Personalized and Safely Planned on the Basis of Serum Calcitonin: 18 Years Experience at One Single Center.

12. 84 subjects 1993-2011 Group 1 (21) Basal CT: pos Stim CT: pos Basal CT 10-60 (7) all T1N0 Basal CT >60(13) 24% T1-3 N0 38% N1 Group 2 (31) Basal CT: neg Stim CT: pos 81% T1N0 19% c-cell hplsa Group 3 (32) Basal CT: neg Stim CT: neg 4 tot thyroid all T1 N0 Results

13. Pediatric-specific results <16 yo (31) 10 MEN2A 18 FMTC 3 MEN2B Elevated basal CT (7) Non MEN2B (4) T1N0 MEN2B (3) N1 or M1 Elevated stimulated CT (8) All T1N0 All disease free at follow up Normal basal and stimulated CT (16) 2-7 year follow up (avg 3.3yr) disease free

14. Conclusions  RET mutation = lifetime risk of medullary thyroid cancer that is progressive with age.  Degree of serum CT elevation correlates to extent of disease  If CT <60 pg/mL, there were no +nodes  Safe to delay total thyroidectomy in select population until indicated by biochemical markers. Advantages:  Later medicalization of children  Help to further define risk with various RET mutation types to avoid childhood surgery

15. Benefit to waiting? Cross sectional analysis of Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS) database  1199 children who underwent partial/total thyroidectomy, parathyroidectomy Children ages 0–6: Longer LOS Increased rate of complications Increased rate of recurrent laryngeal nerve-related injuries

16. Long term follow up data for pediatric thyroidectomy 74 patients between 2001-2011  RLN injury  Incidence of post operative hypoPTH  Medication adherence  Psychological/behavioral problems  Does age of intervention affect rates of the above?

17. Results 74 patients, ages 3-18, median age 12.5  41% MEN 2A  54% thyroid ca  5% benign disease (goiter) 62% underwent node dissection

18.  RLN injury  Incidence of post operative hypoPTH  Medication adherence  Psychological/behavioral problems  Does age of intervention affect rates of the above? None 30% with temporary hypoPTH, 8% with permanent hypoPTH 41% with >= 1 episode: refusal from parents, family issues (dual residences), inappropriate administration of meds) 44% with parent-reported psychologic/behavioral problems. Majority related to abnormal thyroid function tests No significant difference with age at operation

19. References Morris, Lilah, et al. Long-term follow-up data may help manage patient and parent expectations for pediatric patients undergoing thyroidectomy. Surgery. December 2012, 152 (6): 1165- 1171 Rohmer, V. et al. Prognostic Factors of Disease-Free Survival after Thyroidectomy in 170 Young Patients with a RET Germline Mutation: A Multicenter Study of the Groupe Francais d’Etude des Tumeurs Endocrines. J Clin Endocrinol Metab, March 2011, 96(3):E509 –E518 Rossella Elisei et al The Timing of Total Thyroidectomy in RET Gene Mutation Carriers Could Be Personalized and Safely Planned on the Basis of Serum Calcitonin: 18 Years Experience at One Single Center. J Clin Endocrinol Metab, February 2012, 97(2):426–435 Sosa, JA, Roman, SA. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab. Aug 2008; 93(8), 3058=65