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Multiple endocrine neoplasia 2A syndrome: Surgical management
Multiple Endocrine Neoplasia 2A Syndrome: Surgical Management By S. Simon, M. Pavel, J. Hensen, J. Berg, H.-P. Hu¨mmer, and R. Carbon Erlangen, Germany and Hannover, Germany
Background/Purpose: Currently, molecular genetic diagnostics allow familial types of medullary thyroid carcinoma to be detected at an asymptomatic stage and surgery thus to be performed at a time when prognosis is good. The current report aims to determine the appropriate age for safe prophylactic thyroidectomy in children with multiple endocrine neoplasia (MEN) 2A and mutations at codon 609 according to genotype-phenotype correlations and will discuss surgical procedures. Methods: The authors describe the case of a family with hereditary MEN 2A syndrome. A DNA analysis of 7 family members confirmed the diagnosis by a mutation at codon 609 of the RET proto-oncogene. Results: A phaeochromocytoma developed in 2 family members. Four had medullary thyroid carcinoma. A grandson underwent a prophylactic thyroidectomy at the age of 5 on account of genetic evidence. Despite the negative preopera-
T
HYROID MALIGNANCIES are rare and make up 1% of all pediatric malignancies.1 Medullary thyroid carcinoma occurs either sporadically or in familial forms—the hereditary form accounts for 25% of all carcinomas—as a part of the autosomal dominant hereditary MEN 2A syndrome (multiple endocrine neoplasia).2 Patients with a family history of MEN 2A are 100% certain to have medullary thyroid carcinoma at some point of their lives. Currently, the fifth year of life is regarded as the best time to perform a prophylactic thyroidectomy.3-7 Because medullary thyroid carcinomas are observed at a very early infant age, the optimum timing of surgery currently is again under discussion. MATERIALS AND METHODS Clinical diagnostics found the disease in 4 members of a family with hereditary MEN 2A syndrome. The history of the father, an uncle, the grandfather, and the paternal grand aunt of the patient to be studied showed that they had already had a medullary thyroid carcinoma or phaeochromocytoma. A phaeochromocytoma was diagnosed in the grandfather (index case) at the age of 51 years with classical symptoms. Three years later a pathologic pentagastrin stimulation test found a medullary thyroid carcinoma. After total thyroidectomy, no tumor relapse occured, and no metastases were observed up to now at the age of 62 years. Investigations of other family members were initiated because of the known disease of the index case. Examinations of the paternal grand aunt at the age of 51 years found a localized medullary thyroid carcinoma by ultrasound examination. At this time, pentagastrin stimulation test results clearly were abnormal, but urinary catecholamine levels were within the normal range. Two years later, urinary catecholamine levels were highly elevated (metanephrine, 707 Journal of Pediatric Surgery, Vol 37, No 6 (June), 2002: pp 897-900
tive and intraoperative findings he already had an invasive medullary thyroid carcinoma. Conclusions: Few genotype-phenotype correlations have been established for MEN 2A disease. According to the natural history of the disease, families with the genotype RET cys609gly should have a more benign disease than high-risk families (mutations at codon 634, 618). From this report the authors conclude that prophylactic thyroidectomy in “609” families should be performed earlier than actually recommended, favorably at the age of 2 to 4 years. Further multicenter studies are needed to provide more clinical and prognostic data for less frequent (codon 609, 630, 791, and 891) RET genotypes. J Pediatr Surg 37:897-900. Copyright 2002, Elsevier Science (USA). All rights reserved. INDEX WORDS: Multiple endocrine neoplasia 2A, medullary thyroid carcinoma, surgery.
