Merkel Cell Carcinoma: A Population Analysis on Survival

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  • a From Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School; Department of Radiation Oncology, and Department of Medical Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute; and Merkel Cell Carcinoma Clinic, Department of Dermatology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy. However, factors associated with disease presentation and outcomes remain uncertain, especially in light of recent changes in workup, such as sentinel lymph node biopsy. Therefore, this study used the SEER database to examine factors that could affect stage at presentation and treatment. Methods: We identified 4,543 patients and evaluated associations between sex, race, age, primary disease site, disease presentation, and treatment. We also used univariate and multivariate analyses to examine the effect of these factors on disease-specific survival (DSS) and overall survival (OS). We specifically conducted subgroup analyses on a more modern cohort of patients with MCC treated between 2006 and 2012. Results: Male sex, older age, larger tumor size, and primary tumors of the scalp, neck, or trunk were associated with a higher burden of nodal disease. Multivariate predictors of worse DSS/OS in both the recent and overall cohort included age older than 75 years, number of lymph nodes involved, tumors greater than 5 cm, metastatic disease, or lack of radiation therapy. The number of involved nodes was the best predictor of DSS/OS. Associations with radiation therapy were most pronounced in patients with nodal disease and those not undergoing surgery. Conclusions: Sex, age, tumor size, and primary site of disease correlated with burden of nodal disease in MCC. Associations between disease presentation and treatment strategies such as radiation and DSS and OS have remained relatively constant in the modern era from 2006 to 2012 compared with findings from prior studies.

Background

Merkel cell carcinoma (MCC) is a rare, cutaneous neuroendocrine cancer with an aggressive natural history. Epidemiologic studies indicate that MCC affects approximately 2.3 individuals per million, with incidence in the United States tripling between 1986 and 2001.1 The discovery of the Merkel cell polyomavirus has helped explain MCC pathogenesis in some patients, particularly those who are immunosuppressed.24 MCC typically originates in sun-exposed areas of the skin and carries a high risk of spreading to regional lymph nodes. Nodal recurrences and distant metastases are common, with limited survival for patients with advanced disease.5,6

Treatment of localized MCC is variable, focusing on wide local excision, sentinel lymph node biopsy (SLNB), and adjuvant local and regional radiation therapy (RT).7,8 SLNB specifically has become more common during the last decade, potentially impacting staging and treatment. Chemotherapy and concurrent chemoradiation therapy have also been explored as treatment.911 However, given how rarely MCC occurs, evidence regarding prognostic factors and treatment recommendations has been derived from small patient series and single-institution retrospective reviews.1222 More recent population-based studies have described demographics and predictors of overall survival (OS); however, these OS analyses can be problematic, because MCC predominantly occurs in an older population.2325 In contrast, little is known regarding associations between demographic factors, tumor presentation, and disease-specific survival (DSS). Therefore, we used the SEER program to perform an updated analysis evaluating the impacts of sociodemographic and clinical factors on MCC presentation and DSS. By specifically evaluating a more recent cohort of patients, we were able to capture prognostic factors from current staging and evaluation practices.

Methods

Patient Population and Study Design

We used the SEER program to identify US patients diagnosed with MCC from 1988 to 2012, excluding those with prior malignancies or whose primary site of MCC was other than skin. The SEER program, sponsored by the NCI, collects information on cancer prevalence, treatment, and survival from population-based cancer registries. The 17 SEER tumor registries encompass 28% of the US population.

For patients with MCC, we obtained patient demographics including sex, race (categorized as white, black, or other), age, and tumor characteristics, including size at presentation, site of primary tumor, presence of nodal disease, number of pathologically involved nodes, and presence of distant metastases. Tumor stage was recorded according to the AJCC Cancer Staging Manual, 7th edition. We also abstracted treatment parameters, including cancer-directed surgery at the primary site, SLNB and/or lymph node removal, and use of RT. The SEER database codes for SLNB are included with codes for lymph node–specific surgery; there is limited ability to differentiate between these procedures. SEER does not record the site of irradiation nor whether radiation was delivered to the primary site of disease and/or draining lymph nodes. Finally, we collected outcome parameters including follow-up time, DSS, and OS.

