1. Virginia Sanders, MD PGY-1
Timing of Prophylactic Thyroidectomy in Multiple Endocrine Neoplasia Type 2
Virginia Sanders, MD PGY-1

2. Patient: AH 10 year old female
Referred to surgery by genetics for prophylactic thyroidectomy
RET proto-oncogene mutation: MEN 2A
Discovered during family genetic workup for mother with multiple pheochromocytomas
Older sister had prophylactic thyroidectomy at age 12
Patient asymptomatic, normal calcitonin

3. Multiple Endocrine Neoplasia
Group of familial syndromes
Endocrine tumors in multiple organs
Autosomal dominant inheritance
Several subtypes

4. MEN Type 1 MEN1 gene mutations (chromosome 11) “Three Ps”
Pituitary adenomas (30%)
Parathyroid hyperplasia (95%)
Pancreatic islet cell tumors (41%)
Prevalence: 2 in 100,000

5. RET-Associated MEN syndromes
RET proto-oncogene (chromosome 10)
RET expressed in thyroid c-cells, adrenal medulla, neurons
Gain of function mutation causing uncontrolled growth
Multiple known mutations:
MEN 2A, MEN 2B, FMTC

6. RET-Associated MEN syndromes

7. MEN 2A Prevalence: 2.5 in 100,000 RET proto-oncogene mutation
Medullary thyroid carcinoma (>90%)
Pheochromocytoma (40-50%)
Parathyroid hyperplasia (10-20%)
Prevalence: 2.5 in 100,000
RET proto-oncogene mutation

8. MEN 2B Pheochromocytoma (40-50%) Mucosal neuromas Marfanoid habitus
Medullary thyroid carcinoma (>90%)
Pheochromocytoma (40-50%)
Mucosal neuromas
Marfanoid habitus
Prevalence: 2.5 in 100,000
RET proto-oncogene mutation
Earlier onset & more aggressive MTC than 2A

9. Familial Medullary Thyroid Cancer (FMTC)
Variant of MEN 2A
Medullary Thyroid Cancer only
RET proto-oncogene mutation

10. Medullary thyroid carcinoma in all RET-associated MEN is
most common (penetrance ~100%) and deadliest component.
Prevention: total thyroidectomy.
But when?

11. Timing of Thyroidectomy
Pre-1990s: surgery if nodule detected or elevated calcitonin
But disease already present
Move toward prophylactic surgery
1993: genetic testing  specific mutations correlate to age of onset, severity of disease
Various studies to determine best timing for prophylaxis
Balance risks of surgery (recurrent laryngeal nerve damage, hypoparathyroidism, lifelong hormone replacement) vs. risk of MTC
Different ages proposed (age 5-8, under 5, at 10 years, individual considerations…)

12. 2009: American Thyroid Association Guidelines
MTC risk stratified by codon mutation
Risk Levels A (oldest onset, least severe) to D (earliest onset, most severe)
D: codons 883 and 918
C: 634
B: 609, 611, 618, 620, 630
A: 768, 790, 791, 804, 891
Integrate genetic and clinical information

13. Single center (MD Anderson) 56 patients from 1972-2009
Retrospective study
Single center (MD Anderson)
56 patients from
documented RET mutation
All received prophylactic thyroidectomy
No symptoms, no thyroid nodules, no lab evidence of disease
Univariate and multivariate analysis of factors associated with MTC on pathology
Variables: pre-op calcitonin level, ultrasound, severity of family hx, type of procedure

15. Results and Conclusions
ATA guidelines accurately predict MTC in levels A & B
Mutation risk level alone did NOT predict MTC
Risk Levels A & B: if ALL clinical criteria met (normal annual calcitonin, normal ultrasound, mild/mod family hx) 92% negative predictive value
Risk Level C: guidelines not predictive of MTC (no MTC <5 years in sample), sample size too small to draw conclusion given high risk
No patients with risk level D
Increased age at thyroidectomy only single factor associated with presence of MTC on pathology

16. Longitudinal retrospective Multicenter
(French Group of Endocrine Tumors)
170 patients from
Documented RET mutation, age <21 at surgery
Identify prognostic factors to predict long-term disease-free survival (DFS) and “determine impact of [ATA] guidelines on clinical practice”
Univariate and multivariate analysis of factors associated with DFS
Variables: mutation type, pre-op calcitonin level (basal and pentagastrin stimulated), severity of family hx, type of procedure, TNM staging, post-op calcitonin, mortality

17. Results and Conclusions
Factors associated with decreased DFS
age at surgery >10 years
class D genotype
MTC diameter > 10 mm
lymph node metastases
Factor independently associated with presence of MTC
Pre-op basal calcitonin >30 ng/L (90% sens, 81% spec)
Did not assess other ATA criteria: pre-op ultrasound, family hx
DFS best predicted by TNM staging
Tumor size and node mets both independent predictors
DFS improved when surgery before T>10 mm
DFS improved if surgery before node mets

18. Limitations of Research
Retrospective studies
Heterogenous management
Small sample sizes
Multiple codon mutations  heterogeneous disease

19. References
Grubbs EG, Waguespack SG, Rich TA, Xing Y, Ying A, et al. Do the Recent American Thyroid Association Guidelines accurately guide the timing of prophylactic thyroidectomy in MEN 2A? Surgery 2010; 148(6): Rohmer V, Vidal-Trecan G, Bourdelot A, Niccoli P, Murat A, Werneau JL, et al. Prognostic Factors of Disease-Fre Survival after Thyroidectomy in 170 Young Patients with a RET Germline Mutation: A multicenter study of the Groupe Francais d’Etude des Tumeurs Endocrines. Journal of Clinical Endocrinology and Metabolism 2011; 96(3): E509-E518. Schreinemakers J, Vriens M, Valk G, de Groot J, Plukker J, et al. Factors Predicting Outcome of Total Thyroidectomy in Young Patients with Multiple Endocrine Neoplasia Type 2: A Nationwide Long-Term Follow-Up Study Skinner M, Moley J, Dilley W, Owzar K, DeBenedetti M, Wells S. Prophylactic Thyroidectomy in Multiple Endocrine Neoplasia Type 2A. New England Journal of Medicine 2005; 353(11): Spinelli C, Di Giacomo M, Costanzo S, Elisei R, Miccoli P. Role of RET codonic mutations in the surgical management of medullary thyroid carcinoma in pediatric age multiple endocrine neoplasm type 2 syndrome. Journal of Pediatric Surgery 2010; 45: Szinnai G, Meier C, Komminoth P, Zumsteg U. Review of Multiple Endocrine Neoplasia Type 2A in Children: Therapeutic Results of Early Thyroidectomy and Prognostic Value of Codon Analysis. Pediatrics 2003; 111(2): e132-e139.