Modifying impact of RET gene haplotypes on medullary thyroid carcinoma clinical course
Marta Kaczmarek-RyśKatarzyna ZiemnickaAndrzej PławskiBartłomiej BudnyMichał MichalakSzymon HryhorowiczJustyna Hoppe-GołębiewskaPaweł BoruńMonika GołąbMałgorzata CzetwertyńskaMaria SromekMarlena SzalataMarek RuchałaRyszard Słomski
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Abstract:
The clinical course of medullary thyroid carcinoma (MTC) associated with the MEN2A syndrome as well as of sporadic MTC shows considerable heterogeneity. The disease picture varies not only between the same RET proto-oncogene mutation carriers but also among sporadic MTC patients with no RET germinal mutations, which suggests the involvement of additional modulators of the disease. However, genetic factors responsible for this heterogeneity of the MTC clinical course still remain unknown. The aim of this study was to determine if polymorphic variants or specific haplotypes of the RET gene may modify the MTC clinical course. We genotyped the following loci: c.73+9277T>C, c.135G>A, c.1296A>G, c.2071G>A, c.2307T>C, c.2508C>T and c.2712C>G in 142 MTC patients and controls. We demonstrated considerable differences in the genotypes distribution within c.73+9277T>C, c.135G>A and c.2307T>C loci Our results show that the c.73+9277T variant associated with a decreased activity of the MCS+9.7 RET enhancer is rare in hereditary MTC patients with primary hyperparathyroidism, and thus, may influence the MTC clinical picture. The decreased activity of the RET promoter enhancer reduces RET expression level and may counterbalance the activating mutation in this gene. Frequent co-occurrence of the c.73+9277T allele with p.E768D, p.Y791F, p.V804M or p.R844Q RET mutations may be associated with their attenuation and milder clinical picture of the disease. Haplotypes analysis showed that C-G-A-G-T-(C)-C (c.73+9277T>C - c.135G>A - c.1296A>G - c.2071G>A - c.2307T>G - (c.2508C>T) - c.2712C>G) alleles combination predisposes to pheochromocytomas and primary hyperparathyroidism. We consider that RET haplotypes defining may become an auxiliary diagnostic tool in MTC patients.Keywords:
Medullary carcinoma
Medullary carcinoma of the breast is a rare specific type breast cancer. It has peculiar clinical features including favorable prognosis. In a series of 373 cases of breast cancer operated on at the hospital from 1990 to the end of 1997, eight (2.1%) cases were initially diagnosed as medullary carcinoma of the breast by postoperative pathological study. In this study, the specimens from the eight tumors were re-evaluated according to the pathological criteria given by Ridolfi and his coworkers. Five tumors were classified as typical medullary carcinoma (TMC), and three tumors as atypical medullary carcinoma (AMC). Ultrasonography images revealed well-circumscribed, hypoechoic nodules. On mammography the tumors were unclassified masses with indistinct or circumscribed borders. Enhanced magnetic resonance imaging revealed homogeneously enhancing masses with well-defined borders. Although AMC is similar to TMC in pathological findings, AMC lacks in clinical characters of medullary carcinoma, and hence it is important to distinguish TMC from AMC. Any diagnostic modalities could not reliably help to distinguish TMC from AMC.
Medullary carcinoma
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SUMMARY The findings in two cases of medullary carcinoma of the thyroid are reported, the patients being a mother and her daughter. The mother was also found to have previously unsuspected bilateral phæochromocytomas at autopsy. The association of these two tumours represents a rare but well recognized clinical entity. A family study was then undertaken to detect evidence of these conditions in 17 blood relatives. Neither thyroid carcinoma nor phæochromocytoma were detected. However, because of the previously reported familial nature of this syndrome, family and long term follow‐up studies of patients with either medullary thyroid carcinoma or phæochromocytoma, or both of these conditions, are recommended.
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To evaluate the mammographic features of medullary carcinoma, to determine the frequency of pathologic overdiagnosis of this neoplasm, and to assess whether mammography can distinguish true from atypical medullary carcinomas, since this distinction has important prognostic implications.Retrospective review revealed 25 patients with an initial pathologic diagnosis of medullary carcinoma. Histopathologic slides and mammograms were reviewed.After review of histopathologic slides, 14 (56%) lesions were classified as medullary carcinomas and 11 (44%) as atypical medullary carcinomas. At mammography, a circumscribed mass was present in four of the 14 (28%) medullary carcinomas and in one of the 11 (9%) atypical medullary carcinomas (P = .34), an indistinct mass was present in seven of the 14 (50%) medullary carcinomas and in five of the 11 (45%) atypical medullary carcinomas (P = .86), and an obscured mass was present in two of the 14 (14%) medullary carcinomas and in three of the 11 (27%) atypical medullary carcinomas (P = .62). Calcification, which was present in one of the 11 (9%) atypical medullary carcinomas, and s spiculated border, which was present in one of the 11 (9%) atypical medullary carcinomas, were not observed in medullary carcinomas (P = .44).At mammography, medullary carcinoma was usually an uncalcified mass with indistinct or circumscribed borders. Atypical medullary carcinoma may be misdiagnosed as medullary carcinoma. Mammography could not reliably help distinguish true medullary carcinomas from atypical medullary carcinomas.
