Clinical case of familial medullary thyroid carcinoma

Medullary thyroid cancer (MTC) accounts for 5—10 % of all thyroid cancers. Most cases are sporadic (75 %), but the proportion of patients with MTC and familial medullary thyroid carcinoma (FMTC) is the highest among any hereditary cancer syndromes (appro­ximately 25 %), and this risk should be considered when evaluating a patient with MTC. In this clinical case study, case of FMTC has been elucidated. Diagnostic criteria of the disease, molecular-genetic aspects, treatment tactics and post-operative observation findings have been presented. The case study illustrates, the efficacy of genomic profiling for the identification of molecular genetic drivers of the disease and its role in ensuring proper and timely diagnosis and treatment of familial form of MTC. When planning prophylactic thyroidectomy, it is recommended to focus on the stratification of the level of RET gene mutation and the timing of prophylactic thyroidectomy as proposed by the American Thyroid Association. The use of molecular genetic investigations in clinical practice for diagnosing MTC makes it possible to objectify the genetic line of the disease in a particular biological family. The patient was found to have a pathogenic germline missense mutation c.2304 G> T (p.E768D, CM020961) in a heterozygous state, which refers to moderate risk of aggressiveness of MTC. In addition, molecular genetic test was performed for the patient's biological child, a 4-year-old girl. Pathogenic mutation was found in the CHEK2 gene, c.47OT> C (p.Ile 157 Thr) in a heterozygous state. These mutations increase the risk of developing breast cancer by 2-3 times, and by 4-5 times in the presence of family history of cancer. The presence of this mutation increases the risk of developing other types of cancers such as stomach, breast, intestinal, prostate and thyroid cancers. Timely diagnosis of FMTC allows to formulate adequate treatment strategy at the preclinical stage of the disease and can significantly improve the quality and duration of life.

RET Proto-Oncogene Mutational Analysis in 45 Iranian Patients Affected with Medullary Thyroid Carcinoma: Report of a New Variant

Background. The aim of this study was to identify germline mutation of the RET (rearranged during transfection) gene in patients with medullary thyroid carcinoma (MTC) and their first-degree relatives to find presymptomatic carriers for possible prophylactic thyroidectomy. Methods/Patients. We examined all six hot spot exons (exons 10, 11, 13, and 14–16) of the RET gene by PCR and bidirectional Sanger sequencing in 45 Iranian patients with MTC (either sporadic or familial form) from 7 unrelated kindred and 38 apparently sporadic cases. First-degree relatives of RET positive cases were also genotyped for index mutation. Moreover, presymptomatic carriers were referred to the endocrinologist for further clinical management and prophylactic thyroidectomy if needed. Results. Overall, the genetic status of all of the participants was determined by RET mutation screening, including 61 affected individuals, 22 presymptomatic carriers, and 29 genetically healthy subjects. In 37.5% (17 of 45) of the MTC referral index patients, 8 distinct RET germline mutations were found, including p.C634R (35.3%), p.M918T (17.6%), p.C634Y (11.8%), p.C634F (5.9%), p.C611Y (5.9%), p.C618R (5.9%), p.C630R (5.9%), p.L790F (5.9%), and one uncertain variant p.V648I (5.9%). Also, we found a novel variant p.H648R in one of our apparently sporadic patients. Conclusion. RET mutation detection is a promising/golden screening test and provides an accurate presymptomatic diagnostic test for at-risk carriers (the siblings and offspring of the patients) to consider prophylactic thyroidectomy. Thus, according to the ATA recommendations, the screening of the RET proto-oncogene is indicated for patients with MTC.

Late-Onset Medullary Thyroid Cancer in a Patient with a Germline RET Codon C634R Mutation

Background: Multiple endocrine neoplasia type 2A (MEN2A) is a rare, hereditary syndrome resulting from a germline mutation in the RET proto-oncogene and characterized primarily by medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and hyperparathyroidism. Types of RET mutation have been associated with age at onset, clinical outcomes of MTC, and the penetrance of other components. Patients classified as ‘high-risk’ by the American Thyroid Association (ATA), based on the aggressiveness of MTC and the penetrance of other components, are recommended to undergo early prophylactic thyroidectomy at age ≤ 5 years and to be screened for PHEO at age ≥ 11 years. Patients with RET codon C634R mutations have been classified as high-risk. Case presentation: The present study describes a 71-year-old woman newly diagnosed with hereditary MTC related to a RET C634R germline mutation. Her basal serum calcitonin level was high, but there was no evidence of distant metastases. Surgery revealed bilateral MTC with two metastatic lymph nodes. Because microscopic resection was incomplete and extranodal extension was observed, the patient underwent adjuvant external beam radiotherapy. Response to therapy was excellent. Follow-up after 1.5 years showed no evidence of disease or other manifestations of MEN2A. Conclusion: Despite RET C634R carriers being classified as high-risk by the ATA, this patient did not present with either distant MTC or PHEO until her seventies. To our knowledge, only one other patient has shown a similar late identification of a RET C634R mutation, but MTC could not be diagnosed because the patient was lost to follow-up. Further research is required to develop optimal protocols that could allow patients requiring prophylactic thyroidectomy to be differentiated from those who can be monitored closely without early surgery.

