RET PTC ONCOGENE ACTIVATION DEFINES A SUBSET OF PAPILLARY THYROID CARCINOMAS LACKING EVIDENCE OF PROGRESSION TO POORLY DIFFERENTIATED OR UNDIFFERENTIATED TUMOR PHENOTYPES/

Malignant tumors of the thyroid gland vary considerably in aggressiven ess, ranging from a well-differentiated, clinically indolent, to an un differentiated, often lethal phenotype, Undifferentiated (anaplastic) thyroid tumors are supposed to be derived, through a process of progre ssion, from previously differentiated neoplasms, A common genetic alte ration in thyroid tumors is the rearrangement of the tyrosine kinase-e ncoding RET proto-oncogene, leading to the generation of chimeric RET/ PTC oncogenes, To define the characteristics of the thyroid tumor subs et with RET rearrangements, we have investigated its activation by a c ombined immunohistochemistry and reverse transcription-PCR approach in a series of 316 well-characterized thyroid tumors representative of t he main diagnostic groups, RET activation was detected in 81 of 201 (4 0.3%) papillary carcinomas, It correlated with tumors exhibiting the ' 'classic'' morphological features of papillary cancer or with the micr ocarcinoma subtype (P = 0.017), RET activation in papillary carcinoma was not associated with clinical markers (such as large tumor size, ex trathyroidal extension, or metastases) of increased morbidity, Follicu lar-type neoplasms (61 adenomas and 22 carcinomas), as well as the agg ressive poorly differentiated (15 cases) or undifferentiated (anaplast ic) carcinomas (17 cases), were negative. This study demonstrates that all thyroid carcinomas harboring activating RET rearrangements exhibi t a well-differentiated phenotype, that of papillary carcinoma, and in dicates that the subset of RET/PTC-positive papillary carcinomas do no t progress to more aggressive, less differentiated tumor phenotypes.