Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in the world. Among many identified risk factors, immunosuppression is a major factor that contributes to cSCC development. Organ transplant recipients (OTRs) are at markedly increased risk of developing multiple cSCCs with a propensity for advanced metastatic disease, leading to significant morbidity and mortality. The severity of the cSCC phenotype in OTRs highlights the urgent need to identify effective preventive modalities in this population. Despite recent advances in skin cancer prevention (e.g., nicotinamide) and treatment (e.g., immune checkpoint blockade), these modalities have limited utility in OTRs due to the lack of efficacy or significant side effect. Topical treatments against precancerous skin lesions, actinic keratosis (AK), remain the primary strategy to prevent cSCC in OTRs, which also have significant deficiencies in this population. Herein, we review the epidemiology, risk factors, and current cSCC prevention strategies. We highlight the gaps and future clinical strategies to address cSCC risk in high-risk populations.

Periocular squamous cell carcinoma is a common cutaneous malignancy with generally favorable outcomes; however, the periocular region is intrinsically a high-risk location, and there exist a subset of lesions with a propensity for poor outcomes. Orbital invasion, intracranial perineural spread, nodal and distant metastasis are feared complications. There are several staging systems for eyelid carcinoma and cutaneous squamous cell carcinoma, but the definition of high-risk lesions remains heterogeneous. It is unclear exactly which lesions can be safely deescalated, and which require nodal evaluation and adjuvant multimodal therapy. We seek to answer these questions by summarizing the literature on clinicopathologic variables, molecular markers, and gene profiling tests in periocular squamous cell carcinoma, with the extrapolation of data from the cutaneous squamous cell carcinoma literature. Standardized pathology reports with information on tumor dimensions, histological subtype and grade, perineural invasion, and lymphovascular invasion should become uniform. Integration with gene expression profiling assessments will individualize and improve the predictive accuracy of risk stratification tools to ultimately inform multidisciplinary decision-making.

Cutaneous squamous cell carcinoma (cSCC) is a common cancer. Systemic immunosuppression with drugs such as Prednisone results in more aggressive disease. We hypothesise that more aggressive disease in immunosuppression is the result of immune changes in the tumour microenvironment. We characterised T cell, phagocytic and antigen presenting cell subsets in cSCC, and determined if these infiltrates were altered by immunosuppressive therapy. We found a dominant 'CD8 profile' in the centre of cSCC lesions, with CD8 cells correlating with Tbet, FoxP3, OX40 and 'M2-like' macrophages, whereas a 'Tbet and granulocyte profile' with associated inflammation predominated at the margin of the tumour. Individuals on systemic immunosuppressive therapy had lesions that were comparable in size, stage and number of vessels to immune competent individuals however the number of CD11c positive cells in the lesion centre was significantly reduced. We conclude that cSCC lesions are immunologically heterogeneous across the lesion and that systemically immunosuppressed individuals have reduced CD11c positive cells in the centre of the lesion. The role and detailed phenotype of CD11c positive cells in cSCC lesions warrants further investigation.

Knowledge is needed about squamous cell carcinoma (cSCC) risk in solid organ transplant recipients (SOTRs) using contemporary immunosuppressive regimens.

Evaluate risk of cSCC in relation to medications used by SOTRs.

The cohort and nest case-control study included 3,308 SOTRs and 65,883 persons without transplantation during 2009-2019. Incident cSCC was identified from pathology data and medications from pharmacy data. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards analysis, with voriconazole examined as a time-dependent variable.

The annual incidence of cSCC was 1.69% in SOTRs and 0.30% in persons without transplantation. The adjusted HR of cSCC associated with lung transplant was 14.83 (CI 9.85-22.33) for lung and 6.53 to 10.69 for other organs. Risk in Latinx persons was higher than in other non-white groups. Among lung recipients, the HR was 1.14 for each month of voriconazole use (95% CI: 1.04-1.26). Azathioprine use for ≥7 months, relating to mycophenolate mofetil intolerance, was associated with 4.22-fold increased risk of cSCC (95% CI 1.90-9.40). Belatacept and other immunsuppressive medications were not associated with risk.

The number of events was somewhat small.

Knowledge of risks and benefits in diverse patients can translate to care improvements.

Patients with immunosuppression have a higher incidence of cutaneous squamous cell carcinoma (cSCC) and often present with more aggressive, multifocal disease.

To determine the risks for mortality in patients with cSCC and immunosuppression compared with nonimmunosuppression and to compare the difference in mortality risk based on the cause of immunocompromise.

This retrospective cohort study of patients with cSCC of the head and neck recruited participants from a tertiary cancer care center. Patients who underwent no treatment, wide local excision, or biopsy of the lesions were eligible for inclusion from January 1, 1995, to September 30, 2015. Data were analyzed from March 21, 2018, to April 4, 2019.

Immunocompromise, defined as having solid organ transplant, stem cell transplant, hematopoetic malignant disease, autoimmune disease requiring treatment with immunosuppressive therapy, type 1 or 2 diabetes treated with insulin, HIV or AIDS, or other hematoproliferative disorder.

Patients were divided into 2 groups according to their immune status (immunosuppression vs no immunosuppression). The primary outcome measure was disease-specific survival. A Cox proportional hazards regression model was used to determine the association of immune status with disease outcome.

A total of 796 patients (680 men [85.4%]; median age, 69 [range, 27-98] years), including 147 with and 649 without immunosuppression (IS and non-IS groups, respectively), constituted the final cohort. In the IS group, 77 (52.4%) had diabetes, 39 (26.5%) had lymphoma or leukemia, 25 (17.0%) had an organ or stem cell transplant, and 3 (2.0%) had HIV. Five-year disease-specific survival was 68.2% in the IS group compared with 84.1% in the non-IS group (difference, 15.9%; 95% CI, 3.5%-27.4%). Immunosuppression was independently associated with worse disease-specific survival (hazard ratio, 2.32; 95% CI, 1.53-3.50).

This study's findings suggest that immunosuppression is independently associated with a worse outcome in cSCC, with a 2.32 times increased risk of disease-specific death after adjusting for age, history of skin cancer, recurrent or persistent disease status, disease stage, and treatment.