g/L; normal range, ⬍30 g/L; normetanephrine, 772 g/L; normal range, ⬍600 g/L). Computed tomography of the abdomen showed a tumor mass of the left adrenal gland measuring 2 cm, so unilateral adrenalectomy was performed. Currently, at the age of 61 years, no tumor relapse or metastases has occured. Pentagastrin stimulation test also was done in the father and uncle, in whom a localized medullary thyroid carcinoma (MTC) developed at the ages of 33 and 26 years, respectively. Neither the father nor the uncle had a phaeochromocytoma during an observation time of 7 years up to the ages of 40 and 33 years. DNA sequencing found a TGC⬎GGC (cystein⬎glycine) mutation at codon 609 of the RET proto-oncogene in the 4 symptomatic and 3 clinically asymptomatic family members. During the yearly follow-up examinations, CEA (carcinoembryonic antigen) levels and pentagastrin stimulation results were normal in all patients. Parathyroid hormone levels were within the normal range. No family member fell ill with hyperparathyreoidism (Fig 1). The following report includes details of the case of a grandson of the family who underwent a prophylactic thyroidectomy at the age of 5 years based on genetic evidence.
From the Departments of Paediatric Surgery and Endocrinology, Surgical Clinic of the Friedrich-Alexander-Universita¨t Erlangen, Erlangen, Germany, and the Medical Clinic of the Clinic Hannover Nordstadt, Hannover, Germany. Address reprint requests to Dr med. Stefanie-Isabell Simon, Abteilung fu¨r Kinderchirurgie, Chirurgische Klink mit Poliklinik der Friedrich-Alexander-Universita¨t Erlangen, Maximiliansplatz 2, D-91054 Erlangen, Germany. Copyright 2002, Elsevier Science (USA). All rights reserved. 0022-3468/02/3706-0017$35.00/0 doi:10.1053/jpsu.2002.32906 897
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SIMON ET AL
Fig 1.
Preoperative Findings At a preoperative stage, the thyroid displayed clinically, sonographically, or scintigraphically no pathologic findings. The basal calcitonin level was below the detectable limit. Results of pentagastrin stimulation test were within normal limits.
Intraoperative Findings The thyroid was found to be macroscopically and by intraoperative ultrasound scan unsuspicious. Thus, a complete thyroidectomy without an additional central lymphadenectomy was performed.
Histology The histologic examination of the thyroid specimen, however, showed a focal, invasive medullary microcarcinoma in addition to C cell proliferation.
Course The child suffered no tumor relapse until the age of 10 years. After thyroidectomy, no thyroid rest was found either by scintigraphy or by ultrasound scan. The calcitonin level was within the normal limits, and the pentagastrin stimulation test results have remained negative. Follow-up screenings have not yet found a phaeochromocytoma or hyperparathyroidism. The hormone replacement therapy has been carried out in accordance with the usual guidelines. The patient’s younger brother (in the third year of his life) and one of his cousins (in the first year of her life) with the same mutation have not yet undergone prophylactic thyroidectomy.
DISCUSSION
Molecular Diagnostics In 1993, the association of germline mutations of the RET proto-oncogene on chromosome 10 (10q13) and familial medullary thyroid carcinoma (FMTC) as a part of the MEN 2A syndrome was discovered. Until now, more than 20 mainly missense mutations of a total of 13 codons of the RET proto-oncogene have been discovered for type 2A and the familial medullary thyroid carci-
Pedigree in family with MEN 2A.
