Association of Patient Risk Factors, Tumor Characteristics, and Treatment Modality With Poor Outcomes in Primary Cutaneous Squamous Cell Carcinoma

Importance Primary cutaneous squamous cell carcinoma is usually curable; however, a subset of patients develops poor outcomes, including local recurrence, nodal metastasis, distant metastasis, and disease-specific death. Objectives To evaluate all evidence-based reports of patient risk factors and tumor characteristics associated with poor outcomes in primary cutaneous squamous cell carcinoma and to identify treatment modalities that minimize poor outcomes. Data Sources PubMed, Embase, and SCOPUS databases were searched for studies of the topic in humans, published in the English language, from database inception through February 8, 2022. Study Selection Two authors independently screened the identified articles and included those that were original research with a sample size of 10 patients or more and that assessed risk factors and/or treatment modalities associated with poor outcomes among patients with primary cutaneous squamous cell carcinoma. Data Extraction and Synthesis Data extraction was performed by a single author, per international guidelines. The search terms, study objectives, and protocol methods were defined before study initiation. A total of 310 studies were included for full-text assessment. Owing to heterogeneity of the included studies, a random-effects model was used. Data analyses were performed from May 25 to September 15, 2022. Main Outcomes and Measures For studies of risk factors, risk ratios and incidence proportions; and for treatment studies, incidence proportions. Results In all, 129 studies and a total of 137 449 patients with primary cutaneous squamous cell carcinoma and 126 553 tumors were included in the meta-analysis. Several patient risk factors and tumor characteristics were associated with local recurrence, nodal metastasis, distant metastasis, disease-specific death, and all-cause death were identified. Among all factors reported by more than 1 study, the highest risks for local recurrence and disease-specific death were associated with tumor invasion beyond subcutaneous fat (risk ratio, 9.1 [95% CI, 2.8-29.2] and 10.4 [95% CI, 3.0- 36.3], respectively), and the highest risk of any metastasis was associated with perineural invasion (risk ratio, 5.0; 95% CI, 2.3-11.1). Patients who received Mohs micrographic surgery had the lowest incidence of nearly all poor outcomes; however, in some results, the 95% CIs overlapped with those of other treatment modalities. Conclusions and Relevance This meta-analysis identified the prognostic value of several risk factors and the effectiveness of the available treatment modalities. These findings carry important implications for the prognostication, workup, treatment, and follow-up of patients with primary cutaneous squamous cell carcinoma. Trial Registration PROSPERO Identifier: CRD42022311250