Zebra Case of Papillary Thyroid Cancer in MEN-2 Syndrome

Introduction: The occurrence of papillary thyroid cancer in patients with familial medullary thyroid cancer (FMTC) is extremely rare and underreported. Case Presentation: A 51-year-old caucasian female with no past medical history who presented to primary care physician for her annual visit. She denied any complaints. Vital signs were unremarkable. Physical examination was remarkable for large left thyroid nodule without cervical lymph nodes enlargements. Family history was significant for metastatic MTC of her two sisters (at the age of 55, 60) and her niece at age of 21. She previously declined genetic testing. Labs were unremarkable including serum calcium of 8.3 mg/dL. Thyroid function panel revealed a TSH of 2.1 μU/mL, Free T4 of 1.4 ng/dL, Thyroid peroxidase (TPO) antibody of <6 IU/mL. Neck ultrasonography revealed a mid-left thyroid hypoechoic nodule of 1.8 ×1.5 cm, without cervical lymph nodes enlargements. Fine needle biopsy revealed a papillary thyroid cancer, follicular variant. The diagnosis confirmed by two university pathologists, without any evidence of MTC. Genetic testing revealed a germline mutation in RET oncogene exons 13. Further labs revealed normal metanephrines of 12 pg/mL and normal normetanephrine of 31 pg/mL, normal serum calcitonin was less than 2 pg/mL (0-5), normal serum CEA was 2.5 ng/mL (0-5), elevated anti- thyroglobulin (anti-TG) antibodies of 1234 iu/mL (0-0.9), and elevated thyroglobulin of 50 ng/mL (1.5-38.5). The patient was referred to ENT for total thyroidectomy. Further, she was treated with radioactive iodine ablation by 155 mCi of iodine 131. Follow up whole body thyroid scan revealed no evidence of residual or recurrence. The patient was treated with 112 mcg levothyroxine with a target of TSH less than 0.1. On six months follow up, repeated neck ultrasonography revealed no remnant of thyroid tissue. Follow up Thyroglobulin (TG) was less than 0.1 ng/mL, TSH 0.05 μU/mL, FT4 of 1.98 ng/dL, and calcitonin was still less than 2 pg/ml. Genetic testing of her daughters (24, 31) revealed germline mutations in RET-oncogene exons 13 and was referred for prophylactic thyroidectomy. Discussion: FMTC is an inherited syndrome characterized by the presence of only MTC without hyperparathyroidism or pheochromocytoma and is considered a variant of MEN2A. Most cases of MEN2A have been attributed to mutations in the intracellular portion of RET, and somatic mutations in RET have been identified in 50% of cases of sporadic FMTC. We recommend in patients with germline RET mutations and a family history of MTC, the diagnosis of papillary thyroid cancer should be confirmed by two pathologists, and patients should be tested for serum calcitonin, serum calcium, and metanephrines/normetanephrine levels. Genetic testing of first-degree relatives of FMTC at an early age is essential in guiding major management decisions such as the timing of prophylactic thyroidectomy.

Pheochromocytoma: Impact of genetic testing on clinical practice in Vietnam

Introduction: Germline mutations in predisposing genes have been found in 30-40% of pheochromocytoma/paraganglioma patients. Screening for inherited genetic mutations provide clinicians with mutation-positive patient management strategies in addition to identifying family members at risk of disease. However, genetic testing for pheochromocytoma has not been performed widely in Vietnam. Methods: Seven patients diagnosed with pheochromocytoma in Vietnam underwent germline genetic testing in known pheochromocytoma-associated genes by direct sequencing. When a germline mutation was identified the first-degree relatives were counseled and offered genetic testing for the inherited mutation. Results: Mutations were found in five of seven cases and all mutations were in RET proto-oncogene codon 634 indicating a high risk of developing aggressive medullary thyroid cancer and in some cases leading to prophylactic thyroidectomy as recommended. Conclusions: Genetic testing plays an essential role in the clinical management of pheochromocytoma patients. Genetic results have significantly changed the clinical approach in these patients and identified ‘at risk’ family members.

