Context: Histologic examination of thyroid nodules is the current standard to distinguish benign from malignant thyroid epithelial tumors and to classify histologic subtypes. This review analyzes the problems in histological differential diagnosis as well as contradictions between histology and molecular data and describes possibilities to combine histology with molecular data in an effort to more accurately classify thyroid epithelial tumors.

Evidence Acquisition: Published literature, addressing the current recommendations for thyroid tumor classification, as well as literature on the application of histology and molecular studies on the etiology of thyroid tumors is analyzed.

Evidence Synthesis: The current histologic criteria to classify thyroid tumors, especially follicular-patterned tumors, are hampered by considerable interobserver variability. The detection of somatic mutations via genotyping and the definition of potentially-informative gene expression signatures by microarray analyses, which can distinguish cancer subtypes as well as low and high risk cohorts, have recently demonstrated significant diagnostic potential. Moreover, in a routine diagnostic setting, microRNA profiling appears most promising due to their relative stability and the high accuracy of their expression profiles.

Conclusions: It is very likely that molecular definitions of thyroid tumors mentioned in the current WHO classification will be further developed, leading to future progress in defining thyroid tumor types by an integrated histologic and molecular approach. These integrated classifications need to be evaluated for their specific impact on thyroid tumor diagnosis and prognosis.