High‐grade Salivary Gland Adenocarcinoma Harboring ETV6-NTRK3 Fusion: Defined by Morphology or Molecular Aberration?

To the Editor,

With great interest, we noticed the publication by Todorovic et al. highlighting the potential value of routine molecular testing in salivary gland neoplasms [1]. The authors reported a high-grade salivary gland adenocarcinoma harboring an ETV6-NTRK3 fusion. Interestingly, the morphological and immunohistochemical profile were compatible with a salivary duct carcinoma (SDC). However, the detected fusion had been described previously as a molecular hallmark of (mammary analogue) secretory carcinoma [2]. We encountered a similar case of high-grade parotid gland adenocarcinoma in a 22-year-old male. The patient consulted his family doctor because of a preauricular node of 1 year’s duration. He did not have any evidence of facial nerve impairment or other signs or symptoms. On clinical exam, there was a ~ 2 cm mobile node in the preauricular region. In the preoperative MRI scan, an ill-defined contrast-enhancing nodule of 1.2 × 2 × 2.2 cm was described. Histological examination revealed tumor cell nests with an unusual, solid-papillary and slightly glomeruloid growth pattern (Fig. 1a–c). Medium to large, atypical cells were seen as well as brisk mitotic activity accompanied by comedonecrosis (Fig. 1d). In other areas, the tumor was partially cystic and exhibited “intraductal” growth (Fig. 1e, f). Furthermore, genuine infiltration into adjacent stroma was observed (Fig. 1g), but without evidence of perineural invasion. Immunostaining demonstrated focal surrounding by p40 and CK5/6 positive myoepithelial differentiated cells as well as limited but distinct S100 expression. In addition, MUC4 and GATA3 immunolabeling was diffuse and strong, whereas panTRK showed a small area of nuclear positivity; however most of the tumor was only faintly positive (membranous and cytoplasmic). Single cells showed immunoreactivity for androgen receptor (Fig. 1h). Her2 and mammaglobin were negative and p53 consistent with a “wild-type” expression pattern (not shown). The Ki-67 proliferation index was > 60% (Fig. 1h). No clues of an underlying pleomorphic adenoma were evident. Overall, the histological features of this tumor were compatible with SDC. However, androgen receptor expression was sparse and the young age of the patient was unusual. The unexpected faint but suggestive panTRK-expression led to molecular testing with our customized salivary gland neoplasm specific next generation sequencing panel (“SalvGlandDx”). The detection of a classical ETV6-NTRK3 fusion confirmed the weak but suggestive immunohistochemical panTRK result.

Fig. 1.

Overview of the presented parotid gland high-grade adenocarcinoma with unusual morphology and ETV6-NTRK3 fusion. In a hematoxylin and eosin (H&E) overview is shown, depicting a fibrotic stroma with cellular and cystic nests of the neoplasm (scale bar: 2.5 mm). The inset depicts magnification of the prominent comedonecrosis (scale bar: 100 µm). In b and c the solid-papillary and slightly glomeruloid growth pattern can be noted. d An increased magnification of the cystic growth pattern with central tumor cell necrosis. An intraductal growth pattern is visualized in (e), corroborated by p40 positive myoepithelial cells (f). The infiltrative growth pattern in g is characterized by irregular small glands and desmoplastic stromal reaction (scale bar: 100 µm). In h the (heterogeneous) expression of S100, diffuse positivity for MUC4 and GATA3 is seen. PanTRK immunohistochemistry showed a limited focus of nuclear expression (left half), whereas the rest of the tumor was only faintly expressing in a membranous and cytoplasmic pattern. Only single cells were positive for androgen receptor (AR), the Ki-67 proliferation index was high (> 60%; scale bar 100 µm)

Although the morphology of our case does also fit into the reported spectrum of (high-grade) secretory carcinoma, very rare cases have been described [3, 4]. In one case, the authors reported a similar papillary growth pattern [5], and in another publication, comedonecrosis has been described [4]. The low-grade morphology, typically observed in secretory carcinoma with high-grade transformation was not observed. Our case proved difficult-to-classify, since intraductal growth is very uncommon in secretory carcinoma [6]. Alternatively, “intraductal carcinoma” is usually low-grade with a distinct molecular profile [7]. High-grade salivary duct carcinoma is the primary differential diagnosis due to the comedonecrosis and intraductal growth [8]. However, the strong MUC4 expression [9], papillary-cystic morphology, S100 expression and molecular profile favor the spectrum of (high-grade) secretory carcinoma, which was our final diagnosis. Mammaglobin negative secretory carcinoma is uncommon, however has been specifically described in high-grade components [9].

In addition to the challenges of classifying neoplasms with uncharacteristic morphology, this case illustrates the importance of NTRK-screening and subsequent molecular testing. Most of the reported cases harboring the ETV6-NTRK3 fusion show nuclear expression of the panTRK immunohistochemistry, with isolated negative cases also described [10]. With the recent availability of NTRK inhibitors, targeted therapy is now an encouraging option in the appropriate clinical setting [11]. The patient presented underwent neck dissection due to the high-grade morphology. At present, after a very short follow-up of 8 weeks, there is no evidence of lymph node or systemic metastases. In the future, we will be increasingly confronted with conflicting results from standard and emerging diagnostic modalities, underscoring the need for a consensus on the optimal diagnostic approach.

Compliance with Ethical Standards

Conflict of interest

NJR discloses an advisory board function and receipt of honoraria from F. Hoffmann-La Roche AG. The “SalvGlandDx” panel has been developed by a grant from the Iten-Kohaut-Foundation/University Hospital Zurich Foundation to NJR. All other authors declare that they have no conflict of interest.

Informed consent

The patient provided a written informed consent in accordance with the Declaration of Helsinki.