Abstract
This case-control study examines the association of multiple squamous cell carcinoma with poor outcomes in the immunosuppressed patient population.
Squamous cell carcinoma (SCC) is the second most common skin cancer in the United States and is an important cause of morbidity in immunosuppressed patients.1 Studies demonstrate an increased risk of developing a subsequent SCC after the first incidence.1,2,3 Levine et al4 linked multiple SCCs to increased poor outcomes; however, their study cohort consisted of primarily immunocompetent patients. Immunosuppressed patients are believed to have a 65- to 100-fold increase in the incidence of SCC.4 In this study, we aimed to determine the association between multiple SCCs and the risk of poor outcomes in the immunosuppressed population.
Methods
This is a case-control study of primary invasive SCCs treated at a tertiary academic center from January 1, 2005, and December 31, 2015. The study was approved by the Tufts University Health Sciences Campus institutional review board and a waiver of written informed consent was granted owing to the minimal risk involved in the study. Overall, 106 mixed-cause immunosuppressed patients with 412 primary invasive SCCs were matched by age, sex, and race to immunocompetent controls on a 1:2 basis. Demographics, tumor characteristics, and outcome data including local recurrence, nodal metastases (NM), in-transit metastases (ITM), distant metastases (DM), any disease-specific poor outcome, and disease-specific death were recorded. Each cohort was categorized based on number of SCCs (1, 2-9, ≥10). Outcomes were compared using χ2 and Fisher exact statistics. Logistic regressions were used to estimate the effects of immunosuppression on poor outcomes, stratified by number of SCCs (1 or 2-9) and adjusted for tumor stage according to Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer (8th edition) (AJCC-8) criteria (limited to head and neck tumors) with each stage as a covariate.
Results
The most common causes of immunosuppression were organ transplantation (58%; 61 of 106) and inflammatory disease (16%; 17 of 106). A significantly higher proportion of immunosuppressed patients had multiple tumors: 57% (60 of 106) vs 25% (53 of 212) (odds ratio [OR], 3.91; 95% CI, 2.39-6.41; P < .001) for immunocompetent patients. No immunocompetent patient had 10 or more SCCs.
Patients were stratified based on number of tumors. In the immunosuppressed cohort, those with 2 to 9 and 10 or more tumors had increased risk of local recurrence compared with those with single tumor: 30% (14 of 47, P < .001) and 69% (9 of 13, P < .001) vs 4% (2 of 46) respectively (Table 1). A similar trend was observed for any disease-specific poor outcome in the immunosuppressed cohort: single tumor (9%; 4 of 46) vs 2 to 9 (32%; 15 of 47; P = .005) and at least 10 (69%; 9 of 13; P < .001). No significant increases in poor outcomes were observed in the immunocompetent cohort.
Table 1. Incidence of Poor Outcomes in Immunosuppressed and Immunocompetent Patients Stratified by Number of Squamous Cell Carcinoma (SCC) Tumorsa.
| SCCs, No. | Patients, No. (%) | LR | NM | ITM | Any PO | ||||
|---|---|---|---|---|---|---|---|---|---|
| No. (%) | P Value | No. (%) | P Value | No. (%) | P Value | No. (%) | P Value | ||
| Immunosuppressed cases | |||||||||
| 1 | 46 (43.4) | 2 (4.3) | 1 [Reference] | 2 (4.3) | 1 [Reference] | 2 (4.3) | 1 [Reference] | 4 (8.7) | 1 [Reference] |
| 2-9 | 47 (44.3) | 14 (29.8) | .001 | 3 (6.4) | >.99 | 3 (6.4) | >.99 | 15 (31.9) | <.001 |
| ≥10 | 13 (12.3) | 9 (69.2) | <.001 | 1 (7.7) | .53 | 0 | >.99 | 9 (69.2) | <.001 |
| Immunocompetent controls | |||||||||
| 1 | 159 (75.0) | 13 (8.2) | 1 [Reference] | 1 (0.6) | 1 [Reference] | 2 (1.3) | 1 [Reference] | 13 (8.2) | 1 [Reference] |
| 2-9 | 53 (25.0) | 2 (4.0) | .37 | 0 | >.99 | 0 | >.99 | 2 (4.0) | .37 |
| ≥10 | 0 | NA | NA | NA | NA | NA | NA | NA | NA |
Abbreviations: ITM, in-transit metastases; LR, local recurrence; NA, not applicable; NM, nodal metastases; PO, poor outcomes.
