Prophylactic Thyroidectomy in 75 Children and Adolescents with Hereditary Medullary Thyroid Carcinoma: German and Austrian Experience

RET proto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i.e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age ≤ 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0–1/pNX/pN0–1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.     

Unilateral Surgery Supported by Germline RET Oncogene Mutation Analysis in Patients with Sporadic Medullary Thyroid Carcinoma

Compared to hereditary medullary thyroid carcinoma (MTC), sporadic MTC tends to be unicentric and confined to one lobe. Patients with sporadic MTC usually undergo total thyroidectomy because of a possible hereditary or bilateral process. We evaluated the usefulness of germline RET oncogene mutation analysis in surgery for apparently sporadic MTC and performed unilateral surgery on patients without detectable mutation. In 36 patients with a preoperative diagnosis of apparently sporadic MTC, we performed germline RET oncogene mutation analyses: before surgery in 8 recent patients and after surgery in 28 who had been treated before 1996. Of the latter, 5 had bilateral MTC. DNA samples were extracted from their peripheral blood, and the polymerase chain reaction products of the RET proto-oncogene were analyzed using single-strand conformation polymorphism analysis and the direct sequencing methods. Before 1996 we often performed total thyroidectomy but changed to hemithyroidectomy thereafter, except in one patient with associated Graves' ophthalmopathy. Our minimal standard practice included systematic central and ipsilateral neck dissection. The outcome was assessed in terms of gastrin- and calcium-stimulated plasma calcitonin levels. Germline RET mutations were found in six patients. Five of these patients had bilateral MTC, whereas all 30 patients without mutation had unilateral disease. Hemithyroidectomy in seven of our recent patients resulted in normalization of plasma calcitonin levels in all, although four were found to have microscopic lymph node involvement. In conclusion, hemithyroidectomy with systematic central and ipsilateral neck dissection is an appropriate procedure for patients with sporadic MTC without detectable germline RET mutations.     

Surgical Strategy in a Kindred with a Rare RET Protooncogene Mutation of Variable Penetrance with Regard to Multiple Endocrine Neoplasia

Prophylactic thyroidectomy is recommended for carriers of RET protooncogene mutations owing to their nearly complete penetrance for medullary thyroid carcinoma (MTC). However, this guideline is challenged by mutations exhibiting variable penetrance of C-cell pathology. A 38-year-old woman presented with pathologic basal and pentagastrin-stimulated calcitonin levels. Genetic analysis revealed a heterozygous RET protooncogene germline mutation in codon 791 (exon 13) (TAT(Tyr)-->TTT(Phe)), followed by thyroidectomy and systematic central lymph node dissection. Histology showed C-cell hyperplasia (CCH) only. Three additional carriers were identified among family members. The 71-year-old father refused surgery despite pathologic calcitonin levels. The index patient's 37-year-old sister had normal basal and stimulated calcitonin levels, and her 6-year-old son had a 10-fold rise of calcitonin after pentagastrin stimulation. Both patients underwent the same operation as the index patient. The sister had 25 hyperplastic C-cells, but the her son had extensive CCH without MTC. The eldest uncle of the index patient had died of metastatic MTC at the age of 52 with unknown carrier status. Despite variable penetrance, each carrier of a RET protooncogene germline mutation should undergo thyroidectomy, even if basal and stimulated calcitonin levels are normal because at present no test can exclude or predict the age of development of MTC. Moreover, pathologic calcitonin levels cannot differentiate between CCH and MTC. Central lymph node dissection is recommended, as lymph node metastases occur early, significantly worsening the prognosis.     

