Pathologic and Radiologic Response to Neoadjuvant Therapy in Advanced Differentiated thyroid Cancer

Background: Neoadjuvant therapies for locally advanced differentiated thyroid cancer (DTC) aim to downstage disease and thereby reduce the extent of surgical resection without compromising oncologic results. Understanding the histopathologic changes induced by these therapies and their correlation with radiologic response may refine surgical planning and guide optimal treatment protocols. Objective: To characterize the histopathologic effects of neoadjuvant therapies in locally advanced DTC and evaluate their association with radiologic response and surgical outcomes. Methods: This retrospective case series of patients with initially unresectable, locally advanced DTC treated with neoadjuvant therapies, lenvatinib or dabrafenib/trametinib. All patients underwent comprehensive clinical, radiologic, and histopathologic evaluation before and after neoadjuvant therapy. Histopathologic response was assessed on resection specimens using hematoxylin-eosin staining and immunohistochemistry staining for CD3, CD31, and ERG. The primary outcomes were histopathologic response, including tumor fibrosis, tumor necrosis, vascular density, and immune cell infiltration. Secondary outcomes included radiologic response, surgical feasibility, and perioperative morbidity. Results: All 9 patients achieved sufficient tumor regression to allow surgical resection. Histopathology demonstrated therapy-induced tumor fibrosis and necrosis as the predominant changes. Lenvatinib-treated tumors exhibited marked vascular remodeling, reduced microvessel density, and prominent lymphocytic infiltration, whereas BRAF-targeted therapy primarily induced tumor fibrosis without similar vascular or immune changes. The neoadjuvant therapy was well tolerated and did not increase surgical morbidity. Conclusions: Neoadjuvant therapy facilitated R0 resection of locally advanced DTC. Lenvatinib induced vascular remodeling and immune infiltration, in contrast to fibrosis primarily seen with dabrafenib/trametinib. These histologic differences may have implications for future therapeutic decision-making.