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RET
proto-oncogene predisposing to multiple endocrine neoplasia type IIa (MEN-IIa) has allowed a DNA-based approach to diagnosis and treatment by prophylactic thyroidectomy in children testing genetically positive. Although total thyroidectomy is the accepted operation for C cell disease, the necessity of routine total parathyroidectomy and autotra...
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Multiple endocrine neoplasia type 2a results from an activating germline mutation in the RET proto-oncogene. Carriers of a RET mutation are at risk of medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism. Most individuals with multiple endocrine neoplasia type 2a eventually develop medullary thyroid carcinoma and as there...
RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international effor...
Objective:
Specific germline mutations in the RET proto-oncogene are correlated with clinical features in multiple endocrine neoplasia type 2A (MEN2A); however, data are scarce regarding differences in clinical profiles dependent on the type of nucleotide and amino acid substitution at the same codon. We aimed to analyse differences in clinical ri...
The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathy...
Pheochromocytoma (Pheo) is a chromaffin tumor arising from the adrenal medulla. The recent discovery of new germline mutations in RET, SDHA, SDHB, SDHC, SDHD, VHL, NF1, TMEM127, MAX genes, increased the rate of genetic disease from 10% to 28% in patients with apparently sporadic tumor. RET germline mutations cause Multiple Endocrine Neoplasia type...
Citations
... In the study of Decker et al. [6] , which is a study on the need for autotransplantation of parathyroids in prophylactic surgery for MEN2A syndrome after genetic testing, 36 children (aged 1 month to 12 years) from 4 MEN-IIa kindreds at risk of disease underwent genetic testing. Mutation analysis was performed using a highly sensitive PCR-based denaturation gradient gel electrophoresis technique. ...
... Decker et al. [6] Prophylactic surgery for multiple endocrine neoplasia type IIa after genetic diagnosis: is parathyroid transplantation indicated? 1996 ...
Aim : To define the role of prophylactic parathyroidectomy in the surgical treatment of medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type IIa (MEN2A) syndrome through a literature review.
Materials and methods : The database of PubMed was searched using the terms “parathyroidectomy” and “medullary” in the fields “Title” and “Abstract”, as well as the Google Scholar database. Articles without references to parathyroid management strategies were mainly excluded.
Results : Fourteen articles were reviewed as relevant to this study regarding recommendations for the management of parathyroids during prophylactic thyroidectomy in patients with MTC in MEN2A syndrome. Three of them had the same or similar purpose to our work, and the most recent literature review did not clearly support either one of the two management strategies. References to parathyroid management were found in the rest of the articles, but their purpose was not to determine the appropriate management strategy. The majority of the authors support the preservation of macroscopically normal parathyroid glands, while one study favored routine total parathyroidectomy and autografting.
Conclusions : Although there does not seem to be a gold standard, the strategy of preserving macroscopically normal parathyroid glands with routine lab testing and surgical exploration for hyperparathyroidism during thyroidectomy seems to be a safe and effective strategy.
... This strategy is similar to that practiced by other groups who perform thyroidectomy for patients with MEN2. [8][9][10] ...
Objectives:
Patients with multiple endocrine neoplasia type 2 (MEN2) have mutations in the RET protooncogene and virtually all of them will develop medullary thyroid carcinoma. Family members identified by genetic testing are candidates for preventive thyroidectomy. Management of the parathyroids during thyroidectomy is controversial. Some experts advocate total parathyroidectomy with autotransplantation, whereas others recommend preserving the parathyroids in situ.
Methods:
Between 1993 and 2000, we performed preventive thyroidectomies on 50 patients with MEN2A (group A). All patients had a central neck dissection (CND) combined with total parathyroidectomy and autotransplantation of parathyroid slivers to the nondominant forearm or to the neck. Between 2003 and the present, we performed 102 preventive thyroidectomies attempting to preserve the parathyroid glands in situ with an intact vascular pedicle (group B). Individual parathyroids were autotransplanted only if they appeared nonviable or could not be preserved intact. Central neck dissection was done only if the serum calcitonin was greater than 40 pg/mL.
Results:
Permanent hypoparathyroidism occurred in 3 (6%) of 50 patients in group A, compared with 1 (1%) of 102 patients in group B (P = 0.1). After total thyroidectomy, no patient in either group developed permanent recurrent laryngeal nerve injury or hyperparathyroidism. Immediate postoperative serum calcitonin levels were in the normal range (<5 pg/mL) in 100 of 102 patients in group B. No patients in either group have died. Oncologic follow-up of patients in group B is in progress.
Conclusions:
In patients with MEN2A treated by preventive total thyroidectomy routine total parathyroidectomy with autotransplantation and CND gives excellent long-term results. However, preservation of the parathyroids in situ during preventive thyroidectomy combined with selective CND based on preoperative basal serum calcitonin levels is an effective and safe alternative that results in a very low incidence of hypoparathyroidism.
