Squamous Cell Carcinoma And Immunosuppression Risks
Overview
This study aimed to compare the clinical characteristics and outcomes of cutaneous squamous cell carcinoma (cSCC) in immunosuppressed and immunocompetent patients. The retrospective analysis included 935 cSCC cases, with 19.5% of the patients being immunosuppressed. The study revealed several notable findings:
- Immunosuppressed patients with cutaneous squamous cell carcinoma tend to be younger (69.3 years old) compared to immunocompetent patients (74.8 years old).
- There was a higher proportion of males among immunosuppressed patients (78.6%) compared to immunocompetent patients (67.2%).
- Immunocompromised patients presented with higher-grade cutaneous squamous cell carcinoma tumors, characterized by moderate or poor differentiation (25.7% and 9.2%, respectively), whereas immunocompetent patients had lower rates of moderate or poor differentiation (15.8% and 7.2%, respectively).
- However, no significant differences were observed in other tumor characteristics, such as clinical tumor dimensions, Brigham and Women’s Hospital tumor staging, or cumulative risk of metastasis and recurrence.
- Immunosuppressed patients faced an increased risk of disease-specific death, with a hazard ratio (HR) of 2.05.
- The overall survival rate in immunosuppressed patients was worse, with an adjusted HR of 1.83. Notably, solid organ transplant recipients had the lowest overall survival rate among immunosuppressed patients, with an HR of 1.62.
In conclusion, this study demonstrated that immunosuppressed patients with cSCC differ in age, gender distribution, and tumor grade compared to immunocompetent patients. Immunocompromised patients faced a higher risk of disease-specific death and had poorer overall survival, especially among solid organ transplant recipients. These findings can help guide clinical management strategies for cSCC in immunosuppressed individuals.
The study findings indicate that immunosuppressed individuals are more likely to develop poorly differentiated cSCC tumors and experience reduced overall and cSCC-specific survival rates. Notably, existing staging systems for cSCC do not account for the influence of immunosuppression as a risk factor. Therefore, considering a patient’s immune status in these staging systems could be advantageous in improving the accuracy of risk assessment for cutaneous squamous cell carcinoma. This may lead to more precise risk stratification and ultimately enhance clinical management strategies for cSCC.
Introduction
Cutaneous squamous cell carcinoma (cSCC) is a prevalent nonmelanoma skin cancer, with a substantial annual incidence of about 1.8 million cases seen in America. While it often goes under the radar in comparison to melanoma, the number of annual cSCC-related deaths is similarly significant. Various risk factors contribute to cSCC, including age, exposure to ultraviolet light (UV), male gender, a history of skin cancers, and immunosuppression.
Studies on cSCC in immunosuppressed individuals have revealed striking disparities when compared to the general population. These disparities encompass significantly higher incidence rates (up to 100-fold), an elevated risk of metastasis (ranging from 4% to 8%), and a notably increased likelihood of cSCC-related mortality (reaching 30.5%). The immunosuppressed group most extensively studied comprises solid organ transplant recipients (SOTRs). SOTRs tend to develop more aggressive cSCC tumors that are characterized by their larger size, poor differentiation, deep infiltration, and a higher incidence of perineural or lymphovascular invasion. Additionally, these tumors often occur in high-risk areas like the lip or ear. Specific immunosuppressive medications, such as azathioprine and cyclosporine, have been associated with the development of more aggressive cSCCs.
Given the need for a comprehensive understanding of clinical and histologic features, as well as outcomes in the immunosuppressed population, this study aims to examine the connections between immune status and cutaneous squamous cell carcinoma tumor characteristics. It also explores disease-related outcomes, including metastasis, recurrence, cSCC disease-specific death (DSD), and overall survival (OS). Furthermore, the study stratifies its analysis based on the type of immunosuppression to assess potential differences linked to the underlying cause of immunosuppression.
Method
This study, approved by the Mayo Clinic Institutional Review Board, involved a comprehensive analysis of 935 cases of cutaneous squamous cell carcinoma (cSCC). These cases were selected from two distinct databases: the high-risk cutaneous squamous cell carcinoma database and the normal-risk cSCC database, which collectively contained approximately 2,800 cases identified between 1999 and 2016 across Mayo Clinic locations in Jacksonville, Florida, Rochester, Minnesota, and Scottsdale, Arizona.
