RET/PTC3 translocation in a rare hemorrhagic brain metastasis of papillary thyroid cancer post Chernobyl radiation affects vessels ultrastructure

Slow progression and good prognosis are the usual characteristics of papillary thyroid carcinoma (PTC). The presence of brain metastases (0.4–1.2%) is suggestive of a worse prognosis. RET/PTC rearrangements were particularly prevalent in PTCs developed after Chernobyl nuclear accident. A 50-year-old woman born in Slovakia, exposed to radiation resulting from the accident at the Chernobyl nuclear power plant, affected since 2017 by papillary thyroid cancer and in therapy at our hospital, experimented cerebral hemorrhagic metastasis. Biopsy analyses revealed a RET/PTC3 rearrangement, so our aim was to find possible morphological relation between hemorrhagic metastasis and RET/PTC3 translocation. Immunohistochemical analysis showed diffuse and intense positivity for VEGF in endothelial cells of the neoplasm' vascular network. Transmission electron microscopy images showed vessels with unorganized pattern and uneven diameters. In particular, metastasis endothelial cells (MECs) showed irregular shape and size, thickened cytoplasm and swelling of endoplasmic reticulum. MECs organized in irregular monolayers or multiple layers, surrounded by a thickened but unstructured extracellular matrix. Absence of strong junctional complexes among MECs resulted in a further weakened vessels wall. RET/PTC3 translocation causes VEGF overexpression via STAT3 signaling cascade and the increased amount of VEGF adds to the greater amount of VEGFRs expressed by MECs. Our ultrastructural investigation show that this condition creates a massive growth of altered vessels prone to bleeding. The clinical significance of our study consists in alert oncologist and surgeons on possible arising of hemorrhagic brain metastases in patients with PTC and RET/PTC3 translocation exposed to ionizing radiation as people living in areas caught up in Chernobyl or Fukushima disasters.