noma.8 Mutations of the intracellular domain of the gene occur only rarely.8 Timing of Surgery Genetic screening, a highly sensitive and specific method, helps discover patients at a very early age with known risk for carcinomas to a much larger extent than previously assumed and leads to detection of MTC.9 Of note, patients with proven RET proto-oncogene mutation after screening procedures may not have pathologic calcitonin levels despite the presence of MTC limited to the thyroid gland.10 It is now accepted that genetic testing for RET proto-oncogene mutations is far superior to biochemical testing (elevated calcitonin levels) in the detection of MTC. In MEN 2A the codons 611, 618, and 620 in exon 10 and codon 634 in exon 11 are affected most frequently.11 Few genotype-phenotype correlations have been established. Germline mutations in the cysteine domains of exon 10 (codons 609, 611, 618, and 620) seem to entail a lesser activation of the RET proto-oncogene, resulting in a later malignant transformation obviously in both the MEN 2A and FMTC phenotypes.12 Germline mutations in noncysteine domains of exons 13 and 14 (codons 768, 790, and 804) afford weaker activation, resulting in a seemingly attenuated form with late-onset MTC and the FMTC phenotype only.13,14 The significant correlation between RET proto-oncogene mutation and patient age at diagnosis of MTC has important clinical implications. Based on youngest age at diagnosis, 3 groups can be distinguished by RET proto-oncogene mutation according to the velocity of malignant transformation: a highrisk group, encompassing codons 634 and 618, with youngest ages of 3 and 7 years; an intermediate-risk
MEN 2A SYNDROME: SURGICAL MANAGEMENT
group, including codons 790, 620, and 611, with youngest ages of 12 years; and a low-risk group, comprising codons 768 and 804, with ages of 47 and 60 years.12 The fifth year of life currently is recommended for prophylactic thyroidectomy.3-7 It is generally accepted that infants with high-risk mutations may have to undergo prophylactic surgery even earlier.11,17,19 In line with this recommendation, Gill et al15 suggested yearly hormonal screening beginning at age 1 and prophylactic surgery in MEN 2A patients as young as 5 years after observing a 5-year-old girl with MTC and nodal metastases and her 3-year-old sister with MTC focus both harboring the C634R genotype. Van Heurn et al11 reports the case of a family with hereditary MEN 2A syndrome in which histology found carcinomas in 3 children at the ages of 2, 3, and 6 years. All children had a T2548C transition at codon 634 in exon 11 of the RET protooncogene resulting in the substitution of cysteine to arginine. Hassett16 reports a family with MEN 2A who had mutations at codons 618 and 634 on exon 10. Histologic examinations of the thyroidectomy specimens showed microinvasive carcinoma in the 8- and 9-yearold children. Therefore, some investigators advocate for removal of the thyroid gland at the age of 2 years in children with high-risk mutations to obtain an optimal cure rate.11,17 In our opinion, however, this timing of surgery can only be agreed on if the operation presents no complications. Another argument for bringing forward the point of time for surgery is the reduced psychological stress for patients and their parents.16 In contrast to the natural history of the disease, our 5-year-old boy with RET cys609gly mutation should have been expected to present less malignant than 634 families. So we recommend for yearly hormonal screening in “609” families beginning at the first year of life. To ensure an efficient prophylactic and curative therapy we recommend for surgery in “609” families at the age of 2 to 4 years. In low-risk groups the age of 5 years is still recommended. Surgical Procedure The recommended operative technique is a complete thyroidectomy with a removal of the dorsal capsula including the dissection of central lymph nodes.9,18,19 For normal basal and stimulated calcitonin levels, the matter of whether thyroidectomy without a central lymphadenectomy is a sufficient surgical procedure in early infancy is yet to be considered.5,8 Operation in the stage of C cell hyperplasia would eliminate the need for additional lymph node dissection and thus decrease surgical morbidity.20 We are in favor of a thyroidectomy without a systematic lymphadenectomy as prophylactic and cur-
