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Familial medullary thyroid carcinoma (FMTC). Study of one family (treatment criteria)
EJSO 2001; 27: 162–164 doi:10.1053/ejso.2000.1092, available online at http://www.idealibrary.com on
Familial medullary thyroid carcinoma (FMTC). Study of one family (treatment criteria) A. F. Carli∗, F. Mariani†, L. Di Cosmo†, R. Giuli† and A. Neri† † Surgical Science Department and ∗ Endocrine Surgery Unit, University of Siena, Italy
Aim: The nosology of familial medullary thyroid carcinoma (FMTC) has been described as a distinct pathology, genetically determined and with autosomal dominant transmission with a gene penetrance of almost 100%. The diagnosis of this morbid condition can be made if at least four members of the same family are affected by calcitoninsecreting C-cell carcinoma. Methods and Results: We report the analysis of a family in which FMTC was diagnosed between 1993 and 1998. Of the five patients we confirmed as being affected by FMTC, we were able to perform a prophylactic thyroidectomy in only one case. The high possibility of lymph-node metastasis at the time of clinical diagnosis (52–75%), and the high morbidity and radio-chemo-resistance to adjuvant therapies, indicate total thyroidectomy with central lymphnode dissection. Conclusion: It appears that preventive lymphadenectomy does not substantially improve survival, while pre-clinical diagnosis is of greater importance than surgery in improving survival and preventing recurrence. Total preventive thyroidectomy has been recommended in all carriers of ret genetic defects, even in families at risk with mutations of the 618 or 620 codon, because the penetrance of FMTC approaches 100%, and a 100% accordance between presence of the disease and gene carrier status is reported. This procedure would therefore represent the only possibility of achieving a 100% cure in subjects affected by familial medullary thyroid carcinoma. 2001 Harcourt Publishers Ltd Key words: thyroidectomy; medullary thyroid carcinoma; thyroid surgery.
INTRODUCTION Familial medullary thyroid carcinoma (FMTC) has been described as a distinct, genetically determined pathology characterized by autosomal dominant transmission with a gene penetrance of almost 100%.1 Diagnosis can be made when at least four members of the same family are affected by calcitonin-secreting C-cell carcinoma without pheochromocytoma, parathyroid hyperplasia and peculiar phenotypes characterizing multiple endocrine neoplasms (MEN).2 Some point mutations of the germinal line of the RET proto-oncogene have been identified as being responsible for the syndromes MEN 2a and 2b and FMTC.3,4 This proto-oncogene codes for a tyrosine kinase receptor, which is probably involved in the proliferation, migration and/or differentiation of particular neuronal cell lines that are also common in renal embryogenesis.5,6 Most FMTC and MEN 2a present
Correspondence to: Federico Mariani, MD, Surgical Science Department, Endocrine Surgery Unit, University of Siena, Viale Bracci, 53100, Siena, Italy. Tel: +39-577-585690-585151; Fax: +39-577263369; E-mail: [email protected] 0748–7983/01/020162+03 $35.00/0
a mutation in one of the five residues of cysteine in the extracellular region of the RET protein (Cys 609, 611, 618, 620, 634). These are associated with specific alterations in FMTC characterized by mutations in the 768 and 804 codons of tyrosine kinase.7,8 The association between Hirschprung’s disease and mutations inactivating the RET gene has also been reported.9 Pre-clinical diagnosis of FMTC and the identification of families carrying the described genetic alterations are fundamental for therapy. In fact, medullary thyroid carcinoma is frequently burdened by high percentages (52–75%) of lymph-node metastases at the time of diagnosis, with palpable cervical lymphadenopathies possibly accompanied by small neoplasms or even occult carcinomas.10 In 20% of sporadic medullary thyroid carcinomas (MTC), 3.3% in the process of MEN 2a and 12% MEN 2b, distant metastases are also present at the time of diagnosis.11 This percentage seems to be less in patients affected by FMTC in whom the aggressiveness of the neoplasm seems to be lower.1 The diagnosis of MTC is made upon the assessment of the levels of circulating calcitonin, using both basal tests and tests after stimulation with intravenous calcium (2 mg per kg in 1 min) or pentagastrin (0.5 g per kg in 5 sec); the 2001 Harcourt Publishers Ltd
