Immunosuppression Linked to Markedly Poorer Outcomes in Cutaneous Squamous Cell Carcinoma

Chronically immunosuppressed patients with cutaneous squamous cell carcinoma of the head and neck (cSCC-HN) have dramatically worse outcomes after surgery and radiation treatment than do cSCC-HN patients with competent immune status, a new study shows.

Results from the multi-institutional, comparative analysis of 205 immunocompetent and immunosuppressed patients indicate that immunosuppressed patients more frequently presented with high-risk pathologic features, and had significantly lower rates of disease-free survival (43.1 percent vs. 79.7 percent) and locoregional recurrence-free survival (47.3 percent vs. 86.1 percent) at two years after treatment.

“Squamous cell skin cancer tends to be a fairly benign disease, but our study points out that it can be a source of extreme morbidity, and even mortality, for some immunocompromised patients,” says lead author Bindu Manyam, MD, a resident physician collaborating on the study with Shlomo Koyfman, MD. Drs. Manyam and Koyfman are radiation oncologists at Cleveland Clinic Cancer Center. “For these patients, we should consider intensifying treatment,” Dr. Manyam says.

Their findings were presented at the 2016 annual meeting of the American Society for Radiation Oncology (ASTRO) in Boston.

The immunosuppression connection

The relationship between immune system compromise or suppression and the development of skin malignancies is well-documented — including in patients with lymphoid neoplasms and solid-organ transplants — although the biological mechanism underlying this association is not clear. The incidence of cSCC-HN has been shown to increase with duration, degree, and type of immunosuppression. Data suggest a more aggressive phenotype of cSCC-HN in immunosuppressed patients. Ultraviolet light-induced mutation of the p53 tumor suppressor gene and the presence of human papillomavirus infection have been suggested as potential factors.

Drs. Manyam and Koyfman previously examined the effect of immune status on disease outcomes in a smaller cohort of Cleveland Clinic immunosuppressed cSCC-HN patients.

The present multi-institutional study analyzed the effect of immune system status on disease outcomes in patients with primary or recurrent stage I-IV cSCC-HN treated with surgery and postoperative radiotherapy (RT).

Patients and methods

Researchers analyzed outcomes for patients with cSCC-HN who received surgical resection and RT between 1995 and 2015 at Cleveland Clinic, Washington University in St. Louis and the University of California, San Francisco. A total of 138 patients (67.3 percent) were immunocompetent, while 67 patients (32.7 percent) were chronically immunosuppressed. The immunosuppressed group was primarily comprised of organ transplant recipients treated with immunosuppressive therapy ≥ 6 months prior to diagnosis; however, patients with chronic hematologic malignancy or HIV/AIDS also were included.

Immune status and outcomes

On multivariate analysis, immunosuppressed patients had significantly higher rates of locoregional cancer recurrence (HR=3.79). In addition to immunosuppression, recurrent disease, perineural invasion and poor differentiation also were significantly associated with locoregional recurrence. Immunosuppressed patients’ overall survival rates at two years post-treatment were lower than those for immunocompetent patients (60.9 percent vs. 78.1 percent, respectively), but the difference was not statistically significant.

Investigators also found higher rates of perineural invasion and nodal extracapsular extension among immunosuppressed patients compared with immunocompetent patients. “Patients in the immunosuppressed group had worse pathologic features; however, our results suggest that immunosuppression is an independent prognostic factor for aggressive tumor biology and poorer outcomes,” Dr. Manyam says.

Study impact and potential implications

Squamous cell skin cancers are not routinely treated with radiation, but immunosuppressed patients represent a population that may benefit from treatment intensification, Dr. Manyam says. “The difference in outcomes between the two groups is very striking,” she says.

Implications of these results differ by specialty, according to Dr. Manyam. From the transplant physician’s perspective, results suggest that referral of immunosuppressed patients to dermatologists for regular surveillance may be appropriate. Transplant physicians may also consider modifying immunosuppressive therapy in patients diagnosed with aggressive skin cancers.

From the dermatologist or ENT standpoint, results suggest that immunosuppressed cSCC-HN patients with risk factors identified in the study be referred to a radiation oncologist for evaluation, which may not always be the case with immunocompetent patients.

Dr. Manyam cautions, however, that prospective data is required to determine the efficacy of more aggressive treatment strategies, such as offering postoperative RT to immunosuppressed patients with earlier-stage disease who would normally be observed after surgery; the addition of concurrent systemic therapy; or the addition of targeted agents.

Future directions

Dr. Manyam and colleagues continue to examine the question of how immune status affects cutaneous squamous cell carcinomas. The team may propose modifying the current squamous cell cancer staging system to include immune status in an effort to enhance its prognostic value, Dr. Manyam says. The group also is interested in studying the use of immunotherapy in immunosuppressed patients.