899
ative surgery, with the objective of removing the thyroid gland before malignant progression from C cell hyperplasia to medullary carcinoma has occured. Patients with metastasising thyroid carcinoma are, in general, older than 10 years.11 Provided that calcitonin levels after stimulation are within the normal range, we recommend performing a systematic lymphadenectomy after the tenth year of life. If histology findings show lymph node metastases, or the calcitonin levels are increased and the patient is older than 15 years, the lymph node dissection should include both cervicolateral and mediastinal compartment.8,21 In the case of medullary thyroid carcinoma with positive tumor markers, the removal of all regional lymph nodes, which should be as radical as possible, appears to be obligatory.8 If the calcitonin or CEA levels are increased persistently or if the cervical lymph nodes show metastases, a modified neck dissection has to be performed.5 The second most common tumor associated with MEN 2A is the phaeochromocytoma.22 Frequency of phaeochromocytoma depends on specific mutations in families. Mutations of the codon 634 of the RET protooncogene indicate a high risk for the development of phaeochromocytoma and of primary hyperparathyroidism and a lower or absent risk in patients carrying mutations in exon 10, 13, or 14.23 Phaeochromocytomas occur infrequently in families with 609 mutations. If urinary catecholamine excretion is elevated, a phaeochromocytoma has to be localized by means of imaging diagnostics and removed by resection before the thyroidectomy. In young children or in the case of a small tumor mass, thyroidectomy and adrenalectomy can be performed in one session without an increased perioperative risk.24 In the event of an unilateral finding, unilateral adrenalectomy should be performed.25 Because a contralateral phaeochromocytoma may develop at a later stage, approximately one third of all patients must undergo a second operation.26 This procedure is justified by the low malignancy and by the fact that the majority of patients are spared a hypoadrenalism.27 There have been reports on autotransplantation of adrenocortical tissue, but the experiences are limited and results are mostly unsuccessful.27,28 Hyperparathyreoidism in “609” families was not observed.23 With a view to further optimizing the timing of prophylactic thyroidectomy, a multicenter study clearly is needed to provide more exact data for the more common (codons 611, 618, 620, 634, 768, 790, and 804) and additional information on less frequent (codons 609, 630, 791, and 891) RET genotypes. Standardization of genetic typing operative strategies, and biochemical testing are highly recommended.
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REFERENCES 1. Linke F, Wu¨rfel A, Clausner A: Operationsindikationen bei Schilddru¨senerkrankungen im Kindesalter. Monatsschr Kinderheilkd 145:928-932, 1997 2. Buhr HJ, Raue F, Herfarth Ch: Spezielle Tumorbiologie und Chirurgie des C-Zell-Carcinoms. Chirurg 62:529-535, 1991 3. Dralle H, Ho¨ppner W, Raue F: Prophylaktische Thyreoidektomie. ¨ rztebl 93:A-899-901, 1996 Dtsch A 4. Lallier M, St-Vill D, Giroux M, et al: Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN 2 Syndrome. J Pediatr Surg 33:846-848, 1998 5. Scha¨fer K, Senninger N, Roth H, et al: Chirurgisches Vorgehen bei Kindern mit medulla¨rem Schilddru¨senkarzinom unter Beru¨cksichtigung der multiplen endokrinen Neoplasie Typ II. Langenbecks Arch Chir Suppl II 113:202-204, 1996 6. Skinner MA, DeBenedetti MK, Moley JF, et al: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2a and 2b. J Pediatr Surg 31:177-181, 1996 7. Wells SA, Chi DD, Toshima K, et al: Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 3:237-250, 1994 8. Tratzmu¨ller R, Irle U, Knorr D, et al: Multiple endokrine Neoplasie Typ 2 (MEN 2) im Kindes- und Jugendalter. Monatsschr Kinderheilk 147:733-743, 1999 9. Ro¨her HD, Simon D, Goretzki PE, et al: Die prophylaktische Radikaloperation des C-Zell-Carcinoms beim MEN-II-Syndrom auf der Grundlage des genetischen Screenings. Chirurg 66:1196-1202, 