REPORT OF ONE FAMILY WITH FAMILIAL MEDULLARY THYROID CARCINOMA tests are considered positive when plasmatic peaks are at least three times higher than the base concentration or greater than 300 pg/ml.12 In order to exclude a multiple polyendocrine syndrome it is necessary to investigate the possible presence of hyperparathyroidism using assays including total serum calcium, PTH, phosphoraemia, chloraemia and alkaline phosphatase, and via macro and microscopic histological analysis of the parathyroid using biopsies examined at the time of thyroidectomy.13 It is possible to exclude the presence of a pheochromocytoma after assessing the rate of excretion of the urinary catecholamines over 24 h. Today, in the presence of such alterations, the standard abdominal CT examination has been replaced by RNM and scintigraphy with metaiodobenzylguanidine (MIBG).14,15 It is important to describe histologically tissue obtained at the time of surgery, stained with haematoxylin and eosin PASM/ AZAN to improve visualization of basal membranes, and using the technique of indirect immunoperoxidase for calcitonin identification.16 Finally, the patient is tested for the presence of mutations on exons 10 and 11 of the RET proto-oncogene.15 A positive immunoreaction by the C-cells towards the c-myc protein, is associated with higher neoplastic proliferation as well as a subsequent reduction in the disease-free interval in patients affected by medullary thyroid carcinoma. This has been identified as a prognostic factor predicting the clinical behaviour of FMTC and sporadic MTC.17 Surgery is indicated for this pathology. In confirmed neoplasia, a total thyroidectomy with central lymph-node dissection is the minimum treatment. Mono or bilateral laterocervical lymph-node dissection is added as required. Pre-clinical diagnosis is of greater importance than direct surgical intervention to improve survival and prevent recurrence. The 100% penetrance of FMTC and the 100% accordance between presence of the disease and gene carrier status, which excludes the risk of over-treatment for false-positive tests,18 indicate that a total preventive thyroidectomy should be performed in all carriers of ret genetic defects, including families at risks with mutations of the 618 or 620 codon, since this treatment would represent the only possibility of obtaining 100% cure in subjects with medullary thyroid carcinoma.18,19 Adjuvant chemotherapy can be avoided if the operation is performed before the test for C-cell stimulation is positive. A thyroidectomy can be performed prior to the onset of symptoms in selected patients at 5 years of age, when a high risk of complications can be avoided.15 Post-operative evaluation is carried out annually, by way of examination and assays of serum calcium and serum/ urine levels of catecholamine, both basal and after Post-operative normalization of stimulation.1 calcitoninaemia and CEA values marks a better prognosis. Subsequent elevation of these parameters can occur in 10% of treated patients without changing the prognosis.20
163
Negative for gene RET screening Operated on for medullary thyroid carcinoma. Deceased Operated on for medullary thyroid carcinoma. Positive for RET gene screening Prophylactic thyroidectomy Operated on for medullary thyroid carcinoma. Positive for RET gene screening Proband
Figure 1 Genealogy.
Such would indicate the presence of ‘residual disease’ with low aggressiveness.
SUBJECTS Between 1993 and 1998 we observed a family in which a 33-year-old woman with agenesis of the left kidney developed a neoplasm of the thyroid gland. This required a total thyroidectomy with anterior lymphadenectomy and re-operation after 5 years, due to laterocervical lymphadenopathy. The proband’s medical history revealed that her mother was a carrier of medullary thyroid carcinoma, which had been histologically confirmed at the time of the total thyroidectomy in 1978. She also developed prescalenus metachronous lymph-node metastases with high levels of circulating calcitonin. She was treated in 1989 with chemotherapy (hepirubicine and cisplatin) and radiotherapy. In 1995, the proband presented with a right laterocervical adenopathy with cytologically diagnosed medullary thyroid infiltration that required re-operation. Her grandmother had probably died of the same pathology. The year after the proband underwent surgery, her 35-year-old brother also came under our observation with cervical adenopathy from pluricentric medullary carcinoma, for which he had undergone surgery in 1992. The proband has three sons of 15, 13 and 9 years, one of whom was operated on for Hirschprung’s disease at 3 years of age (Fig. 1).