... in less than 5% of cases diagnosis of hPT is made before that mTc or pheochromocitoma are diagnosed[51]. hPT is recognized at a median age of 38 years, ranging from 7 to 71 years[6,50,51]and even if no parathyroid glands pathology is reported in patients who underwent prophylactic total thyroidectomy in pediatric or juvenile age[52,53], we described a case of a 5 years old men2 child who showed a pathologic parathyroid gland, when he underwent prophylactic total thyroidectomy. in 27%-48% of cases just one enlarged gland can be found during surgical exploration of the neck[6,32,51,54], while a double adenoma can be found in 8% of cases[50,54]. in the other cases patterns similar to multiglandular disease or hyperplasia were described in 48% of the patients[50,54]. ...
... Parathyroid glands should be identified during thyroidectomy; however, controversy exists regarding how these glands should be preserved in order to maintain function. Some authors preserve the parathyroids in situ [75] or perform total parathyroidectomy with autotransplantation [76]. Preferred sites for autotransplantation are the muscle of the nondominant forearm (in most patients with MEN 2A) or sternocleidomastoid muscle (in most patients with sporadic MTC, FMTC and MEN 2B). ...
Thyroid cancer is the most common endocrine neoplasm; however, it only accounts for less than 1% of all human malignances. Thyroid cancers are divided into well differentiated and non-well differentiated cancers, according to their histology and behavior. The surgical management options of well-differentiated thyroid cancer include total or near-total thyroidectomy, subtotal thyroidectomy and lobectomy plus isthmusectomy. The extent of surgery for thyroid cancer continues to be an area of controversy. Complications associated with thyroid surgery are directly proportional to the extent of thyroidectomy and inversely proportional to the experience of the operating surgeon. They occur less frequently with good surgical technique and better understanding of surgical anatomy, and include wound healing and infections (seroma, hematoma and wound infection), nerve injury, hypoparathyroidism, hypothyroidism, postoperative hemorrhage and respiratory obstruction.
... Preservation of parathyroid function is critically important and may be accomplished by removal and autotransplantation of the minced parathyroid fragments to the sternocleidomastoid muscle or to a forearm muscle (all parathyroid tissue should be left in the patient.) [28][29][30][31] Some surgeons maintain the blood supply of the parathyroids and leave the glands in situ. This, however, may require leaving significant thyroid or nodal tissue to protect the blood supply to the parathyroids. ...
Medullary thyroid carcinoma (MTC) is a rare malignancy of the thyroid C cells. It occurs in hereditary (25% of cases) and sporadic (75%) forms. Sporadic MTCs frequently metastasize to cervical lymph nodes. Thorough surgical extirpation of the primary tumor and nodal metastases by compartment-oriented resection has been the mainstay of treatment (level IV evidence). Surgical resection of residual and recurrent disease is effective in reducing calcitonin levels and controlling complications of central neck disease (level IV evidence). Radioactive iodine, external beam radiation therapy, and conventional chemotherapy have not been effective. Newer systemic treatments, with agents that target abnormal RET proteins hold promise and are being tested in clinical trials for patients with metastatic disease.
... Additionally, because only 20% to 30% of MEN-2A patients will have PHPT, it is unclear that there is a benefit to performing prophylactic parathyroidectomy in all MEN-2A patients. One study describes 11 children who had prophylactic thyroidectomy between the ages of 2 and 12 years with preservation of the parathyroid glands in situ [20]; however, there are no long-term data available on such children as to the future development of PHPT. One should obviously carefully mark the parathyroid glands with clips or nonabsorbable monofilament suture during total thyroidectomy so that they are easier to identify if hyperparathyroidism recurs. ...
Familial hyperparathyroidism encompasses the diagnoses of multiple endocrine neoplasia (MEN) type 1, MEN type 2A, and familial isolated primary hyperparathyroidism. All patients should undergo bilateral neck exploration and identification of all four or more parathyroid glands to evaluate for gross abnormalities. MEN-1 patients should have subtotal parathyroidectomy and cervical thymectomy because this operation achieves an appropriate balance between optimizing the potential for cure yet minimizing the risk of permanent hypocalcemia. However, MEN-2A patients may best be treated by selective resection of abnormal parathyroid glands, although some experts recommend a total parathyroidectomy and autotransplantation in the forearm. Familial isolated hyperparathyroidism is a rare disorder, and authors have described success in treatment with subtotal parathyroidectomy or limited adenoma resections. Some patients with familial isolated hyperparathyroidism also have jaw tumors, and members of these families are more likely to have parathyroid carcinoma. Concurrent cryopreservation of parathyroid tissue for all of these disorders is recommended if there is any concern for possible permanent hypoparathyroidism.
... Careful preservation of recurrent nerves and parathyroid glands may be difficult in very young children. The risk of injuring recurrent nerves at risk after thyroid surgery in the literature varies between 0% and 4% and symptomatic hypoparathyroidism with calcium supplementation occurs in 0% to 21% [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]. The incidence of complications strongly depends on the experience of the surgeon [44,50,57]. ...
... Even with meticulous dissection however, the blood supply to the parathyroid glands may be impaired. In these circumstances autotransplantation after microscopic verification may reduce the incidence of hypoparathyroidism [40,41,47]. ...
