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Divisions of Dermatology and Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, Washington, USADivision of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy linked to a contributory virus (Merkel cell polyomavirus). Multiple epidemiologic studies have established an increased incidence of MCC among persons with systemic immune suppression. Several forms of immune suppression are associated with increased MCC incidence, including hematologic malignancies, HIV/AIDS, and immunosuppressive medications for autoimmune disease or transplant. Indeed, immune-suppressed individuals represent ∼10% of MCC patients, a significant overrepresentation relative to the general population. We hypothesized that immune-suppressed patients may have a poorer MCC-specific prognosis and examined a cohort of 471 patients with a combined follow-up of 1,427 years (median 2.1 years). Immune-suppressed patients (n=41) demonstrated reduced MCC-specific survival (40% at 3 years) compared with patients with no known systemic immune suppression (n=430; 74% MCC-specific survival at 3 years). By competing risk regression analysis, immune suppression was a stage-independent predictor of worsened MCC-specific survival (hazard ratio 3.8, P<0.01). Thus, immune-suppressed individuals have both an increased chance of developing MCC and poorer MCC-specific survival. It may be appropriate to follow these higher-risk individuals more closely, and, when clinically feasible, there may be a benefit of diminishing iatrogenic systemic immune suppression.
Abbreviations
CLL
chronic lymphocytic leukemia
MCC
Merkel cell carcinoma
SCC
squamous cell carcinoma
Introduction
Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a prognosis poorer than that of melanoma. In 2008, a polyomavirus (Merkel cell polyomavirus) was reported to be a likely causative agent for the majority of MCCs (
It has been well established that immune suppression is associated with increased risk of developing MCC. Indeed, immune-suppressed individuals make up ∼10% of the MCC patient population (
). Multiple forms of systemic immune suppression have been linked with an increased incidence of MCC, including chronic lymphocytic leukemia and other hematologic malignancies (
Chronic lymphocytic leukemia is associated with decreased survival of patients with malignant melanoma and Merkel cell carcinoma in a SEER population-based study.
Conversely, and consistent with a role for antiviral immune responses in protecting against MCC progression, CD8+ and CD3+ intratumoral lymphocyte responses have been found to be associated with improved MCC outcomes (
). In both of these studies, patients with robust lymphocyte infiltration into the tumor make up a minority of patients but exhibit outstanding MCC-specific survival.
One form of systemic immune suppression, chronic lymphocytic leukemia, has recently been associated with reduced MCC survival in a national cancer registry (
Chronic lymphocytic leukemia is associated with decreased survival of patients with malignant melanoma and Merkel cell carcinoma in a SEER population-based study.
). However, to our knowledge, the effect of chronic immune suppression more broadly on MCC outcomes has not been examined. We hypothesized that systemic immune suppression would be associated with worsened MCC-specific survival in a stage-independent manner.
Results
Frequency and distribution of systemic immune suppression among MCC patients
Of the 471 patients with MCC from the United States, a total of 41 (8.7%) had clinically recognized systemic immune suppression. Immune-suppressed patients were similar to those without immune suppression in terms of age at diagnosis and stage of disease at presentation (Table 1), but differed in terms of gender distribution with immune-suppressed individuals more likely to be male (80% vs. 59%; P<0.01). Multiple forms of systemic immune suppression were represented including chronic lymphocytic leukemia (n=16; 3% of MCC patient cohort), other hematologic malignancies (n=5; 1%), HIV/AIDS (n=5; 1%), and long-term immunosuppressive medication regimens used for autoimmune disease (n=3; 1%) or solid organ transplant (n=12; 3%).
Table 1Demographics
Nonimmune suppressed (n=430)
Immune suppressed (n=41)
Characteristic
N
Percent (%)
N
Percent (%)
P-value
Stage at diagnosis
Local
242
56
23
56
0.94 (NS)
Regional
147
34
15
37
Distant
41
10
3
7
Sex
Female
177
41
8
20
<0.01
Male
253
59
33
80
Age at diagnosis
<65 Years
127
30
17
41
0.16 (NS)
≥65 Years
303
70
24
59
Abbreviation: NS, nonsignificant.