Prognostic Significance of Disseminated Tumor Cells in the Connective Tissue of Patients with Medullary Thyroid Carcinoma

Introduction Disseminated tumor cells in the connective tissue (CT-DTCs) do not have any connection to a primary tumor or the lymph nodes. They are identified quite often in patients with medullary thyroid carcinoma (MTC), but nothing is known regarding their prognostic significance. Methods Among 450 patients with MTC, 69 (15%) were identified as having CT-DTCs. A case-control group of patients without CT-DTCs was selected. The two groups were matched concerning TNM classification, age, heredity, and sex. Because many patients with CT-DTCs had extrathyroidal tumor extension (pT4 category), distant metastases (M1 category), or both, only 35 matched pairs could be identified. The TNM classification in both groups was as follows: pT1, n = 8; pT2, n = 15; pT3, n = 4; pT4, n = 8; pN0, n = 4; pN1, n = 31; M0, n = 30; M1, n = 5. The mean age was 46.8 ± 17.0 years in the CT-DTC group and 44.4 ± 15.0 years in the case-control group (NS). Results In both groups, 23 patients had sporadic MTC, and 12 patients had hereditary MTC. Neither mean basal preoperative nor postoperative calcitonin levels differed significantly between the two groups. In contrast, none of the patients with CT-DTCs was biochemically cured (normal calcitonin level after pentagastrin stimulation) compared to eight patients without CT-DTCs (P < 0.005). The two groups did not differ concerning other parameters (basal calcitonin level >3000 pg/ml, more than 10 lymph node metastases, more than two involved locoregional lymph node compartments, mediastinal lymph node metastases) that have been reported to correlate with the lack of or almost (<10%) lack of biochemical cure. Conclusions In patients with MTC, disseminated tumor cells in the connective tissue correlate with advanced tumor stages and appear to be of prognostic significance.     

Single Center Experience in Primary Surgery for Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare disease, and most studies are either based on small numbers or multicenter studies with their inherent difficulties. Since 1995, a total of 440 patients with MTC underwent surgery in our clinic. A primary operation was performed in 188 patients (43% of 440). In 60 patients, the primary operation was performed because of a germline RET mutation (prophylactic surgery). Most (84%, 158/188) of the patients had pathologic calcitonin levels. Notably, MTC was found in almost 10% (3/30) of patients with normal calcitonin levels. However, all patients with lymph node metastases (LNMs) had elevated calcitonin levels. Total thyroidectomy (TTx) was performed in all patients. Lymph node dissection (LND) was performed at various extensions: one-compartment LND in 35% (66/188), three-compartment LND in 31% (58/188), and four-compartment LND in 29% (22/188). In general, lymph node dissection increased the likelihood of complications. LNM and distant metastases (DM) correlated with the extent of the primary tumor (pT category). The presence of LNM ranged from 17% (pT1 tumor) to 100% (pT4 tumor), whereas the presence of DM ranged from 0% (pT1 tumor) to 81% (pT4 tumor). Biochemical cure (normal calcitonin levels) was obtained in 72% (137/188) of patients. All 60 patients undergoing prophylactic surgery (tumor stage pT0/pT1) were biochemically cured. In contrast, only 60% (77/128) of the remaining patients were cured. The data suggest that primary surgery should be scheduled as soon as possible to treat patients at a node-negative stage. In the case of normal basal and elevated stimulated calcitonin levels, TTx and cervicocentral LND is recommended. If the basal calcitonin level is elevated, LND should include the cervicolateral compartment.This article was presented at the International Association of Endocrine Surgeons meeting, Uppsala, Sweden, June 14–17, 2004.     

C-cell cancer – prevention and treatment

Introduction: C-cell cancer of the thyroid or medullary thyroid carcinoma (MTC) exists in a sporadic and a hereditary form, the latter of which is part of the multiple endocrine neoplasia type-2 (MEN-2) syndromes. Discussion: MTC metastasises early to local (lymph nodes) and distant sites (liver, lung, bone). Therefore, early detection is mandatory to enable a chance of cure. In sporadic MTC, the sensitive tumour marker calcitonin enables detection of the disease at an early stage. In hereditary MTC, more than 95% of the patients have germline RET mutations. Thus, MEN-2 has become the paradigm for the practice of molecular medicine, and gene carriers can be identified before MTC even occurs. Surgery is the only chance of cure and recently developed surgical techniques provide the therapeutic prerequisite to achieve calcitonin normalisation in both sporadic and hereditary MTC. Received: 19 November 1998 Accepted: 25 November 1998     

