Date of Award

January 2021

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Benjamin L. Judson


Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy of neuroendocrine origin with increasing incidence in the United States. We retrospectively studied possible drivers of increasing incidence, characterized trends in treatment utilization, and correlated treatment selection with patient outcomes. We hypothesized that age, period of diagnosis, and birth cohort have contributed to the rising disease incidence of MCC of the head and neck. We further hypothesized that treatment would have become more guideline-compliant over time, that compliance would be higher at institutions with high melanoma case volumes, and that guideline-compliant initial surgical management would be associated with improved patient outcomes.

In this study, the National Cancer Database (NCDB), Surveillance, Epidemiology, and End Results Program (SEER), and an institutional database of MCC patients were queried. Analysis was limited to patients with MCC of the head and neck. Epidemiology was assessed using an age-period-cohort (APC) analysis. An APC analysis assesses how age (i.e., changes in physiology associated with aging), period of diagnosis (i.e., changes in diagnostics and clinical awareness), and birth cohort (i.e., true changes in risk factor exposure in successive generations) effects influence disease incidence. Assessment of guideline-compliance was limited to patients with clinically locally confined MCC. Overall survival analyses were performed using inverse probability weighting.

Queries of the NCDB, SEER, and institutional database, revealed 3500, 1627, and 52 patients, respectively, for inclusion. In all databases, MCC was more common amongst White (>95%), male (>55%), and elderly (median age ≥75 years) patients. MCC of the head and neck has approximately tripled in incidence from the time periods of 1982-1986 to 2012-2016. MCC incidence is highest in patients ≥85 years (4.70 per 100,000 in 2012-2016). On APC analysis, the period effect (i.e., changes associated with changes in diagnostics or awareness) has started to plateau, while the birth cohort effect (i.e., changes in risk factor exposure) has continued to increase with time. We project there to be 1143 new cases of MCC of the head and neck in 2025. From 2004 to 2015, guideline-compliant surgical excision of the primary tumor and lymph node examination increased from 30.5% to 49.2% of patients. However, guideline-compliance started to plateau in approximately 2012. Patients evaluated at institutions with high melanoma case volumes (>75th percentile) were more likely to provide guideline-compliant therapy compared to low volume centers regardless of facility academic status. Guideline-compliant surgical excision of the primary tumor and lymph node examination were associated with improved overall survival (HR 0.37, CI: 0.14-0.96) and recurrence-free survival (HR 0.25, CI: 0.09-0.73).

In conclusion, the initial rise in MCC incidence was likely influenced by changes in diagnostics and improved awareness, while future changes in incidence are likely to be driven by changes in risk factor exposure. Treatment of MCC remains varied. Further research and resource allocation are needed to improve provision of guideline-compliant treatment, which is associated with improved patient outcomes.


This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.