RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease

BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.     

Prophylactic thyroidectomy in multiple endocrine neoplasia: the impact of molecular mechanisms of<Emphasis Type="Italic"> RET</Emphasis> proto-oncogene

BACKGROUND: Multiple endocrine neoplasia (MEN) type 2, a cancer syndrome inherited in the dominant fashion, is defined by the occurrence of medullary thyroid carcinoma (MTC), either as a singular lesion (familial medullary thyroid carcinoma, FMTC) or with the variable expression of pheochromocytoma, hyperparathyroidism (MEN 2A), ganglioneuromas, buccal neuromas and Marfanoid-like phenotype (MEN 2B). DISCUSSION: Germline mutations of the RET proto-oncogene, localized on chromosome 10q11.2, have been identified as the underlying genetic cause of the disorder. In the majority of patients with MEN 2A/FMTC missense mutations at exon 10 or exon 11 are identifiable. Cysteine to arginine exchange at codon 634 is the mutation most frequently found. In MEN 2B approximately 95% of patients present with a mutation at codon 918 (exon 16). Additionally, less frequent mutations in other codons have been found in both syndromes. The DNA-based genotype analysis enables the identification of gene carriers at risk of developing MTC and offer them prophylactic thyroidectomy prior to development of any thyroid pathologies. Prophylactic surgery is generally recommended for MEN 2A/FMTC gene carriers at the age of 4-6 years. Due to the aggressiveness of the MEN 2B syndrome gene carriers should be operated by the age of 1 year. Presumably some less virulent mutations allow postponement of the prophylactic treatment to the second to fourth decade of life. CONCLUSIONS: Compared to standard presymptomatic biochemical screening, genetic testing and consecutive prophylactic treatment contribute to better outcome of individuals at risk for MTC.     

散发型甲状腺髓样癌酪氨酸激酶受体基因第918位点基因突变及意义

目的研究不同人种散发型甲状腺髓样癌（sMTC）酪氨酸激酶受体基因（RET）第918位点基因突变及意义。方法提取17例中国人sMTC基因组DNA，聚合酶链反应（PCR）扩增RET基因第16外显子，PCR产物经纯化后直接测序，分析中国人sMTCRET基因第918位点处基因突变，并与文献报道的其他人种sMTC该位点处基因突变比较。结果中国人sMTC此位点处未发现基因突变；黄种人、白种人、棕种人此位点处基因突变率分别为：7．1％、33．5％、50．0％。基因突变形式均为ATG→ACG点突变。白种人与黄种人，棕种人与黄种人间比较均差异有统计学意义（P〈0．05）。结论中国人sMTC发病与RET基因第918位点处基因突变无关；不同人种sMTC此位点处基因突变率有差异；不同人种sMTC发病的基因基础可能不同。     

Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited cancer syndromes that predispose to C-cell hyperplasia and MTC. MEN 2A and FMTC are caused by mutations in the RET proto-oncogene. METHODS: We used a multiplex polymerase chain reaction-based assay to screen exons 10, 11, 13, and 14 of RET for mutations in 2 families with FMTC. We correlated mutation status with calcitonin and pathologic studies to determine genotype-phenotype correlations. RESULTS: We identified a mutation in codon 804 in exon 14 (GTG-->ATG; V804M) in both families. An 86-year-old person who was a gene carrier and other individuals over age 70 who were suspected by pedigree analysis to be gene carriers had no overt clinical evidence of MTC. Four of 21 patients who underwent a thyroidectomy also had papillary thyroid cancer. One individual in each family had metastatic MTC at age 30 and 32 years, and all 26 people having thyroidectomies had either MTC or C-cell hyperplasia, leading us to continue to recommend prophylactic thyroidectomy for all identified patients who were gene carriers. CONCLUSIONS: Because of active MTC in younger members of these families, including metastases, we have continued to advocate thyroid surgery in mutation-positive individuals. While DNA diagnosis of gene carriers and subsequent genetic counseling was relatively straightforward, the acceptance of surgical recommendations was more difficult for some individuals. These families demonstrate that the search for RET mutations should include exons 13, 14, 15, and 16 in patients whose studies in exons 10 and 11 are negative.     

