Parotid secretory carcinoma with high-risk features in a paediatric patient: case report and review of the literature

Introduction

Tumours of the salivary gland represent 2–6% of head and neck cancers (1). Over 40 subtypes of salivary gland tumours, both benign and malignant, have been described (2). Secretory carcinoma (SC) of the salivary glands (SCSG) [formerly known as mammary analogue SC (MASC)] is a rare salivary gland tumour, first described in a case series by Skálová et al. in 2010 and formally classified as a separate entity in 2017 (3,4). A systematic review of SCSG across all ages published in 2022, the largest to date, identified 657 cases in the literature across 109 articles (5). SCSG is characterised by its morphological and immunophenotypic similarity to SC of the breast (6-8). The disease is reported to occur most frequently in the parotid gland, is slightly more common in males, and has a wide age range, with an average age of onset in middle age (5).

SCSG is currently classified as a low-grade salivary gland malignancy and is considered to possess a relatively indolent biology (9-11). Despite this, some cases are known to behave more aggressively, with high-grade transformation, locoregional spread, distant metastasis and disease-related death all reported (4,8,11). Locoregional recurrence following treatment occurs in approximately 10% of cases, with recurrence rates as high as 45% for T4 tumours (2,5,8,12). Factors associated with worse prognosis include high tumour stage, invasive growth pattern [particularly the presence of lymphovascular invasion (LVI), perineural invasion (PNI), or extraglandular extension], regional nodal spread, high Ki67 index, and atypical molecular features (such as absence of ETV6-NTRK3 fusion or presence of ETV6-RET translocation) (2,5,11,13). The mainstay of management for SCSG is surgical resection, typically involving a parotidectomy, with the addition of neck dissection in the setting of nodal metastasis. Adjuvant radiotherapy to the primary site and neck and adjuvant chemotherapy or targeted therapy are indicated in select cases (14-16).

In the paediatric population, salivary gland tumours are rare, with mucoepidermoid carcinoma being the most frequent malignant subtype reported (10). Paediatric SCSG is a very rare diagnosis (7). An age range from 17 to as young as 4 years has been reported (14,17). Two previous systematic reviews have examined the literature on paediatric SCSG, though the number of published cases has since considerably increased (1,18).

There is limited available evidence regarding the natural history or optimal management of SCSG in the paediatric setting. Notably, of the case reports of paediatric SCSG published, the majority describe localised tumours with no high-risk features, managed with surgical resection alone, and with excellent long-term outcomes (1,18). No previous review has specifically examined the subset of cases of paediatric SCSG carrying high-risk pathological features. Therefore, whether the adverse features described for adult SCSG are relevant also to paediatric disease remains unclear. Moreover, in cases where high-risk features are present in paediatric SCSG, there is no existing evidence base to guide treatment decisions such as the necessity for neck dissection and the role of adjuvant chemoradiotherapy.

We present here a case of SCSG in a paediatric patient, notable for its multiple high-risk features and the necessity for multimodality treatment. We then proceed to review the published literature on paediatric SCSG, with a focus on cases with high-risk features, and evaluate aspects of natural history and management for this very rare tumour subtype. We present this article in accordance with the CARE reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-23-181/rc).

Case presentation

A 16-year-old female presented to the emergency department at our hospital in March 2022 with a 2-day history of increased swelling and discomfort of the left parotid region, in the context of a known left parotid mass previously investigated at another centre 1 year prior.

On previous workup, a computed tomography (CT) head/neck had shown a 29 mm × 24 mm mass in the inferior aspect of the left parotid gland, and fine needle aspiration biopsy had indicated ‘oncocytic neoplasm, further subclassification difficult’. A decision had been made to observe the tumour. The lesion had symptomatically remained largely stable in the interval. A follow-up magnetic resonance imaging (MRI) head/neck had been organised, which was completed 1 month prior to representation; the patient was awaiting outpatient review for discussion of the imaging findings. The remainder of the history was non-contributory, with no medical comorbidities or family history of malignancy.

On examination, the parotid lesion was fixed and tender to palpation with no overlying skin change. Facial nerve function was intact, and there was no palpable cervical lymphadenopathy. Review of the recent MRI head/neck demonstrated a 34 mm × 27 mm mass in the deep lobe of the left parotid gland inferiorly, extending to the stylomastoid foramen, associated with an 11 mm left level IIa lymph node (Figure 1).