Timing and Extent of Surgery in Patients with Familial Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia 2A-related <Emphasis Type="Italic">RET</Emphasis> Mutations Not Affecting Codon 634

In hereditary medullary thyroid carcinoma (MTC), recommendations regarding timing and extent of surgery are mainly based on the data of patients with the codon 634 RET mutation, which is the most often affected codon. Little is known about whether these recommendations may also be applied to patients with less common RET mutations. We ascertained the data from 140 patients with FMTC/MEN2A-related RET mutation not affecting codon 634 who have been treated at three specialized centers. The several RET mutations found affected codons 611 (n = 17), 618 (n = 22), 620 (n = 17), 768 (n = 9), 790 (n = 24), 791 (n = 21), 804 (n = 23), and 891 (n = 7). For each codon, the age of the youngest patient with MTC only (41, 7, 18, 29, 13, 47, 20, and 15 years, respectively), MTC with lymph node metastases (46, 24, 21, 34, 46, 47, 50, and 76 years, respectively), and MTC with distant metastases (52, 69, 43, 68, 57, - , - , and 75 years, respectively) was determined. All patients with lymph node metastases had elevated basal calcitonin levels. Based on these data, a more individual recommendation regarding timing and extent of surgery can be given. Because neither gender nor the type of nucleotide substitution for a specific codon appeared to have a significant influence on the age of onset, this recommendation should be based on the affected codon, the age of the patient, and the calcitonin level. Recurrent laryngeal nerve palsy (n = 6) and hypoparathyroidism (n = 3) were rather rare and were found only in patients older than 30 and 43 years, respectively, giving evidence that surgery in young patients can be performed safely.This article was presented at the International Association of Endocrine Surgeons meeting, Uppsala, Sweden, June 14-17, 2004.     

When Is Prophylactic Thyroidectomy Indicated for Patients with the RET Codon 609 Mutation?

Background  Mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2A (MEN2A), and prophylactic thyroidectomy has generally been recommended before the age of 5 years. Patients with codon 609 mutations develop MTC at a later age and therefore the timing of prophylactic thyroidectomy is less clear. We report a three-generation family with C609Y RET mutation where members having prophylactic or therapeutic thyroidectomy call the current recommendations for age at thyroidectomy into question. Methods  Sixteen family members underwent thyroidectomy, for which clinical, laboratory, and pathological data were analyzed. A literature review of RET codon 609 mutations was carried out. Results  Data were collected from 16 patients from this 38-member kindred. None of these affected members had pheochromocytoma, and one had a parathyroid adenoma. Nine of 16 patients had MTC (mean age 44.7 years, range 29–59 years) and elevated basal calcitonin levels; 6 of these 9 had lymph node metastases. Two patients had C-cell hyperplasia (CCH) at ages 18 and 37 years, and five patients had normal thyroid pathology (mean age 16 years, range 5–37 years). In the literature, a family with C609Y mutation was reported, with 15 members having MTC (mean age 42 years, range 21–59 years), and 6 with CCH (mean age 24 years, range 15–37 years). Conclusion  The youngest patient with C609Y RET mutation and MTC was 21 years old, and the youngest patient with CCH was 15 years old at diagnosis. These data suggest that patients with RET C609Y mutations can delay thyroidectomy until 10–15 years of age, with annual calcitonin screening prior to thyroidectomy.     

Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas.