Statistical Methods

We evaluated associations between sociodemographic, tumor, and treatment parameters using the chi-square test. We generated survival curves via the Kaplan-Meier method, and analyzed univariate predictors of DSS and OS using the log-rank test and Cox regression model. We then used the multivariate Cox proportional hazards regression model to determine predictors of DSS and OS, including all potentially relevant parameters, such as sex, race, age, number of positive nodes, site of disease, tumor size, cancer-directed surgery to the primary site or lymph nodes, presence of distant metastatic disease, and use of RT. Patients with missing data on any of these parameters were excluded from the final multivariate model, with 950 patients remaining. Two-sided P values less than 0.05 were considered statistically significant. All statistical analyses were computed using SEER*Stat 8.2.1 (NCI, Bethesda, MD), STATA 14 (StataCorp LP, College Station, TX), or JMP Pro 12 (SAS Institute Inc., Cary, NC).

Results

Patient Characteristics and Treatment

We identified 4,543 patients diagnosed with MCC between 1988 and 2012. Baseline patient characteristics are displayed in Table 1. The average age at diagnosis was 74.5 years (Figure 1). Most patients were white (96%) and older than 50 years (95%), and more than half of the patients were male (59%). The most common sites of involvement were the face (34%) and upper limb and shoulders (23%). Most patients presented with small (<2 cm) tumors (61%); roughly half of all patients presented with nodal involvement (48%) and less than 10% presented with distant metastatic disease. Frequency of stage I through IV disease was 34%, 15%, 36%, and 15%, respectively. Most patients underwent cancer-directed surgery (83%) and slightly less than half of all patients were treated with RT (46%). Approximately 47% of patients with no distant metastatic disease at presentation received RT as part of initial management, either after surgery or as definitive treatment; this frequency increased to 67% when regional lymph nodes were involved.

Associations Between Sociodemographic and Tumor Parameters With Nodal Status

We evaluated associations between sociodemographic factors and tumor characteristics at presentation (Figure 2). Male sex was associated with a higher risk of nodal disease (51% of men were node-positive vs 41% of women [n=1,863]; P<.0001). Older patients were also more likely to present with pathologically involved regional nodes (53% of patients >75 years of

Table 1.

Patient characteristics

Table 1.
age vs ≤45% in younger patients [n=1,863]; P=.0016). This higher rate of pathologic regional lymph node involvement was seen despite the fact that older patients were also less likely to undergo lymph node evaluation compared with younger patients (n=2,982; P<.0001), suggesting we may still have significantly underestimated the actual rate of nodal disease in this population. More than 60% who were diagnosed at younger than 74 years underwent surgical lymph node evaluation and/or SLNB compared with 36% of patients older than 75 years (n=2,982; P<.0001). With respect to race, black patients were found to present with larger tumors (n=2,632; P=.01), and were more likely have distant metastatic disease compared with white patients (n=3,959; P=.04). However, we did not find obvious differences in treatment according
Figure 1.
Figure 1.

Age distribution of patients with Merkel cell carcinoma in the SEER database (1988–2012).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 10; 10.6004/jnccn.2016.0134

to race; black patients were not less likely to undergo nodal surgery/SLNB (n=2,919; P=.28) and also received radiation as frequently as other races (n=4,355; P= 41).

Larger primary tumors were associated with an increased risk of nodal disease; 40% of patients with tumors less than 2 cm demonstrated positive regional nodes compared with 66% of those with tumors greater than 5 cm (n=1,301; P<.0001). Certain primary sites were also associated with higher rates of nodal involvement (n=1,863; P<.0001). Patients with primary trunk and scalp/neck tumors presented with more nodal disease (59% and 57%, respectively) compared with tumors in the face, lower limb/hip, or upper limb/shoulder (all <45%). Conversely, patients with primary tumors of the face and scalp/neck were less likely to undergo SLNB and/or lymph node removal (35%–36%) compared with patients with primary tumors in the trunk, upper, and lower limbs (all >50%; n=1,863; P<.0001). The correlation between tumor size and SLNB and/or lymph node removal trended toward but did not achieve statistical significance (n=1,960; P=.07). Considering all factors that we found to affect nodal status on univariate analyses, sex (P=.010), tumor size (P<.0001), and primary site remained significant (P=.012) on multivariate analysis (n=1,233).

Specifically examining a more recent cohort of patients treated from 2006 to 2012, we again observed that male sex (P=.0002; n=1,157), older age (P=.018; n=1,157), larger primary tumor (P<.0001;

Figure 2.
Figure 2.

