Diagnostic challenges and successful organ‐preserving therapy in a case of secretory carcinoma of minor salivary glands

Abstract Background Secretory carcinoma is a more recently described subtype of salivary gland carcinoma that may pose diagnostic challenges and frequently harbors NTRK fusions that may successfully be targeted by TRK inhibitors in advanced disease. Case We present the case of a female patient with secretory carcinoma arising in the base of tongue with persistent disease after debulking surgery and definitive chemoradiation. As an alternative to salvage surgery, which would have resulted in significant impairment of swallowing and speech function, a targeted therapy with the TRK‐inhibitor larotrectinib against an identified ETV6‐NTRK3 fusion product was initiated. Larotrectinib treatment has been well tolerated, resulted in durable complete response and the patient maintains good swallowing and speech function. Conclusion The presented case underscores the importance of the accurate diagnosis of secretory carcinoma. It further highlights the impact of molecular testing as targeted therapies may play an important role in the management of advanced salivary gland cancers.


| INTRODUCTION
Secretory carcinomas (SC) of the salivary gland were classified over a decade ago, initially thought to be a more aggressive subtype of acinic cell carcinoma that bore some homology to secretory carcinomas of the breast. Initially classified as mammary analogue secretory carcinomas (MASC), 1 the term was revised in the most recent edition of the WHO classification of Head and Neck Tumors (2017). 2 In addition, the initial characteristic t(12,15) (p13;q25) translocation resulting in the ETV6-NTRK3 fusion transcript has been noted in these tumors, and more recently, occurring with some regularity associated with RET fusions. 3,4 This tumor typically occurs in the major salivary glands; however, SC can also occur in atypical locations arising in minor salivary glands. 5,6 The histopathologic diagnosis of SC may be challenging, although it is more commonly recognized since its classification. Initially identified as an aggressive subset of acinic cell carcinomas, it is now recognized to be a more indolent tumor, but with a spectrum of clinical behavior. Although most SC may develop over years, cases with an aggressive disease course, including lymph node metastases along with local recurrence or even distant metastases with lethal outcomes have been reported. 1,7 The rare occurrence of high-grade transformation in SC of major and minor salivary glands is often associated with an unfavorable prognosis. 8 Curative treatment strategies for SC of the salivary glands are identical to those of other salivary gland tumors concentrating on complete surgical resection. Dependent upon tumor stage and specific pathological features such as grade, perineural-and lymphovascular invasion and margin status, additional therapeutic modalities are considered, including adjuvant radiotherapy or chemoradiation. In the case of local recurrence or persistent disease of previously irradiated tumors, surgery, reirradiation or chemoradiation are the therapies of choice. 9 Based on the frequency of fusion kinases associated with these tumors, nearly all, they are ideal candidates for targeted therapy, 1,3,4,7 especially in the setting of advanced, recurrent or palliative disease. With the dominant ETV6-NTRK3 fusion, this tumor entity appears as an ideal candidate for inhibitors targeting tropomyosin receptor kinase (TRK) proteins, like the small-molecules larotrectinib or entrectinib. Indeed, larotrectinib and entrectinib therapy both induced rapid and durable relevant clinical activity in NTRK fusionpositive solid tumors including cases of salivary SC with locally advanced or metastatic disease. [10][11][12] In this case report, we discuss the challenges of the proper diagnosis of SC, and the use of larotrectinib in a potentially salvageable recurrent tumor that would otherwise had exceptionally debilitating outcomes if surgically resected.  but less so as pathologists become more familiar with its diagnosis. In contrast to most AciCC, typically diffusely positive for DOG1 (discovered on GIST-1) by immunohistochemistry, SC are typically diffusely positive for S-100, mammaglobin, and GATA3 and negative for DOG1.

| CASE PRESENTATION
In addition, the detection of a fusion kinase, ETV6-NTRK3 in most SC of salivary glands and ETV6-RET in a significant subset, confirms the diagnosis. 1,4 This characteristic chromosomal translocation can be detected by reverse transcription-polymerase chain reaction (RT-PCR), targeted fusion transcript detection by next generation sequencing or fluorescence in situ hybridization (FISH). 14,15 In routine clinical settings without the option for molecular evaluation, diagnosis will need to focus on strict morphological criteria including a limited immunohistochemical panel if possible. Use of a pan-TRK antibody for immunohistochemistry can provide some aid in the differential diagnosis of SC versus AciCC, but the antibody, although specific, is not particularly sensitive, 16 and given additional fusion partners, an initial screen would benefit more from DOG1/ S100 in the differential, raising follow up testing once a diagnosis of SC is suspected, especially in any case of advanced disease or when the patient is a poor surgical candidate for other reasons. And, as described, although the ETV6-NTRK3 fusion represents the most common genomic aberration in SC of salivary glands, there are oncogenic rearrangements of ETV6 with fusion partners other than NTRK3, such as MAML3 or RET, and cases without ETV6 fusions have been described. 7,17 Whereas in the curative stage, surgery with appropriate adjuvant treatment represents the best treatment modality, in the case of unresectable or metastatic disease, targeted therapy with TRK-inhibitors represents a highly active therapeutic opportunity. In a pooled analysis of phase I and phase II clinical trials of solid tumors with TRK-fusions, 79% and 16% of the patients experienced an objective response and complete response, respectively, upon larotrectinib treatment at a dose of 100 mg BID as administered in the presented case. 12 In patients that responded to the treatment, the median duration of response was 35.2 months. 12 As the development of resistance to TRK-inhibitors is likely, a continuous clinical and radiographic follow up is important. Both, on-and off-target resistance mechanisms to TRK inhibitors in solid TRKfusion positive tumors have been reported. On-target mutations affect the TRK-kinase domain and thus restrict drug binding, and can potentially be circumvented by second-generation TRK inhibitors such as LOXO-195 that is currently evaluated in a clinical trial including NTRK fusion positive solid tumors with intrinsic or evasive resistance to a prior TRK inhibitor (NCT03215511). 18 In contrast, off-target mutations typically cause resistance to second-generation TRK inhibitors and can occur during treatment with first-and second-generation TRK inhibitors. Different off-target genomic alterations that cause activation of the mitogen-activated protein kinase (MAPK) pathway or MET amplification have been reported. 19 Thus, in the presented case, in the event of evasive resistance, a biopsy of the emerging lesion will be critical to determine the molecular mechanism of resistance. Based upon updated genetic alteration data, a follow up treatment strategy will be employed, including further targeted therapies or salvage surgery.
The era of targeted therapies in oncology opens avenues for creative treatment approaches in selected clinical situations. In the presented case, salvage surgery as the standard treatment option of this persistent SC of minor salivary glands would have been technically feasible, yet likely led to significant impairment of the patient's quality of life. As the response rate of TRK-inhibitors in TRK-fusion positive solid tumors is substantially high, a treatment attempt to either downstage the tumor in the case of a partial response to facilitate surgery, or, as in the presented case, due to the complete response that will significantly delay repeat surgery until the likely recurrence of evasive resistance is quite appealing, and as shown in this case, quite successful.

ETHICS STATEMENT
Written informed consent was obtained from the patient. The institutional approval was waived by the Institutional Review Board for this single patient case report.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.