The cases were identified through an extensive, enterprise-wide search, relying on histopathologic diagnoses of cutaneous squamous cell carcinoma found in archived specimens’ pathology reports. The high-risk database encompassed around 400 cases of tumors staged as BWH T2a or higher, including those linked to poor outcomes such as recurrence, metastasis, and disease-specific death (DSD). The normal-risk database, on the other hand, comprised a randomized sampling of 2,400 patients with biopsy-proven cSCC. This sampling accurately represented the average Mayo Clinic patient from the broader cohort, with stratification based on age, gender, and race.
Clinical data, including information on age, gender, and immunosuppression status, were extracted from electronic medical records. Patients were categorized as immunosuppressed if they had documented immunosuppression status before their initial cSCC diagnosis, while immunocompetent patients had no documented immunosuppression status both before their initial diagnosis and through their last follow-up.
The study included cases with adequate tissue for review, available data regarding immunosuppression status, Brigham and Women’s Hospital (BWH) and American Joint Committee on Cancer (AJCC) tumor staging, and a follow-up period of at least 18 months. This follow-up was essential for documenting outcome data, encompassing local and nodal recurrence, regional metastasis (in-transit and nodal), distant metastasis, and disease-associated mortality.
To ensure the accuracy of the findings, all cases underwent a meticulous histopathologic re-review by board-certified dermatopathologists, who confirmed tumor characteristics and staging. Notably, the study utilized the best available tissue samples, with 77.2% originating from initial biopsies and 22.8% from subsequent tumor excision pathology.
Statistical Analysis
Patient demographics and tumor characteristics were thoroughly analyzed in this study. These analyses involved comparisons between immunosuppressed and immunocompetent cohorts, as well as categorization by specific types of immunosuppression. Various statistical tests, including Kruskal-Wallis, analysis of variance, and chi-square tests, were appropriately applied to facilitate these comparisons.
Recurrence, both local and nodal, metastasis, encompassing in-transit and distant cases, and disease-specific death (DSD) were estimated using the Fine-Gray method. This method considers competing risk events, such as death before the event of interest, to provide accurate estimates. Comparisons between these outcomes and clinical variables of interest, including immunosuppression status, were conducted using the Gray k-sample test.
To assess overall survival (OS), the Kaplan-Meier method was employed. Differences in OS were evaluated using the Log rank test. Additionally, the study utilized univariate and multivariable Cox Proportional Hazard models to estimate the risk of cSCC-specific death and OS. The multivariable models were adjusted for age, gender, and tumor differentiation to enhance the accuracy of the findings.
In this analysis, a p-value of less than 0.05 was considered statistically significant. All statistical analytical processes were done with SAS v9.4 (SAS Institute), ensuring rigor and reliability in the study’s results.
Result
This study encompassed a cohort of 935 patients, among which 69.4% were male, and 19.5% were classified as immunosuppressed individuals. The majority of patients were of Caucasian descent (92.9%), with smaller percentages representing other ethnic backgrounds.
Immunosuppressed patients exhibited distinctive characteristics. They were notably younger at the time of cSCC diagnosis (69.3 vs. 74.8, p < 0.001) and had a higher proportion of males (78.6% vs. 67.2%, p = 0.003). These patients had various reasons for immunosuppression, with solid organ transplant accounting for 54.9%, autoimmune disease for 14.8%, hematologic malignancy for 14.8%, solid organ malignancy for 3.8%, and stem cell transplant for 1.6%.
Regarding tumor characteristics, immunosuppressed patients exhibited a higher prevalence of moderately or poorly differentiated tumors (25.7% vs. 15.8%, p = 0.009; 9.2% vs. 7.2%, p = 0.009, respectively). Nevertheless, there were no significant disparities in Brigham and Women’s Hospital (BWH) staging between the immunosuppressed and immunocompetent groups.
