AUSTIN, Texas — Cutaneous squamous cell carcinoma (SCC) is more likely to result in poor outcomes in patients who are immunosuppressed, even when accounting for other tumor features, according to a study presented at the American College of Mohs Surgery (ACMS) Annual Meeting 2026.

The researchers found that solid organ transplant recipients had greater odds of larger tumor size, poor differentiation, deep invasion, and overall poor outcomes. In contrast, patients with immunosuppression related to other causes did not have increased risks.

“The takeaway is that immunosuppression matters,” Amanda Rosenthal, MD, Mohs surgeon at Cedars-Sinai Medical Center, Los Angeles, told attendees. “It independently predicts worse outcomes, even when we control for tumor risk, and more importantly, not all immunosuppressive states are created equally. The higher the degree of immunosuppression, the worse the clinical outcomes.”

While most clinicians have likely been practicing with the underlying belief that a high-risk SCC in a transplant patient has the potential for poor outcomes, the literature has been mixed, Rosenthal said. Multiple studies on immunosuppression and SCC have shown conflicting results in the past decade, most likely because of differences across studies in sample sizes, study designs, definitions for immunosuppression, and selected controls for high-risk tumor features, plus a low overall event rate for SCC in this population. 

Rosenthal and her colleagues therefore aimed to determine whether immunosuppression independently predicts poor outcomes in SCC and whether the subtype of immunosuppression makes a difference in outcomes.

They analyzed data from all patients treated for SCC with Mohs surgery between January 2014 and December 2021 at Cedars-Sinai Medical Center. They gathered data on patient demographics, tumor characteristics, and operative variables, and then looked at five outcomes: local recurrence, nodal involvement, metastasis, SCC-specific death, and all-cause death. The first four of these outcomes were combined for a composite endpoint of poor outcomes.

The population of 929 patients included 83.2% who were immunocompetent and 16.8% who were immunosuppressed, all followed for a minimum of 3 years and an average of 7.6 years.

There were 1053 tumors among the 773 immunocompetent patients (75.2% of tumors for the total population), and 347 tumors in the 156 immunosuppressed patients (24.8% of the total). There were no significant differences between the two groups in age, sex, or number of tumors. The population had an average age of 71, and just over a third (36.9%) were women, with a mean of 1.5 tumors per person.

Just over half the tumors in immunosuppressed patients (53.3%) were in solid organ transplant recipients. The other tumors in immunosuppressed patients were in individuals with immunosuppression due to a bone marrow transplant (4.9%), hematologic malignancy (18.7%), HIV/AIDS (15.3%), iatrogenic cause (7.2%), or other (0.6%) reasons.

Tumors in the immunosuppressed cohort were significantly more likely to be a higher Brigham and Women’s Hospital T stage: Among immunocompetent patients, 1.1% were stage T2b and 0.1% were stage T3 compared with 3.7% and 1.4% among immunosuppressed patients, respectively (P < .0001).

Among the tumors with poor outcomes (1.9% of the total), 4.3% of the tumors among immunosuppressed patients and 1% of those among immunocompetent patients resulted in poor outcomes (P < .0001). For the separate outcomes, the difference was significant between immunocompetent and immunosuppressed patients, respectively, for recurrence (0.9% vs 2.9%; P < .0001), nodal involvement (0.76% vs 2.6%; P < .0001), metastasis (0.5% vs 2.6%; P < .0001), and SCC-specific death (0.5% vs 1.7%; P = .02).

“Now the question becomes, is this simply a reflection of higher-stage tumors, or does immunosuppression independently predict worse outcomes, despite controlling for high-risk tumor features?” Rosenthal asked. To address that question, the researchers conducted a multivariate analysis that accounted for differences in size, differentiation, perineural invasion, and deep invasion.

The analysis found that immunosuppressed patients had significantly higher odds of tumors of 2 cm or larger (adjusted odds ratio [aOR], 2.45; P = .021) and poorly differentiated tumors (aOR, 9.01; P = .0004), but not of perineural invasion or deep invasion. After adjusting for these confounders, the researchers found that immunosuppressed status still conferred three times the odds of a poor outcome (aOR, 3.44; P = .011). 

The researchers then compared outcomes with immunosuppression in solid organ transplant recipients to immunosuppression from other causes. Odds of poor outcomes were more than seven times greater among solid organ transplant recipients than among those without immunosuppression (aOR, 7.21; P = .0002), but patients with other causes of immunosuppression had no increased odds of poor outcomes (P = .79).

Solid organ transplant recipients also had substantially and significantly higher odds of having a larger tumor (aOR, 2.75; P = .016), poor differentiation (aOR, 10.77; P < .0001), and deep invasion (aOR, 8.32; P = .019). 

“If immunosuppression is driving worse outcomes, and the degree of immunosuppression matters, then the next question is understanding why,” Rosenthal said. “One potential explanation is impaired local immune surveillance leading to unchecked tumor growth.” 

But she also speculated on whether high degrees of immunosuppression could potentially reshape the tumor’s biology. “My hypothesis is that it’s probably both — that high degrees of immunosuppression seen in organ transplant patients probably decrease local immune surveillance and alter some of the tumor biology, leading to worse outcomes,” said Rosenthal, who plans to follow that line of research next. 

Douglas Winstanley, DO, dermatologist and Mohs surgeon in Grand Rapids, Michigan, told Medscape Medical News that these findings were among the least surprising discussed at the conference but that the validation of what clinicians suspected was helpful. 

“Most of us operate under that impression” that poor outcomes are more likely in immunosuppressed patients, Winstanley said, “because in dealing with those patients, you see relatively worse outcomes among that population than you do in someone who’s not immunosuppressed.”

While immunosuppression obviously cannot be halted in these patients, these findings point to the importance of identifying new ways to confront this challenge. “In the near term, I think probably the best opportunity for these patients is going to be the intralesional immunosuppressed or immunotherapies that are being investigated now,” Winstanley said. 

Rosenthal and Winstanley reported having no disclosures. No external funding for the study was noted.

Tara Haelle is a science/health journalist based in Dallas.