Recurrence and Mortality Risk of Merkel Cell Carcinoma by Cancer Stage and Time From Diagnosis

Abstract

IMPORTANCE Merkel cell carcinoma (MCC) often behaves aggressively; however, disease-recurrence data are not captured in national databases, and it is unclear what proportion of patients with MCC experience a recurrence (estimates vary from 27%-77%). Stage-specific recurrence data that includes time from diagnosis would provide more precise prognostic information and contribute to risk-appropriate clinical surveillance. OBJECTIVE To estimate risk of stage-specific MCC recurrence and mortality over time since diagnosis. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study included 618 patients with MCC who were prospectively enrolled in a Seattle-based data repository between 2003 and 2019. Of these patients, 223 experienced a recurrence of MCC. Data analysis was performed July 2019 to November 2021. MAIN OUTCOMES AND MEASURESStage-specific recurrence and survival, as well as cumulative incidence and Kaplan-Meier analyses. RESULTS Among the 618 patients included in the analysis (median [range] age, 69 years; 227 [37%] female), the 5-year recurrence rate for MCC was 40%. Risk of recurrence in the first year was high (11% for patients with pathologic stage I, 33% for pathologic stage IIA/IIB, 30% for pathologic stage IIIA, 45% for pathologic stage IIIB, and 58% for pathologic stage IV), with 95% of recurrences occurring within the first 3 years. Median follow-up among living patients was 4.3 years. Beyond stage, 4 factors were associated with increased recurrence risk in univariable analyses: immunosuppression (hazard ratio [HR], 2.4; 95% CI, 1.7-3.3; P < .001), male sex (HR, 1.9; 95% CI, 1.4-2.5; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; 95% CI, 1.4-4.0; P = .001), and older age (HR, 1.1; 95% CI, 1.0-1.3; P = .06 for each 10-year increase). Among 187 deaths in the cohort, 121 (65%) were due to MCC. The MCC-specific survival rate was strongly stage dependent (95% at 5 years for patients with pathologic stage I vs 41% for pathologic stage IV). Among patients presenting with stage I to II MCC, a local recurrence (17 arising within/adjacent to the primary tumor scar) did not appreciably diminish survival compared with patients who had no recurrence (85% vs 88% MCC-specific survival at 5 years). CONCLUSIONS AND RELEVANCEIn this cohort study, the MCC recurrence rate (approximately 40%) was notably different than that reported for invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) following definitive therapy. Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage-and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest.

Best practices in surgical and nonsurgical management of head and neck Merkel cell carcinoma: An update

“…Additionally, at 5 years, 80% of patients with pathologic stage I cancer were without recurrence versus 28% of patients with stage IV. For all stages, the highest risk of recurrence occurred 1–3 years after initial treatment, and 94% of recurrences occurred within the first 3 years after initial treatment 64 . The American Joint Cancer Commission 8th edition (AJCC8) database also reported that the expected 5‐year OS for localized disease (stages 1 and 2) was 50.6% and decreased with increasing tumor size 65 .…”

Epidemiology of Merkel Cell Polyomavirus Infection and Merkel Cell Carcinoma

“…Clinical suspicion of MCC should be confirmed histologically and immuno-histochemically ( Figure 3 b,c), as the described features are nonspecific, and often MCC lesions are presumed to be benign in nature with differential diagnosis including cyst, lipoma, or folliculitis [ 46 ]. Early diagnosis and associated smaller tumor diameter and lower tumor stages are critical for the prognosis of MCC [ 47 , 48 ]. The latest developments in the diagnosis and treatment of MCC have been reviewed recently in this and other journals [ 49 , 50 , 51 , 52 , 53 , 54 ].…”

“…MCC of the head and neck is highly malignant due to the early development of metastases and frequent recurrences. A recent prospective cohort study showed that MCC has a significantly higher 5-year recurrence rate (approximately 40%) than other malignancies of the skin, e.g., invasive malignant melanoma (19%) or SCC (5–9%) [ 48 ]. In a pilot study, it could be shown that similar to other malignancies, MCC changes in the hydroxymethylation pathway may be of relevance for progression [ 97 ].…”

Response to comment on “Merkel cell carcinoma: An updated review of pathogenesis, diagnosis, and treatment options”

“…Recently, Immunomic Therapeutics, Inc., 2 We agree with their point that vaccination for MCC is more likely to be used as adjuvant therapy as opposed to preventative therapy, as in the case of vaccination for human papillomavirus (HPV), given MCC's rarity. Given that recent studies suggest that the risk of recurrence for pathologic Stage I disease after 1-and 5-years are 11% and 20%, respectively, 3 the utility of vaccination may be more appropriate as adjuvant therapy in order to prevent recurrence of local MCC after undergoing appropriate surgical excision with or without radiation therapy. Vaccination could play a crucial role in amplifying the host immune response against migrating oncogenic cells that may have been inadvertently missed in the initial surgical excision.…”

“…4 Recently, recurrence in advanced disease (pathologic stage IV) has been shown to be 58% after 1 year and 72% at 5 years in a cohort of 618 patients. 3 We have previously described the role of immunotherapy, such as programmed death receptor-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors, in advanced disease with response rates ranging from 31.8% to 68%. [5][6][7] Patients that are responsive to such therapy may benefit from a combination treatment in order to potentiate the effects of immune checkpoint blockade.…”