Evaluation of PD-L1, TERT promoter mutations, and BRAFV600E mutation in poorly differentiated, differentiated high grade thyroid carcinoma and anaplastic carcinoma of the thyroid: our institutional experience

Alessia Piermattei; Giuseppe Migliara; Angela Feraco; Carmine Bruno; Luisa Cioni; Qianqian Zhang; Belen Padial-Urtueta; Elisabetta Merenda; Guido Fadda; Marco Raffaelli; Luigi Maria Larocca; Antonino Mule; Alfredo Pontecorvi; Esther Diana Rossi

doi:10.1007/s00428-025-04134-1

Evaluation of PD-L1, TERT promoter mutations, and BRAFV600E mutation in poorly differentiated, differentiated high grade thyroid carcinoma and anaplastic carcinoma of the thyroid: our institutional experience

Virchows Arch. 2025 Jun 7. doi: 10.1007/s00428-025-04134-1. Online ahead of print.

Affiliations

¹ Division of Anatomic Pathology and Histology Fondazione, Policlinico Universitario"Agostino Gemelli"-IRCCS, Rome, Italy.
² Dipartimento Di Sanita' Pubblica E Malattie Infettive, Univerista' La Sapienza, Rome, Italy.
³ Division of Endocrinology Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Rome, Italy.
⁴ Department of Human Pathology of the Adulthood and Developing Age "Gaetano Barresi", Section of Pathology, University of Messina, Messina, Italy.
⁵ Division of Endocrine-Surgery-Fondazione, Policlinico Universitario"Agostino Gemelli"-IRCCS, Rome, Italy.
⁶ Division of Anatomic Pathology and Histology Fondazione, Policlinico Universitario"Agostino Gemelli"-IRCCS, Rome, Italy. esther.rossi@policlinicogemelli.it.

PMID: 40481961
DOI: 10.1007/s00428-025-04134-1

Abstract

Although many thyroid cancers are well-differentiated carcinomas with an indolent behavior, poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) represent a minority of thyroid malignancies with an aggressive and/or lethal course, followed by limited effective treatment options. Recently, the WHO 2022 introduced the concept of high-grade follicular cell-derived malignancy, including both the traditional PDTC as well as the new definition of high-grade differentiated thyroid carcinomas (DHGTC). Both are characterized by increased mitotic activity and tumor necrosis without anaplastic features and similar clinical behavior. In the last years, immune checkpoint inhibitors (ICIs) have shown to be an effective treatment for a variety of carcinomas, especially aggressive types such as PDTC and ATC, with less data available about DHGTC. The current study analyzes a cohort of patients with PDTC, DHGTC and ATC focusing on the expression of programmed cell death-ligand 1 (PD-L1) and BRAFV600E correlated with aggressive features. From January 2010 to December 2023, 73 patients including a diagnosis of PDTC, DHGTC, and ATC were diagnosed. All these cases were analyzed for the PD-L1 expression and BRAFV600E and correlated with the clinic-pathological features. Among the 73 cases, 42 (57.5%) were women. The median age was 64.2 years. Histological diagnoses included 35 (38.4%) PDTC, 8 DHGTC, and 30 (46.1%) ATC. Lymph-nodal involvement was seen in 27 cases (including 12 N1a, and 15 N1b), while vascular invasion in 34 cases. A differentiated component was seen in all DHGTC, 5PDTC, 11 ATC. Evaluating the stage, 60 cases were from pT3a to pT4b. PD-L1 was expressed in 24/73 (5DHGTC, 0 PDTC, 19 ATC); BRAFV600E and TERT were positive in 19 cases and 16 cases respectively. PD-L1 was confirmed to be a potential biomarker for the management of patients with DHGTC and ATC. Although it did not yield a prognostic role in PDTC and ATC, it is likely to define a subset of patients directed to the checkpoint inhibitor therapy. Furthermore, TERT mutations showed a strong correlation with overall survival rate.

Keywords: Anaplastic thyroid carcinoma; PD-L1; Poorly differentiated carcinoma; Thyroid cancer.