Sporadic medullary thyroid carcinoma with a pedunculated intraluminal internal jugular vein recurrence: A case report and literature review

Medullary thyroid carcinoma (MTC) is an uncommon usually slowly progressing neuroendocrine tumour that arises from calcitonin (CT) producing parafollicular C cells of the thyroid gland. It accounts for approximately 5% of all thyroid cancers. The majority of MTCs are sporadic (75%) whilst 25% are part of the MEN 2 hereditary syndrome (MEN 2A and MEN 2B and familial MTC). Mutations of the proto-oncogene, RET (Rearranged during Transfection), found on chromosome 10q11, are present in more than 95% of hereditary MTCs and about 25% of sporadic MTCs. MTC metastasizes primarily via lymphatic spread, to central, and lateral nodal neck compartments and the anterior and superior mediastinum. Distant haematogenous spread targets the lungs, liver, bone and brain, and is presumed to be secondary to a lymphatic pathway. There are no previously documented reports of a focal pedunculated metastases located within the jugular vein. We present the first reported case of a metastatic MTC lesion found in the right internal jugular vein in a man with recurrent MTC.     

Somatic mutations in the RET protooncogene in Japanese and Chinese sporadic medullary thyroid carcinomas

Objective.Despite advances in the understanding of the genotype-phenotype correlation in multiple endocrine neoplasia type 2A and 2B(MEN 2A,MEN 2B),and familial medullary thyroid carcinoma (FMTC),the frequency and prognostic relevance of RET protoonco-gene mutations in sporadic medullary thyroid carcinomas (MTCs) remain controversial.Methods To study somatic mutations in the RET protooncogene in Japanese and Chinese sporadic MTCs and to comparatively analyze the correlation between RET mutation and tumor differentiation,we in-vestigated somatic mutations in the RET protooncogene in 20 Japanese and 20 Chinese sporadic MTCs by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.Results Of the 40 sporadic MTCs,13 had a point mutation in codon 918 of exon 16,a frequency of 32.5%。There was no significant difference in the frequency between Japanese and Chinese sporadic MTCs,as 30% of the Japanese and 35% of the Chinese sporadic MTCs contained this mutation.We did not observe any correlation between the presence or absence of codon 918 mutation and tumor differentiation in either Japanese or Chinese sporadic MTCs.Conclusion Our findings indicate that the frequency of RET somatic mutations is similar in Japanese and Chi-nese sporadic MTCs,and the presence or absence of RET mutation does not correlate with the differentiation of sporadic MTCs.     

Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship

HYPOTHESIS: Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC. DESIGN: Review of endocrine surgery database from 1951 through 2002. SETTING: Tertiary referral center. PATIENTS: Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918). MAIN OUTCOME MEASURES: Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism. RESULTS: RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations. CONCLUSION: Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.     

Phenotypic expression of a family with multiple endocrine neoplasia type 2A due to a RET mutation at codon 618

BACKGROUND: Multiple endocrine neoplasia type 2A (MEN2A) is caused by missense mutations in the RET proto-oncogene on chromosome 10. This paper reports the phenotypic expression of a family with MEN2A, in which serine substitutes for cysteine at codon 618 in exon 10 of the RET gene. It was first claimed that medullary thyroid cancer (MTC) with this rare mutation led to mild disease; this has recently been updated to intermediate-high risk, based on stratified genetic information. METHODS: The family was mapped over six generations. In 1971 family members were invited to join a screening programme. Genetic testing was started in 1994. RESULTS: Twenty-two individuals with MTC were identified, 16 by the screening programme. One screened patient had a phaeochromocytoma and four had hyperparathyroidism. At surgery for MTC 12 patients had local tumour metastases and two young patients also had liver metastases. No screened patient died from MTC during a mean observation time of 19 years. Six other family members were diagnosed with MTC by signs and symptoms, five of whom died from MTC. CONCLUSION: Because of the great interindividual differences in tumour aggressiveness within the family it is impossible to predict whether an individual gene carrier will have an aggressive MTC or not. This unpredictability is an additional argument, besides those obtained in stratified genetic studies, for operating on gene carriers at young age.     

Mutational analysis of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease.