Figure 1 MRI head/neck T1 fat-suppressed (A) axial and (B) coronal slices demonstrating tumour of left parotid gland. MRI, magnetic resonance imaging.

On outpatient follow-up, a decision was made to proceed with left total parotidectomy with facial nerve preservation and excision of left level IIa lymph node. Intraoperatively, the tumour was large, lacking a clear capsule, and adherent to the buccal and marginal mandibular branches of the facial nerve. The patient recovered well postoperatively; a marginal mandibular nerve paresis was transient and had resolved on initial follow-up.

Histopathological review of the parotidectomy specimen demonstrated a well-marginated, unencapsulated, multi-lobular tumour composed of sheets, cords and papillae of eosinophilic cells, in some areas having hobnailing architecture, occupying most of the resected gland. On immunohistochemistry, the tumour was positive for CK7, S100, SOX10, GATA3 and mammaglobin—in keeping with SC of the parotid gland (Figure 2). Fluorescence in situ hybridisation (FISH) testing confirmed ETV6-NTRK translocation. Several additional high-risk features were demonstrated on histopathology, namely focal involvement of the superficial and deep resection margins over a 1 mm front, extensive LVI, focal PNI, one intraparotid lymph node directly involved by tumour, and a 4.5 mm deposit of metastatic carcinoma in the dissected level IIa lymph node.

Figure 2 Histopathological appearance of resected parotid SC. (A) Haematoxylin-eosin staining; (B) immunohistochemistry staining for S-100; (C) immunohistochemistry staining for GATA3; (D) immunohistochemistry staining for mammaglobin. © Copyright—NSW Health Pathology for and on behalf of the Crown in right of the State of New South Wales. SC, secretory carcinoma.

The patient’s case was discussed at the hospital’s head and neck multidisciplinary team meeting. The consensus recommendation was for a staging positron emission tomography (PET) scan and completion left levels II–V neck dissection, with or without adjuvant radiotherapy. PET/CT demonstrated mild focal uptake at level II [maximum standardized uptake value (SUVmax) 3.7] and level V (SUVmax 4.2) cervical lymph nodes (Figure 3). Focal uptake was also seen in the gastric fundus; a gastroscopy with endoscopic ultrasound was scheduled, which revealed no evidence of metastatic disease, confirming the tumour staging as locoregionally advanced disease. The patient then underwent neck reoperation as planned, where the visibly enlarged lymph nodes in level IIa and Va were dissected. Subsequent histopathology revealed non-specific reactive changes, with no malignancy in 0 of 39 dissected nodes.

Figure 3 PET/CT scan demonstrating mild focal uptake in (A) level 2 and (B) level 5 cervical lymph nodes. SUV, standardized uptake value; PET, positron emission tomography; CT, computed tomography.

Given the presence of high-risk pathological features on initial resection, a decision was made to proceed with adjuvant radiotherapy to the parotid bed and the neck, at 66 Gy for 33 fractions. The patient tolerated radiotherapy well, with radiation dermatitis of the parotid region managed with topical steroids. At 12 months postoperatively, and 8 months post-completion of radiotherapy, the patient remains free of disease, and is planned for ongoing oncosurveillance by the otolaryngology and radiation oncology teams.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient and her parent (given the patient’s age less than 18 years old) for publication of this case report and the accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Literature review

Methods

The PubMed and Embase electronic databases were searched using the terms “secretory carcinoma”, “MASC”, “salivary gland”, “parotid”, “paediatric OR pediatric”, and “child” to identify relevant articles in the literature. All non-review journal articles published in the English language from the year 2000 were considered. Titles/abstracts were screened for relevance. In the full-text review, studies of SC in adult patients only were excluded. Reference lists were hand-searched and further relevant articles identified. Data extracted from the included studies were patient demographics, tumour clinical and pathological characteristics, treatment type and follow-up outcome.

Results

The clinical and management-related data for all 52 published cases (across 39 articles) of paediatric SCSG in the literature, including our own case, are presented in Table S1.

Data for the nine cases of paediatric SCSG with evidence of local tumour invasion, nodal involvement, locoregional recurrence, or requiring multimodality treatment are presented in Table 1.

LVI has not been reported prior to our own case. PNI was present in five cases, including our own case (19-21). Lymph node metastasis, confirmed histologically following neck dissection, was present in five cases, including our own case (12,20,22,23). In an additional two cases, neck dissection was performed on the basis of preoperative imaging findings however no evidence of malignancy was identified in the dissected nodes (18,25). There are no documented cases of distant metastasis in paediatric SCSG.

