Tehran University Medical Journal

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In this paper we have reported and discussed an unusual histopathologic feature of medullary carcinoma which is one of the pitfalls in the diagnosis of this tumor. The patient was a 14 years old girl who complained of painless, gradually growing cervical mass from one year ago. She had no history of head and neck radiotherapy of familial history of thyroidal or other endocrine disease. In laboratory investigations a cold thyroid nodule was confirmed and FNA of it was reported as follicular lesion. The patient underwent lobectomy isthmectomy with frozen section wich was reported as Hurthle neoplasm and then the other lobe of patient's thyroid resected. In it's pathologic exam another nodule was observed which mostly composed of spindle cells at last histochemically medullary carcinoma confirmed

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Background: Simple bone cyst is a common benign lesion in the proximal humerus, especially in prepubertal children. Up to 75 percent of patients with the bone cyst have a pathologic fracture and the most significant complication is recurrent pathologic fracture. Since the process of spontaneous healing of these fractures is rare, treatment is required. Ideal treatment for simple bone cyst should stabilize pathologic fractures, assist healing and provide a quick return to normal activity with reduced complication and recurrence.
Methods: In this descriptive case series study, 24 patients with simple bone cysts of the humerus were selected for retrograde flexible intramedullary nailing from the lateral cortex of the distal humerus, since 2000 to 2005 at Imam Khomeini Hospital, Tehran. The mean age of the patients was 14.4 years, ranging from 6-39 years. Results were evaluated by plain radiography using the classification system of Capanna et al.
Results: The mean duration of follow up for 23 of the patients was 31 (9-51) months. One patient with short-term of follow-up was excluded. Of these patients, 91.3% were healed either completely (65.2%) or with residual minor defect (26.1%). Only one cyst (4.3%) persisted with no response to treatment and one patient (4.3%) had a recurrence of the cyst. However, there was no instance of recurrent pathologic fracture among these patients.
Conclusion: This study shows that flexible intramedullary nailing is an effective treatment for humeral simple bone cysts that reduces the chance of complication, recurrence of cyst or pathologic fracture. This technique provides sufficient stability for quick return to normal activity.

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Background: Thyroid carcinoma is the most frequent malignant tumor of the endocrine system in human body and accounts for nearly 1% of all cancers. Medullary thyroid carcinoma is the third frequent of thyroid cancer and accounts about 5-8% of thyroid cancer. Osteocalcin, known as a Bone Gamma-carboxyglutamic Acid-containing Protein (BGLAP), is the most non collagenous protein. Retinol binding proteins are the family of proteins that have diverse actions but mainly transport retinol in human body. In this study to evaluate effect of existence medullary thyroid carcinoma on metabolism of bone and adipose tissue, plasma level of two mentioned proteins had analyzed. Methods: Population in this study consists of 46 individuals with medullary thyroid carcinoma and 44 healthy subjects referred individuals to Research Institute for Endo-crine Sciences, Shahid Beheshti University of Medical Sciences. People with the disease after diagnosis of medullary thyroid carcinoma and pathologically confirmed by biopsy in the initial stages of the study were called. After informed consent, 10 ml of blood from the antecubital vein of left hand in sitting position obtained and after cen-trifugation, plasma was isolated from all samples until analyzed kept in the freezer. Plasma levels of hormones were measured by sandwich type ELISA method. Obtained results were analyzed by SPSS version 16 with independent t-test method. Results: Mean plasma level of osteocalcin in patients was 33.1±3.5 and in healthy sub-jects was 12.5±1.2 ng/ml (Mean±SD) and Odds Ratio (OR) value was 1.04. In patients, mean plasma level of retinol binding protein was 82.5±2.7 and in healthy subjects was 22.8±1.6 μg/ml and OR value was 2.1. The confidence level considered at 95%. These differences of plasma levels were statistically significant (P= 0.001). Conclusion: According to difference between plasma levels of osteocalcin and retinol binding protein-4 in patients suffered of medullary thyroid carcinoma comparison with normal subjects, it can be said that, probably medullary thyroid carcinoma has effect on bone and adipose tissue metabolism, so osteocalcin and retinol binding protein-4 hormones have potential to be used for confirmation of diagnosis or following treatment of medullary thyroid carcinoma.

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Background: Medullary thyroid carcinoma (MTC) occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of the rearranged during transfection (RET) proto-oncogene in MTC development have been well demonstrated. Several studies have been published that indicate the molecular analysis of RET gene may offer early identification of those patients at high risk to develop MTC and may provide the opportunity for early intervention. The aim of this study was to investigate frequency of G691S/S904S haplotype in MTC patients and their relatives. Methods: From 2004 to 2014, 358 participants were studied, including 213 patients (119 female, 94 male) and 145 their relatives (79 female, 66 male) in cellular and molecular research center of Shahid Beheshti Research Institute for Endocrine Sciences, Tehran, Iran. Genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection was performed using PCR and direct DNA sequencing methods. The RET mutations and SNPs, sequences were analyzed. Results: According to DNA sequencing results, 189 individuals (119 patients, 70 relatives) had both G691S (rs1799939) missense mutation in exon11 and S904S (rs1800863) synonymous mutation in exon 15 of RET proto-oncogene. The allele frequency of G691S/S904S haplotype was 35.02% in patients and 29.92% in their relatives. Conclusion: The obtained data showed the frequency of G691S/S904S RET gene haplotype among Iranian MTC patients and their relatives. The G691S and S904S nucleotide changes were in complete linkage disequilibrium, so the results were grouped together and referred to as G691S/S904S haplotype. This haplotype are not considered as oncogenic mutations at this time, its functional role should be investigated. Further analysis is needed to demonstrate the association between this haplotype and MTC development.

