Thyroidectomy For Medullary Thyroid Carcinoma Research Articles

Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: a nationwide survey in Japan 1997-2017.

Background In Japan, prophylactic thyroidectomy involves out-of-pocket expense. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma (MTC) during early childhood in patients with multiple endocrine neoplasia type 2 (MEN2). The ATA reports a high frequency of postoperative complications in childhood, which also influenced the delay of prophylactic thyroidectomy in Japan. Methods This retrospective study of multiple medical centers in Japan included individuals aged <20 years diagnosed with germline RET mutations between 1997 and 2017. The onset and onset possibility were defined based on confirmed lesions or calcitonin levels. The definition of risk and prophylactic thyroidectomy were based on the ATA 2015 revised guideline. Results Twenty-one patients with MEN2 were enrolled (highest risk, n = 5; high risk, n = 5; and moderate risk, n = 11). The cumulative incidence of the onset/onset possibility reached 50% at 5 and 8 years and 100% at 9 years and 17 years in high- and moderate-risk patients, respectively. Of 7 patients with MEN2A, 71% underwent prophylactic thyroidectomy. Only one 5-year-old patient (C634Y) had increased serum calcitonin level after prophylactic thyroidectomy in the MEN2A group. The only permanent complication, which did not occur in patients who underwent total thyroidectomy alone, was hypoparathyroidism (33% of patients). This permanent complication occurred with clinically developed MTC. No permanent postoperative complications occurred in patients aged 5-6 years. Conclusions Prophylactic thyroidectomy reduces recurrence and postoperative complications in pediatric patients with MEN2. Early thyroidectomy based on only calcitonin level could possibly reduce thyroidectomy delay.

Multiple HABP2 variants in familial papillary thyroid carcinoma: A case-control study

Objective A heterozygous germline variant in the HABP2 gene (p.G534E), that negatively impacts its tumor suppressive activity in vitro, has been described in 4 to 14% of kindreds of European ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare genotypes of patients with fPTC with those of “thyroid-checked” controls. Materials and methods We built a control group consisting of 95 European patients who underwent a thyroidectomy for medullary thyroid carcinoma and were devoid of any histologically detectable PTC or follicular-deriving carcinoma. In parallel we recruited 17 patients with fPTC from nine independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Results Two variants (p.G534E and p.R122 W) were found in 2 and 3 patients at the heterozygous level (minor allele frequency (MAF): 5.55% and 8.33%, respectively). The R122 residue lies in the EGF-3 domain of HABP2 which is important for its activation. In controls, the MAF was either lower for the p.R122 W (1.05%, P Discussion In conclusion, our data do not support the pathogenicity of the HABP2 p.G534E variant but highlight the existence of another variant that should be more extensively searched for in fPTC patients.

Extensive Ganglioneuromatosis of Gallbladder

A case of extensive ganglioneuromatosis (GN) of gallbladder is presented. A 38-year-old man presented with a hepatic hilar mass (Ø ~ 48 mm) and gall stones. He had undergone total thyroidectomy for medullary thyroid carcinoma 8 years earlier. The hepatic hilus tumor, which had been clinically suspected to be a lymph node metastasis from the medullary thyroid carcinoma, was found to be pheochromocytoma. The gallbladder, resected with a clinical diagnosis of cholelithiasis, showed extensive transmural GN despite a grossly normal appearance. Taking into account the past history, the patient was diagnosed as having multiple endocrine neoplasia 2b (MEN2b)-associated GN of gallbladder and ectopic pheochromocytoma. As GN of gallbladder in MEN2b has been rarely reported, the histological findings are described in detail and a brief review of literature is carried out.

Simultaneous Eyelid and Choroidal Metastases 36 Years After Diagnosis of Medullary Thyroid Carcinoma

A 56-year-old man had a 6-month history of a progressively enlarging mass of his right upper eyelid. Thirty-six years previously he had undergone thyroidectomy for medullary thyroid carcinoma in the absence of family history. Supraclavicular lymph node metastases were discovered 3 years after initial diagnosis, pulmonary metastasis 26 years later, and cervical lymph node metastases 35 years later. Ocular examination revealed a pedunculated, amelanotic, highly vascularized metastasis involving the right upper eyelid and palpebral conjunctiva. Ophthalmoscopy revealed 2 amelanotic, dome-shaped choroidal metastases in the right eye and 3 similar tumors in the left eye. Medullary thyroid carcinoma not associated with the multiple endocrine neoplasia syndromes can metastasize to the ocular region and metastases can occur decades after the original diagnosis.

