Evaluation of racial disparities in pediatric optic pathway glioma incidence: results from the Surveillance, Epidemiology, and End Results program, 2000–2014

Abstract

Background:

Racial predilection to pediatric cancer exists; however optic pathway glioma (OPG) risk differences by race/ethnicity are undefined. We estimated differences in OPG incidence across racial/ethnic groups in a multi-state cancer surveillance registry in the United States.

Methods:

OPG data were obtained from the Surveillance, Epidemiology, and End Results (SEER-18) program, 2000–2014. Race/ethnicity was categorized as: White; Black; Asian; Other; and Latino/a (“Spanish-Hispanic-Latino”). Latino/a included all races, while all other categories excluded those identified as Latino/a. Age-adjusted incidence rates and rate ratios (IRR) with 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4).

Results:

Data on 709 OPG cases ages 0–19 were abstracted from SEER-18. Minority children experienced lower age-adjusted OPG incidence rates compared to White children (IRR_Black=0.38, 95% CI: 0.28–0.50; IRR_Asian=0.41, 95% CI: 0.29–0.58; and IRR_Latino/a=0.39, 95% CI: 0.32–0.48). In subgroup analyses among the highest risk age categories (0–4, 5–9), minority children experienced lower incidence rates compared to White children. Specific patterns for Latinos/as also emerged. Latino/a children ages 0–4 experienced the lowest incidence rates of all racial/ethnic groups compared to Whites (0.24 per 100,000 person-years versus 0.66 per 100,000 person-years, respectively), whereas among those ages 5–9, Black and Asian children experienced the lowest incidence rates (0.08 per 100,000 person-years each).

Conclusions:

Incidence of OPGs was highest among White children. This study represents one of the largest to assess differences in OPG susceptibility by race/ethnicity. These findings may inform future studies that seek to evaluate modifying factors for this pediatric tumor including tumorigenesis, treatment, outcome, and long-term late effects.

1.1. Introduction

Optic pathway gliomas (OPG) represent 2–5% of intracranial brain tumors in children [1], and are generally low-grade pilocytic astrocytomas with growth patterns ranging from indolent to highly proliferative [2]. Tumor development occurs in the structures of the visual pathway, including the optic nerve and chiasm [3]. Over 65% of OPGs are diagnosed in children under the age of 5 years old [4, 5], with the majority of remaining cases diagnosed between 5 and 15 years of age [1, 6]. Overall incidence is estimated at 3–4 cases per 100,000 [7], with a 5-year survival rate over 95% [8]. While the mortality rate of OPGs is low, over 75% of patients suffer from severe visual impairment [9, 10], which can often lead to life-long blindness [11]. One of the strongest risk factors for developing OPGs includes germline mutations in the NF1 tumor suppressor gene, as reflected by 50–60% of OPGs occurring in individuals diagnosed with neurofibromatosis type 1 (NF1) [3, 12–14].

Aside from NF1, relatively little is known regarding the impact of other inherited factors, such as race/ethnicity, on the epidemiology of OPGs [8, 15]. Some reports suggest that NF1-associated OPG incidence rates may be lower in minority groups compared to non-Latino/a Whites; however, these studies have been limited in sample size and largely descriptive in nature [16, 17]. Other pediatric tumors, including Ewing Sarcoma [18], demonstrate strong racial predilection impacting predisposition, clinical manifestations, and health outcomes [18]. Therefore, we sought to evaluate racial and ethnic differences in the incidence of OPGs using the most recently available data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute in the United States (US).

2.1. Materials and Methods

2.1.1. Study population

OPG incidence and case listing data were obtained from the newest SEER database: SEER 18 (April 2017 release). Incidence data from the time period 2000–2014 were used since SEER 18 only has data available from 2000 onwards for all eighteen registry sites included. SEER registries represent the following states: Alaska, Arizona, Connecticut, California (Greater California, Los Angeles, San Francisco-Oakland, and San Jose-Monterey), Georgia (Atlanta and Rural Georgia), Hawaii, Iowa, Louisiana, Kentucky, Michigan (Detroit), New Jersey, New Mexico, Utah, and Washington (Seattle-Puget Sound). Case data were obtained by these SEER registries from medical records [19]. The SEER program provides population-based cancer incidence and survival data, representing approximately 30% of the US population and a large proportion (38%) of the US Latino/a population, based on 2013 data [19]. Of note, the terms “Hispanic,” “Hispanic/Latino/a,” and “Latino/a” are used interchangeably to describe individuals of Spanish speaking descent. Hispanic can refer to those from Spanish speaking countries including Spain, while Latino is now recognized to reflect those individuals originally from Latin (Central) America. The SEER program currently uses the all-inclusive term “Spanish-Hispanic-Latino,” but similar to other publications [20], we will use the term Latino/a to reflect the geographical origins of a large proportion of this ethnic group.