RESULTS After excluding a MEN syndrome, the proband and her three sons underwent genetic analysis at the Department of Genetics, University of Genova, which disclosed positivity for codons 10 and 11 of the RET gene in the proband and two sons (negatives for C-cells stimulation test and with low levels of calcitoninaemia). The oldest son, who had undergone a total thyroidectomy, showed areas of medullary cellularity at histological analysis. In the other son (9 years old) the thyroidectomy was prophylactic. The family comprised seven members. In
164 all patients, the diagnosis of MTC was made on the basis of evaluation of circulating calcitonin levels, using basal tests and tests after stimulation with pentagastrin; four out of five cases were positive. Hyperparathyroidism was excluded using assays for total serum calcium, PTH, phosphoraemia, chloraemia and alkaline phosphatase. A pheochromocytoma was excluded by the rate of excretion of urinary catecholamines over 24 h. Of the five patients affected by FMTC, we performed two total thyroidectomies with prophylactic intention. In one case we performed a prophylactic operation. At an 18 month follow-up the two patients are clinically disease free with negativity of the assays of serum calcium, serum/urine levels of catecholamine, both basal and after stimulation, and CEA levels, and no pathological evidence at neck CT scan.
DISCUSSION The treatment of choice for medullary thyroid carcinoma is still surgery. The high possibility of lymph-node metastasis at the time of clincal diagnosis (52–75%), the high morbidity and radio-chemo-resistance to adjuvant therapies, and the poor sensitivity of certain indices (neoplastic markers, especially CEA, calcitonin) in predicting the aggressiveness of the disease, indicate total thyroidectomy with central lymph-node dissection. Some authors21 consider that an extended dissection is indicated only in the case of histologically confirmed metastasis. When necessary, mono and bilateral laterocervical lymph-node dissection is also performed. Preventive lymphadenectomy does not appear to improve survival.22 The purpose of dissection in node positive cases is to perform a cytoreduction, thus reducing the levels of circulating calcitoninaemia and neck compression. The pre-clinical diagnosis is important in improving survival and preventing recurrence. A total preventive thryoidectomy has been recommended in all carriers of genetic defects, including members of families with mutations of the 618 or 620 codon, because this procedure represents the only possibility of achieving 100% cure in subjects with medullary thryoid carcinoma. Adjuvant therapy can be avoided if surgery is performed before the test for C-cell stimulation yields a positive result; in cases of medullary thyroid carcinoma with a positive test for C-cell stimulation, definitive healing rates following total thyroidectomy have been reported to reach 93%.23 Thyroidectomy can be performed prior to the onset of symptoms in selected patients at 5 years of age, when there is not a high risk of complications.15 We believe that in young patients with no clincal evidence of disease and negativity of stimulating tests we can avoid central lymph-node dissection even in the presence of histological positivity. Preventive lymphadenectomy does not appear to improve survival.22
A. F. CARLI ET AL.
REFERENCES 1. Farndon JR, Leight OS, Dilley WG, et al. Familiary medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 1986; 73: 278–81. 2. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2a and FMTC. Nature Gen 1994; 6: 70–4. 3. Mulligan LM, Kwok JBJ, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia syndrome type 2a. Nature 1993; 363: 458–60. 4. Landsvater RM, Jansen RPM, Hofstra RMW, et al. Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2a, MEN 2b and FMTC: two novel mutations and one de novo mutation for MEN 2a. Hum Gen 1996; 97: 11–4. 5. Pachnis V, Mankoo B, Costantini F. Expression of the RET protooncogene during mouse embryogenesis. Development 1993; 119: 1005–17. 6. Schuchardt A, D’agati V, Larsson-Blomberg L, et al. Defects in the kidney and enteric nervous system of myce lacking the tyrosine kinase receptor Ret. Nature 1994; 367: 380–3. 