Adrenal and extra-adrenal pheochromocytomas in a family with germline RET V804L mutation.
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Adrenal Gland Neoplasms↗
Biomedical subjects
O Gimm
Publications and source records attributed to O Gimm.
Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation.
The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.
Carcinoma, Medullary↗
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.
Carcinoma, Medullary↗
Mutation and deletion analysis of GFR alpha-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours.
Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRalpha-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRalpha-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRalpha-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRalpha-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRalpha-1 and/or nearby genes may contribute to the pathogenesis of these tumours.
Brain Neoplasms↗
Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma.
Normalization of calcitonin levels after surgery has been regarded as the most powerful prognostic factor for medullary thyroid carcinoma (MTC). Although the prognosis of patients with persistent hypercalcitoninemia may be acceptable, the biochemical cure rate can be improved by new microdissection techniques. This raises certain questions: Can extension of locoregional lymphadenectomy (LA) further improve biochemical cure and survival after primary or reoperative MTC surgery? Which factors concerning TNM categories are associated with the possibility of postoperative normalization of calcitonin levels? This study included 64 patients with sporadic MTC operated on from 1986 to 1997. Altogether 27 patients underwent primary surgery, and 37 patients were reoperated, performing a microdissection of all four locoregional compartments (four-compartment lymphadenectomy, or 4CLA). For primary MTC the biochemical cure rate was 100% in node-negative patients and 33% in node-positive patients; the latter could be improved to 45% after 4CLA. In contrast to reoperative MTC, the rate of lymph node metastases (LNMs) with primary MTC correlated with the pT category (pT1 33%, pT2 53%, pT3 100%, pT4 100%) but not with age or sex. Again in contrast to reoperative MTC, mediastinal LNMs in primary MTC were present only in patients with a pT4 tumor. At reoperation, 4CLA was able to cure 22% of node-positive patients, 28% without proved distant metastases. No patient with extrathyroidal tumor involvement or distant metastases was biochemically cured after either primary or reoperative surgery. For all node-positive MTC patients, in addition to cervicocentral LA at least a bilateral cervicolateral LA is recommended. Transsternal mediastinal lymph node dissection is indicated in patients with LNMs in the cervicomediastinal transition, facilitating biochemical cure in up to 45% after the first operation and 22% after reoperative surgery of sporadic MTC.
Adult↗
Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience.
When mutations of the RETproto-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.
Adolescent↗
Primary hereditary medullary thyroid carcinoma--C-cell morphology and correlation with preoperative calcitonin levels.
Early thyroidectomy offers an opportunity of preventing the development of medullary thyroid carcinoma (MTC) in patients at risk for hereditary MTC. We investigated the thyroid glands of 32 patients with hereditary MTC to identify the changes in C-cell morphology and to correlate these with plasma calcitonin (CT) levels and with clinical data. The entire thyroid gland was processed for histological examination including immunostaining for CT. All glands revealed C-cell hyperplasia (CCH), and MTC was found in 21 patients (66% of 32, youngest patient 6 years, youngest with lymph node metastases [LNM] 17 years). The transition from CCH to MTC was characterized by destruction of the follicular basement membrane and by diminished intensity of CT immunostaining. Normal plasma CT levels after provocation with pentagastrin were found only in patients with CCH. Basally elevated plasma CT levels were restricted to MTC. LNM were only found in multifocal tumours at least 4 mm in diameter. It is not yet clear whether or not CCH in patients at risk for hereditary MTC is a neoplastic change, but in these patients the term 'C-cell hyperplasia' is of doubtful value. All MEN gene carriers reveal CCH, and almost all of them will develop multifocal MTC, so that CCH is probably a precursor lesion of an indubitably malignant tumour. Prophylactic thyroidectomy is justified at the age of 6 to anticipate development of a MTC. Lymphadenectomy is necessary in children if they are older than 10 years or have elevated plasma CT levels.
Adolescent↗
Pattern of lymph node metastases in papillary thyroid carcinoma.
BACKGROUND: Incidence and pattern of lymph node metastasis (LNM) were evaluated in 35 patients who underwent primary surgery for papillary thyroid carcinoma. METHODS: Total thyroidectomy with systematic cervicocentral lymphadenectomy was performed routinely. Additionally, 22 patients underwent lymphadenectomy of the ipsilateral cervicolateral compartment. Sternotomy was performed in four patients. RESULTS: Primary tumour status was: pT1, n = 7; pT2, n = 12; pT3, n = 4; pT4, n = 12. Twenty-four patients had LNM in the ipsilateral cervicocentral compartment (pT1, n = 2; pT2, n = 8; pT3, n = 4; pT4, n = 10). Nineteen had LNM in the ipsilateral cervicolateral compartment (pT1, n = 4; pT2, n = 6; pT3, n = 2; pT4, n = 7). Contralateral cervicocentral LNM was restricted to patients with pT3 tumours (n = 2) or pT4 tumours (n = 3). No patient had LNM in the contralateral cervicolateral compartment. Only one patient (pT3 tumour) had mediastinal LNM. CONCLUSION: The cervicocentral compartment was most commonly involved with metastases, although the ipsilateral cervicolateral compartment was almost as often affected. In some patients ipsilateral cervicolateral LNM was present in the absence of cervicocentral LNM. Contralateral cervicolateral and upper mediastinal LNM, however, were rare. This study helps to plan radical surgery for papillary thyroid carcinoma.
