Novel fusion sarcomas including targetable NTRK and ALK

Ann Diagn Pathol. 2021 Oct:54:151800. doi: 10.1016/j.anndiagpath.2021.151800. Epub 2021 Jul 22.

Abstract

Background: Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up.

Methods: Fusion sarcomas (2020-2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS).

Results: Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases).

Conclusions: Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.

Keywords: ALK-or-NTRK-inhibitor-therapy-treatment; CIC-or-BCOR-or-YHWAE; COVID-19-pandemic; Novel-fusion-sarcoma; STAT6; TPR-and-KANK1-and-ERC1.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Algorithms
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / genetics*
  • Child
  • Child, Preschool
  • Extremities / pathology
  • Female
  • Femoral Neoplasms / diagnosis
  • Femoral Neoplasms / drug therapy
  • Femoral Neoplasms / genetics*
  • Femoral Neoplasms / pathology
  • Gene Fusion*
  • Head and Neck Neoplasms / diagnosis
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Phenotype
  • Prognosis
  • Sarcoma / diagnosis
  • Sarcoma / drug therapy
  • Sarcoma / genetics*
  • Sarcoma / pathology
  • Soft Tissue Neoplasms / diagnosis
  • Soft Tissue Neoplasms / drug therapy
  • Soft Tissue Neoplasms / genetics*
  • Soft Tissue Neoplasms / pathology
  • Thoracic Neoplasms / diagnosis
  • Thoracic Neoplasms / drug therapy
  • Thoracic Neoplasms / genetics*
  • Thoracic Neoplasms / pathology
  • Thoracic Wall / pathology
  • Young Adult

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor