FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale

Front Endocrinol (Lausanne). 2021 Aug 12:12:712107. doi: 10.3389/fendo.2021.712107. eCollection 2021.


Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.

Materials and methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.

Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.

Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

Keywords: FGFR; PD-L1; immune checkpoint inhibitor (ICI); immunohistochemistry; immunotherapy; tyrosine kinase inhibitor (TKI).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen / analysis
  • B7-H1 Antigen / antagonists & inhibitors*
  • Drug Evaluation, Preclinical / methods
  • Female
  • Germany
  • Humans
  • Male
  • Middle Aged
  • Phenylurea Compounds / pharmacology
  • Quinolines / pharmacology
  • RNA, Messenger / analysis
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Receptors, Fibroblast Growth Factor / genetics
  • Thyroid Carcinoma, Anaplastic / chemistry
  • Thyroid Carcinoma, Anaplastic / drug therapy*
  • Thyroid Carcinoma, Anaplastic / pathology
  • Thyroid Neoplasms / chemistry
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / pathology


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • Phenylurea Compounds
  • Quinolines
  • RNA, Messenger
  • Receptors, Fibroblast Growth Factor
  • pembrolizumab
  • lenvatinib