- Email: [email protected]
Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome
Prophylactic By M. Lallier,
Thyroidectomy for Medullary Thyroid in Gene Carriers of MEN2 Syndrome D. St-Vii,
M. Giroux,
C. Huot, L. Gaboury, Montreal, Quebec
Be&ground/Purpose: Although medullary thyroid carcinoma (MTC) can occur sporadically, in the pediatric population it is most often associated with the multiple endocrine neoplasia syndrome (MEN type 2). Traditional screening was based on evaluation of basal and stimulated serum calcitonin levels. The recent cloning of the MEN2 gene on the I?.ET proto-oncogene of chromosome 10 now allows for testing of gene carrier status in individuals at risk who could benefit from prophylactic treatment. The current study was undertaken to determine the appropriate age for safe total prophylactic thyroidectomy. /LJetbods: Over a 16-year period, 12 patients with a family history of MEN2A and one with a MEN2B underwent total thyroidectomy and central neck dissection without parathyroid autotransplantation. Four patients (31%) were treated previously for Hirschsprung’s disease. Results: In seven patients (mean age, 11.8 years) undergoing biochemical screening for diagnosis, multifocal MTC and C cell hyperplasia (CCH) were found in all the resected speci-
A
LTHOUGH THYROID CANCER is rare in children in the United States (375 cases per year),le3 medullary thyroid carcinoma (MTC) accounts for up to 10% of all thyroid malignancies. These tumors can occur sporadically or in familial forms with an autosomal dominant pattern of inheritance with age-related penetrance. The sporadic form of MTC occurs with equal frequency in different parts of the world and little is known about its etiology and pathogenesis. MTC of the familial type can present in association with adrenal medullary and parathyroid proliferative abnormalities (MEN2A) or mucosal and ocular neuromas, pheochromocytoma, and marfanoid habitus (MENZB). In rare instances, familial MTC may occur without other associated endocrine abnormalities.
From the Divisions of Pedratric General Surgev, Pathology, and Endocrinology, HLipital Sainte-Justine, Montreal, Quebec, Carlada. Presented at the 29th Annual Mee&g of the Canadian Assouation of Pae&atric Surgeons, Banj$ Alberta, Canada1 October 3-6, 1997. Address reprint requests to Dickens St-W, MD, H6pital SainteJustine, 3175 Ste. Catherine Rd, Montreal, Quebec, Canada H3T lC5. Copyright 0 1998 by WB. Saunders Company 0022-3468/98/3306-0009$03.00/O
846
L. Oligny,
Carcinoma
and J.G. Desjardins
mens. Of six patients identified with genetic screening (mean age, 9.1 years), two had elevated stimulated calcitonin levels, one (age 14) had evidence of MTC, and one (age 6) had CCH. Four patients with normal calcitonin levels had no evidence of MTC (ages 6, 8, IO) but there was one occurence of CCH (age 1 I). No permanent postoperative hypoparathyroidism or recurrent laryngeal nerve damage occurred in this series. With a mean follow-up of 4 years (range, 1 to 14 years), the overall disease-free survival is 100%. Conc/usiofls~ From this study the authors conclude that total thyroidectomy can be performed safely in children and should be the treatment of choice in patients with a family history of MEN2A carrying a germinal KTmutation even if the serum basal or stimulated serum calcitonin level is normal. Total thyroidectomy should be performed as early as 5 years of age before the occurence of CCH or MTC. J Pediatr Surg 33:846-848. Copyright 0 1998 by W.B. Saunders Company. INDEX WORDS: MEN2, medullarythyroid lactic thyroidectomy, genetic screening.
carcinoma,
prophy-
Traditional screening for MTC was based on the demonstration of increased basal and stimulated serum calcitonin levels, but recent cytogenetic studies have mapped the gene for MEN2 syndrome to a locus nea.r the centromere of chromosome 10, the K!ZTproto-oncogene.4 Demonstration of specsc mutations in families with MEN2 by direct DNA analysis now permits identification of gene carrier status in individuals at high risk for the development MTC who could benefit from prophylactic thyroidectomy. To evaluate the appropriate age for prophylactic thyroidectomy in asymptomatic gene carriers, we reviewed our experience with MTC over the past 16 years.
