Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System

Abstract

Background: The first consensus Merkel cell carcinoma (MCC) staging system was published in 2010. New information on the clinical course prompts review of MCC staging.

Methods: A total of 9387 MCC cases from the National Cancer Data Base Participant User File with follow-up and staging data (1998-2012) were analyzed. Prognostic differences based on clinical and pathological staging were evaluated. Survival estimates were compared by disease extent.

Results: Sixty-five percent of cases presented with local disease, whereas 26 and 8 % presented with nodal and distant disease. Disease extent at presentation was predictive of 5-year overall survival (OS) with estimates of 51, 35, and 14 % for local, nodal, and distant disease. Tumor burden at the regional nodal basin was predictive of 5-year OS with estimates of 40 and 27 % for clinically occult and clinically detected nodal disease. For local disease, we confirm improved prognosis when the regional nodal basin was negative by pathological compared with clinical staging. We identified 336 cases with clinically detected nodal disease and unknown primary tumor and showed improved prognosis over cases presenting with concurrent primary tumor (OS estimates of 42 vs. 27 %).

Conclusions: Analysis of a national dataset of MCC cases validates the predictive value of disease extent at presentation. Separation of clinical and pathological stage groups and regrouping of unknown primary tumors are supported by the analysis. The revised staging system provides more accurate prognostication and has been formally accepted by the AJCC staging committee for inclusion in the 8th edition.

Conflict of interest statement

Disclosures:

KLH, MAH, TMJ, CKB, and SLW have no conflict of interest disclosures.

PN is a consultant for EMD Serono; travel, accommodations, other expenses from EMD Serono; research funding from Brisol Myers Squibb to PN’s institution

AJS has research funding from MELA Sciences; AJS has stock in Merck, Amgen, Teva, and Pfizer

Figures

Figure 1.

Flow diagram for inclusion/exclusion criteria of Merkel cell carcinoma (MCC) cases in the National Cancer Database (NCDB) that were analyzed for survival rates. 14,414 MCC cases were prospectively captured in the NCDB during 1998 to 2012. Of those, 13,093 cases had follow-up data available and were used to stratify TNM categories. Cases without any TNM classification (TxNxMx, n=2,928) were excluded. Cases with a recorded stage that did not represent a valid clinical entity were excluded (e.g. cases where the primary tumor was not assessed but with concurrent occult nodal metastasis noted (TxN1a, n=229) or without nodal metastases (TxN0, n=549) are likely to represent coding errors). Derivation of T, N, and M categories used for analysis is detailed in the Methods section. 9,387 cases with staging information and follow-up data were used for survival analysis.

Figure 2.

Five-year overall survival (OS) in Merkel cell carcinoma (MCC). (a) Survival curves of 9,387 MCC patients stratified by local, nodal, and distant metastatic disease. (b) Survival curves of 6,127 MCC patients presenting with local disease only stratified by primary tumor size using T categories (T1: primary tumor ≤ 2 cm, T2/3: primary tumor > 2 cm, T4: primary tumor invades fascia, muscle, cartilage, or bone). Eleven patients presenting with in situ tumor (Tis) were excluded from analysis given the small sample size. (c) Survival curves of 2,465 MCC patients presenting with nodal metastases stratified by occult nodal disease (N1a), clinically detected nodal disease with known primary tumor (N1b with known primary), clinically detected nodal disease with unknown primary tumor (N1b with unknown primary), and in-transit metastasis (N2). *The N2 category had a small sample size of 60 and survival represents three-year OS instead of five-year OS.

Figure 3.

Five-year overall survival for new MCC clinical (a) and pathological (b) staging shows distinct prognostication. (a) Survival curves of 2,013 patients with clinical staging for local disease when pathological staging data was unavailable. 1,272 patients presented with clinical stage I (T1 N0 M0), 675 presented with clinical stage IIA (T2/3 N0 M0), and 66 patients presented with clinical stage IIB (T4 N0 M0). (b) Survival curves of 5,371 patients with pathological staging, including 1,502 patients with pathological stage I (T1 N0 M0), 493 patients with pathological stage IIA (T2/3 N0 M0)*, 127 patients with pathological stage IIB (T4 N0 M0), 1,536 patients with pathological stage IIIA (T1–4 N1a M0 and T0 N1b M0), 929 patients with pathological stage IIIB (T1–4 N1b M0 and T0–4 N2 M0), and 784 patients with pathological stage IV (Tany Nany M1). *5-year OS for T2N0M0 (n = 414) is 56.0% with 95% confidence interval of 50.1–61.5%; 5-year OS for T3N0M0 (n=79) is 47.3% with 95% confidence interval of 34.3–59.3%.