Timing of Early Preventative Thyroidectomy in Children with MEN 2
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1 Timing of Early Preventative Thyroidectomy in Children with MEN 2 Terry C. Lairmore, M.D. Professor of Surgery Director, Division of Surgical Oncology Texas Chapter of AACE Texas Endocrine Surgical Symposium San Antonio, Texas August 5, 2017
2 Disclosures I have nothing to disclose THE AMERICAN ASSOCIATION OF CLINICAL
3 Thyroid C-cells: Immunoperoxidase stain
4 Medullary (solid) carcinoma of the thyroid: A clinicopathologic entity John Hazard, William Hawk, George Crile, Jr. The Department of Anatomic Pathology and the Department of General Surgery, The Cleveland Clinic Foundation and the Frank E. Buntz Educational Institute, Cleveland, OH J. Clin. Endocrin. Metab. 19: , 1959
5 The association of pheochromocytoma with carcinoma of the thyroid gland John Sipple Department of Medicine, State University of New York Upstate Medical Center and the Veterans Administration Hospital, Syracuse, NY Am. J. Med. 31: , 1961
6 Multiple Endocrine Neoplasia Type 2A Medullary Thyroid Carcinoma Pheochromocytoma Hyperparathyroidism
7 Medullary Thyroid Carcinoma Bilateral Multifocal Small blue cells in cords and trabeculae Amyloid-like stroma
8 Pheochromocytoma
9 MEN 2: Pheochromocytoma and Adrenal Medullary Hyperplasia
10 Hyperparathyroidism in MEN 2
11 Multiple Endocrine Neoplasia Type 2B Medullary Thyroid Carcinoma Pheochromocytoma Mucosal Neuromas Ganglioneuromatosis Characteristic Phenotype
12 MEN 2B: Phenotypic Features
13 MEN 2B: Ganglioneuromatosis Hypertrophied Corneal Nerves
14 The Story of Medullary Thyroid Carcinoma: Contributions of Surgeons Arises from the parafollicular C cell, derived from neural crest Production of calcitonin (tumor marker) Medullary carcinoma is a distinct type of thyroid cancer Germline mutations in RET proto-oncogene Early prophylactic surgery based on genetic testing results Targeted medical therapies
15 Cytogenic and Genetic Linkage Maps for Pericentromeric Region of Chromosome 10 Sex-Average D10S MEN2A FNRB D10S176 RBP3 D10S FNRB D10S176 D10Z1 D10S94 Zn22 Ret D10S102 RBP3 9.4 D10S cm
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19 Early Thyroidectomy for MEN2 Goals of Treatment Complete removal of thyroid gland Early removal of metastatic disease and prevention of the development of lymph node metastases Preservation of parathyroid and laryngeal function Minimize morbidity of treatment and allow for satisfactory neurological growth and development with lowest impact on psychological stress and social development Initiate appropriate, practical evidenced-based screening for development of associated endocrinopathies (pheochromocytoma, hyperparathyroidism) in patients at risk
20 Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia Type 2 Archetype model of a disease for which an operation can be performed based on genetic testing information Surgical intervention intended to prevent cancer from ever developing or removing it while still in situ
21 New England Journal of Medicine Prophylactic Thyroidectomy in M ultiple Endocrine Neoplasia Type 2A M ichael A. Skinner, M.D., Jeffrey F. M oley, M.D., William G. Dilley, Ph.D., Kouros Owzar, Ph.D., M ary K. D ebenedet t i, B.S.N., and Samuel A. Wells, Jr., M.D. ABSTRACT Background Medullary thyroid carcinoma is the most common cause of death in patients with multiple endocrine neoplasia (M EN ) type 2A (M EN -2A) or type 2B or familial medullary thyroid carcinoma. We sought to determine whether total thyroidectomy in asymptomatic young members of kindreds w ith M EN - 2A w ho had a mutated allele of the RET proto-oncogene could prevent or cure medullary thyroid carcinoma. M ethods A total of 50 patients 19 years of age or younger w ho w ere consecutively identified through a genetic screening program as carriers of a RET mutation characteristic of MEN-2A underwent total thyroidectomy. Five to 10 years after the surgery, each patient w as evaluated by physical examination and by determination of plasma calcitonin levels after stimulation with provocative agents. Resul t s In 44 of the 50 patients, basal and stimulated plasma calcitonin levels were at or below the limits of detection of the assay (proportion, 0.88; 95 percent confidence interval, 0.76 to 0.95). Tw o patients had basal and stimulated plasma calcitonin levels above the normal range. Stimulated plasma calcitonin levels had increased but remained w ithin the normal range in four patients. The data suggest that there w as a low er incidence of persistent or recurrent disease in children w ho underw ent total thyroidectomy before eight years of age and in children in w hom there w ere no metastases to cervical lymph nodes. Conclusions In this study, young patients identified by direct DNA analysis as carriers of a RET mutation characteristic of M EN -2A had no evidence of persistent or recurrent medullary thyroid carcinoma five or more years after total thyroidectomy. A longer period of evaluation will be necessary to confirm that they are cured.. N EJM, 353: , 2005.
22 PREVENTION OF HEREDITARY MTC In a genetic screening program, our group identified 50 consecutive patients who had inherited a mutated RET allele characteristic of MEN 2A. The patient s ages ranged from 3 to 19 years (mean age, 10 years) and they had no signs or symptoms of MEN 2A. N EJM, 353: , 2005.
23 PREVENTION OF HEREDITARY MTC A standard operation was performed in each of the 50 patients (total thyroidectomy, resection of lymph nodes in the central zone of the neck, and parathyroid auto-transplantation). Five to 10 years after thyroidectomy (mean 7 years) all patients were evaluated by physical examination and by measurement of plasma calcitonin levels following provocative testing with calcium and pentagastrin. N EJM, 353: , 2005.