MATERIALS
AND
METHODS
The medical records of patients with a family history of MEN type 2 who underwent total thyroidectomy between 1981 and 1997 at Hbpital Sainte-Justme were reviewed retrospectively. Thiieen patients, five boys and eight girls with a mean age of 10.6 years fulfilled the criteria for inclusion in this study. These patients underwent follow-up with annual measurement of the basal and stimulated (after intravenous injection of 0.5 pg/kg pentagastrin [Peptavlon, Wyeth-Ayerst Lab; Philadelpka, PA]) serum calcitonin levels using commercially avalable radimmmunoassays. Relatives of patients with MEN2 have been screened for RET mutation through direct gene sequencing since 1995. As previously described: DNA was extracted from peripheral blood Jo~~rna/ of fediafric
Surgery,
Vol33,
No 6 (June),
1998: pp 846-848
PROPHYLACTIC
THYROIDECTOMY
847
FOR MTC
lymphocytes, amplified with polymerase chrnn reaction (PCR) and probed for the genetic mutation. Total thyroidectomy and central neck chssection were the standard operation performed when serum calcitonin was elevated. Recently, the surgery has been performed as soon as an Individual at risk was found to be a gene carrier. The parathyroid glands were identified and left in situ. Before surgev, urine collections for quantification of catecholemines, abdominal ultrasonography, computed tomography and an 13’1 Meta Iodo Benzyl Guamdine (MIBG, Malhngckrodt, Pointe-Claire. Quebec) scintigraphy were performed searching for an asymptomatic adrenal mass, Postoperatively, patients underwent follow-up with chnical examinations, annual serum calcitomn levels and repeat urine collections. Specimens were sent fresh for patholo~lcal examination. Paraffinembedded sections of thyroid tissue were stained with HPS (hematoxylinphloxine-saffron) and examined histologically. Immunohistochemcal staining directed against calcitonin and Congo-red staining to highlight stromal amyloid were performed when necessary.
RESULTS
Twelve patients with MEN2A and one with MEN2B underwent total thyroidectomy. None had a previous history of parathyroid abnormalities or hypertension; no adrenal mass was found on abdominal ultrasonography, computed tomography or 1311MIBG. Four patients (3 1%) including two sisters, had previously been treated for Hirschsprung’s disease. In seven cases found before 1995, MTC was suspected because of elevated basal or stimulated serum calcitonin level. The mean age of this group was 11.8 years (range, 1.5 to 16 years, median, 14 years). The mean hospital stay was 4.9 days (range, 3 to 7 days). Histological examination findings of the resected specimen showed multicentric medullary carcinoma with areas of C cell hyperplasia (CCH), and no metastatic lesions were noted in excised lymph nodes (Table 1). With a mean follow-up of 7 years (range, 3 to 14 years; median, 5 years) survival is 100%. One patient presented 5 years after total thyroidectomy with a cervical mass and Table 1. Outcome
and Histological Findings in Patients Biochemical Screening Results Elevated calcmnln Lk?Vf?l
PatK?nt NO.
SW
1
F
14
+
MTC
2
M
IO
+
3
F
15
+
MTC + CCH, bilobar MTC + CCH,
+
superior pole MTC + CCH,
+
multifocal MTC + CCH,
Aw b/d
Pathological Findings
+ CCH,
With
Positive
Follow-Up Without Recurrence (yr)
3
bilobar
4* 5
Fl5 F
15
multifocal
6*
F
7t
M
*Patient tPatient
with with
12 1.5 Hirschsprung’s MENZB.
+ +
MTC + CCH, bilobar MTC, right lobe disease.