Early Thyroidectomy for Medullary Thyroid Carcinoma in Siblings with Multiple Endocrine Neoplasia Type 2A

Early Thyroidectomy for Medullary Thyroid Carcinoma in Siblings with Multiple Endocrine Neoplasia Type 2A

Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome

Background/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 RET 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. Methods: 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 specimens. 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, 10) but there was one occurence of CCH (age 11). 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%. Conclusions: 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 RET mutation 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.

A nationwide clinical survey of patients with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma in Japan.

MEN (multiple endocrine neoplasia) type 2 syndrome is an inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism and/or developmental anomalies. Germ-line mutations of the RET proto-oncogene have recently been identified as the underlying cause of the syndrome. Accordingly, several investigators have advocated prophylactic total thyroidectomy for medullary thyroid carcinoma at an early age in MEN 2 gene carriers identified by DNA analysis. Before applying this strategy in Japan, the biological behavior of each category of tumor in MEN 2 syndrome, and medullary thyroid carcinoma in particular, should be well understood. We conducted a nationwide questionnaire survey to clarify the clinicopathological features of MEN 2 in Japan, obtaining data for 230 patients diagnosed as having MEN 2. They included 84 males and 146 females, with a median age of 37.5 years (range 5-83). Patients were categorized as 179 with MEN 2A, 17 with MEN 2B, 12 with familial medullary thyroid carcinoma and 22 'other'. Medullary thyroid carcinoma, pheochromocytoma and parathyroid lesions occurred in 224 (97%), 132 (57%) and 25 (11%) patients respectively. Twelve patients (5.2%) died of medullary thyroid carcinoma and 11 patients died of other or unknown causes. Of 163 patients for whom follow-up data were obtained, 82 (50%) experienced recurrences of medullary thyroid carcinoma, including symptomatic recurrent tumors in 24 patients and elevated calcitonin levels alone in 54. In the era of RET mutational analysis for screening relatives of patients with MEN 2, these data provide useful information about surgical management for patients with MEN 2 in Japan.

Parathyroid Autotransplantation During Thyroidectomy

Permanent hypoparathyroidism is a recognized complication of thyroidectomy. Operative strategies to prevent this complication include preservation of parathyroid glands in situ and autotransplantation of parathyroid glands resected or devascularized during thyroidectomy. An analysis of 194 patients having thyroidectomy and simultaneous parathyroid autotransplantation at Barnes Hospital from 1990 to 1994 was performed. Data were collected regarding patient demographics, indication for thyroidectomy, operative procedure, pathologic diagnoses, and postoperative course, including biochemical assessment of parathyroid autograft function. Of 194 patients having either total, subtotal, or completion thyroidectomy, 104 (54%) experienced a [Ca(+2)]nadir less than or equal to 8.0 mg/dL and had symptoms and signs of hypocalcemia. Parathyroid autotransplantation was successful in 103 (99%) of these 104 cases and resulted in a 1.0% incidence of hypoparathyroidism in this series. Although preservation of parathyroid glands in situ is desirable, routine parathyroid autotransplantation during thyroidectomy virtually eliminates postoperative hypoparathyroidism. Normal parathyroid glands resected or devascularized during thyroidectomy for well-differentiated thyroid carcinoma or benign disease should be transplanted in the sternocleidomastoid muscle. Patients with Multiple Endocrine Neoplasia type 2A should have parathyroid glands resected at the time of thyroidectomy for medullary thyroid carcinoma and transplanted in the nondominant forearm. Postoperative management in most patients after thyroidectomy and parathyroid autotransplantation involves temporary calcium and vitamin D replacement and close biochemical evaluation. This precautionary measure of parathyroid autotransplantation markedly reduces the incidence of permanent postoperative hypoparathyroidism.