MTC is a rare neuroendocrine thyroid tumour accounting for 3% to 10% of all thyroid malignancies. It can occur in a sporadic and a hereditary clinical setting. Hereditary MTC may either occur alone (familial MTC, FMTC) or as part of multiple endocrine neoplasia (MEN) type 2A, or MEN 2B. These disorders are due to germline mutations in the RET (REarranged during Transfection) gene. In carriers of MEN 2B-associated RET mutations, prophylactic thyroidectomy is indicated before the first year of life. In the case of MEN 2A-associated germline RET mutations with a high-risk profile, total thyroidectomy is warranted before the age of 2 years and certainly before the age of 4 years. At that age the risk of invasive MTC and metastases is acceptably low. Depending on the type of RET mutation, thyroidectomy can take place at an older age in patients with a lower risk profile. In case of elevated basal or stimulated serum calcitonin, preventive surgery including total thyroidectomy and central compartment dissection should be performed regardless of age. When MTC presents as a palpable tumour, total thyroidectomy should be combined with extensive lymph node dissection of levels II-V on both sides and level VI to prevent locoregional recurrences.
... Other surgeons advocate leaving the parathyroid glands in situ with their vascular pedicles intact, marked with a surgical clip for future identification. 12,56 If the parathyroid's vascular supply appears to be compromised, the gland should be confirmed by frozen section, then autotransplanted into the forearm. ...
Hereditary medullary thyroid cancer syndromes comprise familial medullary thyroid cancer (FMTC) and multiple endocrine neoplasia types 2A and 2B. Hereditary medullary thyroid cancers have an autosomal dominant pattern of inheritance and are caused by activating germline point mutations in the RET proto-oncogene. Evaluation of the onset, extent, and progression of hereditary medullary thyroid cancer associated with specific RET mutations has enabled clinicians to treat patients based on the level of risk associated with their specific mutation. Children identified by RET screening to be at risk for the development of medullary thyroid cancer can be treated with prophylactic thyroidectomy before developing the disease. This review covers the diagnosis, evaluation, timing of surgical management, and optimal follow-up of patients with hereditary medullary thyroid cancer syndromes.
... All parathyroid glands should be identified during thyroidectomy, however controversy exists regarding how these glands should be preserved to maintain function. Whilst some authors preserve the parathyroids in situ [31,[36][37][38], at our institution, we often perform total parathyroidectomy with autotransplantation [39]. The parathyroid glands are removed and preserved in cold saline at the time of thyroidectomy and sliced into 1 · 3-mm fragments. ...
Cohen, MS Moley, JF (Washington University School of Medicine, St Louis, MO, USA). Surgical treatment of medullary thyroid carcinoma (Minisymposium). J Intern Med 2003; 253: 616–626.
Medullary thyroid carcinoma (MTC) is a malignancy of the parafollicular C cells of the thyroid gland. It occurs sporadically or as part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes. Patients who have inherited a mutation in the RET proto-oncogene should have thyroidectomy early in life to prevent formation and spread of this cancer. Most patients with sporadic disease present with a palpable neck mass. The diagnosis is made by fine needle aspiration biopsy and by measuring calcitonin levels in the blood. Primary treatment consists of surgical resection including a total thyroidectomy, central neck nodal dissection and functional lateral neck nodal dissections. Most patients with a palpable primary tumour have nodal disease present at the time of operation, and nodal involvement is often bilateral. Adequate resection of the primary tumour and cervical lymph nodes is important to optimize outcome and minimize the risk of recurrent disease. Proper handling of the parathyroid glands prevents hypoparathyroidism. Following primary surgical resection, more than half of the patients will have recurrent disease with persistent elevation of calcitonin levels. Currently, there is no adequate systemic therapy for treating recurrent disease. Surgical reoperation or conservative observation are the best available options. Diagnostic laparoscopy for liver evaluation is the most sensitive diagnostic test to detect the presence of distant metastases.
... 1,2 To twofold: 1) to examine the genotype pattern of germline MEN 2a and FMTC mutations in an unselected date, the described mutations predisposing to MEN 2a and FMTC involve DNA alterations at one of six ethnically diverse North American population; and 2) to assess the sensitivity of a more comprehensive ap-highly conserved cysteines within the extracellular domain of RET at codons 609, 611, 618, 620, 630, and proach to RET mutation detection that included RET exons 13 and 14. 634. [1][2][3][4][5][6] Less frequently, single base (missense) changes affecting the tyrosine catalytic domain occur in RET exons 13 and 14 at codons 768 and 804, respectively, ...
The RET protooncogene is responsible for the inherited cancer syndromes multiple endocrine neoplasia type 2a (MEN 2a) and familial medullary thyroid carcinoma (FMTC). Identification of predisposing germline RET mutations has allowed a DNA-based approach to diagnosis. Despite known mutational occurrences in RET exons 10,11,13, and 14, the majority of national diagnostic laboratories, with rare exception, continue to limit genetic analysis for MEN 2a and FMTC to RET exons 10 and 11. This study was undertaken to examine the genotype pattern of germline MEN 2a/FMTC RET mutations in an ethnically diverse North American population and assess the sensitivity of a more comprehensive testing approach to mutation detection that encompassed RET exons 10, 11, 13, and 14.