7. Eng C, Smith DP, Mulligan LM, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 1995; 10: 509–13. 8. Bolino A, Schuffenecker I, Luo Y, et al. RET mutations in exons 13 and 14 of FMTC patients. Oncogene 1995; 10: 2415–9. 9. Romeo G, Ronchetto P, Luo Y, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschprung’s disease. Nature 1994; 367: 377–8. 10. Pelizzo MR, Bernante P, Piotto A, et al. The extent of surgery for thyroid medullary cancer. Tumori 1994; 80: 427–32. 11. Soybell DI, Wells SA. Medullary thyroid carcinoma. In: Blacke Cady, Ricardo L, Rossi WB (eds) Surgery of the Thyroid and Parathyroid Glands. (3rd ed.) WB Saunders, Philadelphia, 1991: 152–78. 12. Wells SA Jr, Baylin SB, Linehan WM, et al. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 1978; 188: 139. 13. Wells SA Jr, Farndon JR, Dale JK, et al. Long term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980; 192: 451. 14. Baylin SB. Medullary carcinoma of the thyroid gland: use of biochemical parameters in detection and surgical management of the tumour. Surg Clin North Am 1974; 54: 309. 15. Moers AMJ, Landsvater RM, Schaap C, et al. Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family. Am J Med 1996; 101: 635–41. 16. Lips CJM, Landsvater RM, Hoppener JW, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. NEJM 1994; 331: 828–35. 17. Roncalli M, Viale G, Grimelius L, et al. Prognostic value of n-myc immunoreactivity in medullary thyroid carcinoma. Cancer 1994; 74-1: 134–41. 18. Pacini F, Romei C, Miccoli P, et al. Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations. Surgery 1995; 118-6: 1031–5. 19. Takami H, Thosen T, Shirahama S, et al. Does the syndrome of familial medullary thyroid carcinoma describe a distinct clinical entity? Eur J Cancer 1998; 34: 1639–40. 20. Cance WG, Wells SA Jr. Multiple endocrine neoplasia type IIa. Curr Probl Surg 1985; 22: 1–56. 21. Wells SA Jr, Bayling SB, Leight GS, et al. The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 1982; 195: 595–9. 22. Paliaga A, Amadi CE, Belvederesi M, et al. Studio anatomico clinico e prognostico su 31 casi di carcinoma midollare della tiroide sporadico ed ereditario. Acta Oncologica 1987; 8: 25. 23. Wells SA Jr, Dilley WG, Farndon JA, et al. Early diagnosis and treatment of medullary thyroid carcinoma. Arch Intern Med 1985; 145: 1248–52.
Accepted for publication 16 November 2000
Familial medullary thyroid carcinoma (FMTC). Study of one family (treatment criteria) A. F. Carli∗, F. Mariani†, L. Di Cosmo†, R. Giuli† and A. Neri† † Surgical Science Department and ∗ Endocrine Surgery Unit, University of Siena, Italy
Aim: The nosology of familial medullary thyroid carcinoma (FMTC) has been described as a distinct pathology, genetically determined and with autosomal dominant transmission with a gene penetrance of almost 100%. The diagnosis of this morbid condition can be made if at least four members of the same family are affected by calcitoninsecreting C-cell carcinoma. Methods and Results: We report the analysis of a family in which FMTC was diagnosed between 1993 and 1998. Of the five patients we confirmed as being affected by FMTC, we were able to perform a prophylactic thyroidectomy in only one case. The high possibility of lymph-node metastasis at the time of clinical diagnosis (52–75%), and the high morbidity and radio-chemo-resistance to adjuvant therapies, indicate total thyroidectomy with central lymphnode dissection. Conclusion: It appears that preventive lymphadenectomy does not substantially improve survival, while pre-clinical diagnosis is of greater importance than surgery in improving survival and preventing recurrence. Total preventive thyroidectomy has been recommended in all carriers of ret genetic defects, even in families at risk with mutations of the 618 or 620 codon, because the penetrance of FMTC approaches 100%, and a 100% accordance between presence of the disease and gene carrier status is reported. This procedure would therefore represent the only possibility of achieving a 100% cure in subjects affected by familial medullary thyroid carcinoma. 2001 Harcourt Publishers Ltd Key words: thyroidectomy; medullary thyroid carcinoma; thyroid surgery.