1995 10. Gimm O, Dralle H: C-cell cancer—Prevention and treatment. Langenbeck Arch Surg 384:16-23, 1999 11. van Heurn LW, Schaap C, Sie G, et al: Predictive DNA Testing for multiple endocrine neoplasia 2: A therapeutic challenge of prophylactic thyroidectomy in very young children. J Pediatr Surg 34:568571, 1999 12. Machens A, Gimm O, Hinze R, et al: Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: Oncological features and biochemical properties. J Clin Endocrinol Metab 86:11041109, 2001 13. Eng C, Clayton D, Schuffenecker I, et al: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. JAMA 276:1575-1579, 1996 14. Bolino A, Schuffenecker I, Luo Y, et al: RET mutations in exons 13 and 14 of FMTC patients. Oncogene 10:2415-2419, 1995
15. Gill JR, Reyes-Mugica M, Iyengar S, et al: Early presentation of metastatic medullary carcinoma in multiple endocrine neoplasia, Type IIa: Implications for therapy. J Pediatr 129:459-464, 1996 16. Hassett S, Costigan C, McDermott M, et al: Prophylactic thyroidectomy in the treatment of thyroid medullary carcinoma. Age for surgery? Eur J Pediatr Surg 10:334-336, 2000 17. Uchino S, Noguchi S, Sato M, et al: Presymptomatic detection and treatment of Japanese carriers on the Multiple Endocrine Neoplasia Type 2a gene. Surg Today 29:862-867, 1999 18. Telander RL, Zimmermann D, Sizemore GW, et al: Medullary carcinoma in children. Arch Surg 124:841-843, 1989 19. Waag KL, Hanisch E, Kallmann F, et al: Erfahrung mit der operativen Therapie von Schilddru¨senerkrankungen im Kindesalter. Z Kinderchir 43:232-235, 1988 20. Henry JF, Gramatica L, Denizot A, et al: Morbidity of prophylactic lymph node dissection in the central neck area in patients with papillary thyroid carcinoma. Langenbeck Arch Surg 383:167-169, 1998 21. Dralle H, Gimm O, Simon D, et al: Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 22:744751, 1998 22. Carney JA, Sizemore GW, Sheps SG: Adrenal medullary disease in multiple endocrine neoplasia type 2: Phaeochromocytoma and its precursors. Am J Clin Pathol 66:279-290, 1976 23. Schuffenecker I, Billaud M, Calender A, et al: RET protooncogene mutations in French MEN 2A and FMTC families. Hum Mol Genet 3:1939-1943, 1994 24. Dralle H, Scheumann GFW, Kotzerke J, et al: Surgical management of MEN 2. Recent Results Cancer Res 125:167-195, 1992 25. Frank-Raue K, Ho¨ppner W, Frilling A, et al: Mutations of the ret protooncogene in German multiple endocrine neoplasia families: Relation between genotype and phenotype. J Clin Endocrinol Metab 81:1780-1783, 1996 26. Evans DB, Lee JE, Merrell RC, et al: Adrenal medullary disease in multiple endocrine neoplasia type 2. Appropriate management. Endocrinol Metab Clin North Am 23:167-175, 1994 27. Dralle H, Ipta M, Henschel E, et al: Operative Therapie des sporadischen und familia¨ren Pha¨ochromozytoms. Acta Med Austriaca 15:108-111, 1988 28. Klempa I, Menzel J, Baca I: Subtotale Adrenalektomie versus Autotransplantation der Nebennierenrinde—Alternativverfahren bei der bilateralen Adrenalektomie bei MEN II? Chirurg 60:266-272, 1989
Background/Purpose: Currently, molecular genetic diagnostics allow familial types of medullary thyroid carcinoma to be detected at an asymptomatic stage and surgery thus to be performed at a time when prognosis is good. The current report aims to determine the appropriate age for safe prophylactic thyroidectomy in children with multiple endocrine neoplasia (MEN) 2A and mutations at codon 609 according to genotype-phenotype correlations and will discuss surgical procedures. Methods: The authors describe the case of a family with hereditary MEN 2A syndrome. A DNA analysis of 7 family members confirmed the diagnosis by a mutation at codon 609 of the RET proto-oncogene. Results: A phaeochromocytoma developed in 2 family members. Four had medullary thyroid carcinoma. A grandson underwent a prophylactic thyroidectomy at the age of 5 on account of genetic evidence. Despite the negative preopera-
T