Correlations with nodal disease. (A) Male patients present with more nodal disease (P<.0001; n=1,863). Older patients present with (B) more nodal disease (P=.0016; n=1,863) and (C) are less likely to undergo nodal surgery (P<.0001; n=2,982). (D) Black patients present with larger tumors (P=.0155; n=2,632). (E) Larger tumors correlate with more nodal disease (P<.0001; n=1,301). (F) Certain sites of Merkel cell carcinoma correlate with higher burden of nodal disease (P<.0001; n=1,863).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 10; 10.6004/jnccn.2016.0134

n=879), and primary trunk and scalp/neck site tumors (P<.0001; n=1,157) were all associated with higher nodal burden, as seen in a larger cohort. In addition, more than 60% of patients diagnosed at younger than 74 years underwent surgical lymph node evaluation and/or SLNB compared with 40% of patients older than 75 years (n=2,197; P<.0001). Interestingly, a correlation was seen between tumor size and SLNB and/or lymph node removal in the more recent era but not in the larger cohort (n=1,503; P=.0487).

DSS and OS

Median follow-up for all subjects was 25 months (interquartile range, 10–61 months). We found DSS rates of 89% at 1 year and 73% at 5 years (Table 2), and OS rates of 76% at 1 year and 42% at 5 years (Table 3). Univariate analyses showed that male sex, black race, older age, increased number of involved nodes, larger tumors, metastatic disease, higher stage, and tumors with primary site in the scalp and neck were associated with poorer DSS and OS (Figure 3A–D). Cancer-directed surgery at the primary site and SLNB and/or lymph node removal were associated with improved DSS. On multivariate analysis, male sex, age older than 75 years, number of lymph nodes involved, tumors larger than 5 cm, and metastatic disease remained significantly associated with both DSS and OS (n=950). The number of lymph nodes involved was the most significant predictor of DSS and OS (hazard ratio [HR], 3.66–8.46; P<.0001). Indeed, there was a nearly linear relationship between the HR for DSS/OS and the number of involved nodes.

Although not significant on univariate analysis, radiation significantly improved DSS (HR, 0.67; P=.02) and OS (HR, 0.62; P<.0001) on multivariate analysis (Figure 3E–G). If regional nodes were pathologically involved, radiation was associated with a DSS of 59% compared with 49% at 5 years (P=.03). For patients in whom surgery was not attempted, radiation was associated with an even more significant DSS of 73% compared with 54% at 5 years (P<.0001).

We also conducted a focused subgroup analysis of 2,271 patients diagnosed in 2006 to 2012 to evaluate potential differences in the era of modern Merkel management involving routine SLNB use (see supplemental eTables 1 and 2, available with this article at JNCCN.org; n=763). Number of involved nodes (P<.0001), age older than 75 years (P=.01), large tumor size (P=.02), and metastatic disease (P=.007) were all associated with poorer DSS and OS on multivariate analysis (n=763). RT was associated with improved DSS (P=.05) and OS (P=.002) on multivariate analysis. SLNB was linked to better DSS and OS on univariate analysis, but this association did not remain significant on multivariate analysis.

As expected, multivariate regression (supplemental eTable 3) that included stage at diagnosis (n=1,843), instead of individual components such as tumor size, nodal involvement, and confirmed higher stage at diagnosis, was also predictive of worse DSS and OS (P<.0001; n=1,843). This regression did not indicate a correlation between DSS and radiation (P=.51) but did confirm an improved OS from radiation (P=.0003). This may be due to the more common use of radiation in patients with increased overall nodal burden, who would be classified as stage III (P<.0001; n=1,823).

Discussion

This study used the SEER database to explore the effect of sociodemographic, clinical, and treatment factors on the diagnosis and outcomes of MCC. We also conducted a focused analysis of patients with MCC between 2006 and 2012 to provide reference for prognosis and treatment in relation to more modern staging practices, including the more frequent use of SLNB. Analysis of this relatively large data set of more than 4,500 patients indicates that most patients are diagnosed with locoregionally advanced disease. We identified a higher rate of nodal involvement compared with previous studies,6 possibly due to this increased use of diagnostic imaging and/or SLNB.

We identified several sociodemographic and clinical factors that were associated with features at diagnosis and subsequent treatment that remained constant among the more recently treated patients. Older patients, men, and patients with primary disease on the scalp, neck, and trunk were more likely to present with nodal disease. Black patients were more likely to have larger tumors or distant metastatic disease at diagnosis, likely due to a combination of clinical and socioeconomic factors.26 Although older patients were less likely to undergo nodal evaluation overall, they still had a higher incidence of pathologic

Table 2.