INTRODUCTION Familial medullary thyroid carcinoma (FMTC) has been described as a distinct, genetically determined pathology characterized by autosomal dominant transmission with a gene penetrance of almost 100%.1 Diagnosis can be made when at least four members of the same family are affected by calcitonin-secreting C-cell carcinoma without pheochromocytoma, parathyroid hyperplasia and peculiar phenotypes characterizing multiple endocrine neoplasms (MEN).2 Some point mutations of the germinal line of the RET proto-oncogene have been identified as being responsible for the syndromes MEN 2a and 2b and FMTC.3,4 This proto-oncogene codes for a tyrosine kinase receptor, which is probably involved in the proliferation, migration and/or differentiation of particular neuronal cell lines that are also common in renal embryogenesis.5,6 Most FMTC and MEN 2a present
Correspondence to: Federico Mariani, MD, Surgical Science Department, Endocrine Surgery Unit, University of Siena, Viale Bracci, 53100, Siena, Italy. Tel: +39-577-585690-585151; Fax: +39-577263369; E-mail: [email protected] 0748–7983/01/020162+03 $35.00/0
a mutation in one of the five residues of cysteine in the extracellular region of the RET protein (Cys 609, 611, 618, 620, 634). These are associated with specific alterations in FMTC characterized by mutations in the 768 and 804 codons of tyrosine kinase.7,8 The association between Hirschprung’s disease and mutations inactivating the RET gene has also been reported.9 Pre-clinical diagnosis of FMTC and the identification of families carrying the described genetic alterations are fundamental for therapy. In fact, medullary thyroid carcinoma is frequently burdened by high percentages (52–75%) of lymph-node metastases at the time of diagnosis, with palpable cervical lymphadenopathies possibly accompanied by small neoplasms or even occult carcinomas.10 In 20% of sporadic medullary thyroid carcinomas (MTC), 3.3% in the process of MEN 2a and 12% MEN 2b, distant metastases are also present at the time of diagnosis.11 This percentage seems to be less in patients affected by FMTC in whom the aggressiveness of the neoplasm seems to be lower.1 The diagnosis of MTC is made upon the assessment of the levels of circulating calcitonin, using both basal tests and tests after stimulation with intravenous calcium (2 mg per kg in 1 min) or pentagastrin (0.5 g per kg in 5 sec); the 2001 Harcourt Publishers Ltd
REPORT OF ONE FAMILY WITH FAMILIAL MEDULLARY THYROID CARCINOMA tests are considered positive when plasmatic peaks are at least three times higher than the base concentration or greater than 300 pg/ml.12 In order to exclude a multiple polyendocrine syndrome it is necessary to investigate the possible presence of hyperparathyroidism using assays including total serum calcium, PTH, phosphoraemia, chloraemia and alkaline phosphatase, and via macro and microscopic histological analysis of the parathyroid using biopsies examined at the time of thyroidectomy.13 It is possible to exclude the presence of a pheochromocytoma after assessing the rate of excretion of the urinary catecholamines over 24 h. Today, in the presence of such alterations, the standard abdominal CT examination has been replaced by RNM and scintigraphy with metaiodobenzylguanidine (MIBG).14,15 It is important to describe histologically tissue obtained at the time of surgery, stained with haematoxylin and eosin PASM/ AZAN to improve visualization of basal membranes, and using the technique of indirect immunoperoxidase for calcitonin identification.16 Finally, the patient is tested for the presence of mutations on exons 10 and 11 of the RET proto-oncogene.15 A positive immunoreaction by the C-cells towards the c-myc protein, is associated with higher neoplastic proliferation as well as a subsequent reduction in the disease-free interval in patients affected by medullary thyroid carcinoma. This has been identified as a prognostic factor predicting the clinical behaviour of FMTC and sporadic MTC.17 Surgery is indicated for this pathology. In confirmed neoplasia, a total thyroidectomy with central lymph-node dissection is the minimum treatment. Mono or bilateral laterocervical lymph-node dissection is added as required. Pre-clinical diagnosis is of greater importance than direct surgical intervention to improve survival and prevent recurrence. The 100% penetrance of FMTC and the 100% accordance between presence of the disease and gene carrier status, which excludes the risk of over-treatment for false-positive tests,18 indicate that a total preventive thyroidectomy should be performed in all carriers of ret genetic defects, including families at risks with mutations of the 618 or 620 codon, since this treatment would represent the only possibility of obtaining 100% cure in subjects with medullary thyroid carcinoma.18,19 Adjuvant chemotherapy can be avoided if the operation is performed before the test for C-cell stimulation is positive. A thyroidectomy can be performed prior to the onset of symptoms in selected patients at 5 years of age, when a high risk of complications can be avoided.15 Post-operative evaluation is carried out annually, by way of examination and assays of serum calcium and serum/ urine levels of catecholamine, both basal and after Post-operative normalization of stimulation.1 calcitoninaemia and CEA values marks a better prognosis. Subsequent elevation of these parameters can occur in 10% of treated patients without changing the prognosis.20
163
Negative for gene RET screening Operated on for medullary thyroid carcinoma. Deceased Operated on for medullary thyroid carcinoma. Positive for RET gene screening Prophylactic thyroidectomy Operated on for medullary thyroid carcinoma. Positive for RET gene screening Proband
Figure 1 Genealogy.
