ANAPLASTIC TRANSFORMATION OF BRAF AND TERT PROMOTER DOUBLE MUTANT PAPILLARY THYROID CARCINOMA: CLINICAL, MORPHOLOGICAL, AND MOLECULAR GENETIC FEATURES

Abstract

Background. We report the case of a 74-year-old woman with BRAF and TERT promoter double-mutation, with an
aggressive papillary thyroid carcinoma (PTC) with a focal undifferentiated component.
Case presentation. PTC was diagnosed via cytological analysis and total thyroidectomy and lymph node dissection
were performed 15 months before her death. Pathological diagnosis revealed stump-positive PTC pT4aN1bM1, Stage IVB.
An initial radioiodine ablative dose (150 mCi) was administered. Thereafter, the mediastinal lymph node and multiple bilateral
lung metastases were observed upon computed tomography. Six months later, recurrent lesions were irradiated with
external beam radiation (39 Gy/13 fr). Within the next five months, she developed multiple-organ metastases. A month
before death, recurrent lesions increased rapidly and an undifferentiated cancer was diagnosed upon biopsy. The multifocal
disease was rendered inoperable. After gradual progression of respiratory failure, the patient died.
During initial resection, a focal invasion component with severe nuclear atypia and spindle-shaped, giant cells were
noted, thereby increasing the probability of focal undifferentiated transformation. A focal hobnail pattern and minor necrosis
were observed. Upon autopsy, lung and multiple-organ metastases and massive mediastinal invasion were observed. The
immunohistochemically undifferentiated lung cancer expressed vimentin, AE1/AE3, CK7, and p53, but not thyroglobulin,
TTF-1, and Napsin A. Furthermore, a PTC component was observed in the lung, showing micropapillary architecture with a
prominent hobnail pattern. Molecular analysis revealed a double-mutation in BRAF (V600E) and TERT (C228T) promoters.
The Ki-67 labeling index of surgical papillary carcinoma tissue was 34%. BRAF mutations associated with p53 mutations
triggered an additional TERT promoter mutation with upregulated Ki-67 in primary PTC, which can be a network of genetic
alterations driving tumor progression and distant metastasis to the undifferentiated/anaplastic phenotype.
Conclusions. The above mentioned molecular genetic features with the histologically hobnail component should be
considered and tumor recurrence should be assessed carefully.