Endoscopic ultrasound fine-needle biopsy to assess DAXX/ATRX expression and alternative lengthening of telomeres status in non-functional pancreatic neuroendocrine tumors

Pancreatology. 2023 Jun;23(4):429-436. doi: 10.1016/j.pan.2023.05.002. Epub 2023 May 5.

Abstract

Background/objectives: Death domain-associated protein (DAXX) and/or α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes mutations and alternative lengthening of telomeres (ALT) activation are associated with more aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PanNETs). We aimed to evaluate the reliability of such markers on endoscopic-ultrasound fine-needle biopsy (EUS-FNB) specimens.

Methods: Patients who underwent EUS-FNB and subsequent surgical resection for PanNETs between January 2017 and December 2019 were retrospectively identified. Immunohistochemistry (IHC) to evaluate DAXX/ATRX expression and fluorescence in situ hybridization (FISH) for ALT status were performed. Primary outcome was the concordance rate of markers expression between EUS-FNB and surgical specimens. Secondary aims were association between markers and lesion aggressiveness, their diagnostic performance in predicting aggressiveness, and agreement of preoperative and post-surgical Ki67-based grading.

Results: Forty-one NF-PanNETs (mean diameter 36.1 ± 26.5 mm) were included. Twenty-four showed features of lesion aggressiveness. Concordance of expressions of DAXX, ATRX, and ALT status between EUS-FNB and surgical specimens were 95.1% (κ = 0.828; p < 0.001), 92.7% (κ = 0.626; p < 0.001), and 100% (κ = 1; p < 0.001), respectively. DAXX/ATRX loss and ALT-positivity were significantly (p < 0.05) associated with metastatic lymphnodes and lymphovascular invasion. The combination of all tumor markers (DAXX/ATRX loss + ALT-positivity + grade 2) reached an accuracy of 73.2% (95%CI 57.1-85.8) in identifying aggressive lesions. Pre- and post-operative ki-67-based grading was concordant in 80.5% of cases (k = 0.573; p < 0.001).

Conclusion: DAXX/ATRX expression and ALT status can be accurately evaluated in a preoperative setting on EUS-FNB samples, potentially improving the identification of patients with increased risk and poorer prognosis.

Keywords: ALT; FISH; Immunohistochemistry; Pancreatic cancer; Pancreatic tumor.

MeSH terms

  • Biopsy, Fine-Needle
  • Co-Repressor Proteins / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Intellectual Disability*
  • Molecular Chaperones / genetics
  • Neuroendocrine Tumors* / diagnosis
  • Neuroendocrine Tumors* / genetics
  • Neuroendocrine Tumors* / surgery
  • Pancreatic Neoplasms* / diagnosis
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / surgery
  • Reproducibility of Results
  • Retrospective Studies
  • Telomere / genetics
  • Telomere / metabolism
  • Telomere / pathology
  • X-linked Nuclear Protein / genetics
  • X-linked Nuclear Protein / metabolism
  • alpha-Thalassemia*

Substances

  • X-linked Nuclear Protein
  • ATRX protein, human
  • DAXX protein, human
  • Molecular Chaperones
  • Co-Repressor Proteins