Elsevier

European Journal of Cancer

Volume 111, April 2019, Pages 107-115
European Journal of Cancer

Original Research
The prognostic value of sentinel lymph nodes on distant metastasis–free survival in patients with high-risk squamous cell carcinoma

https://doi.org/10.1016/j.ejca.2019.02.004Get rights and content

Highlights

  • Cutaneous squamous cell cacrinoma (cSCC) is the second most common skin cancer after basal cell carcinoma.

  • The risk to metastasise is markedly elevated for cSCCs with a tumor depth > 4 mm, undifferentiated or perineural growth.

  • The value of sentinel lymph node ex in hrcSCCs is highly controversial.

Abstract

Background

Cutaneous squamous cell carcinoma (cSCC) is the second most common cutaneous cancer worldwide. Several tumour characteristics are considered to pose an elevated risk for systemic spread of carcinoma cells (‘high-risk’ features). Early detection of subclinical metastases could permit early treatment and improve overall survival. To detect occult metastases and evaluate risk of future distant metastases, diagnostic extirpation of the sentinel lymph node (SLNE) is routinely performed in cutaneous melanoma and can be offered in high-risk cutaneous squamous cell carcinoma (hrcSCC). However, the clinical utility of SLNE in patients with hrcSCC remains unknown.

Material and methods

An ambidirectional cohort study with prospective patient recruitment was performed. Between July 2008 and April 2017, of 139 eligible patients, SLNE was performed in 114 cases (25 patients refused). Median follow-up was 23.7 months.

Results

We analysed the characteristics of 114 patients with hrcSCC who underwent SLNE. Eighty-nine patients (78.1%) were men, and 25 patients (21.9%) were women (median age 72.2 years). In multivariable analyses, histopathological detection of ulceration (hazard ratio, HR 2.9 [95% confidence interval, CI 0.7–12.2]), perineural growth (HR 3.0 [95% CI 0.6–14.6]) and clinically occult SLN metastases (HR 10.7 [95% CI 1.9–60.6]) were strongly associated with future occurrence of distant metastases. A positive predictive value of 50% was noted for patients where SLN metastasis was detected to develop distant metastases. However, distant metastases also occurred in seven patients when histopathological SLN evaluation had shown no evidence of metastases.

Conclusions

Our data suggest SLNE is not a reliable diagnostic approach to evaluate the risk of future systemic carcinoma spread and development of distant metastases in patients with hrcSCC.

Introduction

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer after basal cell carcinoma [1]. Sun exposure, advanced age and ultraviolet radiation (UVR)-sensitive skin number are among the most prominent risk factors for cSCC [2]. The majority of patients with cSCC is cured by complete excision or local destructive therapies and has a favourable prognosis [1], [3], [4], [5]. In total, cSCCs have a metastasis rate of 3–5%. The risk to metastasise is markedly elevated for undifferentiated carcinomas (33%), for a tumour depth (TD) > 4 mm (45%) and for cSCC demonstrating perineural growth (47%) [6]. In comparison with the general population, organ transplant recipients have a 65- to 250-fold increased risk of developing metastases [7], [8], [9]. According to the 7th American Joint Committee on Cancer Cancer (AJCC) staging guidelines applicable for our cohort, TD of >2 mm, Clark level ≥ 4, perineural growth, localisation on the ear or non–hair-bearing lip, poor differentiation or undifferentiated growth are considered high-risk features [10]. In the new 8th AJCC staging guidelines, high-risk features are neglected in stage T1 and T2 and include any of the following: TD > 6 mm, invasion beyond the subcutaneous fat, perineural invasion (with additional subclassification) and minor bone erosion [11]. The Brigham and Women's Hospital staging system includes tumour diameter ≥2 cm, poorly differentiated cSCC, perineural invasion ≥0.1 mm and tumour invasion beyond fat as high-risk factors [12]. As regional nodal involvement represents an important prognostic factor [13], [14], [15], early detection of subclinical nodal disease enabling timely treatment might contribute to a prolongation of overall survival [16], [17]. In contrast to melanoma, where the prognostic value of extirpation of the sentinel lymph node (SLNE) is well documented and generally accepted, the value of SLNE in high-risk cutaneous squamous cell carcinomas (hrcSCCs) is highly controversial.

Therefore, we conducted an ambidirectional cohort study with prospective patient recruitment, offering SLNE to 139 patients having hrcSCC as defined by the German guidelines (vertical growth > 2 mm, localisation on the ear or lower lip, dedifferentiation and perineural infiltration). We explored the association between these risk factors and distant metastasis–free survival. In addition, diagnostic indices and predictive values of SLN status for distant metastasis–free survival were assessed.

Section snippets

Study design and patients

Patients were included based on the German guidelines for cSCC [18]. According to the German guidelines, SLNE may be offered to hrcSCC patients with elevated risk for metastases. The following features are defined as high-risk features: vertical growth > 2 mm, localisation on the ear or lower lip, dedifferentiation and perineural infiltration. Complete excision of the squamous cell carcinoma was performed in all patients. Excision margins were controlled micrographically. SLNE was offered to

Patients and tumour characteristics

We analysed the characteristics of 114 patients with hrcSCC who underwent SLNE in our department. In total, 89 patients (78.1%) were men and 25 patients (21.9%) women. Twenty-nine patients were immunosuppressed; 85 patients were immunocompetent. The median age at SLNE was 72.2 years (standard deviation, SD 11.3; mean 69.4 years [range 42–89]). In total, 87 hrcSCCs were located in the head/neck region and 27 hrcSCCs on the trunk. SLNE was performed in the head region (n = 69), the cervical

Discussion

To the best of our knowledge, this is the largest study ever performed to evaluate the clinical utility of SLNE for patients with hrcSCC. In univariable and multivariable analyses, perineural growth and ulceration in primary hrcSCC were found to be associated with future occurrence of distant metastases, in line with previous observation [6], [18]. Although we could not detect an elevated HR for TD being associated with distant metastases when we dichotomised TD (≤6 mm and >6 mm), we still

Conclusion

Clinical utility of SLNE in hrcSCC using high-risk criteria is limited, as outlined previously. In our cohort, negative SLN is not a reliable procedure to exclude occurrence of distant metastases in patients with hrcSCCs. Novel diagnostic approaches for patients with hrcSCC should be evaluated.

Author contributions

J.K. and I.S. had full access to all the data in the study, took responsibility for the integrity of the data and the accuracy of the data analysis, contributed in study concept and design and carried out study supervision. Acquisition, analysis and interpretation of data were carried out by all the authors. Drafting of the manuscript was carried out by P.J., A.S., I.S. and J.K. The manuscript was critically revised for important intellectual content by all the authors. Statistical analysis was

Funding support

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Conflict of interest statement

D.S. reported receiving consultancy fees, having board membership and receiving lecture fees from GlaxoSmithKline, Novartis, Amgen, Bristol-Myers Squibb, Roche, Genentech, Boehringer Ingelheim and MSD. The other authors declare no competing financial interests.

Acknowledgements

The authors would like to thank the Imaging Center Essen (IMCES) (Institute for Experimental Immunology and Imaging) team members for their support and advice.

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    Both authors contributed equally to this work.

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