We have analyzed incidence and survival rates, as well as trends, for two major RMS subtypes in children and adolescents diagnosed at younger than age 20 years from 13 1975 to 2005 using SEER Program data. We are not aware of any prior SEER reports specifically addressing trends in incidence and survival of pediatric and adolescent RMS subtypes. We found a 4.20% (95% CI=2.60%–5.82%) annual increase in the incidence of ARMS. Further, and unexpectedly, we found that five year survival rates for ARMS have not improved significantly over the last 30 years, rising only 7.7% during this entire period. For ERMS, incidence rates have not changed significantly, while 5-year survival rates have largely improved (from 60.9% during the 1976–1980 period to 73.4% during 1996–2000).
Many changes in classification and diagnosis of RMS were introduced over the last three decades(30
). In 1995 a consensus classification of RMS, the International Classification of RMS (ICR) was established(33
), thus improving the reproducibility of classification as well as prediction of outcome(34
). Review of 800 cases of different RMS subtypes showed high concordance between the review using the new ICR criteria and initial diagnosis established at individual institutions for the ERMS subtype.
However, there was a “disturbing level” of disconcordant diagnosis (37%) reported for the ARMS subtype, which was thought to reflect poor recognition of some of ARMS histologies (34
). For example, a solid form of ARMS morphologically resembles ERMS and is associated with a misdiagnosis rate of about 20%(35
). As we examined the incidence of RMS during the period of 1975–2005, the vast majority of diagnoses were based on histology. Only within the last decade has the biology of tumors been taken into consideration during diagnosis relying on advances in immunologic and molecular methods. While immunologic studies are not necessary to establish the histologic diagnosis in the majority of cases, approximately one fifth of cases require such analyses in order to establish or confirm diagnosis.(34
) In addition, the application of molecular methods to detect translocations t(1, 13) and t(2, 13) characteristic for ARMS(36
) is useful in confirming diagnosis. These changes in classification and application of novel methods over the last decade may have partly contributed to the rise in incidence rates of ARMS and the decrease in RMS, NOS and to a lesser extent the decrease in ERMS we have observed. However, given the relatively smaller number of RMS, NOS cases in any given time period, this change in classification would attenuate, but likely not eliminate, the annual increase in ARMS we observed.
Many of our findings affirm previous incidence reports of RMS, including early age of onset (more than half of RMS cases are diagnosed before the age of 10 years) and a strong male predominance. We showed that this male predominance was driven by ERMS, while there were no sex differences in ARMS incidence. Further, we found slightly higher incidence rates of RMS and ARMS for black children compared to white children.
We also observed a bimodal distribution of ERMS incidence rates with a larger peak during the first 5 years of life and a smaller peak between the ages of 12 and 17 years. Importantly this second peak was only observed in males. It is not clear why males would experience an increased incidence of ERMS in adolescence compared to females. Anecdotally, a recent study showed that pre-pubertal girls and boys have similar muscle size, while androgens have a strong impact on muscle enlargement resulting in larger muscle gain in males during puberty(37
). It is therefore plausible that the smaller peak of ERMS incidence rates observed during adolescence in males only may be related to these sex-specific hormonal differences; this would be of interest to investigate further.
Our analyses of race/ethnic differences in RMS incidence and survival were exploratory, as many of the categories compared were comprised of relatively small numbers. In a previous analysis of childhood STS in the SEER 9 registries during the period 1975–1995(2
), only white and black race were considered. While black children had higher incidence rates of all STS, the authors found no differences by histological subgroups, acknowledging that this may be due to small numbers.
Strengths of our analysis include evaluation of an additional 10 years of data, inclusion of both RMS subtypes, and exploration of additional races/ethnicities. Compared to whites, black children and American Indian/Alaskan Native/Asian/Pacific Islander children had better 5-year survival rates, most strikingly for ARMS; there were notably few cases among these subgroups, however. The only exception was Hispanic children, who tended to fare more poorly than non-Hispanic white and black children, most notably for the ERMS subtype (1996–2000: 57.3% survival, compared to 79.2% in non-Hispanic whites and 82.5% in non-Hispanic blacks).
The observed differences in 5-year survival rates among black and white children are notable. Ries et al(2
) found that white children had slightly better 5-year survival rates for STS compared to black children. These authors analyzed all STS together for the time period (1985–1994), while we focused on 1996–2000, and explored the histological subtypes of RMS, which may account for differences in findings.
The considerable variation in incidence patterns observed here for the two major subtypes of RMS strengthens the notion that these tumors are etiologically diverse. Molecular evidence comparing ERMS and ARMS gene expression further indicates that these tumors have distinct gene signatures(38
). ERMS frequently shows loss of the chromosome 11p15 locus resulting in loss of heterozygosity (LOH) in the region that contains a number of imprinted genes implicated in oncogenesis, including H19
and insulin-like growth factor-2 (IGF-2
). In contrast, translocations are a hallmark of ARMS, present in 80% of all cases(41
) and most commonly involving the PAX3-FKHR or PAX7-FKHR fusion(42
). Such translocations can arise in somatic muscle cells independently throughout adulthood; notably we observed no significant variation in ARMS incidence by age. Several studies have implicated DNA repair pathways in neoplastic transformation involving translocations(43
), but this has not been explored in ARMS.
There are a few limitations to this study. Our review of children with RMS and its two main subtypes reported to a population-based registry does not suffer from ascertainment biases reflecting referral patterns to regional centers that may be present in other epidemiologic studies. However, cancer registry data are limited by the information they are provided. These reports are based upon diagnoses rendered by multiple pathologists and oncologists with variable expertise and equipment(45
) over an extended period of time; this may be especially pertinent for RMS in which molecular classification has changed over the past several decades. However, as diagnostic techniques have improved for RMS, there is higher confidence in the most recent decade regarding accurate diagnosis. New cases registered using ICD-O-3 (begun on January 1, 2001) include more information on RMS subtypes. These data hold promise for future explorations of the relationship between RMS subtypes, race/ethnicity, incidence and survival.
In summary, the observed gender, age, and racial/ethnic differences in incidence and survival of two major RMS subtypes further support the view that these tumors have a distinct underlying etiology. Exploration of these differences presents the opportunity to increase our knowledge of RMS. As improvements in cure rates of RMS, especially ARMS, are slowing, progress will, at least in part, depend on improved understanding of tumor and host biology.(41