Here we present the prognostic analysis used to derive the first unified staging system for MCC. It is anticipated that this staging system, along with the recent introduction of 7 new MCC-specific diagnostic (ICD 9 CM) codes21
will aid in standardizing language used to describe MCC and its prognosis among patients, clinicians, and researchers. This staging system is the result of multidisciplinary consensus meetings that analyzed NCDB data from more than twenty times as many patients as any of the prior MCC staging systems.
Analysis of this dataset verified that primary tumor size (≤2 cm vs >2 cm) is predictive of survival and identified two aspects of nodal involvement that are highly significant for prognosis and are thus incorporated into the new staging system. These relevant characteristics of nodal disease are the method by which negative lymph node status was determined and whether involved lymph nodes were clinically apparent or only microscopically detectable. Pathologic staging of clinically uninvolved lymph nodes (for example, via sentinel lymph node biopsy) is important to accurately determine prognosis in MCC patients who present with local-only disease.
There are numerous differences among the five prior MCC staging systems and the new consensus system. Inclusion of 2.0 cm lesions with smaller tumors in stage I is consistent with the earlier AJCC system but differs from some of the prior staging systems that included 2.0 cm lesions with larger tumors. The new staging system now explicitly includes a stage IIC, for deeply invasive tumors (T4; invasion of bone, muscle, fascia, or cartilage) that carry a poorer prognosis than other localized disease categories (). In-transit metastases are now included as N2 (stage IIIB disease).
The most significant difference between the new system and the prior systems is that the method of determining negative node status will now be included. Overall, approximately one-third of MCC patients who only undergo clinical nodal evaluation are under-staged as they in fact have occult microscopic nodal involvement22
. This difference is both clinically and statistically significant. It is clear, however, that many patients will not be staged pathologically for diverse reasons. Because the new staging system takes into account the best information available for each patient, it provides the most accurate possible prognostic data by not including patients whose nodes were negative by pathology together with patients who only had clinical node examination.
There are several limitations to the NCDB data set. The NCDB does not collect disease-specific survival data. Therefore, relative survival was calculated (see Methods). A limitation of this type of calculation is that it would over-estimate MCC-associated mortality if MCC patients have coexisting co-morbidities (such as profound immunosuppression) that can themselves augment mortality.
A further limitation of the data set is that clinical lymph node data were often not recorded in the past if pathologic lymph node data were available. This means that the NCDB does not provide a direct source of data for stage IIIA patients (micrometastatic nodal disease). Specifically, the survival of true stage IIIA patients is predicted to be somewhat better than the “Stage IIIA*” curve presented () as there was likely some inclusion of clinically node positive patients in this group. Nonetheless, survival of patients in the “IIIA*” group (42% at five years) is markedly better than the clinically node-positive IIIB group (26% at five years). This suggests that many of the patients in the IIIA* group likely had only microscopic nodal disease although this was not explicitly captured. This limitation will be less significant in future analyses as both clinical and pathologic node data are now being collected by the NCDB.
An additional limitation of the data set is that information on tumor recurrence was not available, meaning that disease-free survival could not be calculated. Prior study has indicated that the vast majority of MCC recurrences happen within the first three years after diagnosis8
. Although NCDB did not provide information on MCC recurrences for this analysis, MCC-associated mortality in the current study becomes much less prominent in years four and five ().
Future refinement of this new staging system will be dependent on the availability of additional parameters for analysis. Tumor registrars in the United States are already collecting more specific and detailed data on MCC patients than in the past. This information includes both clinical and pathologic data on regional lymph node status as well as the presence or absence of profound immune suppression. Additional new parameters planned to be captured for later analysis include tumor thickness, lymphovascular invasion23
, tumor-infiltrating lymphocytes23
, growth pattern of the tumor (circumscribed or infiltrative)23
, and extracapsular extension/size of nodal tumor nests. A set of guidelines for pathologic evaluation of MCC has been developed by the College of American Pathologists and recommends capture of many of these features24
In addition to traditional TNM-type staging, other prognostic systems may be useful in the future. These would include nomograms25, 26
that allow weighted integration of continuous variables based on their significance in multivariate analyses. Histologic or molecular features of MCC that are prognostically validated in the future could thus be incorporated. Such tools will likely exist in parallel with traditional TNM staging as their functions are complementary.