Such would indicate the presence of ‘residual disease’ with low aggressiveness.
SUBJECTS Between 1993 and 1998 we observed a family in which a 33-year-old woman with agenesis of the left kidney developed a neoplasm of the thyroid gland. This required a total thyroidectomy with anterior lymphadenectomy and re-operation after 5 years, due to laterocervical lymphadenopathy. The proband’s medical history revealed that her mother was a carrier of medullary thyroid carcinoma, which had been histologically confirmed at the time of the total thyroidectomy in 1978. She also developed prescalenus metachronous lymph-node metastases with high levels of circulating calcitonin. She was treated in 1989 with chemotherapy (hepirubicine and cisplatin) and radiotherapy. In 1995, the proband presented with a right laterocervical adenopathy with cytologically diagnosed medullary thyroid infiltration that required re-operation. Her grandmother had probably died of the same pathology. The year after the proband underwent surgery, her 35-year-old brother also came under our observation with cervical adenopathy from pluricentric medullary carcinoma, for which he had undergone surgery in 1992. The proband has three sons of 15, 13 and 9 years, one of whom was operated on for Hirschprung’s disease at 3 years of age (Fig. 1).
RESULTS After excluding a MEN syndrome, the proband and her three sons underwent genetic analysis at the Department of Genetics, University of Genova, which disclosed positivity for codons 10 and 11 of the RET gene in the proband and two sons (negatives for C-cells stimulation test and with low levels of calcitoninaemia). The oldest son, who had undergone a total thyroidectomy, showed areas of medullary cellularity at histological analysis. In the other son (9 years old) the thyroidectomy was prophylactic. The family comprised seven members. In
164 all patients, the diagnosis of MTC was made on the basis of evaluation of circulating calcitonin levels, using basal tests and tests after stimulation with pentagastrin; four out of five cases were positive. Hyperparathyroidism was excluded using assays for total serum calcium, PTH, phosphoraemia, chloraemia and alkaline phosphatase. A pheochromocytoma was excluded by the rate of excretion of urinary catecholamines over 24 h. Of the five patients affected by FMTC, we performed two total thyroidectomies with prophylactic intention. In one case we performed a prophylactic operation. At an 18 month follow-up the two patients are clinically disease free with negativity of the assays of serum calcium, serum/urine levels of catecholamine, both basal and after stimulation, and CEA levels, and no pathological evidence at neck CT scan.
DISCUSSION The treatment of choice for medullary thyroid carcinoma is still surgery. The high possibility of lymph-node metastasis at the time of clincal diagnosis (52–75%), the high morbidity and radio-chemo-resistance to adjuvant therapies, and the poor sensitivity of certain indices (neoplastic markers, especially CEA, calcitonin) in predicting the aggressiveness of the disease, indicate total thyroidectomy with central lymph-node dissection. Some authors21 consider that an extended dissection is indicated only in the case of histologically confirmed metastasis. When necessary, mono and bilateral laterocervical lymph-node dissection is also performed. Preventive lymphadenectomy does not appear to improve survival.22 The purpose of dissection in node positive cases is to perform a cytoreduction, thus reducing the levels of circulating calcitoninaemia and neck compression. The pre-clinical diagnosis is important in improving survival and preventing recurrence. A total preventive thryoidectomy has been recommended in all carriers of genetic defects, including members of families with mutations of the 618 or 620 codon, because this procedure represents the only possibility of achieving 100% cure in subjects with medullary thryoid carcinoma. Adjuvant therapy can be avoided if surgery is performed before the test for C-cell stimulation yields a positive result; in cases of medullary thyroid carcinoma with a positive test for C-cell stimulation, definitive healing rates following total thyroidectomy have been reported to reach 93%.23 Thyroidectomy can be performed prior to the onset of symptoms in selected patients at 5 years of age, when there is not a high risk of complications.15 We believe that in young patients with no clincal evidence of disease and negativity of stimulating tests we can avoid central lymph-node dissection even in the presence of histological positivity. Preventive lymphadenectomy does not appear to improve survival.22