BACKGROUND/PURPOSE: Germline mutations of the RET proto-oncogene (RET; 10q11.2) have been reported in multiple endocrine neoplasia type 2A (MEN 2A) and Hirschsprung's disease. The authors investigated a Japanese kindred in which MEN 2A and Hirschsprung's disease frequently have been found. METHODS: The pedigree consisted of 28 members (11 boys and 17 girls) spanning 4 generations, of whom, 8 were affected with MEN 2A or Hirschsprung's disease. RESULTS: Direct sequence DNA analysis of the RET proto-oncogene showed a heterozygosity for a G to C transition at the second nucleotide of codon 620 (exon 10) in the patients, resulting in the replacement of cysteine by a serine residue in the affected Ret protein. This family added a novel RET missense mutation (C620S) predisposing to the association of MEN 2A and Hirschsprung's disease. CONCLUSION: Detection of the mutated RET gene carriers may be used for genetic counseling of potential risk for Hirschsprung's disease as well as MEN 2A in the affected families.     

Absence of RET Proto-Oncogene Mutations in a Father and Son with Pheochromocytoma and Pancreatic Islet Cell Tumor

Background We describe a father and son with a combination of pheochromocytoma and pancreatic islet cell tumor. Although its familial occurrence is rare, this syndrome could be called overlapping-type multiple endocrine neoplasia (MEN), since it fulfills the criteria for both type 1 and type 2 MEN. Recently, germ line mutations of the RET proto-oncogene (RET) were found to be related to tumorigenesis and disease phenotypes in type 2 MEN.
Methods Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, we looked for germ line mutations of RET in 8 members of this family, including the 2 patients.
Results Analysis of RET exons 10, 11 and 16, which contain the hot-spot codons for MEN type 2, revealed no mutations in any individual examined.
Conclusion These findings suggest that these 3 exons in RET are not related to tumorigenesis in overlapping-type MEN.     

Genetic screening in hereditary medullary thyroid carcinoma

Summary Background: Medullary thyroid carcinoma (MTC) is sporadic in the great majority of cases but is the sine qua non of multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer syndrome. Depending on the tissues affected, MEN 2 is divided into 3 subtypes. MEN 2A is characterized by the presence of MTC, pheochromocytoma and hyperparathyroidism. MEN 2B is characterized by MTC, pheochromocytoma and typical stigmata. FMTC comprises MTC as the only disease feature. Germline mutations in theRET protooncogene, which encodes a receptor tyrosine kinase, have been shown to cause all 3 subtypes of MEN 2. Methods: Analyses utilize PCR-based protocols targeted at exons 10, 11, 13, 14 and 16: target exonic sequences are amplified either for direct sequencing and/or restriction endonuclease digestion where mutations would create or cause loss of specific sites. Results: Mutations in one of codons 609, 611, 618, 620 (exon 10) and 634 (exon 11) are associated with MEN 2A while mutation in codon 916 (codon 16) causes MEN 2B. Recently mutations in codons 768 and 804 were shown to be associated with FMTC only. Conclusions: These findings have made accurate DNA-based genetic testing possible, thus targettingRET mutation positive individuals for prophylactic surgery and/or surveillance while mutation negative individuals can be reassured.      

Medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is subdivided into sporadic (75 %) and hereditary (25 %) forms. Several germline mutations in the RET proto-oncogene are the source of distinct clinical phenotypes in hereditary MTC including familial MTC (FMTC) and multiple endocrine neoplasia 2A (MEN 2A) and 2B (MEN 2B). The higher the penetrance of the MEN 2 phenotype the earlier the progression of MTC which forms the basis for the currently recommended codon-related concept of prophylactic thyroidectomy. In patients with sporadic MTC, routine calcitonin (CT) measurement in nodular goiter patients has been shown to reduce the frequency of advanced tumor stages. Patients with CT levels over 100 pg/ml after pentagastrin stimulation are recommended for total thyroidectomy. In patients with unexpected sporadic MTC after histological examination, completion thyroidectomy is currently only recommended when CT levels remain elevated. The extent of lymph node dissection in patients with MTC is controversial. However, with respect to lymphonodal micrometastases, systematic compartment-oriented microdissection has been shown to reduce the frequency of lymphonodal recurrence. On the other hand, to avoid unnecessary lymph node dissection, a more individualized concept is required in the future. New chemotherapeutic agents (tyrosine kinase inhibitors), therapeutic nuclids (90Yttrium-labeled octreotide), and chemoembolization of liver metastases are currently the most promising therapeutical concepts in patients with distant metastases.     