Adolescent↗
Surgical strategies in papillary thyroid carcinoma.
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Adolescent↗
Ectopic intrathyroidal thymus diagnosed as a solid thyroid lesion: case report and review of the literature.
The authors report a case of a 6-year-old boy in whom aberrant thymic tissue was misdiagnosed as an intrathyroidal solid lesion. The patient underwent hemithyroidectomy and did well. Because cervical ectopic thymus rarely produces symptoms, the true incidence in children is unclear. Surgeons need to consider this rare entity, not to mistake it as a thyroid neoplasm, and not to perform extensive thyroid resection.
Child↗
Reoperation in metastasizing medullary thyroid carcinoma: is a tumor stage-oriented approach justified?
BACKGROUND: Lymph node metastases (LNM) are very often found in medullary thyroid carcinoma. After primary therapy, elevated levels of calcitonin are measurable in many patients. Because of the low sensitivity and specificity of diagnostic tools to detect micrometastases, the question remains whether an extended lymphadenectomy improves the chance of cure and whether this approach should be tumor stage oriented. METHODS: We analyzed the results of 36 patients with medullary thyroid carcinoma consecutively reoperated from 1988 to 1996, performing microdissection of all four locoregional lymph node compartments. RESULTS: Pathologic tumor stage (pT) category was classified as pT1, n = 3; pT2 n = 22; pT3, n = 6; and pT4, n = 5. LNM were found in 34 patients (94%). The cervicocentral compartment contained LNM in 85%, the cervicolateral compartments in 41% to 54%, and the upper mediastinum in 36%. Patients with different pT category did not differ in the rate of LNM. Ipsilateral cervicolateral LNM were found in 50% to 71% and contralateral cervicolateral LNM in 14% to 40%. Nine (35%) of 26 patients without distant metastases were biochemically cured. In 10 patients (38%) calcitonin level decreased more than 50%. CONCLUSIONS: LNM were almost always (94%) found in patients who have elevated calcitonin levels after primary therapy. In patients without distant metastases, four-compartment lymphadenectomy gives a chance of cure in 35%. A tumor stage-oriented approach does not seem to be justified.
Adolescent↗
Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation.
The autosomal dominant multiple endocrine neoplasia type 2 syndromes (MEN 2) comprise three clinically distinct entities, MEN 2A, familial medullary thyroid carcinoma and MEN 2B, which share a common clinical feature: medullary thyroid carcinoma (MTC). MEN 2B is considered to have the most aggressive form of MTC. Therefore, early detection of MEN 2B in order to prevent potentially lethal MTC is important. More than 95% of all MEN 2B cases are caused by germline mutation at codon 918 (M918T) in exon 16 of the RET proto-oncogene. In this study, we demonstrate the presence of germline codon 883 mutation (A883F) in 2 of 3 unrelated MEN 2B cases without codon 918 mutation. Our data demonstrate a novel etiologic event which may have roles in predisposition to MEN 2B when present in the germline and in the pathogenesis of sporadic MTC when somatic.
Alanine↗
[Lymph node excision in thyroid carcinoma].
The prognostic value of lymph node metastases in thyroid cancer has been a matter of controversy for many years. However, during the past decade most multivariate analyses have shown a prognostic influence of lymph node metastases in papillary as well as medullary thyroid carcinoma constituting the basis for a standardized concept of lymphadenectomy oriented to the lymph node classification of the UICC (1993). Due to the frequency of lymph node metastases in the ipsilateral cervicocentral compartment (42-86%), in the ipsilateral cervicolateral compartment (32-68%), in the contralateral cervicolateral compartment (12-24%), and in the mediastinal compartment (3-20%), these compartments can be defined as the lymph node regions of the first, second, third and fourth order, respectively. Cervicocentral systematic lymphadenectomy should be part of the en bloc resection of the thyroid gland and the first lymph node region in any thyroid cancer. Cervicolateral as well as mediastinal lymphadenectomy should be performed according to the extent of lymph node involvement, i.e. systematically when multiple lymph node metastases are present, otherwise selectively. One exception is in medullary thyroid carcinoma, where a four-compartment lymphadenectomy is recommended in any patient with positive lymph nodes. Performing a gentle technique using magnifying glasses and bipolar coagulation forceps, systematic lymphadenectomy does not increase the rate of complications, can decrease the recurrence rate and improve survival.