OPG cases were abstracted from SEER 18 if they had malignant behavior; a primary site originating in the optic nerve (C72.3); and histologic types 9380 (Glioma), 9382 (Mixed Glioma), or 9400–9421 (Astrocytoma) as defined by the International Classification of Diseases for Oncology 3^rd edition (ICD-O-3). SEER has defined the term “malignant” to mean cases had a behavior code of 3 (“malignant”) in both ICD-O-2 and ICD-O-3 databases (https://seer.cancer.gov/behavrecode/). As OPGs occur primarily in those patients less than 19 years of age, we restricted our analysis to those individuals with tumors between 0–19 years of age [3]. Age at and year of diagnosis, sex, race/ethnicity and number of primary tumors were abstracted for these analyses.

2.1.2. Statistical analyses

SEER 18 incidence data were used to estimate incidence rates (IR), age-adjusted incidence rate-ratios (IRR), and 95% confidence intervals (CIs) to assess the association between race/ethnicity and incidence of OPGs during 2000–2014. IRs, IRRs and 95% CIs were estimated using SEER*Stat software version 8.3.4 (seer.cancer.gov/seerstat). Incidence rates were age-adjusted to the 2000 US standard population using single ages up to 19 years of age for OPGs, and the Tiwari method was used for confidence interval calculations [21]. We estimated incidence rates for all cases ages 0–19. To identify any differences in OPG incidence by race/ethnicity among those in the highest risk age categories (0–4 and 5–9), we conducted subgroup analyses. Demographic characteristics were tabulated in STATA v13.1.

Using the SEER*Stat variables, we created a merged variable “race/ethnicity” by combining the SEER variables “race recode” and “origin recode NHIA.” This variable allowed us to obtain more accurate incidence rates by race/ethnicity for the following racial/ethnic groups: non-Latino/a White (White); non-Latino/a Black (Black); non-Latino/a Asian/Pacific Islander (Asian); non-Latino/a Other (Other); and Latino/a (regardless of race). American Indians and those of multiple races were merged with the “Other” category due to limited sample size. Due to sparse data concerns in specific racial/ethnic groups (e.g. non-Latino/a Other), we present results for White, Black, Asian, and Latino/a racial/ethnic groups.

3.1. Results

A total of 709 incident OPGs in children ages 0–19 were abstracted from SEER 18 for the period 2000–2014 (Table 1). Over 80% of OPG cases occurred prior to 10 years of age, with 56% percent of cases occurring in those ages 0–4. Nearly 70% of cases occurred in White children; no difference in OPG incidence was detected by sex. For the majority of children (89%), this OPG diagnosis was the first primary tumor experienced. Slightly under half of the children (41%) were diagnosed in the period 2000–2006.

Table 1.

Select Demographic and Clinical Characteristics of Pediatric Optic Pathway Gliomas (Ages 0–19), SEER 18 2000–2014.

	Optic Pathway Gliomas
Characteristic	Ages 0–19 (n = 709)
Age at Diagnosis, n (%)
0–4 years	394 (55.57)
5–9 years	193 (27.22)
10–14 years	91 (12.83)
15–19 years	31 (4.37)
Sex, n (%)
Male	342 (48.24)
Female	367 (51.76)
Racial/Ethnic Groupa, n (%)
White	478 (67.42)
Black	52 (7.33)
Asian	36 (5.08)
Other	23 (3.24)
Latino/a	120 (16.93)
Number of Primary Tumors, n (%)
1	631 (89.00)
≥2	78 (11.00)
Time Period of Diagnosis, n (%)
2000–2006	292 (41.18)
2007–2014	417 (58.85)
Diagnostic Confirmation, n (%)
Positive Microscopic Confirmation	171 (24.1)
No Microscopic Confirmation	22 (3.1)
Radiography and Other Imaging Techniques, No Microscopic Confirmation	504 (71.1)
Unknown if Microscopically Confirmed, Death Certificate Only	12 (1.7)

^aThe Latino/a category includes those of all races, while all other race categories exclude those identified as Latino/a.

Overall, children from racial minority backgrounds ages 0–19 experienced lower rates and age-adjusted incidence rate ratios of OPGs compared to White children (Table 2). In White children, the rate of OPGs (IR_White=0.29 per 100,000 person-years) was more than double the rate of OPGs in Black children (IR_Black=0.11 per 100,000 person-years). Specifically, Blacks were ~60% less likely than Whites to develop an OPG (IRR_Black=0.38, 95% CI: 0.28–0.50). Similar to Blacks, the OPG incidence rate among Asian children was half that identified among White children (IR_Asian=0.12 per 100,000 person-years). Asians were also ~60% less likely to develop an OPG compared to Whites (IRR_Asian=0.41, 95% CI: 0.29–0.58). As with other minority children in this study, Latinos/as were significantly less likely to develop an OPG compared to Whites during this time period (IR_Latino/a=0.11 per 100,000 person-years and IRR_Latino/a=0.39, 95% CI: 0.32–0.48).

Table 2.

