• Family of receptor tyrosine kinases (NTRK1/2/3 genes with encode Trk-A, Trk-B, Trk-C protein kinases)
• Pan-TRK antibody recognizes C terminal domain of Trk-A, Trk-B and Trk-C (also available are Trk-A and Trk-C antibodies)
• 2 clones, EPR17341 and A7H6R, with concordance in NTRK rearranged tumors
• Neurotrophin signaling through these receptor kinases activate cellular pathways involved in cellular proliferation and survival, particularly within the embryonic nervous system (Annu Rev Biochem 2003;72:609, Annu Rev Neurosci 2001;24:677)
• Within embryonal development, regulate neuronal differentiation, axonal growth, dendritic growth and pruning and membrane trafficking, among other functions (Annu Rev Biochem 2003;72:609, Annu Rev Neurosci 2001;24:677)
• In adults, involved in synaptic strength and plasticity (Annu Rev Biochem 2003;72:609, Annu Rev Neurosci 2001;24:677)

• Pan-TRK antibody recognizing C terminal domain of the Trk-A, Trk-B and Trk-C proteins encoded by the NTRK1/2/3 genes
• Can help identify tumors harboring NTRK1/2/3 fusions
• Variable expression pattern, depending on which NTRK gene is involved
• Variable sensitivity, depending on which NTRK gene is involved with lower sensitivity in NTRK3 gene fusions

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• Tumors harboring NTRK1/2 fusions demonstrate cytoplasmic expression; rare perinuclear and nuclear membrane staining has been reported
• Tumors harboring NTRK3 fusions demonstrate cytoplasmic or nuclear expression
• Some authors consider positive staining to be if ≥ 1% of tumor cells show expression, particularly for nuclear expression in NTRK3 fusions which may show only sparse staining (Mod Pathol 2020;33:38)
• Interpretation is best made in the context of morphology; false positive staining has rarely been reported in tumors in the absence of NTRK fusions, including BCOR rearranged sarcomas / primitive myxoid mesenchymal tumors of infancy (PMMTI), fibrous hamartoma of infancy (primitive mesenchymal component), neuroblastoma, oligodendroglioma, carcinomas with neuroendocrine differentiation, invasive ductal carcinoma of the breast and adenoid cystic carcinoma, among others; some of these tumors harbor structural rearrangements or amplifications in NTRK1-3 without gene fusions (Histopathology 2018;73:634, Mod Pathol 2020;33:38)

• Aid in identification / diagnosis of NTRK fusion tumors (Am J Surg Pathol 2017;41:1547, Am J Surg Pathol 2018;42:927, Am J Surg Pathol 2018;42:791, Histopathology 2018;73:634)
• Screening tool or surrogate for molecular testing to confirm NTRK fusions (Am J Surg Pathol 2017;41:1547, Am J Surg Pathol 2018;42:927, Appl Immunohistochem Mol Morphol 2017;25:513)
• Sensitivity and specificity are generally high, with some exceptions depending on which gene is involved (i.e., lower sensitivity for NTRK3 fusions) and tumor type (see Mod Pathol 2020;33:38 for tumor specific sensitivity and specificity) (Am J Surg Pathol 2017;41:1547, Am J Surg Pathol 2018;42:927, Histopathology 2018;73:634, Mod Pathol 2019;32:147)

Contributed by Jessica L. Davis, M.D.

• Testes (Am J Surg Pathol 2017;41:1547)
• Neural tissue (Mod Pathol 2020;33:38)
• Muscle tissue (Mod Pathol 2020;33:38)

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A 2 month old boy presents with a large intramuscular thigh mass with encasement of the femoral neurovascular bundle. Biopsy shows a spindle cell neoplasm with infiltrative borders into skeletal muscle and subcutaneous adipose tissue. By immunohistochemistry, the tumor shows patchy expression of SMA, rare CD34 and diffuse expression of pan-TRK. What is the most likely diagnosis?

1. Cellular congenital mesoblastic nephroma
2. Infantile fibrosarcoma
3. Lipofibromatosis
4. Myofibroma

B. Infantile fibrosarcoma. Infantile fibrosarcoma is the most common soft tissue sarcoma of infancy. The morphology can be variable but typically presents with primitive to spindle cells in a myxoid to collagenized stroma; the diagnosis can be confirmed with pan-TRK antibody staining. Tumors harbor an ETV6::NTRK3 fusion in ~70% of cases; however, recently other variant NTRK fusions have been described (Pediatr Dev Pathol 2018;21:68, Mod Pathol 2018;31:463).

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Reference: Pan-TRK (EPR17341) [NTRK]

A 20 year old woman presents with a breast mass and a needle core biopsy is performed demonstrating morphology suggestive of secretory carcinoma. Which stain combination would be most consistent with secretory breast carcinoma?


1. Pan-TRK+, S100+, MUC4+, ER-, GATA3+
2. Pan-TRK+, S100-, MUC4+, ER+, GATA3+
3. Pan-TRK-, S100-, MUC4+, ER+, GATA3+
4. Pan-TRK+, S100+, MUC4+, ER+, GATA3+

A. Pan-TRK+, S100+, MUC4+, ER-, GATA3+. Secretory carcinomas of the breast, salivary gland and skin are most commonly ETV6::NTRK3 driven tumors; rare ETV6 to other fusion partners have been described (Am J Surg Pathol 2015;39:602). Pan-TRK staining is seen, often with nuclear expression (NTRK3 fusion tumors). Breast secretory carcinomas also express S100, SOX10, MUC4 and GATA3 but are triple negative (ER / PR / HER2-).

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Reference: Pan-TRK (EPR17341) [NTRK]