8 5 4 Recurrence 5 years postoperatively 5 2 14
Table 2. Outcome
and Histological Findings Genetic Screening
of Patients
Identified
Follow-Up WIthout RWXlW3lCE! WI
Patk?nt NO
sex
Age Cyr)
Elevated Calcmnin Lk?V-Sl
1
M
14
+
2*
F
6
Normal
C 620
Normal
1
3
F
4 5*
F M
8 10
Normal Normal
C 620 C 620
Normal Normal
1 1
6
M
11 6
Normal +
C 620 C 620
CCH CCH
1 I
*Hirschsprung’s
Pathologml Fmdings
by
Genetm Mutation
C 634
MTC + CCH, multifocal
2
disease,
required reexploration. Histological examination findings showed recurrent MTC; she is tumor free 5 years later. Six patients had total thyroidectomy after genetic screening demonstrated a germinal RET mutation. The mutation was on codon 620 for five patients (83%) and on codon 634 for the other one (17%). The mean age was 9.1 years (range, 6 to 14 years; median, 8 years). Calcitonin levels (basal and stimulated) were normal in four patients and elevated in two (ages 6 and 14 years). Pathological examination findings showed a multicentric MTC and CCH in the 14-year-old patient, and the other had evidence of multifocal C cell hyperplasia. Of the four patients with normal calcitonin level, there was no MTC found, but one 11-year-old patient had multifocal CCH (Table 2). The mean hospital stay was 2.5 days (range 2-3 days). With a mean follow-up of 10 months (range, 6 to 18 months) all patients are well and free of tumor. Total thyroidectomy and central neck dissection were easy to perform in these young patients. As much as possible, the parathyroid glands were identified and preserved. Three patients experienced episodes of transient hypocalcemia that improved spontaneously within 3 days, but none had permanent hypocalcemia or recurrent laryngeal nerve damage postoperatively. DISCUSSION
The sporadic form of medullary thyroid carcinoma primarily is a tumor of middle-aged adults who usually present with unilateral involvement of the thyroid with or without associated cervical nodes metastases. In contrast, the mean age at diagnosis of MTC associated with MEN2A and 2B diagnosed by biochemical screening is 20 years and 15 years, respectively with a slightly higher incidence in women (l.3:l).s Our results are similar to those of previous reports, with MTC associated with MEN2 syndrome and type 2B occuring at younger age (1.5 years v 13 years) and being more aggressive. In most large series, the 5-year survival rate is 60% to 70% with significant correlation with age, sex, and stage of the disease. Patients less than 40 years of age and women have a better prognosis.5 Previously, screening for famil-
848
LALLIER
ial MTC was done by detecting an elevation in the basal or pentagastrin-stimulated serum calcitonin level. Although highly sensitive, biochemical screening had limitations because of the side effects of pentagastin injection, annual testing required of all family members, and extent of the disease at diagnosis, with patients having already invasive MTC and lymph node metastases.6 In 1987, Simpson et al7 and Mathew et al8 reported on the genetic mapping for MEN2A to the region of chromosome 10 and opened the way for genetic screening. The MEN2 gene has been identified as the RET protooncogene coding for a tyrosine kinase receptor with a cysteine-rich region. It is likely involved in the development and differentiation of tissues originating from the neural crest such as neuroblastomas, MTC, and pheochromocytomas. In MEN2A, point mutations affect one of five cysteine residues in codons 609, 611, 618, 620, and 634 leading to the replacement of cysteine by arginine, tyrosine, or phenylalanine. In MEN2B the point mutation occurs in codon 9 1S.9 In the current study, all patients with biochemical screening had evidence of diffuse MTC and CCH. Although all lymph nodes were negative for metastases, one patient had recurrence of tumor in the cervical area suggestive of advanced disease at the time of surgery. Patients with genetic screening were younger (9.1 years v 11.8 years) than those who had undergone provocation testing, and most had a normal basal or stimulated calcitonin level. The 14-year-old boy was known to have an elevated calcitonin level, but identification of the gene carrier status finally convinced his family that surgery was mandatory. This was the only case of MTC in this group. All patients with normal calcitonin
ET AL
levels had no evidence of MTC, but one had CCH found on histological examination confirming the occurence of CCH, a precursor of MTC before the onset of elevated calcitonin levels. Total thyroidectomy and central neck dissection is the treatment of choice for proven MTC. The management of the parathyroid gland remained controversial.1,6 Although some investigatorslo suggested total parathyroidectomy with heterotopic autotransplantation, parathyroid anomalies will eventually develop in only 10% to 20% of individuals with MEN2A. Individuals with the point mutation on codon 634 are at higher risk (30%).r” Thus, we do not recommend total parathyroidectomy for all patients. The dual occurence of MTC and Hirschsprung’s disease is also underlined in this study. This association can be explained by a common origin of both cell types (C cells of the thyroid and intestinal enterochromaffin cells) from the neural crest.n Because the gene for familial Hirschsprung’s disease has been mapped to chromosome 10,rz a point mutation in the RET protooncogene region could explain the occurence of both diseases. Familial Hirschsprung’s disease thus could be an early manifestation of MEN2 syndrome, and a high index of suspicion is needed. Genetic screening is highly sensitive and helps to identify children at risk of the development of MTC because penetrance of MTC in MEN2 is essentially lOO%.2Prophylactic thyroidectomy should be performed as early as 5 years of age for children with a point mutation. Total parathyroidectomy with autotransplantation of parathyroid tissue and central neck dissection are not necessary.
REFERENCES 1, Decker R.4, Geiger JD, Cox CE, et al: Prophylactic surgery for multiple endocrine neoplasia type IIa after genetic diagnosis: Is parathyroid transplantation indicated? World J Surg 20:814-821, 1996 2. G’Riordain DS, O’Brien T, Weaver AL: Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surg 116:1017-1023,1994 3. Geiger JD, Thompson NW Thyroid tumors in children. Otolaryngo1 Clin North Am 29:711-719. 1996 4. Shimotake T, Iwai N, Inoue K, et al: Germline mutations of the RETproto-oncogene in pedigree with MEN type 2A: DNA analysis and its imphcations for pediatric surgery. J Pediatr Surg 31:779-781, 1996 5. Rosai J, Carcangiu ML, DeLelhs RA: Tumors of the thyroid gland, in Rosat. Sobin teds): Atlas of Tumor Pathology. Armed Forces Institute of Pathology. Washington, DC. 1992. pp 207-240 6. Skinner MA, DeBenedetti MK, Moley JF, et al: Medullary thyroid carcinoma m chrldren with multiple endocrine neoplasia types 2A and 2B. J PediatrSurg31:177-182,1996
7. Simpson NE. Kidd KK. Goodfellow PJ. et al: Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 328:S28-530, 1987 8. Mathew CGP. Easton DF, Nakamura screening for multiple endocrine neoplasta markers. Lancet 337:7-11. 1991 9 Frilling A, Hoppner screening in fannlies with Med 73:229-233. 1995
Y. et al: Presymptomatic type 2A with linked DNA
W, Eng C, et al: Presymptomatic genetic multiple endocrme neoplasia type 2. J Mol
10. Wells SA, Cht DD, Toshima K, et al: Predictive DNA prophylactic thyroidectomy in patients at risk for multiple neoplasia type 2A. Ann Surg 220:237.1994 11. Rakover Y, Dharan M. Luboshitsky associated with isolated familial medullary Pediatr Endocrinol7:373-377.1994
testing and endocrine
R: Hirschspnmg’s disease carcinoma of the thyroid. J
Thyroidectomy for Medullary Thyroid in Gene Carriers of MEN2 Syndrome D. St-Vii,
M. Giroux,
C. Huot, L. Gaboury, Montreal, Quebec
Be&ground/Purpose: Although medullary thyroid carcinoma (MTC) can occur sporadically, in the pediatric population it is most often associated with the multiple endocrine neoplasia syndrome (MEN type 2). Traditional screening was based on evaluation of basal and stimulated serum calcitonin levels. The recent cloning of the MEN2 gene on the I?.ET proto-oncogene of chromosome 10 now allows for testing of gene carrier status in individuals at risk who could benefit from prophylactic treatment. The current study was undertaken to determine the appropriate age for safe total prophylactic thyroidectomy. /LJetbods: Over a 16-year period, 12 patients with a family history of MEN2A and one with a MEN2B underwent total thyroidectomy and central neck dissection without parathyroid autotransplantation. Four patients (31%) were treated previously for Hirschsprung’s disease. Results: In seven patients (mean age, 11.8 years) undergoing biochemical screening for diagnosis, multifocal MTC and C cell hyperplasia (CCH) were found in all the resected speci-
A
LTHOUGH THYROID CANCER is rare in children in the United States (375 cases per year),le3 medullary thyroid carcinoma (MTC) accounts for up to 10% of all thyroid malignancies. These tumors can occur sporadically or in familial forms with an autosomal dominant pattern of inheritance with age-related penetrance. The sporadic form of MTC occurs with equal frequency in different parts of the world and little is known about its etiology and pathogenesis. MTC of the familial type can present in association with adrenal medullary and parathyroid proliferative abnormalities (MEN2A) or mucosal and ocular neuromas, pheochromocytoma, and marfanoid habitus (MENZB). In rare instances, familial MTC may occur without other associated endocrine abnormalities.
From the Divisions of Pedratric General Surgev, Pathology, and Endocrinology, HLipital Sainte-Justine, Montreal, Quebec, Carlada. Presented at the 29th Annual Mee&g of the Canadian Assouation of Pae&atric Surgeons, Banj$ Alberta, Canada1 October 3-6, 1997. Address reprint requests to Dickens St-W, MD, H6pital SainteJustine, 3175 Ste. Catherine Rd, Montreal, Quebec, Canada H3T lC5. Copyright 0 1998 by WB. Saunders Company 0022-3468/98/3306-0009$03.00/O
846
L. Oligny,
Carcinoma
and J.G. Desjardins
mens. Of six patients identified with genetic screening (mean age, 9.1 years), two had elevated stimulated calcitonin levels, one (age 14) had evidence of MTC, and one (age 6) had CCH. Four patients with normal calcitonin levels had no evidence of MTC (ages 6, 8, IO) but there was one occurence of CCH (age 1 I). No permanent postoperative hypoparathyroidism or recurrent laryngeal nerve damage occurred in this series. With a mean follow-up of 4 years (range, 1 to 14 years), the overall disease-free survival is 100%. Conc/usiofls~ From this study the authors conclude that total thyroidectomy can be performed safely in children and should be the treatment of choice in patients with a family history of MEN2A carrying a germinal KTmutation even if the serum basal or stimulated serum calcitonin level is normal. Total thyroidectomy should be performed as early as 5 years of age before the occurence of CCH or MTC. J Pediatr Surg 33:846-848. Copyright 0 1998 by W.B. Saunders Company. INDEX WORDS: MEN2, medullarythyroid lactic thyroidectomy, genetic screening.
carcinoma,
prophy-
Traditional screening for MTC was based on the demonstration of increased basal and stimulated serum calcitonin levels, but recent cytogenetic studies have mapped the gene for MEN2 syndrome to a locus nea.r the centromere of chromosome 10, the K!ZTproto-oncogene.4 Demonstration of specsc mutations in families with MEN2 by direct DNA analysis now permits identification of gene carrier status in individuals at high risk for the development MTC who could benefit from prophylactic thyroidectomy. To evaluate the appropriate age for prophylactic thyroidectomy in asymptomatic gene carriers, we reviewed our experience with MTC over the past 16 years.
MATERIALS
AND
METHODS
The medical records of patients with a family history of MEN type 2 who underwent total thyroidectomy between 1981 and 1997 at Hbpital Sainte-Justme were reviewed retrospectively. Thiieen patients, five boys and eight girls with a mean age of 10.6 years fulfilled the criteria for inclusion in this study. These patients underwent follow-up with annual measurement of the basal and stimulated (after intravenous injection of 0.5 pg/kg pentagastrin [Peptavlon, Wyeth-Ayerst Lab; Philadelpka, PA]) serum calcitonin levels using commercially avalable radimmmunoassays. Relatives of patients with MEN2 have been screened for RET mutation through direct gene sequencing since 1995. As previously described: DNA was extracted from peripheral blood Jo~~rna/ of fediafric
Surgery,
Vol33,
No 6 (June),
1998: pp 846-848
PROPHYLACTIC
THYROIDECTOMY
847
FOR MTC
lymphocytes, amplified with polymerase chrnn reaction (PCR) and probed for the genetic mutation. Total thyroidectomy and central neck chssection were the standard operation performed when serum calcitonin was elevated. Recently, the surgery has been performed as soon as an Individual at risk was found to be a gene carrier. The parathyroid glands were identified and left in situ. Before surgev, urine collections for quantification of catecholemines, abdominal ultrasonography, computed tomography and an 13’1 Meta Iodo Benzyl Guamdine (MIBG, Malhngckrodt, Pointe-Claire. Quebec) scintigraphy were performed searching for an asymptomatic adrenal mass, Postoperatively, patients underwent follow-up with chnical examinations, annual serum calcitomn levels and repeat urine collections. Specimens were sent fresh for patholo~lcal examination. Paraffinembedded sections of thyroid tissue were stained with HPS (hematoxylinphloxine-saffron) and examined histologically. Immunohistochemcal staining directed against calcitonin and Congo-red staining to highlight stromal amyloid were performed when necessary.