BACKGROUND: This study evaluated the outcome of total thyroidectomy and modified radical neck dissection in primary treatment of patients with medullary thyroid carcinoma (MTC). METHODS: Thirty-six patients with sporadic (n = 16) and hereditary (n = 20) MTC underwent thyroidectomy and systematic central and lateral lymph node dissection (unilateral, 23; bilateral, 13) between 1994 and 2000. Postoperative serum calcitonin levels were correlated with immediate or delayed surgery, tumor categories, and lymph node metastases. RESULTS: Sixteen of 36 (44%) patients with clinically evident MTC treated with central and lateral neck dissection exhibited normal basal and stimulated calcitonin levels at a median follow-up of 3.7 years. Lymph node involvement was detected in 75% of these patients and correlated with the TNM stages. Biochemical cure was achieved according to the T categories in 83% of the patients in stage T1, 42% in stage T2, and none of the patients in stage T4 (P = .011). Basal and stimulated calcitonin levels were found to be normal in 89% of the patients without lymph node involvement and in 30% of the patients with lymph node metastases (P = .005). CONCLUSIONS: Screening for MTC and primary treatment with total thyroidectomy and modified radical neck dissection are essential for biochemical cure of MTC.     

Emergence of medullary thyroid carcinoma in a family with the Cys630Arg RET germline mutation

BACKGROUND: Individual germline mutations in the RET (REarranged during Transfection) proto-oncogene may set the time window for malignant progression from C-cell hyperplasia to familial medullary thyroid carcinoma. Owing to the close genotype-phenotype correlation, genetic information may lend to individual timing of prophylactic thyroidectomy according to RET genotype. Limited information exists on the Cys630 RET genotype. Most of the few published carriers of this genotype who developed medullary thyroid carcinomas (MTCs) were in their mid-30s. METHODS: This case series of a German RET family with the Cys630Arg genotype was assembled to study malignant progression of MTC in this rare RET genotype. RESULTS: There was considerable variability of malignant progression from C-cell hyperplasia to MTC in carriers of the Cys630Arg genotype. In these persons, MTCs had developed by the age of 32 years (index patient, pT2bN0M0), and 15 years and 1 year (non-index patients; pT1apN1bM0 and pT1bpN0M0, respectively). The Cys630Arg genotype always segregated with the familial medullary thyroid carcinoma phenotype. CONCLUSIONS: The Cys630 RET genotype may have a more vigorous transforming activity than currently thought and can cause MTC in RET gene carriers within the first year of life. Starting in early infancy, identified RET gene carriers should be scrutinized until stimulated serum calcitonin levels become positive or, when these remain normal, should undergo prophylactic thyroidectomy before they reach 5 years of age.     

Alternative Surgical Strategies and Favorable Outcomes in Patients with Medullary Thyroid Carcinoma in Japan: Experience of a Single Institution

Background  Medullary thyroid carcinoma (MTC) accounts only for 1.4% of all thyroid malignancies in Japan. Since 1996, we have performed hemithyroidectomy, instead of total thyroidectomy, for sporadic nonhereditary MTC when the primary lesion is located in only one lobe. Regarding lymph node dissection, modified radical neck dissection (MND) at least ipsilateral to the tumor has been routinely performed, even if there is no clinically apparent metastasis. We investigated the clinical outcomes of MTC patients in our department. Methods  A series of 118 patients with MTC who underwent initial surgery between 1975 and 2005 were enrolled in this study. The RET gene mutations were analyzed for all patients and 46 had germline RET gene mutations. Of those 46 patients, 26 were diagnosed as MEN 2A and 2 were diagnosed as MEN 2B. Postoperative follow-up periods averaged 141 months. Results  Of 115 patients who did not have distant metastasis at surgery and who underwent locally curative surgery, 78 (67.8%) were biochemically cured. All patients without pathological lymph node metastasis were biochemically cured, and 44.8% of patients with node metastasis were also biochemically cured. The 10-year and 20-year disease-free survival rates were 89.0% and 82.5%, respectively. None of the patients who did not show lymph node metastasis and only 2 (2.6%) of 78 patients who were biochemically cured showed clinically apparent carcinoma recurrence. The 10-year and 20-year cause-specific survival rates were 96.6% and 91.7%, respectively. Lymph node metastasis, tumor size >4 cm, extrathyroid and extranodal tumor extensions significantly affected cause-specific survival of patients. Conclusions  Clinical outcomes of MTC patients in our series were better than those in Western countries, a result that might have resulted in part because of our routine MND regardless of whether clinically apparent node metastasis was detected.     

