According to the latest GLOBOCAN report, non-melanoma skin cancer (excluding basal cell carcinoma) is the fifth most common malignant tumor in the world.1 Moreover, in the next 20 years, an increase of 90.2 % is expected, leading to an incidence of almost 2 million people by 2040.2 Cutaneous squamous cell carcinoma (CSCC) is the most common form of non-melanoma skin cancer, when basal cell carcinoma is excluded. The head and neck regions are affected in more than 80 % of cases. Fortunately, the prognosis is usually very good, and the low percentage of deaths occurs mainly due to metastatic disease. Regional metastases of CSCC occur in approximately 5 % of cases3 and malignant cells have the potential to metastasize to intraglandular parotid and/or neck lymph nodes.4 Besides directly affecting the mortality of CSCC, the presence of regional metastasis has an important effect on morbidity, once patients might require multimodality treatment such as neck dissection, different extents of parotidectomy (with or without facial nerve preservation), and postoperative radiation therapy.5

Staging systems represent a pivotal tool for prognostic stratification enabling physicians to plan treatment based on tumor risk.6 Currently, the American Joint Committee on Cancer (AJCC) staging manual represents the reference guideline for classifying patients with different types of cancer, including CSCC. This manual is continually revised to incorporate important features that might affect the prognosis on high evidence-based levels. Since its first release in 1997, eight editions have been produced. In the seventh edition, important features such as depth of invasion, perineural invasion, and histologic grade were included for the first time.7 Launched in 2017, the eighth edition has incorporated different and important risk factors based on cohort studies that emerged since the seventh edition, such as large caliber or subdermal perineural invasion, minor bone erosion, and invasion beyond subcutaneous tissue or depth of invasion (DOI) > 6 mm. Concerning the nodal metastasis (N) category, the presence of Extranodal Extension (ECE) must now be taken into account and denotes a more advanced stage.8 Recently, Moeckelmann et al. evaluated the performance of the AJCC 8 nodal staging system in a retrospective Australian cohort of 382 head and neck CSCC cases. The current nodal staging system did not provide any risk stratification, suggesting CSCC merits an independent nodal staging system.9

In 2002, O’Brien et al. published the first report demonstrating better prognosis of parotid involvement compared with neck disease.10 Since then, several reports have been conducted in this subject and heterogeneous findings obtained.11–15 The current TNM staging system considers that although preliminary data suggest that cervical nodal disease may portend a worse prognosis than parotid disease, the data are insufficient to support this separation yet.16 The purpose of this study was to revisit this topic and evaluate the prognostic features among patients with head and neck CSCC regional metastasis.

The fast evolution of knowledge in cancer biology imposes the necessity of continuous questioning and updates in staging systems aiming to supply cancer care providers the best evidence-based resource for classifying patients, defining prognosis, and determining the most appropriate treatment protocol. The AJCC Eighth Edition Team made important efforts to build a more “personalized” approach for cancer staging. Recent evidence has already demonstrated that the new proposed system for CSCC has improved homogeneity and monotonicity besides having a better prognostic value.17 In spite of that, an Australian group recently demonstrated that the current nodal staging system does not add any prognostic information, suggesting that an independent nodal staging system would be more appropriate concerning head and neck CSCC.9 Our clinical impression led us to question whether the site of node involvement should not be taken into consideration for the analysis of the N category. Here, we demonstrated a better prognosis for cases with parotid versus neck metastasis in our cohort of patients. This finding might reignite the debate of the possibility to incorporate this feature in a future staging system.

In 2002, O’Brien et al.10 hypothesized that, regarding head and neck CSCC, better prognostic discrimination might be achieved by dividing parotid and neck disease. Analyzing a sample of 87 cases, the authors found that, among patients with metastatic CSCC involving the parotid gland, those who also had the disease in the neck had a statistically significantly worse outcome.10 A following multicenter study was conducted on 322 patients from three Australian and three North American institutions in 2006, confirming initial impressions that the addition of parotid and neck stages adds valuable prognostic information about cancer-specific survival.11 Ch’ng et al.12 revisited this issue, showing worse prognosis according to parotid or neck progression of the disease, and impact on outcomes of cumulative parotid and neck metastasis compared with single site disease. Nevertheless, conflicting subsequent results13–15 made the current AJCC staging system team consider that there were insufficient data to support a separation of parotid and neck disease at this time.16 Probably the most impacting results are from Hirshoren et al. that studied 183 cases of metastatic head and neck CSCC. They found no association between overall survival and site of metastasis (parotid versus neck versus both), but only with lymph node ratio.13 Those results followed a trend in head and neck oncology, joining with several other publications regarding different head and neck topographies.18

According to the AJCC, current and future changes to AJCC staging content must rely on evidence and the highest cancer level of evidence comprehends “consistent results from multiple large, well-designed, and well-conducted national and international studies in appropriate patient populations, with appropriate endpoints and appropriate treatments”. To our knowledge, this is the first study to address the role of site of metastasis as a prognostic marker in a South American population. We believe that this is important because it might increase the level of evidence for this issue by identifying consistent findings in our population to those previously found in Australia,10,11 New Zealand,12 and North America.11 We recognize that our sample size might represent a limiting factor in our study. Previous reports on this subject had samples that ranged from 6712 to 322 patients.11 This last one represented a multicenter study that comprised six different institutions. We believe that further studies with such representative samples are still needed. Our results stress this necessity and might encourage larger multicenter cohort studies.

Herein, we emphasize the association of site of metastasis as a prognostic marker, other clinical and pathological features were also identified as associated with a disease-free interval in our sample. This includes the site of the primary tumor, tumor diameter, DOI, invasion beyond subcutaneous fat, neck metastasis at first presentation, TNM stage, and number of positive lymph nodes. It is important to highlight that all our parotid metastases included a solitary node or solitary mass composed of fused nodes not countable. So why do those cases of parotid-only metastases tend to have better outcomes? Is it a site-specific trend or a bias related to a usually single nodular disease? There is insufficient literature to support that a patient with a single parotid metastasis has a different prognosis compared with one with a single neck metastasis. An interesting study by Ebrahimi et al. found both single parotid and neck node presentations associated with favorable outcomes, although the authors did not show an internal comparison between neck and parotid metastasis. We did not find the same better outcomes in this group of solitary parotid metastasis. About 1/3 of this group from our study died by disease, different from the 92 % of 5 year DSS found by Ebrahimi et al.19

In conclusion, our results demonstrated a better survival in patients with isolated involvement of parotid lymph nodes compared with those with neck involvement. We believe that such cases of isolated metastasis in the parotid have an intermediate outcome between non-metastatic cases and those with neck disease. Our findings are in agreement with previous reports conducted in different populations. However, we support a recommendation that further study comprising larger samples need to be performed to confirm if a review of the current staging system is in fact necessary.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

As this study was retrospective and with no intervention, no informed consent was applied.

The authors declare no conflicts of interest.