Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network

Abstract

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network

“…This requires a coordinated effort, worldwide, to achieve this goal given the rarity of certain histotypes. This is currently being conducted by intergroup studies, and international networks such as WSN or more recently EURACAN [26][27][28]. This work also confirms the importance of national registries to investigate these rare subtypes.…”

“…Overall, this calls for a revision of the criteria to define standard treatment for such rare tumors where phase III are hardly or not feasible [26][27][28][29]. Health authorities and reimbursement bodies should adapt their decisions on approval and reimbursement on the feasible level of evidence which could be reached for tumors with and incidence <1/10 6 per year in order not to discriminate against patients with rare cancers.…”

Chromosomal imbalances detected in NTRK‐rearranged sarcomas by the use of comparative genomic hybridisation

“…Given the relatively low incidence of NTRK gene rearrangements across a range of tumour types, it remains extremely challenging to identify these rearrangements in routine clinical practice. A range of different techniques, including IHC, FISH, reverse transcription PCR, and massive parallel sequencing, have been used 7,34,35,36 . As no single approach is perfectly sensitive or specific, there is an emerging consensus that combinations of different techniques are most appropriate in different settings, depending on the pre‐test probability of gene rearrangement 7,13,34 .…”

“…For example, in sarcomas with a very high pre‐test probability of NTRK rearrangement (e.g. infantile fibrosarcoma), upfront testing with two methods may be appropriate 35 . For sarcomas with a low incidence of NTRK rearrangement, either screening IHC with follow‐up testing only in cases with positive staining, 13 or molecular testing only of sarcomas known to lack canonical oncogene alterations, may be more appropriate 35 …”

Update on Molecular Genetics of Gastrointestinal Stromal Tumors

“…The excellent clinical response and outcome in patients harboring NTRK -rearranged tumors treated with these agents have been demonstrated in several studies [ 114 , 115 , 116 ]. Even though pan-TRK IHC is wildly used as a reliable and affordable screening method for the detection of NTRK -fusions in most of the pathology departments [ 117 , 118 ], it has its limitations. The positive expression has been reported in a subset of neoplasms with neuronal and smooth muscle differentiation, as well as GIST, where diffuse, moderate to strong cytoplasmic pan-TRK expression has been described ( Figure 7 ) with lack of an NTRK1-3 -fusions by RNA sequencing [ 119 ].…”