A. F. CARLI ET AL.
REFERENCES 1. Farndon JR, Leight OS, Dilley WG, et al. Familiary medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 1986; 73: 278–81. 2. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2a and FMTC. Nature Gen 1994; 6: 70–4. 3. Mulligan LM, Kwok JBJ, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia syndrome type 2a. Nature 1993; 363: 458–60. 4. Landsvater RM, Jansen RPM, Hofstra RMW, et al. Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2a, MEN 2b and FMTC: two novel mutations and one de novo mutation for MEN 2a. Hum Gen 1996; 97: 11–4. 5. Pachnis V, Mankoo B, Costantini F. Expression of the RET protooncogene during mouse embryogenesis. Development 1993; 119: 1005–17. 6. Schuchardt A, D’agati V, Larsson-Blomberg L, et al. Defects in the kidney and enteric nervous system of myce lacking the tyrosine kinase receptor Ret. Nature 1994; 367: 380–3. 7. Eng C, Smith DP, Mulligan LM, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 1995; 10: 509–13. 8. Bolino A, Schuffenecker I, Luo Y, et al. RET mutations in exons 13 and 14 of FMTC patients. Oncogene 1995; 10: 2415–9. 9. Romeo G, Ronchetto P, Luo Y, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschprung’s disease. Nature 1994; 367: 377–8. 10. Pelizzo MR, Bernante P, Piotto A, et al. The extent of surgery for thyroid medullary cancer. Tumori 1994; 80: 427–32. 11. Soybell DI, Wells SA. Medullary thyroid carcinoma. In: Blacke Cady, Ricardo L, Rossi WB (eds) Surgery of the Thyroid and Parathyroid Glands. (3rd ed.) WB Saunders, Philadelphia, 1991: 152–78. 12. Wells SA Jr, Baylin SB, Linehan WM, et al. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 1978; 188: 139. 13. Wells SA Jr, Farndon JR, Dale JK, et al. Long term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980; 192: 451. 14. Baylin SB. Medullary carcinoma of the thyroid gland: use of biochemical parameters in detection and surgical management of the tumour. Surg Clin North Am 1974; 54: 309. 15. Moers AMJ, Landsvater RM, Schaap C, et al. Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family. Am J Med 1996; 101: 635–41. 16. Lips CJM, Landsvater RM, Hoppener JW, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. NEJM 1994; 331: 828–35. 17. Roncalli M, Viale G, Grimelius L, et al. Prognostic value of n-myc immunoreactivity in medullary thyroid carcinoma. Cancer 1994; 74-1: 134–41. 18. Pacini F, Romei C, Miccoli P, et al. Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations. Surgery 1995; 118-6: 1031–5. 19. Takami H, Thosen T, Shirahama S, et al. Does the syndrome of familial medullary thyroid carcinoma describe a distinct clinical entity? Eur J Cancer 1998; 34: 1639–40. 20. Cance WG, Wells SA Jr. Multiple endocrine neoplasia type IIa. Curr Probl Surg 1985; 22: 1–56. 21. Wells SA Jr, Bayling SB, Leight GS, et al. The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma. Ann Surg 1982; 195: 595–9. 22. Paliaga A, Amadi CE, Belvederesi M, et al. Studio anatomico clinico e prognostico su 31 casi di carcinoma midollare della tiroide sporadico ed ereditario. Acta Oncologica 1987; 8: 25. 23. Wells SA Jr, Dilley WG, Farndon JA, et al. Early diagnosis and treatment of medullary thyroid carcinoma. Arch Intern Med 1985; 145: 1248–52.
Accepted for publication 16 November 2000