Univariate and Multivariate Analysis of Factors Affecting Merkel Cell Carcinoma–Specific Survival

Table 2.
Table 2.
nodal involvement compared with younger patients, suggesting a significantly elevated risk.

We confirmed that MCC remains a potentially lethal disease, with DSS rates of 89% and 73% at 1 and 5 years, respectively. For patients with regionally advanced (stage III) or metastatic (stage IV) disease, the DSS and OS rates at 5 years decrease to 58% and 35% and 32% and 13%, respectively, consistent with previous observations.14 As expected, size of primary tumor, regional lymph node status, number of involved lymph nodes, and stage at diagnosis are highly predictive of DSS. On multivariate analyses, male sex, advanced age, advanced nodal status, larger tumor size, presence of metastatic disease, and overall stage were all associated significantly with worse DSS, and the use of RT was associated with better DSS. Number of involved lymph nodes, in particular, was very significantly associated with worse outcomes.

Our findings significantly expand what is known about factors that influence the presentation, treatment, and outcomes relevant to MCC, and extend these findings to a more modern era between 2006 and 2012. Previously conducted SEER analyses identified male sex and higher stage to confer poorer DSS, whereas RT improved OS, as confirmed by our study.2325 However, these studies did not evaluate nodal involvement, sentinel lymph node intervention, or primary site of disease in detail. Several of our findings are in line with previous National Cancer Data Base (NCDB) analyses, which indicated that even small tumors have high rates of regional lymph node involvement, and correlated with poorer survival.27 Unlike SEER, the NCDB does not provide the cause of death, and therefore does not capture DSS. We similarly found that approximately 40% of patients with tumors less than 2 cm harbor nodal disease and that both lymph node involvement and number of lymph nodes involved are highly predictive of DSS and OS. We also found that the use of SLNB and/or lymph node dissection was associated with improved survival on univariate analysis (HR, 0.8; 95% CI, 0.68–0.94; P=.005), but this parameter was not significant on multivariate analysis. Interestingly, even when examining the more modern subgroup of patients diagnosed between 2006 to 2012, SLNB was associated with improved DSS on univariate (HR, 0.8; 95% CI, 0.66–0.97; P=.02) but not multivariate analysis. It is possible that patients who had a positive SLNB were selected for further adjuvant therapy and thus did better, as has been noted in other large, single-institution studies of SLNB in MCC.28

Table 3.

Univariate and Multivariate Analysis of Factors Affecting Overall Survival

Table 3.
Table 3.

Among treatment parameters, only RT was significantly associated with improved DSS on multivariate analysis. More specifically, RT improved DSS at 5 years by 20% in patients with node-positive disease, and by 35% in patients for whom no surgery was undertaken at the primary site. Conversely, node-negative disease likely represents a heterogeneous population of patients, including those with small tumors treated with wide local excision and nodal evaluation. In these patients, the improved survival from RT may be minimal. It is also important to note that SEER does not encode whether RT was delivered to the primary or nodal site when interpreting these results. Interestingly, when examining the more modern cohort of patients between 2006 and 2012, the results obtained from the multivariate analysis indicate similar associations between radiation and improved DSS/OS, as with the larger cohort.

MCC is generally a radiosensitive tumor, but the precise role of RT in patients with MCC remains controversial.29 Previous population-based studies have reached variable conclusions, with one arguing that radiation did not improve DSS, whereas both indicated improved OS.24,25 Prior institutional experiences and a single prospective randomized study have found radiation to be associated with improvements in locoregional control, but lacked the power to detect an improved association in DSS or OS.16,17 Here, we found that RT is most beneficial for patients with node-positive disease, and may potentially help compensate for nonsurgical management. Along similar lines, a case series of 106 patients showed that patients presenting with gross nodal disease treated with definitive RT to a median of 65 Gy experienced successful regional control.22 Two separate institutional analyses also corroborate our results regarding radiation monotherapy. Data from 43 patients with local or locoregional disease treated to a median of 51 Gy to the primary site and regional lymph nodes indicated an OS rate of 40% at 5 years.16 An additional 57 patients with stage I–III MCC treated with RT alone to a median dose of 52.1 Gy to the primary site and regional nodes demonstrated that doses greater than 50 Gy were associated with a better DSS.20

Our population-based study evaluated associations between nodal involvement, site of disease, and sentinel node–specific surgery and demographic factors, treatment, and DSS. We found that male sex was associated with increased nodal risk and poorer DSS on univariate and multivariate analyses. A recent NCDB study examining MCC of the head and neck also suggested that male patients have poorer OS.30

Our analysis has several limitations. The median follow-up time is relatively modest because we included

Figure 3.
Figure 3.