HYROID MALIGNANCIES are rare and make up 1% of all pediatric malignancies.1 Medullary thyroid carcinoma occurs either sporadically or in familial forms—the hereditary form accounts for 25% of all carcinomas—as a part of the autosomal dominant hereditary MEN 2A syndrome (multiple endocrine neoplasia).2 Patients with a family history of MEN 2A are 100% certain to have medullary thyroid carcinoma at some point of their lives. Currently, the fifth year of life is regarded as the best time to perform a prophylactic thyroidectomy.3-7 Because medullary thyroid carcinomas are observed at a very early infant age, the optimum timing of surgery currently is again under discussion. MATERIALS AND METHODS Clinical diagnostics found the disease in 4 members of a family with hereditary MEN 2A syndrome. The history of the father, an uncle, the grandfather, and the paternal grand aunt of the patient to be studied showed that they had already had a medullary thyroid carcinoma or phaeochromocytoma. A phaeochromocytoma was diagnosed in the grandfather (index case) at the age of 51 years with classical symptoms. Three years later a pathologic pentagastrin stimulation test found a medullary thyroid carcinoma. After total thyroidectomy, no tumor relapse occured, and no metastases were observed up to now at the age of 62 years. Investigations of other family members were initiated because of the known disease of the index case. Examinations of the paternal grand aunt at the age of 51 years found a localized medullary thyroid carcinoma by ultrasound examination. At this time, pentagastrin stimulation test results clearly were abnormal, but urinary catecholamine levels were within the normal range. Two years later, urinary catecholamine levels were highly elevated (metanephrine, 707 Journal of Pediatric Surgery, Vol 37, No 6 (June), 2002: pp 897-900
tive and intraoperative findings he already had an invasive medullary thyroid carcinoma. Conclusions: Few genotype-phenotype correlations have been established for MEN 2A disease. According to the natural history of the disease, families with the genotype RET cys609gly should have a more benign disease than high-risk families (mutations at codon 634, 618). From this report the authors conclude that prophylactic thyroidectomy in “609” families should be performed earlier than actually recommended, favorably at the age of 2 to 4 years. Further multicenter studies are needed to provide more clinical and prognostic data for less frequent (codon 609, 630, 791, and 891) RET genotypes. J Pediatr Surg 37:897-900. Copyright 2002, Elsevier Science (USA). All rights reserved. INDEX WORDS: Multiple endocrine neoplasia 2A, medullary thyroid carcinoma, surgery.
g/L; normal range, ⬍30 g/L; normetanephrine, 772 g/L; normal range, ⬍600 g/L). Computed tomography of the abdomen showed a tumor mass of the left adrenal gland measuring 2 cm, so unilateral adrenalectomy was performed. Currently, at the age of 61 years, no tumor relapse or metastases has occured. Pentagastrin stimulation test also was done in the father and uncle, in whom a localized medullary thyroid carcinoma (MTC) developed at the ages of 33 and 26 years, respectively. Neither the father nor the uncle had a phaeochromocytoma during an observation time of 7 years up to the ages of 40 and 33 years. DNA sequencing found a TGC⬎GGC (cystein⬎glycine) mutation at codon 609 of the RET proto-oncogene in the 4 symptomatic and 3 clinically asymptomatic family members. During the yearly follow-up examinations, CEA (carcinoembryonic antigen) levels and pentagastrin stimulation results were normal in all patients. Parathyroid hormone levels were within the normal range. No family member fell ill with hyperparathyreoidism (Fig 1). The following report includes details of the case of a grandson of the family who underwent a prophylactic thyroidectomy at the age of 5 years based on genetic evidence.
From the Departments of Paediatric Surgery and Endocrinology, Surgical Clinic of the Friedrich-Alexander-Universita¨t Erlangen, Erlangen, Germany, and the Medical Clinic of the Clinic Hannover Nordstadt, Hannover, Germany. Address reprint requests to Dr med. Stefanie-Isabell Simon, Abteilung fu¨r Kinderchirurgie, Chirurgische Klink mit Poliklinik der Friedrich-Alexander-Universita¨t Erlangen, Maximiliansplatz 2, D-91054 Erlangen, Germany. Copyright 2002, Elsevier Science (USA). All rights reserved. 0022-3468/02/3706-0017$35.00/0 doi:10.1053/jpsu.2002.32906 897
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SIMON ET AL
Fig 1.
