NTRK-rearranged soft tissue neoplasm

Last revised by Arlene Campos on 8 May 2024

NTRK-rearranged soft tissue neoplasms (emerging), lipofibromatosis-like neural tumors or NTRK-positive tumor-resembling peripheral nerve sheath tumors are a group of rare molecularly defined spindle cell neoplasms excluding infantile fibrosarcoma 1.2. The tumors form a provisional category of uncertain differentiation, including lipofibromatosis-like neural tumors and tumors that are similar to peripheral nerve sheath tumors.

Many NTRK-rearranged soft tissue neoplasms occur in children and adolescents in the first two decades of life especially lipofibromatosis-like neural tumors and more than half of the cases of NTRK-positive tumor-resembling peripheral nerve sheath tumors occur in the pediatric group 1,2

The diagnosis of NTRK-rearranged soft tissue neoplasms is established with histological, immunohistochemical and molecular pathological criteria.

Diagnostic criteria according to the WHO classification of tumors: soft tissue and bone (5th edition) 1:

  • wide spectrum of histological appearances

  • arbitrary arranged monomorphic spindle cells

  • infiltrative growth within fat

  • stromal and perivascular keloid collagen

  • immunoreactivity to S100 and CD34 with negativity for SOX10

  • immunoreactivity to NTRK1

The following immunohistological criterion is desirable for therapy decisions 1:

  • detection of NTRK fusions

Most NTRK-rearranged soft tissue tumors present as painless palpable soft tissue mass 1.

NTRK-rearranged soft tissue neoplasms show a wide range of histological morphologies often displaying a monomorphic spindle cell morphology, infiltrative growth and immunoreactivity to S100 and CD34 1,2.

The etiology of NTRK-rearranged soft tissue neoplasms is unknown 1.

NTRK-rearranged soft tissue neoplasms are usually found in the superficial and deep soft tissues of the trunk and the extremities 1.

There are no specific definitions of the macroscopic appearance of NTRK-rearranged soft tissue neoplasms 1.

Histologically NTRK-rearranged soft tissue neoplasms form a morphological spectrum and are characterized by different features 1-3.

lipofibromatosis-like neural tumors:

  • arbitrarily arranged spindle cells

  • a highly infiltrative pattern within the subcutaneous fatty tissue similar to lipofibromatosis

  • sometimes increased cellularity and cytological atypia

  • low mitoses

  • no necrosis

another subset:

  • solid growth pattern

  • uniform spindle cells in a streaming or random pattern

  • distinctive stromal and perivascular keloid-like collagen deposition

tumors resembling malignant peripheral nerve sheath tumors:

  • wide histological spectrum from low-grade to higher-grade

  • zonal structure with merging cellular and paucicellular zones

  • collageneous or myxoid stroma

  • intersecting fascicles

  • variable cellularity and mitotic activity

  • possible necrosis

Immunohistochemistry stains are usually positive for S100 and CD34 whereas reactivity for SOX10 is absent 1,2. Most of them seem to retain HZ3K27me3 expression in contrast to many malignant nerve sheath tumors 4. Apart from that they usually show pan-TRK and TRK-A immunoreactivity 1,2.

NTRK-rearranged soft tissue neoplasms often harbor fusions of the NTRK1 gene with different partner genes and less often NTRK2 or NTRK3 aberrations 1-3.

On PET-CT NTRK-rearranged soft tissue neoplasms seem to show FDG avidity 6.

The radiological report should include a description of the following:

  • form, location and size

  • tumor margins

  • relation to muscular fasciae and skeletal muscles in soft tissues

  • relationship to local nerves and vessels

The prognosis seem to be related to the histological grade 1. The benign lipofibromatosis-like neural tumors seem to have a predisposition for recurrence. Higher-grade neoplasms might behave more aggressively and metastasize.  However, they are therapeutically targetable via oncogenic tropomyosin receptor kinase such as TRK-A, TRK-B and TRK-C potentially improving prognosis 1,2.

NTRK-rearranged soft tissue neoplasms have been added as an emerging entity of uncertain differentition into the WHO classification of soft tissue tumors in 2020 1.

Differential diagnoses include the following 3:

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