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Background: Medullary thyroid cancer (MTC), includes 5-10% of all the thyroid cancers. RET proto-oncogene mutations have been found in association with MTC development. Therefore, identification of the mutations in RET can allow early diagnosis of the families who are at the risk of the disease. The goal of this study was to investigate existence and association between mutations in exon 19 of the RET proto-oncogene in an Iranian population medullary thyroid cancer patients and their family members. Methods: This study was run in the research laboratory of Research Institute for Endocrine Research Center Shahid Beheshti University of Medical Sciences from May, 2013 to May, 2014. In this study, 110 patients with confirmed medullary thyroid carcinoma were selected and examined. At first, the genomic DNA content of the peripheral white blood cells (WBC) of the samples were extracted using a saturated salting out and proteinase K standard method. Exon 19 of the RET proto-oncogene using polymerase chain reaction (PCR) method was amplified. Then the desired PCR products formation was confirmed by electrophoresis technique for true amplification, and finally the amplified samples were used for direct sequenced for finding and assessing any possible mutations Results: In this study, two nucleotide changes at position rs2075912 (Y: T/C) and position rs2075913 (W: T/A) exon 19 RET proto-oncogene were found in the patients with medullary thyroid cancer. The frequency of both nucleotide changes were higher in men than women with medullary thyroid cancer. The frequency of the rs2075912 and rs2075913 were 11.2 and 6.3% higher in men than women. But in statistical analysis, there was no association between age, sex and the founded two mutations. Conclusion: In addition to mutations in other exons of proto-RET, mutations in exon 19 can also be used for early detection and confirmation of medullary thyroid carcinomas.

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Background: Thyroid carcinoma is the most common endocrine malignancy. Medullary thyroid carcinoma (MTC) approximately accounts for 5-10% of all thyroid carcinoma. Nowadays, it is obviously, the mutations in REarranged during transfection (RET) proto-oncogene, especially, mutations in exons 10, 11 and 16 are associated with MTC pathogenesis and occurrence. Thus, early diagnosis of MTC by mutation detection in RET proto-oncogene allows to identify patients who do not have any developed symptoms. The aim of this study was to screening of germline mutations in RET proto-oncogene exons 17 and 18 in MTC patients and their first degree relatives in Iranian population.

Methods: In this cross-sectional study, three hundred eleven participates (190 patients, 121 their relatives) were referred to endocrine research center, Shahid Beheshti University of Medical Science during September 2013 until September 2015. The inclusion criteria were pathological and clinical diagnosis. After whole blood sampling, genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection in exons 17 and 18 was performed using PCR and direct DNA sequencing methods.

Results: In this study, twenty missense mutations [CGC>TGC, c.2944C>T, p.Arg982Cys (rs17158558)] which included 16 heterozygote and 4 homozygote mutations were found in codon 982 (exon 18). In the present study, 154 G>A (rs2742236) and 4 C>T (rs370072408) nucleotide changes were detected in exons 18 and intron 17 respectively. There was no mutation in exon 17. Conclusion: It seems that because of arginine to cysteine substitutions in RET tyrosine kinase protein structure and its polyphen score (0.955) and SIFT score (0.01) the mutation in codon 982 (exon 18) could be have pathogenic effects. On the other hands, the mentioned mutation frequency was 6.4% among MTC patients, so this mutation of exon 18 could be checked in genetic screening tests of RET proto-oncogene. Although this needs more study.

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Medullary thyroid cancer accounts for 5-10% of thyroid carcinomas. RET proto-oncogene mutations occur in all of the hereditary MTCs and about 66% of the sporadic MTCs. So, the detection of the RET mutations is necessary for rapid and proper diagnosis and treatment. This systematic review seeks to find a comprehensive list of RET gene mutations in the diagnosis of medullary thyroid cancer.
The previous studies on RET proto-oncogene mutations in the diagnosis of medullary thyroid cancer were searched in the major databases including PubMed, Scopus, Medline, Embase and NCBI between 2010 and 2021.
Missense mutations in exons 10, 11, 13, 14, 15, and 16 of the RET proto-oncogene have the highest frequency in MTCs. The most common mutations in FMTC, are in codons 609, 611, 618, and 620 in exon 10, codon 768 in exon 13, codon 804 in exon 14, and codon 634 in exon 11. In the case of MEN2A, RET gene mutations have been observed in exons 5, 8, 10, 11, with the highest mutations in exons 10 (codons 609, 611, 618, and 620) and exon 11 (codons 630 and 634). Moreover, M918T mutation in exon 16 and A883F mutation in exon 15 have been detected in 95% and 5% of the patients with MEN2B respectively. In the case of MTC, the M918T mutation in exon 16 is the most common mutation, which is associated with a poor prognosis. RET genetic screening is crucial for an exact approach to the diagnosis and treatment of MTC. Anyone with MTC, even without a family history of MEN2, should be genetically tested for the RET mutations to confirm or rule out the inherited disease and, if necessary, preventive thyroidectomy. This systematic review provided a comprehensive list of the reported mutations in the RET gene for the diagnosis of medullary thyroid cancer.