Medullary thyroid carcinoma: state of the art

Medullary thyroid carcinoma (MTC) constitutes about 3-10% of all thyroid cancers. It arises from the parafollicular C cells that produce calcitonin (CT) and occurs as a sporadic form. or less commonly, as a hereditary form, as part of multiple endocrine neoplasia syndromes types 2A (MEN 2A) and 2B (MEN 2B). The hereditary forms are autosomal dominant traits associated with germline mutations of RET proto-oncogene. Progresses in genetics have permitted an improvement of management, screening and treatment. Surgery is the only successful treatment for MTC, as there is no effective adjuvant therapy for residual disease. A total thyroidectomy and vigilant management and surveillance of the neck are recommended. Interdisciplinary management including surgeons, endocrinologists, pathologists, radiotherapists, radiologists, and oncologists should be considered.     

Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre

BACKGROUND: Evidence that germline mutations in the RET proto-oncogene are the underlying cause of the familial form of medullary thyroid carcinoma (MTC) made it possible to identify gene carriers with a very high degree of accuracy. Aiming to define the mutational profile observed in our patients and to assess gene carriers' compliance with an early surgery, we reviewed results of molecular analysis of RET performed at our institution since 1994. METHODS: One hundred fifty-eight individuals were screened for germline mutations of the RET proto-oncogene. Seventy-seven patients had apparently sporadic MTC; 8 patients had both MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B despite a negative family history; 8 patients were known to belong to affected kindreds; and 65 individuals were at-risk individuals to develop MTC. RESULTS: A germline mutation in RET was identified in 4% of apparently sporadic MTC patients, in 100% of patients with MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B, and in 100% of probands of clinically established kindreds. The most affected codon was 634 (58%) followed by codon 804 (16%). Among at-risk individuals, 49% were identified as gene carriers. Seven individuals were submitted to prophylactic thyroidectomy (mean age, 17.7 +/- 12.5 years; range: 3-42 years), and all but 1 had MTC. CONCLUSIONS: RET mutational spectrum observed in the present population disclosed a higher frequency of codon 804 mutations than expected. Compliance with an early prophylactic surgery seemed to be influenced not only by medical advice and cultural factors but also by the aggressiveness of disease in gene carriers' families.     

Medullary thyroid carcinoma. Genetic screening and prophylactic thyroidectomies

Medullary thyroid cancer is a rare, neuroendocrine, tumor. It arises from parafollicular or C-cells with the ability to produce and secrete different bioactive substances like calcitonin (TC) and CEA (1-5) TC is ideal tumor marker in early diagnosis, in patents' follow up and in evaluation of their treatment. TC determinations after ca/pentagastrine stimulation test give us even more accurate results and the procedure is used for biochemical family screening. MTC occurs as a sporadic tumor or in hereditary settings MEN 2A, MEN 2B and FMCT. Germ/line point mutations in RET proto/onkogene are responsible for tumor arise and inheritance of settings. Genetic screening provides information of these RET mutations in family members even before pathologic changes occur. These individuals with MEN 2A, 2B and FMCT characteristic RET mutations are almost certain to acquire MTC (95% penetrance) in their lives and are candidates for preventive total thyroidectomy (TT), with or without central neck dissection (CND). Surgery is still the treatment of choice for MTC and only C-cell hyperplasia and early stage of MTC can be cured. Prophylactic thyroid surgery eliminates the possibility of MTC but doesn't influence appearance of other diseases (PHEO, HPTH) of MEN 2 syndromes.     

A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease

Purpose

The RET proto-oncogene is involved in neural crest disorders. Activating germline mutations in the RET proto-oncogene cause the development of familial medullary thyroid carcinoma (FMTC) or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Inactivating germline mutations in the RET proto-oncogene are detected in Hirschsprung's disease (HSCR). Only in a very small number of families are these 2 diseases expressed together.

Methods

This study presents a novel Czech kindred with FMTC-HSCR phenotype. Two family members (mother and daughter) were tested for RET germline mutations in exons 10, 11, 13, 14, 15, and 16.

