RET/papillary thyroid cancer rearrangement in nonneoplastic thyrocytes: follicular cells of Hashimoto's thyroiditis share low-level recombination events with a subset of papillary carcinoma

The Journal of clinical endocrinology and metabolism 01/2006; 91:2414-23.


CONTEXT: RET/papillary thyroid cancer (PTC) is a marker for papillary thyroid carcinoma, but its specificity has been questioned because of the disputed identification of RET/PTC in Hashimoto's thyroiditis (HT), oncocytic tumors, and other thyroid lesions. OBJECTIVE: The objective of this study was to determine 1) whether RET/PTC occurs in nonneoplastic follicular cells of HT, and 2) its recombination rate in thyroid tumors. DESIGN/PATIENTS: Forty-three samples from 31 cases of HT were examined using interphase fluorescence in situ hybridization (FISH) with RET probes spanning the breakpoint region; real-time RT-PCR to quantify RET/PTC1, RET/PTC3, and c-RET transcripts; and RT-PCR after laser capture microdissection to enrich samples for follicular cells. The results were compared with those similarly obtained in 34 papillary carcinomas, eight thyroid oncocytic tumors, and 21 normal thyroids. RESULTS: Normal samples showed no RET rearrangement. Sixty-eight percent (15 of 22) of HT were positive by FISH; in all thyroiditis, signals were localized to rare nonneoplastic follicular cells; low-level RET/PTC was identified in 17% (five of 29) of thyroiditis cases by real-time RT-PCR and in an additional six of 11 real-time negative cases after increasing sensitivity with laser capture microdissection. Low RET/PTC1 levels were detected in 26% (nine of 34) of papillary carcinomas with an expression pattern and proportion of FISH-positive cells similar to those of the thyroiditis. Forty-seven percent (16 of 34) of papillary carcinomas and one oncocytic carcinoma expressed high RET/PTC1 mRNA levels. CONCLUSIONS: Low-level RET/PTC recombination occurs in nonneoplastic follicular cells in HT and in a subset of papillary thyroid carcinomas. RET/PTC expression variability should be taken into account for the molecular diagnosis of thyroid lesions. Overlapping molecular mechanisms may govern early stages of tumor development and inflammation in the thyroid.

8 Reads
  • Source
    • "In addition, Muzza et al. found RET/PTC1 being more represented in PTCs associated with autoimmunity than in PTC without autoimmunity, suggesting that the association between RET/PTC1 and thyroiditis points to a critical role of this oncoprotein in the modulation of the autoimmune response [41]. Rhoden et al. showed that low-level RET/PTC recombination occurs in nonneoplastic follicular cells of HT and in a subset of papillary thyroid carcinomas, indicating that overlapping molecular mechanisms may govern early stages of tumor development and inflammation in the thyroid [91]. Kang et al. studied the RET/PTC-RAS-BRAF in oxyphil cells in the vicinity of large lymphoid HT infiltrates and in malignant PTC cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cooccurrences of chronic lymphocytic thyroiditis (CLT) and thyroid cancer (DTC) have been repeatedly reported. Both CLT and DTC, mainly papillary thyroid carcinoma (PTC), share some epidemiological and molecular features. In fact, thyroid lymphocytic inflammatory reaction has been observed in association with PTC at variable frequency, although the precise relationship between the two diseases is still debated. It also remains a matter of debate whether the association with a CLT or even an autoimmune disorder could influence the prognosis of PTC. A better understanding about clinical implications of autoimmunity in concurrent thyroid cancer could raise new insights of thyroid cancer immunotherapy. In addition, elucidating the molecular mechanisms involved in autoimmune disease and concurrent cancer allowed us to identify new therapeutic strategies against thyroid cancer. The objective of this article was to review recent literature on the association of these disorders and its potential significance.
    Journal of Thyroid Research 02/2011; 2011:387062. DOI:10.4061/2011/387062
  • Source
    • "was preferentially located in tumour tissues of PTC, which indicated that the virus was active in PTC lesions and the productive infection of the virus might play some role, directly or indirectly, as a cofactor in the pathogenesis of the tumour. In addition, as benign thyroid proliferative disease may become neoplastic (Pang et al, 1994; Bravo et al, 2003; Moore, 2006) and some benign thyroid diseases without histopathological evidence of PTC harbour similar molecular genetic changes with PTC (Wirtschafter et al, 1997; Rhoden et al, 2006), the detection of B19 VP1/VP2 antigen in 6.25% of normal controls, 10% of tumouradjacent tissues, 20.5% of benign thyroid tissues and 63.2% of PTC samples suggests that B19 expression may occur relatively early in carcinogenesis of PTC. Parvovirus is tightly dependent on host functions to complete their life cycle (Wolter et al, 1980). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate whether parvovirus B19, a common human pathogen, was also involved in papillary thyroid carcinoma (PTC), 112 paraffin-embedded thyroid specimens of benign nodules, papillary, medullary and follicular carcinomas, and normal controls were examined for B19 DNA and capsid protein by nested PCR, in situ hybridisation (ISH) and immunohistochemistry (IHC). The expression of the nuclear factor-kappaB (NF-kappaB) was investigated by IHC. The results showed B19 DNA commonly exists in human thyroid tissues; however, there were significant differences between PTC group and normal controls, and between PTC and nonneoplastic adjacent tissues (P<0.001). The presence of viral DNA in PTC neoplastic epithelium was confirmed by laser-capture microdissection and sequencing of nested PCR products. B19 capsid protein in PTC group was significantly higher than that of all the control groups and nonneoplastic adjacent tissues (P<or=0.001). Compared with control groups, the activation of NF-kappaB in PTC group was significantly increased (P<or=0.02), except for medullary carcinomas, and the activation of NF-kappaB was correlated with the viral protein presence (P=0.002). Moreover, NF-kappaB was colocalised with B19 DNA in the neoplastic epithelium of PTC by double staining of IHC and ISH. These results indicate for the first time a possible role of B19 in pathogenesis of PTC.
    British Journal of Cancer 03/2008; 98(3):611-8. DOI:10.1038/sj.bjc.6604196 · 4.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Real-time elastography (RTE) is a non-invasive ultrasound method of estimation of tissue stiffness by measuring the degree of local tissue displacements after a small compression. Recent data has shown its ability to differentiate benign from malignant tumours. The aim of this study was to evaluate the accuracy of RTE in the diagnosis of malignant and benign thyroid nodules. 71 thyroid nodules in 52 patients: 42 females and 10 males aged 28-77 were examined using conventional ultrasonography (US), fine-flow CD imaging and RTE. All nodules previously underwent fine-needle aspiration biopsy (FNAB), and patients with malignant and suspicious cytological results were referred for surgery. The final diagnosis was based on FNAB results in patients with benign cytology and on the histopathology reading in those who underwent surgery. An elasticity score (ES) from 1 to 5 was determined for each nodule according to the Ueno classification. An elasticity score (ES) of 4 or 5 was found in 19 out of 22 (86.5%) thyroid cancers and in only 1 out of 31 (3%) benign nodules. This was strongly indicative for malignancy (p 〈 0.0001) with sensitivity 86%, specificity 97%, positive predictive value (PPV) 95% and negative predictive value (NPV) 91%. RTE is a highly sensitive and specific method of diagnosing thyroid nodules. This technique can be employed in selecting thyroid nodules for fine-needle aspiration biopsy.
    Endokrynologia Polska 01/2010; 61(6):652-7. · 0.99 Impact Factor
Show more