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Overdiagnosis
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Objective To investigate the relationship between the sonographic and histologic appearances of breast medullary carcinoma, and to determine the value of sonography in the differentiation of typical and atypical breast medullary carcinoma. Methods We retrospectively reviewed ultrasonographic appearances of 19 cases of breast medullary carcinoma which were confirmed by pathology. Results Eight of 19 medullary carcinomas were classified as typical and 11 were atypical. On sonography,a smooth outline was visualized in 6 of the 8 typical medullary carcinomas but in none of 11 atypical carcinomas. A jagged margin was sonographically visualized in 10 of 11 atypical carcinomas, and a focal irregularity in the margin was visualized in 1 of the 11 atypical carcinomas. Four of the typical medullary carcinomas had posterior enhancement, and 8 of the atypical medullary carcinomas showed retrotumoral shadowing. The difference of tumor margin regularity between typical and atypical medullary carcinomas was statistically significant. Conclusions Treatment and prognosis of typical and atypical medullary carcinomas are different. Ultrasonography is useful in the differential diagnosis of typical and atypical medullary carcinomas.
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Three medullary, eight atypical medullary and four non-medullary carcinomas of the breast were studied by transmission electron microscopy. Detailed comparison of a number of structural, cytoplasmic and nuclear features failed to confirm previous suggestions that medullary carcinoma cells have a distinctive ultrastructure. Electron microscopy is thus unlikely to be useful in the differential diagnosis of the tumours, nor does it suggest a basis for the good prognosis of medullary carcinoma.
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To determine the clinicopathological and molecular features of gastric medullary cancer.Clinicopathological review and microsatellite instability (MSI) analysis were carried out on 17 gastric medullary and 64 non-medullary cancers. In addition to characteristic histopathology, gastric medullary cancers had certain prominent features: (i) the average survival time was longer in medullary and low-grade non-medullary cancers than in high-grade (P = 0.004); (ii) serosal involvement was less common in medullary cancers (29.4%, 5/17) than in non-medullary cancers (9.4%, 6/64) (P < 0.05) while pushing borders were more common in medullary cancers (70.6%, 12/17 versus 17.2%, 11/64, P = 0); (iii) the presence of intraepithelial lymphocytes (IELs) in medullary and non-medullary cancers was 2380/10 high-power field (HPF) and 147/10 HPF (P = 0), respectively. Both peritumoural infiltrating lymphocytes (pTIL) and a Crohn's-like reaction were more common in medullary cancers than in non-medullary (pTIL 35.3%, 6/17 versus 3.1%, 2/64; a Crohn's-like reaction 70.6%, 12/17 versus 32.8%, 21/64; P < 0.05); (iv) medullary and high-grade non-medullary cancers were more associated with reduced ECD expression in comparison with low-grade cancers (P < 0.05); (v) higher MSI-H (Bat26+) rate was observed in medullary cancers (41.2%, 7/17) than in non-medullary (1.6%, 1/64) (P = 0).Gastric medullary cancer has distinct clinicopathological features and genetic alterations. Two subtypes of gastric medullary cancers, Bat26+ and Bat26-, might have prognostic implications, thus analysis of Bat26 may be of clinical value.
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Objective To evaluate mammography in distinguishing medullary carcinoma from fibroadenoma and in distinguishing true from atypical medullary carcinoma.Materials and Methods Mammographic findings of 27 medullary carcinomas and 34 fibroadenomas were retrospectively analyzed. The findings were compared with pathologic results.Results The most common finding was non-calcified mass for both medullary carcinoma (78%) and fibroadenoma (74%). Usually, the mass was of high-density for medullary carcinoma (19/25) and of iso-density for fibroadenoma (19/28), with significant difference between two tumors (P=0.001). Most medullary carcinomas showed an infiltrating or lobulated border (23/25), while most fibroadenomas had a clear border or could be demonstrated only on a certain direction exposure (25/28), with significant difference between two tumors (P0.001). Of 27 medullary carcinomas, 9 were atypical. No obvious difference in tumor's shape (P=0.670), margin (P=0.394) and density (P=0.637) existed between the true and the atypical medullary carcinomas. Conclusion Breast medullary carcinoma has certain mammographic features, which are well correlated with its pathology and based on which differentiation from fibroadenoma can be made. Pathologically, medullary carcinoma can be further divided into true type and atypical type. Nevertheless, it is almost impossible to make a correct differentiation of the two types on the mammogram.
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Breast Fibroadenoma
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Objective:To investigate the dignosis and treatment of familial medullary thyroid carcinoma in order to provide basis for its early diagnosis and treatment.Methods: We summarized the clinical data of familial medullary thyroid carcinoma,and combined with literature to investigate its etiology,early diagnosis and treatment.Results:Familial medullary thyroid carcinoma is aeuchromosome obvious syndrome arosed by RET break.It is bilateral and many focus,and mostly is young blood;Reasonable operation can get satisfactory result in the treatment for familial medullary thyroid carcinoma.Conclutions:FMTC is a kind of hereditary diseases;there is satisfactory result when early diagnosis and reasonable operation are applied.Follow-up survey of family members should be performed in a long period of time.
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Objective To investigate the clinical features and bilogical characteristics of the medullary carcinoma of the breast. Methods 27 cases of typical medullary carcinoma and 34 cases of atypical medullary carcinoma were analyzed. Results The results showed that the incidence of medullary carcinoma of breast was 6.6% of the total breast cancers, and the 3-,5- year survived rates were 96.29%,88.88% in the typical medullary carcinoma; 91.17%,79.41% in the atypical medullary carcinoma.Conclusion The common features of medullary carcinoma were fairly clear boundary mass.This suggest that medullary carcinoma should be made a definite diagnosis by needle and freeze biopsy.
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Breast carcinoma
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We have studied the hypocalcemic effect of serum from three patients with disseminated medullary carcinoma. Only one of three patients studied revealed significant hypocalcemic activity. The procedure we have described is simple to perform and, quite possibly, diagnostic when positive, but it is not sensitive enough to justify its use as a screening procedure in patients with suspected thyroid tumor. It might, however, be of interest and possible value in follow-up studies of patients with known medullary carcinoma, or in studies of the relatives of such patients. More sensitive methodology will be required for the consistent detection of this tumor and its hormonal by-products.
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