RET Proto-Oncogene Mutational Analysis in Patients With Medullary Thyroid Carcinoma

Background: The aim of this study was to identify germline mutation of the RET (rearranged during transfection) gene in patients with Medullary Thyroid Carcinoma (MTC) and their first-degree relatives to find pre-symptomatic carriers for possible prophylactic thyroidectomy.Methods and results: We examined all six hot spot exons (exons 10, 11, 13, and 14-16) of the RET gene by PCR and bidirectional sanger sequencing in 45 Iranian patients with MTC (either sporadic or familial form) from 7 unrelated kindreds and 38 apparently sporadic cases. First-degree relatives of RET positive cases were also genotyped for index mutation. Moreover, pre-symptomatic carriers were referred to the endocrinologist for further clinical management and prophylactic thyroidectomy if needed. Overall, the genetic status of all of the participants was determined by RET mutation screening, including 61 affected individuals, 22 pre-symptomatic carriers and 29 genetically healthy subjects. In 37.5% (17 of 45) of the MTC referral index patients, seven distinct RET germline mutations were found, including p.C634R (35.3%), p.M918T (17.6%), p.C634Y (11.8%), p.C634F (5.9%), p.C611Y (5.9%), p.C618R (5.9%), p.C630R (5.9%), p.L790F (5.9%) and an uncertain variant p.V648I (5.9%). Conclusion: RET mutation detection is a promising/golden screening test and provides an accurate pre-symptomatic diagnostic test for at-risk carriers (the siblings and offspring of the patients) to consider prophylactic thyroidectomy. Thus, mutation screening of the RET hot spot exons could be suggested for any MTC patient to find pre-symptomatic RET carriers in their relatives.

MON-450 Prophylactic Thyroidectomy in a Patient with Codon 891 Mutation of the RET Proto-Oncogene

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland, accounting for 1-2% of thyroid cancers in the United States. About 25% MTCs are familial as a part of the MEN2 syndrome or familial MTC (FMTC). Germline mutations in codon 891 are predominantly associated with FMTC. Case: 65-year-old Caucasian male was referred to the Endocrinology clinic after bilateral thyroid nodules were found on thyroid US. The patient had requested an ultrasound of his thyroid after his brother was diagnosed with MTC following fine-needle aspiration for an incidental thyroid nodule prompting total thyroidectomy and genetic testing. The patient’s brother was found to be heterozygous for RET mutation (c.2617T>G;pSer891Ala). This resulted in screening of the other siblings including this patient, also found to be heterozygous for this mutation. Both parents were deceased, and their clinical history is not known. Only one of the remaining two siblings had genetic testing; one brother refused testing for the mutation and one sister was positive for the mutation but had no thyroid nodules on ultrasound. She underwent prophylactic thyroidectomy. Neither the patient, nor his siblings, have any progeny. The patient screened negative for primary hyperparathyroidism and pheochromocytoma. Calcitonin (739, normal </=14.3 pg/mL)and CEA levels (31.7, 0-3.0 ng/mL) were elevated. Thyroid ultrasound (US) showed two solid hypoechoic nodules with lobulated margins and internal coarse calcifications in the right and two in the left thyroid lobe; 1.5 cm and 1.2 cm in maximum diameter, and 1.2 cm and 3 mm in maximum diameter, respectively. Based on elevated calcitonin and CEA levels, known RET mutation and evidence for thyroid nodules, we recommended a total thyroidectomy and central neck dissection. Pathology revealed multifocal, bilateral medullary carcinoma (largest focus of 1.5 cm), with 4/4 lymph nodes positive for metastasis. This was classified as mpT1bN1aM0 (Stage III). Patient was started on levothyroxine with plans to repeat calcitonin and CEA levels and neck ultrasound, 3 months following surgery. CT chest, abdomen and pelvis did not reveal any distant metastasis. Conclusion: Inherited MTCs are rare. Early diagnoses by screening of at-risk family members in MEN2 kindreds is important because MTC can be life-threatening and can be cured and prevented by early thyroidectomy. While our suspicion for FMTC in this patient and his siblings is high, FMTC is now considered a variant of MEN2A and ongoing screening for pheochromocytoma and primary hyperparathyroidism is recommended.

Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A in children: a single centre experience

Background To describe the complications and long-term results in patients with multiple endocrine neoplasia type 2A (MEN 2A) syndrome in whom a prophylactic thyroidectomy was performed, in relation to the recommendations of the American Thyroid Association (ATA). Methods A retrospective study of 14 patients with MEN 2A thyroidectomized between 2000 and 2017. We reviewed demographic, clinical, analytical and radiological data. Postoperative complications and long-term follow-up were analyzed. Results We treated eight boys and six girls with a median age of 5 years old (range 2–10). The predominant genetic mutation belonged to codon 634 (8/14, 57.14%). Total thyroidectomy (TT) without cervical lymphadenectomy was performed in all patients. A right upper parathyroidectomy was performed in one patient due to intraoperative suspicion of increased volume. Histological study revealed no alterations. Two patients presented transient hypocalcemia postoperatively and no patient had permanent hypocalcemia or nerve damage. Pathological anatomy confirmed medullary thyroid microcarcinoma in 5/14 patients: all carrying codon 634 mutation and three of them with preoperative basal calcitonin levels <20 pg/mL. No recurrences or metastases have been detected after a mean follow-up of 8 years. A patient with codon 634 mutation developed a unilateral pheochromocytoma at 25 years of age. No patient has presented hyperparathyroidism. Conclusions Prophylactic thyroidectomy without cervical lymphadenectomy is an effective and safe preventive treatment in patients with MEN 2A syndrome when it is performed by experienced surgeons in reference centers.