Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

Abstract

Aims Secretory carcinoma (previously known as mammary analogue secretory carcinoma) is characterised by ETV6 rearrangements, most often ETV6–NTRK3 fusion. Given its histological overlap with other salivary gland tumours, secretory carcinoma can be difficult to diagnose without genetic confirmation. A recently developed pan‐TRK antibody shows promise for identifying tumours with NTRK fusions. The aim of this study was to evaluate the utility of pan‐TRK immunohistochemistry in distinguishing secretory carcinoma from mimics. Methods and results We examined whole‐tissue sections from 86 tumours, including 14 secretory carcinomas (12 parotid primaries and one buccal primary, and one metastasis; five with ETV6 rearrangement confirmed by fluorescence in‐situ hybridisation, and one with ETV6–NTRK3 fusion and one with ETV6–RET fusion detected by targeted sequencing), 14 acinic cell carcinomas, 18 polymorphous adenocarcinomas, 20 low‐grade mucoepidermoid carcinomas, and 20 pleomorphic adenomas. Immunohistochemistry was performed with a pan‐TRK rabbit monoclonal antibody. Pan‐TRK staining was detected in nine (64%) secretory carcinomas, all with a nuclear pattern and four with diffuse staining (>50% of cells). Among other tumour types, pan‐TRK immunoreactivity was observed in all (100%) pleomorphic adenomas (particularly myoepithelial cell‐rich, myxoid areas), 15 (83%) polymorphous adenocarcinomas, and four (20%) low‐grade mucoepidermoid carcinomas, all with predominantly membranous/cytoplasmic immunoreactivity; only six cases showed focal (<10%) nuclear staining. All acinic cell carcinomas were entirely negative. Conclusions Although pan‐TRK expression is not entirely sensitive or specific for secretory carcinoma, nuclear staining distinguishes secretory carcinoma from mimics. Acinic cell carcinomas are negative for pan‐TRK, though membranous expression of TRK is common in other salivary gland neoplasms. The lack of pan‐TRK immunoreactivity in a subset of secretory carcinomas may suggest non‐NTRK fusion partners.

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

“…Overall, NTRK fusions seem to be rarely present (<1%) in unselected large series of tumors; conversely, it can be practically considered a pathognomonic marker of specific rare neoplasms including breast secretory carcinomas, mammary analogue secretory carcinoma of the salivary glands, infantile fibrosarcomas and congenital/infantile mesoblastic nephroma, narrowing a 100% prevalence [76][77][78][79][80]. Of interest, tumors harboring NTRK fusions often (>50%) present other genomic co-alterations in genes related to the NTRK intracellular pathways, such as the MAPK and the PI3K signaling cascades, TP53-associated genes, cell-cycle regulatory proteins and other tyrosine kinases, although strong mitogenic/driver alterations are usually mutually exclusive [70,81].…”

“…Considered that NTRK was discovered as a potential oncogene in colorectal cancer (CRC) [27,88], and that tumors in which NTRK fusions can be considered pathognomonic belong to non-CNS cell-lineages as well, the oncogenic potential of this signaling pathway is not restricted to tissues with NTRK physiological expression [76][77][78][79][80].…”

“…Different TRK antibodies are available, staining either single receptors (so far, antibodies for TRK-A and TRK-B are available as well as a cocktail of anti-TRK-A and anti-TRK-B) or all TRK proteins (pan-TRK antibody, clone EPR17341), which is also available for in vitro diagnostics (Ventana Medical Systems Inc., Tucson, AZ, USA). Of note, different staining patterns can be expected based on the involved genes: for example, NTRK3 fusions more often lead to a nuclear staining and a higher rate of false negatives (up to 45%) [77][78][79][80]106,158,159]. IHC can thus be used as an effective screening tool for most tumor types, but unfortunately specificity in CNS neoplasms seems to be low due to the physiological expression of NTRK in neural tissues.…”

Pan‐Trk immunohistochemistry is a sensitive and specific ancillary tool for diagnosing secretory carcinoma of the salivary gland and detecting ETV6–NTRK3 fusion

“…In contrast, a recent study by Hung et al . reported a relatively low sensitivity (64%) and low specificity (44%) of pan‐Trk IHC in diagnosing SC . It appears that pan‐Trk IHC is a promising diagnostic marker, but its efficacy in salivary gland neoplasms remains to be validated.…”

Molecular Diagnostics in Non-Small Cell Lung Carcinoma

“…Immunohistochemistry for Pan-TRK using an antibody that recognizes a conserved C-terminal sequence of TRK proteins can effectively identify tumors with NTRK fusions; however, its performance characteristics have largely been tested in sarcomas and head and neck tumors and remain insufficiently tested in NSCLC. [101][102][103][104] RET Oncogenic rearrangements of RET are present in 1 to 2% of NSCLC, most commonly as a result of fusion to KIF5B. 80,88,[105][106][107][108] Less common partners include CCDC6, NCOA4, TRIM33, and others.…”