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Improving risk classification in cutaneous squamous cell carcinoma

Presented by
Dr Marlies Wakkee, Erasmus MC Rotterdam, the Netherlands
DDD 2024
The latest guidelines on cutaneous squamous cell carcinoma (SCC) differentiate between staging systems and risk classification. According to the latest evidence, what is the metastatic risk for patients with SCC? And how can we estimate this risk accurately in the population of patients with SCC? Dr Marlies Wakkee (Erasmus MC Rotterdam, the Netherlands) discussed the progress made in recent years.

“Due to the increasing incidence of cutaneous SCC, the number of follow-up appointments for these patients is rising sharply,” stated Dr Wakkee [1,2]. “It is, therefore, time to reconsider skin cancer-related follow-up visits.” Although the risk for metastases is small in SCC, approximately 30% of the patients die from locally advanced SCC [3].

“With over 2 million newly diagnosed patients with SCC worldwide, we are approaching the mortality of melanoma,” commented Dr Wakkee. She highlighted that selecting the right patients for the right management and follow-up is challenging.
Treatment strategies based on risk classification

The predictive values of the current staging systems for cutaneous SCC, the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC8) and the Brigham and Women’s Hospital Tumour Classification System (BWH), are quite poor [4]. “Although staging is still recommended in the revised SCC guideline of the NVDV, risk classification may further select patients at low- and high-risk for disease progression,” said Dr Wakkee. She outlined that low-risk patients are those with T1 staging, while intermediate-risk patients encompass T2 patients or T1 patients with poorly differentiated or undifferentiated SCC, lymphovascular invasion, or dermal perineural invasion of each nerve diameter outside the tumour outline. High-risk patients include individuals classified with T3 or higher staging, those with a recurrent tumour, or patients with T2 tumours and at least 1 of the aforementioned risk factors.

“The treatment policy differs for the various risk categories,” continued Dr Wakkee. “For example, in low-risk patients, we aim for a free margin of 1 mm with excision surgery, whereas a margin of 2 mm is advised for intermediate- and high-risk patients.” In addition, micrographic-controlled surgery is an option for all patients, irrespective of risk classification. For low-risk patients, scheduling 1 visit every 6–12 months is recommended during the first 2 years after surgery. In intermediate- and high-risk patients, the novel guideline recommends a follow-up for 3 and 5 years, respectively.
A novel absolute risk prediction model for metastasis

“Besides this risk classification, it is recommended to use an absolute risk prediction model in case the dermatologist needs an accurate estimation of the metastatic risk in a patient with SCC,” said Dr Wakkee. For this purpose, a national nested case-control study was conducted, which collected data from patients who had their first cutaneous SCC in 2007/2008 (n=12,325) [5]. The investigators observed whether patients had subsequent cutaneous SCC, tracked how many patients had metastasising disease, and documented the proportion of patients who died from SCC.

Of the 12,325 included patients, 195 developed metastasising disease. The incidence of metastases among this population of patients with cutaneous SCC was 1.9%. Older age, male sex, a higher number of prior cutaneous SCC, and facial tumours were clinical factors associated with an increased risk for metastasising disease. In contrast, SCC located in the neck or scalp region was associated with a reduced risk for metastasising disease. A larger tumour diameter, the involvement of subcutaneous fat, the involvement of tissue beyond subcutaneous fat, poorly or undifferentiated tumours, and the presence of perineural or lymphovascular invasion were pathological factors associated with an increased risk for metastasising disease. “With a C-index of 0.84 and after external validation with a nested case-control study from the UK (n=696), we created an absolute risk model to predict metastases in patients with cutaneous SCC, which is available online,” said Dr Wakkee [5,6].

The latest European guidelines also classify cutaneous SCC as low-risk or high-risk, and suggest similar risk factors for recurrence or metastasis [7]. “Following these risk factors, we see that low-risk patients have a 0.4% metastatic risk and high-risk patients have a 3% risk of metastasising disease,” according to Dr Wakkee. “This is a low risk for both groups, considering that adjuvant radiotherapy is usually given at a risk of 20%.” If these risk factors are combined with the absolute risk prediction model developed by Dr Wakkee and colleagues, a small group of patients has a risk larger than 10%, whereas the risk for most patients is below 2%. Dr Wakkee expects that artificial intelligence will be used to further analyse histopathological features and gene expression profiles of cutaneous SCC, improving the risk estimation for patients with these tumours.
Another predictive model

Locally advanced SCC is also being investigated in the Dutch Keratinocyte Cancer Collaborative [8]. This study evaluates and predicts treatment response and disease progression with respect to mortality. “The model developed to identify patients with advanced cutaneous SCC from pathology reports performs well, with a sensitivity of 91.9% and a positive predictive value of 78.5%,” added Dr Wakkee. The study will further analyse the incidence of advanced cutaneous SCC, the metastatic risk in these patients, and various characteristics of metastases.

  1. Wakkee M. Ontwikkelingen op het gebied van stadiering van plaveiselcelcarcinomen. Dermatologendagen 2024, 11–12 April, Amsterdam, the Netherlands.
  2. Smak Gregoor AM, et al. British Journal of Dermatology. 2023;189(5):633-635.
  3. Karia PS, et al. J Am Acad Dermatol. 2013;68(6):957-966.
  4. Venables ZC, et al. British Journal of Dermatology. 2022;186;835-842.
  5. Rentroia-Pacheco B, et al. eClinicalMedicine. 2023;63:102150.
  6. Prediction of metastatic risk in patients with cutaneous squamous cell carcinoma (cSCC) [Internet]. Available from: https://emc-dermatology.shinyapps.io/cscc-abs- met-risk/.
  7. Stratigos AJ, et al. Eur J Cancer. 2023;193:113251.
  8. Eggermont C, et al. Journal of Investigational Dermatology. 2023;143(1):98-104.

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