Preoperative Findings At a preoperative stage, the thyroid displayed clinically, sonographically, or scintigraphically no pathologic findings. The basal calcitonin level was below the detectable limit. Results of pentagastrin stimulation test were within normal limits.
Intraoperative Findings The thyroid was found to be macroscopically and by intraoperative ultrasound scan unsuspicious. Thus, a complete thyroidectomy without an additional central lymphadenectomy was performed.
Histology The histologic examination of the thyroid specimen, however, showed a focal, invasive medullary microcarcinoma in addition to C cell proliferation.
Course The child suffered no tumor relapse until the age of 10 years. After thyroidectomy, no thyroid rest was found either by scintigraphy or by ultrasound scan. The calcitonin level was within the normal limits, and the pentagastrin stimulation test results have remained negative. Follow-up screenings have not yet found a phaeochromocytoma or hyperparathyroidism. The hormone replacement therapy has been carried out in accordance with the usual guidelines. The patient’s younger brother (in the third year of his life) and one of his cousins (in the first year of her life) with the same mutation have not yet undergone prophylactic thyroidectomy.
DISCUSSION
Molecular Diagnostics In 1993, the association of germline mutations of the RET proto-oncogene on chromosome 10 (10q13) and familial medullary thyroid carcinoma (FMTC) as a part of the MEN 2A syndrome was discovered. Until now, more than 20 mainly missense mutations of a total of 13 codons of the RET proto-oncogene have been discovered for type 2A and the familial medullary thyroid carci-
Pedigree in family with MEN 2A.
noma.8 Mutations of the intracellular domain of the gene occur only rarely.8 Timing of Surgery Genetic screening, a highly sensitive and specific method, helps discover patients at a very early age with known risk for carcinomas to a much larger extent than previously assumed and leads to detection of MTC.9 Of note, patients with proven RET proto-oncogene mutation after screening procedures may not have pathologic calcitonin levels despite the presence of MTC limited to the thyroid gland.10 It is now accepted that genetic testing for RET proto-oncogene mutations is far superior to biochemical testing (elevated calcitonin levels) in the detection of MTC. In MEN 2A the codons 611, 618, and 620 in exon 10 and codon 634 in exon 11 are affected most frequently.11 Few genotype-phenotype correlations have been established. Germline mutations in the cysteine domains of exon 10 (codons 609, 611, 618, and 620) seem to entail a lesser activation of the RET proto-oncogene, resulting in a later malignant transformation obviously in both the MEN 2A and FMTC phenotypes.12 Germline mutations in noncysteine domains of exons 13 and 14 (codons 768, 790, and 804) afford weaker activation, resulting in a seemingly attenuated form with late-onset MTC and the FMTC phenotype only.13,14 The significant correlation between RET proto-oncogene mutation and patient age at diagnosis of MTC has important clinical implications. Based on youngest age at diagnosis, 3 groups can be distinguished by RET proto-oncogene mutation according to the velocity of malignant transformation: a highrisk group, encompassing codons 634 and 618, with youngest ages of 3 and 7 years; an intermediate-risk
MEN 2A SYNDROME: SURGICAL MANAGEMENT
group, including codons 790, 620, and 611, with youngest ages of 12 years; and a low-risk group, comprising codons 768 and 804, with ages of 47 and 60 years.12 The fifth year of life currently is recommended for prophylactic thyroidectomy.3-7 It is generally accepted that infants with high-risk mutations may have to undergo prophylactic surgery even earlier.11,17,19 In line with this recommendation, Gill et al15 suggested yearly hormonal screening beginning at age 1 and prophylactic surgery in MEN 2A patients as young as 5 years after observing a 5-year-old girl with MTC and nodal metastases and her 3-year-old sister with MTC focus both harboring the C634R genotype. Van Heurn et al11 reports the case of a family with hereditary MEN 2A syndrome in which histology found carcinomas in 3 children at the ages of 2, 3, and 6 years. All children had a T2548C transition at codon 634 in exon 11 of the RET protooncogene resulting in the substitution of cysteine to arginine. Hassett16 reports a family with