RESULTS
Twelve patients with MEN2A and one with MEN2B underwent total thyroidectomy. None had a previous history of parathyroid abnormalities or hypertension; no adrenal mass was found on abdominal ultrasonography, computed tomography or 1311MIBG. Four patients (3 1%) including two sisters, had previously been treated for Hirschsprung’s disease. In seven cases found before 1995, MTC was suspected because of elevated basal or stimulated serum calcitonin level. The mean age of this group was 11.8 years (range, 1.5 to 16 years, median, 14 years). The mean hospital stay was 4.9 days (range, 3 to 7 days). Histological examination findings of the resected specimen showed multicentric medullary carcinoma with areas of C cell hyperplasia (CCH), and no metastatic lesions were noted in excised lymph nodes (Table 1). With a mean follow-up of 7 years (range, 3 to 14 years; median, 5 years) survival is 100%. One patient presented 5 years after total thyroidectomy with a cervical mass and Table 1. Outcome
and Histological Findings in Patients Biochemical Screening Results Elevated calcmnln Lk?Vf?l
PatK?nt NO.
SW
1
F
14
+
MTC
2
M
IO
+
3
F
15
+
MTC + CCH, bilobar MTC + CCH,
+
superior pole MTC + CCH,
+
multifocal MTC + CCH,
Aw b/d
Pathological Findings
+ CCH,
With
Positive
Follow-Up Without Recurrence (yr)
3
bilobar
4* 5
Fl5 F
15
multifocal
6*
F
7t
M
*Patient tPatient
with with
12 1.5 Hirschsprung’s MENZB.
+ +
MTC + CCH, bilobar MTC, right lobe disease.
8 5 4 Recurrence 5 years postoperatively 5 2 14
Table 2. Outcome
and Histological Findings Genetic Screening
of Patients
Identified
Follow-Up WIthout RWXlW3lCE! WI
Patk?nt NO
sex
Age Cyr)
Elevated Calcmnin Lk?V-Sl
1
M
14
+
2*
F
6
Normal
C 620
Normal
1
3
F
4 5*
F M
8 10
Normal Normal
C 620 C 620
Normal Normal
1 1
6
M
11 6
Normal +
C 620 C 620
CCH CCH
1 I
*Hirschsprung’s
Pathologml Fmdings
by
Genetm Mutation
C 634
MTC + CCH, multifocal
2
disease,
required reexploration. Histological examination findings showed recurrent MTC; she is tumor free 5 years later. Six patients had total thyroidectomy after genetic screening demonstrated a germinal RET mutation. The mutation was on codon 620 for five patients (83%) and on codon 634 for the other one (17%). The mean age was 9.1 years (range, 6 to 14 years; median, 8 years). Calcitonin levels (basal and stimulated) were normal in four patients and elevated in two (ages 6 and 14 years). Pathological examination findings showed a multicentric MTC and CCH in the 14-year-old patient, and the other had evidence of multifocal C cell hyperplasia. Of the four patients with normal calcitonin level, there was no MTC found, but one 11-year-old patient had multifocal CCH (Table 2). The mean hospital stay was 2.5 days (range 2-3 days). With a mean follow-up of 10 months (range, 6 to 18 months) all patients are well and free of tumor. Total thyroidectomy and central neck dissection were easy to perform in these young patients. As much as possible, the parathyroid glands were identified and preserved. Three patients experienced episodes of transient hypocalcemia that improved spontaneously within 3 days, but none had permanent hypocalcemia or recurrent laryngeal nerve damage postoperatively. DISCUSSION
The sporadic form of medullary thyroid carcinoma primarily is a tumor of middle-aged adults who usually present with unilateral involvement of the thyroid with or without associated cervical nodes metastases. In contrast, the mean age at diagnosis of MTC associated with MEN2A and 2B diagnosed by biochemical screening is 20 years and 15 years, respectively with a slightly higher incidence in women (l.3:l).s Our results are similar to those of previous reports, with MTC associated with MEN2 syndrome and type 2B occuring at younger age (1.5 years v 13 years) and being more aggressive. In most large series, the 5-year survival rate is 60% to 70% with significant correlation with age, sex, and stage of the disease. Patients less than 40 years of age and women have a better prognosis.5 Previously, screening for famil-
848
LALLIER
ial MTC was done by detecting an elevation in the basal or pentagastrin-stimulated serum calcitonin level. Although highly sensitive, biochemical screening had limitations because of the side effects of pentagastin injection, annual testing required of all family members, and extent of the disease at diagnosis, with patients having already invasive MTC and lymph node metastases.6 In 1987, Simpson et al7 and Mathew et al8 reported on the genetic mapping for MEN2A to the region of chromosome 10 and opened the way for genetic screening. The MEN2 gene has been identified as the RET protooncogene coding for a tyrosine kinase receptor with a cysteine-rich region. It is likely involved in the development and differentiation of tissues originating from the neural crest such as neuroblastomas, MTC, and pheochromocytomas. In MEN2A, point mutations affect one of five cysteine residues in codons 609, 611, 618, 620, and 634 leading to the replacement of cysteine by arginine, tyrosine, or phenylalanine. In MEN2B the point mutation occurs in codon 9 1S.9 In the current study, all patients with biochemical screening had evidence of diffuse MTC and CCH. Although all lymph nodes were negative for metastases, one patient had recurrence of tumor in the cervical area suggestive of advanced disease at the time of surgery. Patients with genetic screening were younger (9.1 years v 11.8 years) than those who had undergone provocation testing, and most had a normal basal or stimulated calcitonin level. The 14-year-old boy was known to have an elevated calcitonin level, but identification of the gene carrier status finally convinced his family that surgery was mandatory. This was the only case of MTC in this group. All patients with normal calcitonin
ET AL
levels had no evidence of MTC, but one had CCH found on histological examination confirming the occurence of CCH, a precursor of MTC before the onset of elevated calcitonin levels. Total thyroidectomy and central neck dissection is the treatment of choice for proven MTC. The management of the parathyroid gland remained controversial.1,6 Although some investigatorslo suggested total parathyroidectomy with heterotopic autotransplantation, parathyroid anomalies will eventually develop in only 10% to 20% of individuals with MEN2A. Individuals with the point mutation on codon 634 are at higher risk (30%).r” Thus, we do not recommend total parathyroidectomy for all patients. The dual occurence of MTC and Hirschsprung’s disease is also underlined in this study. This association can be explained by a common origin of both cell types (C cells of the thyroid and intestinal enterochromaffin cells) from the neural crest.n Because the gene for familial Hirschsprung’s disease has been mapped to chromosome 10,rz a point mutation in the RET protooncogene region could explain the occurence of both diseases. Familial Hirschsprung’s disease thus could be an early manifestation of MEN2 syndrome, and a high index of suspicion is needed. Genetic screening is highly sensitive and helps to identify children at risk of the development of MTC because penetrance of MTC in MEN2 is essentially lOO%.2Prophylactic thyroidectomy should be performed as early as 5 years of age for children with a point mutation. Total parathyroidectomy with autotransplantation of parathyroid tissue and central neck dissection are not necessary.
REFERENCES 1, Decker R.4, Geiger JD, Cox CE, et al: Prophylactic surgery for multiple endocrine neoplasia type IIa after genetic diagnosis: Is parathyroid transplantation indicated? World J Surg 20:814-821, 1996 2. G’Riordain DS, O’Brien T, Weaver AL: Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surg 116:1017-1023,1994 3. Geiger JD, Thompson NW Thyroid tumors in children. Otolaryngo1 Clin North Am 29:711-719. 1996 4. Shimotake T, Iwai N, Inoue K, et al: Germline mutations of the RETproto-oncogene in pedigree with MEN type 2A: DNA analysis and its imphcations for pediatric surgery. J Pediatr Surg 31:779-781, 1996 5. Rosai J, Carcangiu ML, DeLelhs RA: Tumors of the thyroid gland, in Rosat. Sobin teds): Atlas of Tumor Pathology. Armed Forces Institute of Pathology. Washington, DC. 1992. pp 207-240 6. Skinner MA, DeBenedetti MK, Moley JF, et al: Medullary thyroid carcinoma m chrldren with multiple endocrine neoplasia types 2A and 2B. J PediatrSurg31:177-182,1996
7. Simpson NE. Kidd KK. Goodfellow PJ. et al: Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 328:S28-530, 1987 8. Mathew CGP. Easton DF, Nakamura screening for multiple endocrine neoplasta markers. Lancet 337:7-11. 1991 9 Frilling A, Hoppner screening in fannlies with Med 73:229-233. 1995
Y. et al: Presymptomatic type 2A with linked DNA
W, Eng C, et al: Presymptomatic genetic multiple endocrme neoplasia type 2. J Mol
10. Wells SA, Cht DD, Toshima K, et al: Predictive DNA prophylactic thyroidectomy in patients at risk for multiple neoplasia type 2A. Ann Surg 220:237.1994 11. Rakover Y, Dharan M. Luboshitsky associated with isolated familial medullary Pediatr Endocrinol7:373-377.1994
testing and endocrine
R: Hirschspnmg’s disease carcinoma of the thyroid. J