Immune-suppressed and nonimmune-suppressed patient groups were similar in terms of stage at diagnosis and patient age but differed in their gender distributions, with immune-suppressed patients being more likely to be male.
Age quartiles for the 25th, 50th, and 75th percentile were 63, 72, and 79 years for the nonimmune-suppressed group and 58, 67, and 77 years for the immune-suppressed group, respectively. Comparisons were made using the Fisher’s exact test. N=471.
Persons with systemic immune suppression and MCC have diminished overall survival
A combined 1,427 years of follow-up was available for the 471 patients with MCC (median 2.1 years). Patients with MCC and systemic immune suppression had worsened overall survival as compared with patients with MCC and no systemic immune suppression (hazard ratio 2.1; P<0.01). Three-year overall survival was 33% in the immune-suppressed group and 59% in the comparison group.
Persons with systemic immune suppression have worsened MCC-specific survival
We hypothesized that individuals with systemic immune suppression would have worsened MCC-specific survival as compared with individuals without systemic immune suppression because of failed immune surveillance of the cancer. We also reasoned that the groups were likely to have different rates of non-MCC death. Therefore, to account for possible differences in the death rate from other causes between the two groups, we performed competing risk regression analysis where only deaths from MCC were considered to be events, and deaths from other causes (including non-MCC deaths related to the immune suppression process) were considered to be competing events.
Immune-suppressed individuals (n=41) had statistically significantly worsened MCC-specific survival as compared with individuals without immune suppression (n=430) (hazard ratio 3.0; 95% confidence interval 1.8–4.8; P<0.01; Table 2 ). Furthermore, this difference was clinically appreciable, with immune-suppressed patients having a 3-year survival proportion that was approximately half than that of the nonimmune-suppressed patients (40% vs. 74%; P<0.05 for point comparison; Figure 1).
Table 2Multivariate competing risk regression analyses demonstrate immune suppression is an independent predictor of poor Merkel cell carcinoma–specific survival
Figure 1Merkel cell carcinoma (MCC) survival and immune suppression. Large graph: individuals with immune suppression (n=41) had significantly worsened MCC-specific survival as compared with those without systemic immune suppression (n=430) on univariate (hazard ratio 3.0; P<0.01) and multivariate (hazard ratio 3.8; P<0.01) competing risk regression analyses (Table 2). Numbers at risk at 1, 3, 5, and 7 years indicated below. Small graphs: effects of immune suppression persisted across stage at presentation.
Our patient population represents a nonoverlapping mixture of patients enrolled either as individuals (n=228) or as part of records review in institutional sets (n=243). To ensure that our results were similar between the two categories of patients, we looked at each subgroup independently and found that in each case immune suppression was a significant predictor of worsened outcome (records based enrollment: hazard ratio 2.5; P=0.01) (individual enrollment: hazard ratio 4.0; P<0.01).
Immune suppression is a stage-independent predictor of diminished MCC-specific survival
We observed significantly reduced MCC-specific survival among immune-suppressed patients at all stages of presentation (Figure 1). To formally test whether immune suppression represents an independent predictor of MCC outcome, we performed multivariate competing risk regression analysis accounting for stage at presentation (local–regional–distant stage), age at diagnosis, and gender in addition to immune suppression (Table 2). Immune suppression represented a significant independent predictor of worsened MCC-specific survival (hazard ratio 3.8; 95% CI 2.2–6.4; P<0.01).
We initially performed our analysis using local–regional–distant stage to minimize the number of variables in the model. However, we repeated this analysis using the current American Joint Committee on Cancer 7th Edition staging (
Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.
) instead to determine whether immune suppression adds information to current consensus staging. Of the 471 patients, 395 patients had sufficient information to determine American Joint Committee on Cancer substage at presentation. Again, immune suppression was a significant stage-independent predictor of poorer MCC-specific outcome (hazard ratio 4.2; 95% CI 2.4–7.4; P<0.01; Supplementary Table S1 online). We performed a third analysis also including lymphovascular invasion status in the model (data available for 149 patients); results were similar and remained significant (hazard ratio 8.9; 95% CI 3.8–21.2; P<0.01).
Discussion
MCC is an aggressive skin cancer. At least 75% of MCC cases have a viral etiology. It has been well established that multiple forms of immune suppression (including HIV, hematologic malignancies, and immunosuppressive medications) are linked with an increased risk of developing MCC (
). However, the effect of systemic immune suppression on MCC prognosis has not been well studied.