Fisher exact statistics were used when cell sample size was fewer than 5.
The unadjusted odds of having local recurrence or any disease-specific poor outcome increased by 10- to 11-fold (OR, 10.82; 95% CI, 2.31-50.71; P = .002; OR, 11.95; 95% CI, 2.56-55.76; P = .001, respectively) for immunosuppressed patients compared with immunocompetent patients with 2 to 9 tumors (Table 2). This observation was consistent when adjusted for tumor stage using BWH and AJCC-8 criteria.
Table 2. Odds Ratios of Poor Outcomes of IS Patients vs IC Controls Stratified by Number of Tumors and Adjusted for Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer, 8th Edition (AJCC-8)a Staging Criteria.
| SCCs, No. | LR | NM | ITM | Any PO | ||||
|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | P Value | OR (95% CI) | P Value | OR (95% CI) | P Value | OR (95% CI) | P Value | |
| Unadjusted | ||||||||
| 1 | 0.51 (0.11-2.35) | .39 | 7.18 (0.64-81.06) | .11 | 3.57 (0.49-26.06) | .21 | 1.07 (0.33-3.45) | .91 |
| 2-9 | 10.82 (2.31-50.71) | .002 | NA | NA | NA | NA | 11.95 (2.56-55.76) | .002 |
| Adjusted for BWH stage | ||||||||
| 1 | 0.53 (0.11-2.47) | .05 | 10.00 (0.81-123.99) | .07 | 4.88 (0.60-39.91) | .14 | 1.15 (0.35-3.81) | .82 |
| 2-9 | 11.62 (2.33-57.81) | .003 | NA | NA | NA | NA | 13.52 (2.69-67.97) | .002 |
| Adjusted for AJCC-8 stage | ||||||||
| 1 | 0.54 (0.12-2.52) | .44 | 9.35 (0.78-112.41) | .08 | 4.83 (0.61-38.26) | .14 | 1.16 (0.35-3.80) | .81 |
| 2-9 | 11.55 (2.40-55.58) | .002 | NA | NA | NA | NA | 13.29 (2.74-64.47) | .001 |
Abbreviations: IC, immunocompetent patients; IS, immunosuppressed; ITM, in-transit metastases; LR, local recurrence; NA, not applicable; NM, nodal metastases; PO, poor outcomes; SCC, squamous cell carcinoma.
The AJCC-8 adjusted odds ratios were calculated for tumors limited to the head and neck region.
Discussion
In this single-center case-control study, we compared poor outcomes in immunosuppressed and immunocompetent patients with primary invasive SCC. The immunosuppressed patients with multiple tumors had more poor outcomes than those with a single SCC, primarily owing to rates of local recurrence. The risk of local recurrence and disease-specific poor outcome were 10 to 13 times more likely in the immunosuppressed cohort compared with immunocompetent controls even when adjusted for tumor stage based on BWH and AJCC-8 criteria. The immunosuppressed patients were more likely to have multiple SCC tumors compared with immunocompetent controls, an observation that is consistent with several studies.3,5,6 No immunocompetent patient had more than 10 tumors, highlighting the key role of immunosuppression in multiple SCCs. This finding may be owing to the age-matching process, which resulted in selection of younger immunocompetent patients with lower tumor burdens than what would typically be seen. This may also explain why there was no increase in poor outcomes with increasing number of tumors in the immunocompetent cohort.
Conclusions
We demonstrate that multiple SCCs in the setting of immunosuppression is associated with an increased risk of poor outcomes. These findings support the clinical practice of vigilant screening and aggressive treatment for immunosuppressed patients with multiple SCCs.
References
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