Using pan-TRK and RET Immunohistochemistry for the Detection of Fusion Types of Salivary Gland Secretory Carcinoma

Abstract

Secretory carcinoma (SC) is a low-grade salivary gland carcinoma characterized by recurrent ETV6 rearrangements. Most cases have ETV6-NTRK3 fusions, while the minority of cases have non-NTRK3 fusions, including ETV6-RET and ETV6-MET. Detection of the fusion partner has become important, as there are TRK or RET inhibitors that may benefit patients with advanced SC. Currently, there are different methods to detect gene rearrangement in SCs, such as next-generation sequencing, reverse transcriptionpolymerase chain reaction, or fluorescence in situ hybridization. Immunohistochemistry (IHC) has greater accessibility, quick turnaround time, and can serve as a screening tool for confirmatory molecular tests. Pan-TRK and RET antibodies have been used to detect gene fusions in different tumors. Here, pan-TRK and RET IHC assays were performed on 28 salivary gland SCs, including 27 cases with ETV6-NTRK3 and one with ETV6-RET fusion confirmed by fluorescence in situ hybridization. Pan-TRK staining was positive in 26/27 (96.3%) of NTRK3 fusion-positive SCs with a nuclear staining pattern in more than 50% of tumor cells, and negative in the RET-rearranged case. RET IHC showed positive staining in most cases (26/28), but only three cases (including the RET-rearranged case) had diffuse and strong staining. RET IHC can be considered an effective screening test when diffuse/strong reactivity is present in pan-TRK IHCnegative cases. This study showed that pan-TRK staining has high sensitivity and specificity for SC with NTRK3 fusion. Whereas pan-TRK IHC is a useful screening method, further studies are needed to assess the value of RET IHC as a second sequential step.

Diagnostic accuracy of pan‐TRK immunohistochemistry in differentiating secretory carcinoma from acinic cell carcinoma of salivary gland—A systematic review

“…In this phase, 2 case reports 23,24 were excluded and finally, 13 articles were included for quantitative synthesis (Figure 1). 7,8,[12][13][14][15][16][17][18][19][20][21][22] 3.1 | Methodological characteristics of the studies Data extracted from all 13 studies including details on the country of origin, authors, total number, and histopathological type of SGTs and pattern of pan-TRK IHC manifestation are provided in Tables S1 & 1.…”

“…The included studies were conducted between 2017 and 2022, in more than 5 different countries: 4 in the USA, 7,12-14 2 in France, 16,18 3 in Japan, 8,15,21 2 in China 19,20 1 in Taiwan, 22 and 1 was multicentric. 17 A total of 623 different SGTs including 255 SCs and 82 AciCCs were identified.…”

“…The demographic and clinical details were availed only in 10 studies 7,8,[15][16][17][18][19][20][21][22] and are tabulated in Table S1.…”

“…In addition to pan-TRK immunohistochemistry, 4 studies 17,19,20,22 have also used other markers as a comparative analysis with pan-TRK. S100, MMG, and CK7 were found to be having positive expression in all included SCs (84 of 84 cases) whereas GATA3 positivity was seen in 35 of 35 cases.…”

“…In addition to pan-TRK immunohistochemistry, data pertaining to genetic rearrangement were available in 12 7,8,[12][13][14][15][16][17][18][19][20]22 3.5 | Quality assessment (risk of bias and applicability concern)…”