Risk factors for metastatic cutaneous squamous cell carcinoma may help refine staging systems

The inclusion of nonlinear relationships for diameter and thickness, clinical characteristics such as sex and tumour location, and differentiation can improve the staging systems of cutaneous squamous cell carcinoma (cSCC), suggests a recent study.

“Comparison of our final set of risk factors with the American Joint Committee on Cancer eighth edition (AJCC8) and Brigham and Women’s Hospital (BWH) showed higher pseudo R² measures in both data sets,” the researchers said.

“Following tumour diameter and thickness, poor differentiation proved an important risk factor for metastasis, despite being omitted from the AJCC8, thereby emphasizing the importance of reviewing and refining current staging systems,” they added.

Metastatic cases were selected from English and Dutch nationwide cancer registry cohorts and matched 1:1 to controls to analyse and replicate risk factors for metastatic cSCC. The researchers extracted variables from pathology reports from the National Disease Registration Service in England. In the Netherlands, a dermatopathologist revised histopathologic slides from the Dutch Pathology Registry.

Using backward logistic regression, the researchers performed model building in the English data set (n=1,774). They also carried out replication using the Dutch data set (n=434).

Apart from diameter and thickness, the following variables were significantly associated with the risk of metastatic cSCC in the English data set: poor differentiation (odds ratio [OR], 4.56, 95 percent confidence interval [CI], 2.99‒6.94), invasion in (OR, 1.69, 95 percent CI, 1.05‒2.71) or beyond subcutaneous fat (OR, 4.43, 95 percent CI, 1.98‒9.90), male sex (OR, 2.59, 95 percent CI, 1.70‒3.96), perineural/lymphovascular invasion (OR, 2.12, 95 percent CI, 1.21‒3.71), and facial localization (OR, 1.57, 95 percent CI, 1.02‒2.41). [J Am Acad Dermatol 2022;87:64-71]

Diameter and thickness had a significant nonlinear association with metastasis. In addition, ORs seen in the Dutch data set were comparable.

“We confirmed the previously found significant associations for diameter, thickness, poor differentiation, deep invasion, and perineural/lymphovascular invasion,” the researchers said. “Clinical parameters such as sex and body site were also significant risk factors, whereas immune status did not remain in the model.”

The ORs for all risk factors in the present study were more accurate with narrower CIs compared with those from earlier studies, providing a greater capability to refine staging systems. [JAMA Dermatol 2013;149:541-547; J Am Acad Dermatol 1992;26:976-990; Lancet Oncol 2008;9:713-720; JAMA Dermatol 2016;152:419-428; J Surg Oncol 2012;106:811-815]

Of note, the current staging systems do not include sex, which is an important risk factor in the current study and has been previously observed for melanoma. [J Clin Oncol 2012;30:2240-2247]

“This could be due to biological sex differences, delayed presentation, greater UV-exposure secondary to less protection from hair coverage, or outdoor occupations/hobbies,” the researchers said.

The present study was limited by the retrospective use of pathology reports in the English data set.

“CSCC is one of the most common cancers worldwide with metastatic potential,” according to the researchers. [Br J Dermatol 2012;166:1069-1080; JAMA Dermatol 2020;156:1300-1306]

“The high incidence of primary cSCC makes it challenging to correctly identify the small percentage (2 percent to 5 percent) of patients who are at high risk of metastasis and would benefit from intense surveillance and/or adjuvant treatment strategies,” they added.