24 HISTOLOGY RESULTS IN PATIENTS WITH MEN 2A THYROID (50 patients) NED: 4 patients (8%) CCH: 11 patients (22%) MIC or MAC MTC: 35 patients (70%) LYMPH NODE (49/50 patients) Mean 10.8/patient, range (3-23); Metastases: 10 y (2+/6), 11 y (3+/11) and 11 y (1+/8) N EJM, 353: , 2005.
25 PLASMA CALCITONIN LEVELS IN MEN2A PATIENTS PREOPERATIVE: Basal levels elevated; 31/50 (62%) IMMEDIATELY POSTOPERATIVE: Basal levels undetectable; 50/50 (100%) FIVE TO TEN YEARS POSTOPERTIVE Stimulated levels undetectable: 44/50 (88%) Stimulated levels (within normal rng.): 4/50 (8%) Stimulated levels (above normal rng): 2/50 (4%) N EJM, 353: , 2005.
26 Postoperative Serum Calcium Levels 12 Calcium Years
27 RESULTS IN PATIENTS WITH MEN 2A The only significant factors related to prevention or cure of MTC were age at the time of thyroidectomy and absence of lymph node metastases. The cure rate was significantly higher in patients having thyroidectomy performed prior to eight years compared to after eight years (p<0.029) N EJM, 353: , 2005.
28 Management of Hereditary MTC Based on Genetic Testing Total thyroidectomy and central compartment lymphadenectomy Management of parathyroid glands controversial Early thyroidectomy at approximately age 5 years for MEN 2A Early thyroidectomy as soon as diagnosis made (first year) for MEN 2B
29 Early Preventative Thyroidectomy Recurrent Laryngeal Nerve Inferior Parathyroid Gland
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32 Central Zone Lymphadenectomy
33 I--Submental and submandibular nodes II--Upper jugulodigastric group III--Middle jugular nodes IV--Inferior jugular nodes V-- Posterior triangle nodes VI--Anterior compartment (central lymph nodes)
34 Modified Radical (Functional) Neck Dissection RLN Superior parathyroid Parathyroid glands Recurrent and superior laryngeal nerves Vagus nerve Thoracic duct (left) Marginal mandibular branch of facial nerve Phrenic nerve Spinal accessory nerve (CN XI)
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36 Simplified Classification for MEN 2 Genotypic Risk Stratification High Risk Intermediate Risk Low Risk
37 Summary: Timing of Thyroidectomy for MEN 2 In patients with highest risk, an early preventative thyroidectomy should be performed as soon as possible shortly after birth, optimally within the first year of life. In patients with intermediate risk, an early preventative thyroidectomy should be performed within the first 5 years of life especially for patients with codon 634 mutations. For patients with other mutations in the intermediate risk group, more variable behavior is possible and timing can be individualized. In patient with the lowest risk, monitoring should be performed in years 3 to 5 and preventative thyroidectomy can be offered after 5 years of age depending on the exact clinical parameters.
38 Summary: Central Lymph Node Dissection In patients with highest risk, an early preventative thyroidectomy should be accompanied by a routine CLND. These patients are the most likely to have lymph node metastases even with small tumors and they have been documented in the first year of life 22, 31. In patients with intermediate risk, an early preventative thyroidectomy should optimally be accompanied with a routine CLND, based on individual patient factors and expert clinical judgement. These patients often have an occult MTC on final pathology. A few patients had lymph node involvement with recurrence and also had elevated calcitonin levels in long term followup; particularly if the patient is > 8 yrs of age. Although no lymph nodes with metastatic disease were identified in any patient series, codons 618 and 620 were associated with recurrence in one series 17. In patient with the lowest risk, an early preventative thyroidectomy does not require a routine concomitant CLND but this may still be considered based upon patient or surgeon preference and other factors. The risks of CLND may outweigh the benefit and may increase complications from treatment.
39 Management of Parathyroid Glands During Early Thyroidectomy for MEN 2
40 MTC/MEN2 as Model for Operative Intervention to Prevent Cancer Strong genetic predisposition to cancer development Availability of diagnostic genetic test that can be performed at any age Natural history of disease warrants an invasive surgical procedure that does not carry an inordinate risk of adverse clinical consequences, and for which there is no better alternative therapy Ability to remove safely and completely remove the target organ(s) at risk with a resultant high success rate in preventing the subsequent development of invasive cancer Availability of an effective medication or treatment to replace the function of the organ removed A reliable tumor marker or screening test to detect persistent or recurrent disease.
41 Surgery to Prevent Cancer the pre-emptive operative removal of an organ prior to malignant transformation or while the cancer is in situ. The role of prophylactic surgery in cancer prevention. World J Surg, (3): p
42 The extirpation of the thyroid gland...typifies, perhaps better than any operation, the supreme triumph of the surgeon s art... A feat which today can be accomplished by any competent operator without danger of mishap and which was conceived more than one thousand years ago... There are operations today more delicate and perhaps more difficult... But is there any operative problem propounded so long ago and attacked by so many...which has yielded results as bountiful and so adequate? -Dr. William S. Haltsed, 1920
43 Summary Early preventative total thyroidectomy in patients with an MEN 2-associated RET mutation represents one of the first and perhaps still the purest archetype of a cancer syndrome for which operation is indicated based on a molecular genetic diagnosis, with intent of complete removal of the target organ and prevention of cancer development or its removal when still organ-confined.
44 Acknowledgements Mentors Samuel A. Wells, Jr., MD Helen Donis-Keller, PhD Research Colleagues James R. Howe, IV, MD David Chi, MD Jeffrey F. Moley, MD Shen shen Dou
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