Medullary Thyroid Carcinoma: Long-Term Outcomes of Surgical Treatment

Background

Medullary thyroid carcinoma (MTC) accounts for 5 to 10% of all thyroid cancers but is responsible for a disproportionate number of deaths.

Methods

We performed a retrospective review to describe clinical outcomes in patients with medullary thyroid carcinoma, screening a subset of patients for somatic mutations in the RET and p18 genes and performing genotype-phenotype correlation in a tertiary-care referral hospital from 1967 to 2009.

Results

We studied a total of 94 patients identified from a prospectively maintained thyroid cancer database. Data gathered included patient demographics, serum calcitonin, clinical outcomes, histopathology, genetic analysis, and status at final follow-up. A subset cohort (n = 50) was screened for somatic mutations in the RET gene and the three exons of the p18 gene. The subset cohort was composed of hereditary medullary thyroid carcinoma (HMTC) (n = 19, index patients = 10, screen detected = 9) and sporadic medullary thyroid carcinoma (SMTC) (n = 31). There were no mutations in the p18 gene in the subset cohort.

Conclusions

A total of 67 SMTC and 27 (28.7%) HMTC cases identified. SMTC were older at initial presentation (52 vs. 34, P = 0.003), had higher preoperative serum calcitonin levels (7968 vs. 1346 ng/L, P = 0.008), and had lymph node recurrence (P = 0.001) compared to HMTC. The tumors were smaller in HMTC (P = 0.038). Overall 10-year survival in SMTC versus HMTC was 69 versus 93% (P = 0.12). On multivariate analysis, vascular invasion (hazard ratio 6.4, P = 0.019) was an adverse predictor for disease-free survival. HMTC in the era of RET analysis presents with a smaller primary tumor, lower preoperative serum calcitonin levels, and lower rates of lymph node metastasis. Mutations in the p18 gene were not a major factor in medullary thyroid carcinoma tumorigenesis.     

Early thyroidectomy for medullary thyroid carcinoma in children and young adults with the multiple endocrine neoplasia type 2A (MEN 2A) syndrome.

A South African family, at risk for the multiple endocrine neoplasia type 2A (MEN 2A) syndrome, was identified. The Bloemfontein MEN Study Group was founded, inter alia, to study the effects of early detection of medullary carcinoma of the thyroid (MTC) and treatment by total thyroidectomy in children and young adults with MEN 2A. Genotypes were identified by DNA probe and MTC diagnosed by basal and stimulated calcitonin levels. Between 1986 and 1989, 10 members of the family underwent total thyroidectomy and central lymph node dissection for MTC. There were 6 female and 4 male patients (mean age 22,0 years; range 10 - 35 years). Histological examination of the resected thyroid revealed MTC in all patients; 8 had bilateral disease and 2 unilateral. Lymph nodes were negative for MTC in all patients. None of the patients suffered injury to the recurrent nerve, while 1 experienced transient hypoparathyroidism postoperatively. Replacement therapy is maintaining thyroid hormone levels in all patients. Screening should probably begin at the age of 1 year, and total thyroidectomy should be performed when an elevated calcitonin level is observed.     