Adjuvant radiotherapy was utilised in five cases, including our own case (12,19,20,24). Adjuvant cytotoxic chemotherapy and targeted therapy with larotrectinib were utilised in one case (19).

Locoregional recurrence has been reported in only one paediatric case in the literature (21). In the remaining included studies patients remained disease-free on follow-up, with observation periods ranging from 12 months postoperatively to a maximum of 13 years.

Discussion

Our case is notable for the aggressive course of the patient’s tumour at time of operation. The natural history of paediatric SCSG is considered indolent and readily treatable on the basis of the existing literature: the majority of cases have presented as localised tumours with no high-risk pathological features and favourable long-term outcome (1,18). In the handful of reports of more advanced paediatric disease, most involve a single high-risk pathological factor, such as isolated PNI (19,23), or isolated nodal involvement (21,22). The case most comparable to our own was that published by Skálová et al. of a 15-year-old male with a submandibular SC, in which both PNI and nodal metastasis were identified (20). Nevertheless, our case remains the only published instance of paediatric LVI—a feature shown in the adult SCSG literature to be an independent poor prognostic factor on multivariate analysis (26). In the adult setting, while low-grade localised disease is again most common, the existence of a subset of tumours with an accelerated clinical course is now well recognised. These latter tumours appear predisposed to metastasis, so mimicking high-grade salivary gland malignancies (16,27). The prognostic factor identified most consistently in the SCSG adult literature is T4 disease (2,26). A systematic review by Janik et al. demonstrated a significantly increased risk of lymph node metastasis (57%) and distant recurrence (46%) with T4 tumours. The authors concluded that T4 SCSG behaves significantly more aggressively and therefore warrants extended treatment strategies and close follow-up (2). While these data must at present be extrapolated to the paediatric setting, future research confirming the natural history and prognostic factors of paediatric SCSG specifically is necessary.

Both completion neck dissection and adjuvant radiotherapy to the parotid bed and neck were offered in our patient. The role of such multimodality treatment in paediatric SCSG has not been previously reviewed. In the vast majority of published paediatric cases, since no high-risk features are present, surgical resection of the tumour has been considered sufficient and no additional treatments provided (8). The most extensive treatment regimen in a paediatric SCSG patient on our review was that published by Cardoni et al., in which neoadjuvant chemotherapy and targeted therapy and adjuvant proton therapy to the disease site and neck (without neck dissection) were used for SC of the maxillary sinus (19). Only one previous published case of paediatric SCSG reports the use of both neck dissection and adjuvant therapy, comparable to our own patient—Forner et al. describe a 6-year-old with a right parotid tumour who, in addition to right parotidectomy, underwent selective neck dissection, contralateral parotidectomy and adjuvant radiotherapy (12). In the adult SCSG literature, multimodality treatment is more frequently utilised. Radiotherapy to the primary site is indicated in adult SCSG where adverse features such as T4 disease, positive resection margins, LVI and PNI are present—analogous to the recommendations for other salivary gland malignancies (5). Neck dissection is performed in 15–25% of cases, and postoperative radiation to the neck (together with primary site radiotherapy) in 20–30% of cases. The key indication for management of the neck is evidence of nodal metastasis, with some authors concluding that prophylactic neck dissection in the absence of known nodal involvement is not recommended for SCSG (5,7,12). Adjuvant chemotherapy is utilised in 2–4% of cases: the tropomyosin receptor kinase inhibitor larotrectinib—an agent which blocks the ETV6-NTRK3 fusion gene implicated in SCSG—represents a promising systemic treatment modality for these tumours, demonstrating favourable efficacy and safety profiles in a recent analysis (5,7,28). Again, much remains unknown regarding the optimal management approach for paediatric cases specifically. While the extreme rarity of SCSG in the paediatric cohort makes designing interventional studies of these tumours unfeasible, further published data are necessary to clarify whether the recommendations for adult SCSG are also appropriate in children with the disease.

Conclusions

We report a paediatric case of SCSG, notable for its multiple high-risk features and the necessity for multimodality treatment. There is a limited body of evidence to guide treatment decisions in paediatric SCSG, especially for cases with high-risk features such as LVI or PNI and nodal metastasis. Further research is required to clarify the natural history and optimal management of children with this rare tumour subtype.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-23-181/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-23-181/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-23-181/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient and her parent (given the patient’s age less than 18 years old) for publication of this case report and the accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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