Sarcomas

NTRK tumour epidemiology

Sarcomas are rare tumors, that can arise from soft tissue and bone of any site of the body. The American Cancer Society estimates about 13,190 new soft tissue sarcomas cases (7,590 in males and 5,600 in females) and about 5,130 new deaths (2,740 males and 2,390 females) due to soft tissue sarcomas in the United States for 2022. These statistics include both adults and children (https://www.cancer.net/cancer-types/sarcomas-soft-tissue/statistics). Sarcomas account for over 20% of all paediatric solid malignant cancers and less than 1% of all adult solid malignant cancers [1].

Sarcomas comprise more than 80 histologic types. In adults the most common types include undifferentiated pleomorphic sarcoma (UPS), liposarcoma, and leiomyosarcoma. Among paediatric sarcomas, infantile fibrosarcoma (IFS) is a sarcoma type that typically presents at birth or in the first two years of life. It has a variable anatomic distribution, with a predilection for the soft tissues of the extremities, and less commonly the trunk and head and neck area. NTRK-rearranged spindle-cell neoplasm is an emerging category in the latest edition of the World Health Organization (WHO) Classification of soft-tissue and bone tumors [2].

Prevalence of NTRK fusion

In soft tissue sarcomas, NTRK fusions are rare, occurring at a frequency < 1%. In contrast, specific types of rare sarcomas such as infantile fibrosarcoma (IFS) are defined by NTRK3 oncogenic activation, exhibiting a high prevalence for this type of fusions. Lipofibromatosis-like neural tumours on the other hand are defined by NTRK1 oncogenic activation and in bone tumours, NTRK fusions are extremely rare (see table and publications below).

Which NTRK fusion is more frequent: NTRK1/2/3 and partners?

NTRK1 and NTRK3 fusions occur at a relatively similar frequency in sarcomas, whereas NTRK2 fusions are rather rare, with only few cases reported to date. ETV6 is the preferred and most common partner for NTRK3, with less common partners including TPM4, EEF1A1, RBPMS, SPECC1L, and EML4. LMNA, TPM3, and TPR are the most frequent partners for NTRK1 (see previous table).

References

1. Burningham Z, Hashibe M, Spector L et al. The epidemiology of sarcoma. Clin Sarcoma Res 2012; 2:14.
2. WHO Classification of Tumours Editorial Board, ed. Soft Tissue and Bone Tumours. 5th ed. International Agency for Research on Cancer; 2020.
3. Lam SW, Briaire-de Bruijn IH, van Wezel T et al. NTRK fusions are extremely rare in bone tumours. Histopathology. 2021;79(5):880-885.
4. Rosen EY, Goldman DA, Hechtman JF et al. TRK fusions are enriched in cancers with uncommon histologies and the absence of canonical driver Mutations. Clin Cancer Res. 2020;26(7):1624-1632.
5. Solomon JP, Linkov I, Rosado A et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol. 2020;33(1):38-46.
6. Okamura R, Boichard A, Kato S et al. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol. 2018;2018:PO.18.00183.
7. Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol. 2019;32(1):147-153.
8. Church AJ, Calicchio ML, Nardi V et al. Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Mod Pathol. 2018;31(3):463-473.
9. Wong DD, Vargas AC, Bonar F et al. NTRK-rearranged mesenchymal tumours: diagnostic challenges, morphological patterns and proposed testing algorithm. Pathology. 2020;52(4):401-409.
10. Chiang S, Cotzia P, Hyman DM et al. NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol. 2018;42(6):791-798.
11. Croce S, Hostein I, Longacre TA et al. Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms. Mod Pathol. 2019;32(7):1008-1022.
12. Rabban JT, Devine WP, Sangoi AR et al. NTRK fusion cervical sarcoma: a report of three cases, emphasising morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma. Histopathology. 2020;77(1):100-111.
13. Suurmeijer AJH, Dickson BC, Swanson D et al. A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Genes Chromosomes Cancer. 2018;57(12):611-621.
14. Rudzinski ER, Lockwood CM, Stohr BA et al. Pan-Trk immunohistochemistry identifies NTRK rearrangements in pediatric mesenchymal tumors. Am J Surg Pathol. 2018;42(7):927-935.
15. Nozzoli F, Lazar AJ, Castiglione F et al. NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities. Pathol Oncol Res. 2022;28:1610237.