Kalzitoninbestimmung zur Frühdiagnose des medullären Schilddrüsenkarzinoms

Calcitonin is considered to be a sensitive marker for medullary thyroid cancer (MTC) therefore early detection and surgical treatment may help to improve the clinical prognosis of MTC. Routine calcitonin measurement has therefore been recommended in the diagnostic evaluation of patients with nodular thyroid disease. In the case of elevated serum calcitonin (>20 pg/ml) stimulation testing is recommended to improve the predictive power for MTC particularly in patients with small nodules. Serum calcitonin measurement cannot reliably discriminate between micro-MTC (<10 mm) and C cell hyperplasia. In patients with stimulated calcitonin levels exceeding 100 pg/ml thyroidectomy is recommended because of a high inherent risk of MTC. Highly elevated basal and stimulated serum calcitonin levels are strongly suggestive of MTC with practical implications for surgical management.     

Prospective trial of unilateral surgery for nonhereditary medullary thyroid carcinoma in patients without germline RET mutations

Although sporadic medullary thyroid carcinoma (MTC) tends to be unicentric and confined to one lobe, total thyroidectomy is usually performed because of the risk of a hereditary or bilateral process. Germline RET mutation analysis can discriminate hereditary MTC and truly sporadic, nonhereditary MTC. We analyzed 72 of 94 patients with MTC to establish the genetic nature and the clinical features of nonhereditary MTC. Since 1996 we have prospectively treated 15 patients with nonhereditary MTC (prospective study group, or PSG) according to a unilateral surgery policy. A group of 22 previously operated patients in whom the nonhereditary nature was established served as controls (retrospective study group, or RSG). Systematic central and ipsilateral neck dissection was performed in both groups. Outcome was assessed using postoperative stimulated serum calcitonin levels; a normal value was considered a biochemical cure. All 24 hereditary MTC patients carried germline RET mutations: 8 of 48 patients with apparently sporadic MTC had the mutations, and 6 of the 8 had bilateral MTC. All 40 patients without mutations had a unilateral tumor. In the RSG group 15 of 22 (68%) patients underwent total thyroidectomy, and the biochemical cure rate was 68%. Although only 3 of 15 (20%) of the PSG patients underwent total thyroidectomy, 12 of the 15 (80%) achieved biochemical cure. Univariate analyses revealed that pathologic node involvement- high T and N stages-was adversely related to biochemical cure. The extent of thyroid resection was not related to biochemical cure. Of 20 patients with node involvement, 10 achieved biochemical cure, indicating the importance of systematic neck dissection. Hemithyroidectomy with systematic central and ipsilateral neck dissection is appropriate surgery for nonhereditary MTC.     

Appraisal of surgical resection of gallbladder cancer with special reference to lymph node dissection

BACKGROUND: Radical lymph node dissection in surgery for advanced gallbladder cancer is controversial. The purpose of this study is to evaluate the role of lymph node dissection based on the clinico-pathologic results. PATIENTS: Seventy-three patients who underwent radical surgery including systematic dissection of the N1+N2 region lymph node plus some of the para-aortic nodes were reviewed. RESULTS: pT1 patients had no lymph node metastasis, but pT2 and pT3/pT4 patients had lymph node metastasis at a rate of 50.0% (13/26) and 83.3% (25/30), respectively. As infiltration of the hepatoduodenal ligament (Binf) became severe, the rate and extent of lymph node metastasis increased. There were four 5-year survivors with lymph node involvement. The 5-year survival rates are 77.0% in pN0 cases and 27.3% in pN1 cases (P<0.01). There was no difference in survival between pN1 and pN2 patients. However, significant differences in survival were observed between pN0/1 and pN2/3 patients when these patients were limited to Binf0/1. Examination of the recurrence pattern showed that most patients with pN0/1/2 had no regional lymph node recurrence, but there was para-aortic lymph node recurrence in patients with pN3 outside the dissected region. Significant prognostic factors influencing survival after surgery by multivariate analysis were pN2/3, pT, and residual tumor. CONCLUSION: Systematic lymph node dissection of N1, N2, and part of the para-aortic region improves survival in advanced gallbladder cancer patients, especially in those without either para-aortic lymph node metastases or Binf2/3.     

Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma

Lymph node metastases have been proven to be the main prognostic factor in medullary thyroid carcinoma (MTC). This retrospective study was undertaken to evaluate the efficiency of two surgical techniques of regional lymph node dissection with regard to the normalization of pentagastrin-stimulated serum calcitonin level and patient survival: selective lymphadenectomy, i.e., the excision of macroscopically or microscopically involved lymph nodes, versus a systematic lymphadenectomy performed by the new technique of a compartment-oriented microdissection. From 1970 to 1990, 82 patients with sporadic (n=57) and hereditary (n=25) MTC underwent a total of 142 operations including 63 selective lymphadenectomies and, since 1986, 35 systematic lymphadenectomies. The study revealed that in node-positive MTC the rate of interventions with a postoperative normalization of pentagastrin-stimulated serum calcitonin was higher after systematic lymphadenectomy (29.2%) than after selective lymphadenectomy (8.5%) (P<0.01). The rate of patients undergoing repeat surgery due to a recurrence of MTC was 48% after selective lymphadenectomy and 10% after systematic lymphadenectomy. Survival was significantly better for patients after systematic versus selective lymphadenectomy (P<0.005). This study thus emphasizes that systematic lymphadenectomy, using the technique of a compartment-oriented microdissection of cervicomediastinal lymph nodes, represents the preferred surgical treatment as well as the optimum technique in primary as well as secondary node-positive MTC.     

No correlation between RET immunostaining and the codon 918 mutation in sporadic medullary thyroid carcinoma

Introduction: Medullary thyroid carcinoma (MTC) occurs sporadically or as part of the inherited cancer syndrome, multiple endocrine neoplasia (MEN) type 2. The MEN2 gene has been identified as the RET proto-oncogene. Mutations in the RET proto-oncogene are associated with the pathogenesis of MTC. Approximately 23–40% of sporadic MTCs (sMTCs) have a somatic RET codon 918 mutation within the catalytic core of the tyrosine kinase, which is a mutation found in over 98% of all MEN 2B cases as a germline mutation. Methods: In order to elucidate the role of this mutation, we examined 40 sMTCs for the codon 918 mutation. Simultaneously, we looked for overexpression of the RET protein by means of immunohistochemistry with a newly developed RET antibody. Results: In 8 of 40 tumors (20%), we were able to find a RET codon 918 mutation. Nine of 40 tumors (22.5%) showed immunoreactivity with the RET antibody. Conclusion: The presence of the somatic RET codon 918 mutations did not correlate with the presence of positive RET immunostaining. Received: 29 January 1998 Accepted: 18 July 1998     

Skip metastases in medullary thyroid carcinoma: A single-center experience

PURPOSE: Total thyroidectomy (TT) with level VI and VII central neck dissection is the initial treatment for medullary thyroid carcinoma (MTC) without identifiable neck metastasis. Level II to V lateral neck dissection is performed if neck metastasis is present or suspected. We conducted this study to identify the frequency and clinical determinants of skip neck metastasis in MTC. METHODS: We reviewed the medical records of 32 patients who underwent TT and bilateral neck dissection for MTC. The clinical features were correlated with pN status in the central versus lateral compartments of the neck. RESULTS: Neck lymph node metastasis (pN+) was found in 20 patients (62.5%) and skip metastases were found in 7 (35%) patients. The sensitivity of the pN status of the central compartment of the neck to predict the pN status of the lateral compartment of the neck was 53.8% and specificity was 63.2%. We found pN+ in 90% of the patients with lymph nodes >15 mm in diameter versus 50% in those with lymph nodes <15 mm in diameter. CONCLUSIONS: There is skip metastasis in MTC. It is unsafe to use the lymph node status of the central compartment of the neck to define the pN status of the lateral neck. A lymph node greater than 15 mm in diameter is related to pN status.