Merkel cell carcinoma disease-specific survival (DSS). (A) Black patients (P=.04; n=4,442), (B) older patients (P<.0001; n=4,533), those with (C) more involved nodes (n=1,759), and (D) those with higher disease stage (n=2,386) show poorer DSS (P<.0001). Radiation therapy is associated with improved DSS in (E) patients who have node-positive disease (P=.03; n=874) and (F) those not undergoing cancer-directed surgery (P<.0001; n=746), but does not show improved DSS in (G) patients who have node-negative disease (P=.09; n=949).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 10; 10.6004/jnccn.2016.0134

patients diagnosed with MCC more recently, for whom follow-up is limited. The SEER database does not provide information on medical comorbidities (eg, immunosuppression), chemotherapy use, surgical margin status, RT dose and site, or recurrence. Particularly in regard to the lack of radiation details, we are unfortunately unable to differentiate between the impact of radiation to the primary site and its impact to the draining lymph node basin. Because MCC typically affects older individuals, it is conceivable that many patients have additional comorbidities that can affect the decision to undergo various treatment modalities. However, this SEER-based analysis also avoids the referral and treatment biases inherent in single-institution series, and includes data from a wide spectrum of treatment centers and clinical protocols. Moreover, population-level analyses possess sufficient power to study factors affecting diagnosis, treatment, and DSS in this rare disease.

Conclusions

Our data indicate that sociodemographic variables such as male sex and older age correlate with tumor size, nodal involvement, and sentinel node surgery and impact DSS. We also show that RT correlates with improved DSS and OS in patients with MCC who have nodal disease or in whom cancer-directed surgery is not performed. Examining a modern cohort (2006–2012) of patients with MCC also confirms these findings in the era of more extensive staging evaluation, often including SLNB. Given the aggressive course of MCC and its increasing incidence, a better understanding of disease presentation and predictive factors is critical. Recent studies have also indicated a role for immunotherapy, with an impressive response rate observed with PD-1 inhibitors in the treatment of advanced and metastatic MCC.31 The findings in this study can help guide the use of these future treatments in patients at highest risk.

Dr. Rabinowits has disclosed that he is on the scientific advisory board for EMD Serono, Inc. Dr. Schoenfeld has disclosed that he receives support from the Claudia Adams Barr Program for Innovative Cancer Research. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

See JNCCN.org for supplemental online content.

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Correspondence: Jonathan D. Schoenfeld, MD, MPhil, MPH, Dana-Farber/Brigham and Women's Cancer Center, Department of Radiation Oncology, 450 Brookline Avenue, DA L2-57, Boston, MA 02114. E-mail: jdschoenfeld@partners.org

Supplementary Materials

  • View in gallery

    Age distribution of patients with Merkel cell carcinoma in the SEER database (1988–2012).

  • View in gallery

    Correlations with nodal disease. (A) Male patients present with more nodal disease (P<.0001; n=1,863). Older patients present with (B) more nodal disease (P=.0016; n=1,863) and (C) are less likely to undergo nodal surgery (P<.0001; n=2,982). (D) Black patients present with larger tumors (P=.0155; n=2,632). (E) Larger tumors correlate with more nodal disease (P<.0001; n=1,301). (F) Certain sites of Merkel cell carcinoma correlate with higher burden of nodal disease (P<.0001; n=1,863).

  • View in gallery

    Merkel cell carcinoma disease-specific survival (DSS). (A) Black patients (P=.04; n=4,442), (B) older patients (P<.0001; n=4,533), those with (C) more involved nodes (n=1,759), and (D) those with higher disease stage (n=2,386) show poorer DSS (P<.0001). Radiation therapy is associated with improved DSS in (E) patients who have node-positive disease (P=.03; n=874) and (F) those not undergoing cancer-directed surgery (P<.0001; n=746), but does not show improved DSS in (G) patients who have node-negative disease (P=.09; n=949).

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