The study’s outcomes revealed that immunosuppression had no significant impact on the rates of tumor recurrence, cumulative metastasis, or metastasis incidence between immunocompetent and immunosuppressed individuals. However, overall survival (OS) was notably worse in the immunosuppressed population, with a hazard ratio (HR) of 1.83 [95% confidence interval, CI: 1.42–2.35], p < 0.001. This finding remained consistent even after adjusting for age, gender, and tumor differentiation, with an adjusted HR of 2.48 [95% CI: 1.84–3.35], p < 0.001.
Concerning disease-specific death (DSD), univariate analysis revealed that immunosuppressed patients had a higher risk compared to immunocompetent individuals (HR [95% CI: 2.05 [1.13–3.74], p = 0.0128). After adjusting for age, gender, and tumor differentiation, there was a trend towards increased DSD in immunosuppressed patients, although this did not reach statistical significance (adjusted HR [95% CI: 1.89 [0.90–3.99], p = 0.095).
The study also stratified immunosuppressed patients by the cause of immunosuppression. Solid organ transplant recipients (SOTRs) displayed the highest rates of DSD (HR [95% CI: 2.84 [1.47–5.50], p = 0.0045) and the lowest OS (HR [95% CI: 1.62 [1.17–2.24], p < 0.0001) compared to both immunocompetent individuals and non-SOTR immunosuppressed patients. These findings provide valuable insights into the clinical management of immunosuppressed individuals with cSCC.
Conclusion
This study provides a comprehensive comparison of cutaneous squamous cell carcinoma (cSCC) tumor characteristics and disease-related outcomes, shedding light on the clinical management of immunosuppressed patients. It aligns with previous findings by revealing that individuals with immunosuppression, particularly solid organ transplant recipients (SOTRs), are more likely to be males and are diagnosed with cSCC at a younger age compared to their immunocompetent counterparts.
Immunosuppressed patients presented with tumors that exhibited higher rates of moderate or poor differentiation, reaching 34.9% compared to 23.0% in immunocompetent patients. Notably, poor differentiation, a tumor characteristic, emerged as an independent risk factor for both disease-specific death (DSD) and reduced overall survival (OS).
The existing literature has shown some inconsistencies concerning tumor characteristics and outcomes in cutaneous squamous cell carcinoma patients with immunosuppression. While some studies have reported less differentiated and more deeply infiltrative tumors in immunosuppressed cohorts, others did not observe significant differences in tumor depth or differentiation.
Furthermore, previous research has produced mixed findings on the impact of immunosuppression on outcomes such as OS, DSD, and metastasis. While some studies indicated a significant association between immunosuppression and adverse outcomes, others failed to establish such a connection. This study contributed to the body of knowledge by revealing a lower OS in immunosuppressed patients, with an adjusted hazard ratio of 2.48 [95% CI: 1.84–3.35], though no significant disparities were observed in the rates of tumor recurrence or metastasis compared to immunocompetent patients. Immunocompromised individuals exhibited a twofold increase in the risk of DSD without adjustment. SOTRs, in particular, faced the highest risk of DSD within the stratified immunosuppressed groups.
The diverse array of iatrogenic and disease-induced immunosuppression and the complex interplay between these factors contribute to the variability in disease susceptibility and outcomes. The lack of standardized definitions and subgroup stratifications for immunosuppressed populations may contribute to the inconclusive nature of the findings across studies.
This study highlights the need for further research into specific immunosuppressed subgroups to better understand their risk of adverse outcomes in cSCC. The study underscores the potential benefits of incorporating immune status and considering the etiology of immunosuppression in cutaneous squamous cell carcinoma risk stratification. Additionally, exploring the molecular profiles of tumors in immunosuppressed patients may unveil genomic biomarkers that predict outcomes within this unique population.
In summary, this retrospective cohort study involving 935 cutaneous squamous cell carcinoma patients revealed that immunosuppression correlated with a younger age at diagnosis, male gender, and higher-grade tumors. Furthermore, immunocompromised status was linked to an elevated risk of DSD and reduced OS. Among these immunosuppressed patients, SOTRs experienced the most unfavorable outcomes, characterized by the highest DSD rates and the lowest OS.
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