Progression of postoperative residual medullary thyroid carcinoma as monitored by plasma calcitonin levels

Patients operated on for medullary thyroid carcinoma (MTC) frequently have persistent elevated plasma calcitonin concentrations after operation, indicating remaining tumor. The plasma calcitonin concentration in a patient with MTC roughly reflects the endogenous tumor burden. The only effective treatment for MTC is surgical. The decision about whether a patient with persistent MTC should have a repeat operation would be influenced by knowledge of the natural course of the disease. Forty patients with persistently elevated peak plasma calcitonin concentrations after thyroidectomy for MTC were monitored for a mean of 6 years. Serial determinations of plasma calcitonin levels were obtained before and after intravenous injection of calcium and pentagastrin. At the first postoperative test 63% of the patients had undetectable basal calcitonin values, although their stimulated plasma calcitonin concentrations were elevated. The mean annual increase in stimulated plasma calcitonin concentrations was 117%, but plasma calcitonin concentrations were stable in three patients and decreased in one patient. Five patients are known to have experienced distant metastases. MTC is a progressive disease in most patients with persistent hypercalcitoninemia after thyroidectomy. Stimulated peak plasma calcitonin levels are more meaningful than basal levels in the serial postoperative evaluation of patients with persistent hypercalcitoninemia after thyroidectomy for MTC.

Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B

Recently it has become possible to identify persons who have multiple endocrine neoplasia (MEN) syndrome types 2A and 2B based on the presence of missense mutations in the RET protooncogene. Kindred members who have inherited these syndromes can be identified before clinical or biochemical evidence of medullary thyroid carcinoma (MTC) develops, the malignancy that occurs in all affected patients. It is not known whether prophylactic removal of the thyroid gland early in childhood, based on a positive genetic test result, has a better clinical outcome than that associated with thyroidectomy after MTC is diagnosed clinically or biochemically. The authors' goal was to determine the long-term outcome for patients with MEN 2A and 2B who had thyroidectomy for MTC during childhood. These results were compared with those of patients who had prophylactic removal of the thyroid gland after the genetic diagnosis of MEN 2A was established. The hospital records of 49 children with MEN 2A or 2B were reviewed. Each patient had thyroidectomy for MTC before 16 years of age. The mean age at the time of operation was 10 years, and the mean follow-up period for those who had surgery before the availability of direct DNA genetic testing was 9.8 years. The indications for surgery included an elevated basal or stimulated plasma calcitonin level, a positive genetic test result, a thyroid mass, family history of MTC, or a phenotype diagnostic of MEN 2B. All children for whom the diagnosis of MEN 2A was established by direct genetic testing had thyroidectomy within the last 2 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, 10 had MTC, and only three (27%) remain free of disease after the mean follow-up period of 11 years. One patient died, and seven are alive with persistent MTC. Among the 24 patients with MEN 2A who had their thyroid glands removed because of a family history of MTC or because of biochemical evidence of the disease, 5 (21%) have persistent or recurrent MTC after the mean follow-up period of 9.3 years. In four of these, the MTC was confined to the thyroid gland at the time of thyroidectomy. Of the 14 children who had thyroidectomy based on direct DNA testing, MTC was present in 11. Only four had elevated levels of stimulated plasma calcitonin before surgery. None had lymph node metastasis or surgical complications. The authors conclude that a significant number of patients with MEN 2A or 2B who undergo thyroidectomy in childhood for MTC have persistent or recurrent disease long-term. The genetic diagnosis of patients with these syndromes may allow for prophylactic surgery before the development of biochemical or clinical evidence of MTC. This approach is safe, but longer clinical follow-up will be necessary to confirm that MTC has been cured.

Disappearance rate of serum calcitonin after total thyroidectomy for medullary thyroid carcinoma.

We studied the half-life of serum calcitonin (CT) in patients subjected to total thyroidectomy for medullary thyroid carcinoma (MTC). One patient showed a rapid serum CT component with a half-life of 3 hours and a slow component with a half-life of 30 hours; in another case only the 30-hour component was found. By chromatography of tumor extracts, we found that all the immunoreactive CT had a molecular weight of 3,600. After surgery, normalization of serum CT was achieved within 15 days in 4 patients, at 3 months and at 6 months in 2 other patients, while 1 patient never normalized. Normalization of serum CT after surgery is not an index of definitive cure in MTC, as demonstrated by one patient who relapsed 3 months after normalization of serum CT. However, as a general rule, patients who reach undetectable serum CT levels soon after surgery, are those having the best prognosis.

Relatively good prognosis of multiple endocrine neoplasia type 2B in Japanese: review of cases in Japan and analysis of genetic changes in tumors.

