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

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

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

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

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

RET-Associated MEN syndromes

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

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

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

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

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…)

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

Single center (MD Anderson) 56 patients from 1972-2009 Retrospective study Single center (MD Anderson) 56 patients from 1972-2009 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

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

Longitudinal retrospective Multicenter (French Group of Endocrine Tumors) 170 patients from 1977-2006 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

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

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

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): 1302-1310. 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): 1105-1113. 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: 1610-1616. 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.