Survival after parotid gland metastases of cutaneous squamous cell carcinoma of the head and neck

Salivary gland carcinomas (SGC) account for less than 1% of all cancer types in Europe [1]. SGC are most frequently localised in the parotid gland, although the proportion of malignant to benign tumours in the small salivary glands is higher [2]. According to the huge diversity of tumour subtypes and the low incidence, appropriate treatment remains challenging. Twenty subtypes of SGC have been defined by the World Health Organisation yielding different histological and molecular characteristics [3]. Mucoepidermoid carcinoma is the most common subtype [4, 5].

Due to possible facial nerve involvement, parotid gland carcinomas (PGC) can be challenging for head and neck surgeons. The biological aggressiveness of PGC varies considerably between the different entities. For example, the overall survival ranges between 95–100% for low-grade adenocarcinoma [6] and 23–50% in high-grade mucoepidermoid carcinoma cases [7]. Prognosis is significantly impaired by loco-regional lymph node metastases [4].

Complete tumour removal (R0) is the most effective treatment for PGC. Elective treatment of the N0 neck remains a controversial issue. Radiotherapy can be used as adjuvant therapy in patients with risk factors [2].

Squamous cell carcinomas (SCC) of the parotid gland have a worse prognosis as compared to other malignant tumours of the parotid gland, such as adenoid cystic, mucoepidermoid, and acinic cell carcinomas [8]. Tumorigenesis of squamous cell carcinoma of the parotid gland [9] is still under discussion: While some might consider primary SCC of the salivary glands as being non-existent, the vast majority of patients report on a previous cutaneous squamous cell carcinoma (CSCC) in the head and neck area [10, 11], typically 1 year after onset of disease [12]. Therefore, these parotid tumours are in fact representing CSCC-derived lymph node metastases [13]. Eighty percent of all CSCC are found in the head and neck region [14]. High exposure to ultraviolet (UV) and ionising radiation as found in Australia was reported to foster the formation of CSCC [11].

The objective of our study was to analyse and compare the clinical behaviour of primary PGC and CSCC metastatic parotid cancers with special emphasis on therapy and oncologic outcome.

All patients with histologically proven malignant tumours of the parotid gland who underwent combined surgery and radiation therapy or surgery alone at the Department of Otorhinolaryngology, Head and Neck Surgery of the University Hospital Cologne, Germany, between January 1987 and December 2015 were retrospectively assessed thus identifying all cases of metastatic parotid CSCC. Clinical data were retrieved from patients’ medical records, histology reports, and radiographic imaging. TNM staging was performed according to the 8th edition of the American Joint Committee on Cancer (AJCC) [15]. Demographic data as well as oncological outcomes were compared between metastatic CSCC of the parotid gland and primary parotid gland tumours.

A total of 342 patients suffering from malignant tumours of the parotid gland were identified. Forty-nine out of these were diagnosed with metastatic CSCC of the parotid gland.

In contrast to other previously published studies, this study focuses on malignancies of the parotid gland and distinguishes between primary and secondary tumours with respect to clinical and therapeutic characteristics as well as 5-year overall survival. PGC were mainly classified as adenocarcinoma NOS, mucoepidermoid, adenoid cystic, and acinic cell carcinoma. A total of 77.2% 5-year overall survival rate is comparable to previously published results [18, 19].

In the CSCC group, the majority of patients were male. This is consistent with already published data of PGC [20]. The age distribution of the CSCC patients with parotid involvement presented here also agrees with data from previously published patient cohorts thus confirming that older patients are particularly affected by that disease [20].

Primary CSCC were most often located in the area of the auricle, temple, and forehead. This is in accordance with previous reports [12, 21]. Creighton and colleagues showed that CSCC preferentially metastasise to the forehead (85%), periauricular area (76%), and in 30% to the scalp, cheek, and infraauricular region [21]. Hirshoren et al. further demonstrated that the majority of CSCC originating from the scalp, auricle, and cheek area metastasise to the parotid gland [12].

Despite multimodal therapeutic strategies, the 5-year OS remained poor in CSCC patients (32.6%) as compared to PGC (77.2%). These results are in line with previously published data of other authors [11, 20, 22] and are due to a generally higher tumour stadium as a consequence of lymph node metastasis in the CSCC group. It is noteworthy that even PGC patients having loco-regional metastasis had a better 5-year OS as compared to CSCC patients irrespective of neck node metastasis (CSCC_N- and CSCC_N+). Cervical metastases were demonstrated to significantly worsen the prognosis of CSCC patients [11, 20]. However, in our study, we could not find a significant difference in 5-year overall survival for CSCC patients without further neck lymph node metastases (CSCC_N-) compared to CSCC with neck lymph node metastases (CSCC_N+).

It should be discussed how the overall survival in this group could be improved: On the one hand, studies indicate that an improvement in diagnosis and consistent implementation of adequate staging and timely initiation of therapy can improve overall survival. Deilhes et al. demonstrated that 37% of patients were not diagnosed until the disease was in an advanced stage, indicating a lack of CSCC identification. For the remaining 69 patients, 7% did not receive treatment within 3 months of the CSCC being identified, 62% had an incomplete histological report, and 37% had incomplete treatment [23]. On the other hand, an escalation of therapy in order to improve overall survival seems reasonable. But at least, all patients with advanced CSCC, like in our study, had received both radical surgery as well as adjuvant radiotherapy. Increasing the radicality of the surgery might lead to a better survival. Coombs et al. concluded that more extensive surgery, including lateral temporal bone resection, could improve the local control rate in cases of advanced disease [24]. For better overall survival, immunotherapy might also be added to standard therapy in an adjuvant or neoadjuvant setting in the future. Current drug therapy options were examined in a palliative setting by several authors. Montaudie et al reported on cetuximab as monomodal therapeutic option in unresectable palliative CSCC patients (n = 58, mean age 83.2 years) [25]. The overall response rate (ORR) was 53% and 42% after six and 12 weeks, respectively. The authors conclude that cetuximab delays disease progression [25]. In a review by de Lima et al., the authors summarised studies on CSCC drug therapy. Again, the application of cetuximab was discussed in combination with checkpoint inhibitors [26]. Checkpoint inhibitors could serve as a therapeutic alternative in case of recurrent CSCC yielding parotideal metastases. Compared to platinum-based chemotherapy, modern immunotherapeutic strategies are considered as being better tolerated especially in elderly patients. Recently, the PD-1-blocking antibody cemiplimab was approved by the FDA and EMA for advanced CSCC treatment. However, detailed guidelines for indication are still missing which might be—at least in part—due to a lack of appropriate clinical studies for patients with recurrent or metastasised CSCC [27]. Steeb et al. reviewed the previous studies and experiences using checkpoint inhibitors in advanced CSCC and concluded that cemiplimab and pembrolizumab immunotherapy could result in a response rate of 40–55% in a first-line palliative setting [27‐29]. These promising results might be due to a high immunogenicity of CSCC [30]. However, the exact setting or composition in which immunotherapy should be applied remains a matter of debate.

The retrospective character of our study and potentially associated selection bias as well as the relatively low number of patients with CSCC limits clinical validity.

The present study retrospectively evaluated 342 patients with primary PGC (n = 293) and CSCC metastatic cancer to the parotid gland (n = 49) thus yielding a significantly worse prognosis for metastasised CSCC despite an intense multimodal therapeutic effort (radical surgery and adjuvant radiotherapy.