Results

Direct fluorescent sequencing of genomic DNA revealed a heterozygous mutation in the RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was reclassified, thanks to genetic screening from the apparently sporadic MTC-HSCR to FMTC-HSCR.

Conclusion

The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be added to the small worldwide cohort of families with MEN2A/FMTC-HSCR.     

多发性内分泌肿瘤2型的诊断和外科处理

目的 探讨多发性内分泌肿瘤2型（multiple endocrine neoplasia,MEN2）的诊断和外科处理方法.方法 回顾性研究1997年6月至2006年6月我院诊断和治疗的MEN2患者28例的临床资料.结果 MEN2a型25例,其中23例分属7个家系,均有RET基因11外显子634编码子突变;MEN2b型3例,无家族史,为RET基因16外显子918编码子突变.MEN2a型中22例有甲状腺肿物伴降钙素升高,其中17例经病理证实为甲状腺髓样癌;12例合并嗜铬细胞瘤,其中5例为多发性,2例恶性;5例合并甲状旁腺功能亢进症,3例无临床症状及生化改变.3例MEN2b型均为甲状腺髓样癌合并黏膜神经瘤病和马凡样体形,其中1例伴双侧肾上腺嗜铬细胞瘤.MEN2a型中12例接受双侧甲状腺全切除＋双侧颈淋巴清扫,5例行甲状腺肿物切除;甲状旁腺病变在甲状腺手术时一并处理;9例接受11次肾上腺肿瘤摘除术,3例为双侧肾上腺手术.3例MEN2b型均行双侧甲状腺全切除＋双侧颈淋巴清扫.结论 MEN2型以甲状腺髓样癌为主要病变,基因筛查可帮助早期诊断.根治性甲状腺切除能预防和治疗甲状腺髓样癌.     

Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children

BACKGROUND: Patients with multiple endocrine neoplasia (MEN) type 2 are at risk for early medullary thyroid carcinoma (MTC). Recently, the cloning of the ret oncogene has made it possible to identify patients at risk for MEN 2 syndrome with a high degree of reliability before presenting any symptoms. METHODS: Children of families with MEN 2 were screened genetically if one of the parents was a known gene carrier of the RET proto-oncogene. If they were carriers, thyroidectomy was performed. RESULTS: The authors report five children with MEN 2 who underwent prophylactic thyroidectomy irrespective of the results of calcitonin screening tests after genetic screening had shown that they were carrier of the RET proto-oncogene. Apart from a temporary hypocalcemia in one, the operations were uneventful. Pathology results showed MTC in three children of one family with MEN 2A at age 2, 3, and 6 years. In two families with MEN 2B the thyroidectomy specimen showed bilateral MTC in a 1-year-old and a 3-year-old child. CONCLUSIONS: These findings show that MTC occurs at very young age in children with MEN 2. The authors advocate performing prophylactic thyroidectomy in the first year of life in children with MEN 2B and at age 2 years in children with MEN 2A to obtain an optimal cure rate.     

A high level of carcinoembryonic antigen as initial manifestation of medullary thyroid carcinoma in a patient with subclinical hyperthyroidism

Carcinoembryonic antigen (CEA), a tumor marker with a glycoprotein structure, is frequently used in follow-up gastrointestinal malignancies. CEA levels may also increase in neuroendocrine tumors, including medullary thyroid carcinoma (MTC), and in some benign diseases. Patients whose blood tests show high CEA levels should have additional tests regarding MTC. Although MTC comprises only 3%-11% of all thyroid cancers, it should be tested because it has a poor prognosis and may accompany multiple endocrine neoplasia. We present the case of a 76-year-old man with subclinical hyperthyroidism with sporadic MTC who presented with initial high serum CEA levels. He underwent total thyroidectomy and left modified neck dissection. Pathologic specimens stained strongly for CEA. The patient's blood was analyzed for mutations in exons 10, 11, 13, 14, 15, and 16, but the RET proto-oncogene revealed no mutations. The patient was regularly followed by measurement of serum CEA levels and performance of positron emission tomography-computed tomography. Seventeen months after surgery, the patient has remained well and showed no signs of tumor recurrence.