Adenocarcinoma↗
Completion thyroidectomy in 131 patients with differentiated thyroid carcinoma.
OBJECTIVE: To evaluate the prognostic factors that influence survival and recurrence after "completion" thyroidectomy (removal of the total thyroid remnant after diagnosis of carcinoma has been made in a specimen that was incompletely excised for a benign condition). DESIGN: Open study. SETTING: Teaching hospital, Germany. SUBJECTS: 131 Patients (65 with papillary and 66 with follicular thyroid cancer) who underwent completion thyroidectomy after primary subtotal resection. INTERVENTIONS: Indications for further operation were: tumour stage worse than pT1 ( n = 116), tumour stage pT1 and the suspicion of persistence of the tumour (n = 13), and incompletely resected tumour (n = 2). Multivariate analysis by Cox's proportional hazards model. MAIN OUTCOME MEASURES: Recurrence, development of metastases, and length of survival. RESULTS: Patients who underwent their completion thyroidectomies within six months of the primary operation had significantly fewer recurrences, fewer lymph node metastases, fewer haematogenous metastases and survived significantly longer than those in whom the second operation was delayed for longer than six months. The age at the time of diagnosis and the stage of the tumour influenced survival, whereas sex and type of tumour did not. CONCLUSION: Completion thyroidectomy as soon as possible after incomplete resection of the tumour may improve prognosis in differentiated thyroid cancers the stage of which is worse than pT1 or in patients whose recurrent tumour is diagnosed at follow-up.
Adenocarcinoma, Follicular↗
Clinical significance of E-cadherin as a prognostic marker in thyroid carcinomas.
The aim of this study was to evaluate the expression of E-cadherin as a potential marker for the prognosis of thyroid carcinomas. In normal thyroid (n = 8), the expression of E-cadherin messenger ribonucleic acid levels was uniformly high and seemed to be restricted to thyrocytes. Steady-state messenger ribonucleic acid levels and immunostaining were both completely lost in undifferentiated thyroid carcinomas (n = 7) and were variably reduced in differentiated thyroid carcinomas (n = 44). In a follow-up study during a mean of 4.5 +/- 1.4 yr, E-cadherin messenger ribonucleic acid and immunohistochemical expression were compared with the initial clinicopathological parameters and with locoregional recurrence and the development of nodal or distant metastases in differentiated thyroid carcinomas. Immunohistochemical expression of E-cadherin was greatly reduced with the progression to primary tumor stage 4 (pT4) tumors. In parallel, patients with pT4 tumors had a higher rate of locoregional tumor recurrence and distant metastasis than did the group of patients with pT1-3 tumors. In 5 of 29 patients with pT4 tumors, positive E-cadherin staining of more than 30% of the cells was detected. None of these patients showed signs of a regional recurrence or distant metastases during an observation period of 4.3 +/- 1.1 yr. In 13 patients with E-cadherin-positive tumors, none developed new distant metastases which was in contrast to 7 of the group of 31 patients with less than 30% E-cadherin-positive cells. Thus, E-cadherin expression seems to be associated with the dedifferentiation, progression, and metastatic spread of thyroid carcinomas and may be a useful marker for the prognosis of these tumors.
Adenocarcinoma, Follicular↗
Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer.
We studied the records of 342 patients with papillary thyroid carcinoma out of a total of 728 thyroid cancer patients treated at the Medical School of Hannover (MHH) from 1972 through 1992. The comprehensive data-abstracting forms were designed, and the acquired information was coded, stored, maintained, and evaluated by the Clinical Cancer Registry of the MHH. A total of 160 patients (46.8%) initially had lymph node metastases (N1 status). The N status significantly influenced recurrence (p < 0.00001) and survival (p < 0.00001). Excluding other risk factors developed by univariate and multivariate analysis, such as high age (age > 45 years, p < 0.001), tumor invasion (T4 tumor, p < 0.005), and distant metastases (M1, p < 0.001), lymph node metastases remained an independent, highly significant prognostic marker for more aggressive papillary thyroid cancer. N1 status did not influence survival of patients with T4 tumor but did influence those with T1-T3 status (p < 0.001). The influence of N1 status remained significant in patients older (p < 0.001) and younger (p < 0.05) than 45 years of age. Systematic compartment-oriented dissection of lymph node metastases improved survival (p < 0.005, T1-T3) and recurrence (p < 0.00001, T1-T3) especially in patients with T1-T3 tumors. In conclusion, lymph node metastases with a significant incidence at a young age and male sex had a substantial effect on survival and recurrence especially in those with tumor status T1-T3. Systematic compartment-oriented dissection of the lymph node metastases results in better survival and a lower recurrence rate.
Adolescent↗