MEN 2A who had mutations at codons 618 and 634 on exon 10. Histologic examinations of the thyroidectomy specimens showed microinvasive carcinoma in the 8- and 9-yearold children. Therefore, some investigators advocate for removal of the thyroid gland at the age of 2 years in children with high-risk mutations to obtain an optimal cure rate.11,17 In our opinion, however, this timing of surgery can only be agreed on if the operation presents no complications. Another argument for bringing forward the point of time for surgery is the reduced psychological stress for patients and their parents.16 In contrast to the natural history of the disease, our 5-year-old boy with RET cys609gly mutation should have been expected to present less malignant than 634 families. So we recommend for yearly hormonal screening in “609” families beginning at the first year of life. To ensure an efficient prophylactic and curative therapy we recommend for surgery in “609” families at the age of 2 to 4 years. In low-risk groups the age of 5 years is still recommended. Surgical Procedure The recommended operative technique is a complete thyroidectomy with a removal of the dorsal capsula including the dissection of central lymph nodes.9,18,19 For normal basal and stimulated calcitonin levels, the matter of whether thyroidectomy without a central lymphadenectomy is a sufficient surgical procedure in early infancy is yet to be considered.5,8 Operation in the stage of C cell hyperplasia would eliminate the need for additional lymph node dissection and thus decrease surgical morbidity.20 We are in favor of a thyroidectomy without a systematic lymphadenectomy as prophylactic and cur-
899
ative surgery, with the objective of removing the thyroid gland before malignant progression from C cell hyperplasia to medullary carcinoma has occured. Patients with metastasising thyroid carcinoma are, in general, older than 10 years.11 Provided that calcitonin levels after stimulation are within the normal range, we recommend performing a systematic lymphadenectomy after the tenth year of life. If histology findings show lymph node metastases, or the calcitonin levels are increased and the patient is older than 15 years, the lymph node dissection should include both cervicolateral and mediastinal compartment.8,21 In the case of medullary thyroid carcinoma with positive tumor markers, the removal of all regional lymph nodes, which should be as radical as possible, appears to be obligatory.8 If the calcitonin or CEA levels are increased persistently or if the cervical lymph nodes show metastases, a modified neck dissection has to be performed.5 The second most common tumor associated with MEN 2A is the phaeochromocytoma.22 Frequency of phaeochromocytoma depends on specific mutations in families. Mutations of the codon 634 of the RET protooncogene indicate a high risk for the development of phaeochromocytoma and of primary hyperparathyroidism and a lower or absent risk in patients carrying mutations in exon 10, 13, or 14.23 Phaeochromocytomas occur infrequently in families with 609 mutations. If urinary catecholamine excretion is elevated, a phaeochromocytoma has to be localized by means of imaging diagnostics and removed by resection before the thyroidectomy. In young children or in the case of a small tumor mass, thyroidectomy and adrenalectomy can be performed in one session without an increased perioperative risk.24 In the event of an unilateral finding, unilateral adrenalectomy should be performed.25 Because a contralateral phaeochromocytoma may develop at a later stage, approximately one third of all patients must undergo a second operation.26 This procedure is justified by the low malignancy and by the fact that the majority of patients are spared a hypoadrenalism.27 There have been reports on autotransplantation of adrenocortical tissue, but the experiences are limited and results are mostly unsuccessful.27,28 Hyperparathyreoidism in “609” families was not observed.23 With a view to further optimizing the timing of prophylactic thyroidectomy, a multicenter study clearly is needed to provide more exact data for the more common (codons 611, 618, 620, 634, 768, 790, and 804) and additional information on less frequent (codons 609, 630, 791, and 891) RET genotypes. Standardization of genetic typing operative strategies, and biochemical testing are highly recommended.
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