Since 1968, a total of 23 patients with multiple endocrine neoplasia type 2B (MEN 2B) have been identified in Japan. The mean age at diagnosis was 20.3 years (range, 6 to 39 years). All patients had neuromas and bumpy lips. All patients underwent thyroidectomy for medullary thyroid carcinoma (MTC). Ten of 23 patients had pheochromocytomas. One patient died of cerebral bleeding at the age of 43, 2 patients died of MTC at the age of 35 and 12. Five-, 10-, and 15-year survival rates were 100%, 92%, and 88%, respectively. The clinical course of MTC in MEN 2B in Japanese is not so aggressive when compared with about a 50% 10-year survival reported for Caucasians. Genetic analysis of 4 MTC and 1 pheochromocytoma from 4 patients with MEN 2B revealed no common changes in regard to loss of heterozygosity on 21 chromosomes or point mutations of the ras, Gs alpha, or p53 genes.

(131I)Meta-iodobenzylguanidine scintigraphy and selective venous catheterization after thyroidectomy for medullary thyroid carcinoma

Fifteen patients with medullary carcinoma of the thyroid (MCT), who had persistently elevated levels of serum calcitonin (CT) and carcinoembryonic antigen (CEA) after total thyroidectomy, were studied in order to localize the sites of the recurrent disease. Routine diagnostic examinations, including ultrasonography (US) and computed axial tomography (CAT), were carried out in all the cases. Scintigraphy with radio-iodinated metaiodobenzylguanidine ((131I)-MIBG) was performed in 13 cases; selective venous catheterization (SVC) to reveal a gradient of CT levels was performed in 12 cases. Ten patients underwent both (131I)-MIBG scintigraphy and SVC. US and CAT revealed the sites of recurrent tumor in only 4 out of the total 15 patients. SVC in basal conditions showed the presence of small metastases in 2 cases, and after intravenous stimulus with pentagastrin in 4 others. The MIBG scan showed metastatic foci of sporadic MCT in 2 patients, residual medullary thyroid tissue in 4 others, and a pheochromocytoma in a previously undiagnosed patient with Sipple's syndrome. More particularly, MIBG scan and SVC showed the localization of residual or metastatic tumor in 10 cases. In all 10 cases, results of the MIBG scan and SVC were confirmed as true positive by subsequent surgery and histopathologic examination.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2

Children with multiple endocrine neoplasia type 2 (MEN2) often develop medullary carcinoma of the thyroid (MCT) or its precursor, C-cell hyperplasia. Survival results are improved if malignancy is diagnosed early from the results of plasma immunoreactive calcitonin (iCT) measurement. The effect of early detection and thyroidectomy in children with MEN2 syndrome was determined by reviewing the experience between 1975 and 1985. Seventeen children with MEN2 who were 12 years old or younger underwent a total thyroidectomy for MCT or C-cell hyperplasia. iCT was measured in all patients preoperatively and postoperatively. Of the 17 children, 14 (82%) had MEN2a and 3 (18%) had MEN2b. There were 14 (82%) female and three (18%) male patients; their mean age was 6.97 years (range 1.5 to 12 years). In all patients, the diagnosis of MCT was made from initial elevated levels of iCT after stimulation with pentagastrin. Three patients had clinical evidence of disease preoperatively. All patients underwent a total thyroidectomy and lymph nodes were removed from the central zone; a neck dissection was performed in the three with clinically obvious disease. MCT with C-cell hyperplasia was found in 11 children and C-cell hyperplasia alone in six. Of the 11 with carcinoma, eight had bilateral disease and three unilateral. Six children had bilateral C-cell hyperplasia. All 17 children were alive and feeling well at the time of this report; however, three had evidence of metastatic disease according to iCT measurements. None of the children had recurrent nerve injuries; one had evidence of hypoparathyroidism. All 14 children with occult disease diagnosed by iCT determinations survived and remained free of disease at follow-up. The three children with clinical disease when first examined, although alive, are presumed to have persistent metastatic disease. The youngest child with C-cell hyperplasia at operation was 20 months old, and the youngest with MCT was 3 years old. Therefore, we recommend initiating screening at age 1 year and total thyroidectomy when the diagnosis is made.

Radioiodine as an Adjunct to the Surgical Treatment of Medullary Thyroid Carcinoma*

After total thyroidectomy for medullary thyroid carcinoma, a 50-yr-old male was found to have decreased but still abnormally elevated plasma calcitonin levels. A thyroid scan with 131I revealed remaining thyroid tissue primarily in the form of a thyroglossal duct remnant. Two courses of 131I treatment of 30 and 150 mCi, respectively, produced a gradual decrease in plasma calcitonin. This study demonstrates that carefully selected patients may benefit from the use of 131I treatment as an adjunct to surgery in medullary thyroid carcinoma.