We find that systemic immune suppression is a stage-independent predictor of worsened survival among patients with MCC. To account for possible differences in overall health between immune-suppressed and nonimmune-suppressed individuals, we performed the competing risk regression analysis specifically considering the cause of death. Notably, 3-year MCC-specific survival was nearly twice as good in the nonimmune-suppressed group, suggesting systemic immune suppression is of significant clinical importance.
Individuals with systemic immune suppression have been found to be at an increased risk of developing other skin cancers, including squamous cell carcinoma (SCC), basal cell carcinoma, and melanoma. SCC incidence is at least 50-fold increased among solid organ transplant recipients (
). Combined with our findings regarding MCC, these data highlight the importance of carefully following the skin of immune-suppressed individuals and having a low threshold for biopsy of suspicious lesions.
Limitations
Our study had several limitations. Many of the patients were enrolled through referral to tertiary centers, thus suggesting a source of ascertainment bias. To mitigate this as much as possible, we limited the inclusion of patients who presented within 180 days of diagnosis. Given the variable nature of human disease, we were unable to control for the relative degree of immune suppression between various immune-suppressed patients. Finally, although MCC is increasing in incidence it remains an uncommon disease. Although our study size of 471 is large for MCC, we still did not have a sufficient number of immune-suppressed patients to determine the relative impact of each of the various forms of immune suppression on survival.
Immune suppression is associated with both increased MCC incidence and worsened MCC outcome. Conversely, strong intratumoral immune responses are associated with improved MCC survival (
). Given these associations and the known viral immune targets in MCC, immune therapy holds significant promise for the future treatment of MCC. At this time, in the treatment of patients with immune suppression and MCC, it would appear prudent to follow these higher-risk patients very closely and also consider reducing or modifying iatrogenic immune suppression whenever feasible, given the clinical context.
Materials and methods
Patient enrollment
All studies were approved by the institutional review board (FHCRC IRB# 6585), conducted in accordance with the Declaration of Helsinki Principles, and written informed patient consent was obtained. All MCC patients in the FHCRC repository of data and specimens were considered for inclusion and all were enrolled in the United States. Enrollment criteria included (all must be present): a diagnosis of MCC confirmed by two pathologists, the presence of follow-up information, known stage at diagnosis (local–regional–distant), known age at diagnosis, known gender, and known immune suppression status. Patients in the repository enroll in one of the two approaches: either as individuals (through our tertiary referral clinic and the internet) or through records review as part of a patient set from one of the several institutions (including a 186 patient cohort from Kaiser Permanente, a large integrated health care delivery system in Northern California). Patients were represented only once. Patients enrolling as individuals after 180 days of diagnosis were eliminated to reduce ascertainment bias. A total of 471 unique patients with MCC met all criteria (243 from institution cohorts and 228 as individuals); demographics are described in Table 1.
Statistical analyses
Demographic and stage information were compared between immune-suppressed and nonimmune-suppressed persons using the Fisher’s exact test. Overall survival analyses (considering deaths from any cause to be events) were performed using the Cox regression. Disease-specific survival analyses were performed with competing risk regression. For competing risk regression, deaths from MCC were considered to be events (n=126), deaths from other causes were considered to be competing events (n=75), deaths from unknown causes were censored on the day of death (n=31), and living patients were censored on the date of last follow-up (n=239). Kaplan–Meier curves were generated to visually compare survival between groups. Statistical analyses were performed using the Stata version 11.0 software (College Station, TX) for Macintosh. A P-value of 0.05 was considered to be the cutpoint for statistical significance.
ACKNOWLEDGMENTS
This work was funded by NIH-RC2CA147820 (to PN), American Cancer Society RSG-08-115-01-CCE (to PN), NIH-K24-CA139052 (to PN), Michael Piepkorn Endowment, Cora May Poncin Foundation (to KGP), MCC Patient Gift Fund, and David & Rosalind Bloom Fund for MCC.
Chronic lymphocytic leukemia is associated with decreased survival of patients with malignant melanoma and Merkel cell carcinoma in a SEER population-based study.
Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.
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