Age-Adjusted Pediatric Optic Pathway Glioma Incidence Rates by Race/Ethnicity, Ages 0–19, SEER 18 2000–2014.

Race/Ethnicitya	Rateb	SE	Lower CIc	Upper CI	Count	Rate Ratio (95% CI)	Population
White	0.29	0.01	0.26	0.32	478	Reference (1.00)	168,901,724
Black	0.11*	0.02	0.08	0.14	52	0.38 (0.28–0.50)	48,398,048
Asian	0.12*	0.02	0.08	0.17	36	0.41 (0.29–0.58)	29,900,666
Latino/a	0.11*	0.01	0.09	0.14	120	0.39 (0.32–0.48)	101,619,959

^aThe Latino/a category includes those of all races, while all other race categories exclude those identified as Latino/a;

^bRates are per 100,000 persons and age-adjusted to the 2000 US Standard Population (19 age groups - Census P25-1130) standard;

^cConfidence intervals (Tiwari mod) are 95% for rates and ratios;

^*The rate is significantly different than the rate for Whites (P<0.05).

Data for “Non-Latino/a Other” not shown due to limited sample size.

Results from subgroup analyses among OPG cases in the highest risk age categories of 0–4 and 5–9 years were similar with those findings among all cases ages 0–19 (Table 3). Overall, minority children experienced lower incidence rates and rate ratios compared to Whites in both age subgroups. However, where incidence rates and rate ratios were approximately the same for all minority children among those ages 0–19, specific patterns for Latinos/as emerged in each age subgroup compared to other minority children. Specifically, Latino/a children ages 0–4 experienced the lowest incidence rates of all racial/ethnic groups compared to Whites (IR_Latino/a=0.24 per 100,000 person-years and IR_White=0.66 per 100,000 person-years, respectively), whereas among those ages 5–9, Black and Asian children experienced the lowest incidence rates compared to Whites (IR=0.08 per 100,000 person-years in each Black and Asian children versus IR_White=0.16 per 100,000 person-years). Notably, the incidence rates of Blacks and Asians ages 5–9 compared to Whites were half that of Latinos/as compared to Whites (IR_Latino/a=0.16 per 100,000 person-years).

Table 3.

Age-Adjusted Pediatric Optic Pathway Glioma Incidence Rates by Race/Ethnicity Among Young Children, Ages 0–4 and 5–9, SEER 18 2000–2014.

	Ages 0–4							Ages 5–9
Race/Ethnicitya	Rateb	SE	Lower CIc	Upper CI	Count	Rate Ratio (95% CI)	Population	Rate	SE	Lower CI	Upper CI	Count	Rate Ratio (95% CI)	Population
White	0.66	0.04	0.58	0.74	259	Reference (1.00)	39,337,831	0.32	0.03	0.26	0.38	130	Reference (1.00)	40,917,721
Black	0.29*	0.05	0.20	0.41	33	0.44 (0.30–0.64)	11,335,870	0.08*	0.03	0.04	0.16	10	0.27 (0.13–0.51)	11,777,635
Asian	0.31*	0.07	0.20	0.47	23	0.48 (0.30–0.73)	7,326,458	0.08*	0.03	0.03	0.18	6	0.26 (0.09–0.58)	7,321,100
Latino/a	0.24*	0.03	0.19	0.31	66	0.37 (0.28–0.49)	27,041,206	0.16*	0.03	0.12	0.22	41	0.51 (0.35–0.73)	25,446,039

^aThe Latino/a category includes those of all races, while all other race categories exclude those identified as Latino/a;

^bRates are per 100,000 persons and age-adjusted to the 2000 US Standard Population (19 age groups - Census P25-1130) standard;

^cConfidence intervals (Tiwari mod) are 95% for rates and ratios;

^*The rate is significantly different than the rate for Whites (P<0.05).

Data for “Non-Latino/a Other” not shown due to limited sample size.

4.1. Discussion

In this study, we identified differences in the incidence rates of OPGs by race/ethnicity through the SEER Program. Lower rates of OPGs were identified among Blacks, Asians, and Latinos/as compared to Whites among those 0–19 years of age. Our case series of OPGs were distributed similarly to other reports in the literature with respect to age and sex. As with previous reports, the majority of OPGs were diagnosed in children among the youngest age categories [1, 5, 15].

In the present study, we report OPG incidence rates that are statistically significantly reduced in Black, Asian and Latino/a children compared to White children. NF1-associated OPGs have been noted to occur less frequently in Blacks and other minority groups including Latinos/as [3, 16]; however, a gap in the literature exists regarding non-NF1-asociated OPG risk differences by race/ethnicity. A recent study utilizing pooled data within the NF1 Patient Registry reported results similar to those observed here [22]. Abadin et al. reported that, compared to Whites, Blacks experienced a decreased odds of developing a childhood NF1-related OPG (odds ratio [OR] = 0.13; 95% CI: 0.05–0.31), as did Asians (OR = 0.15; 95% CI: 0.04–0.64), and those of Other/unknown racial/ethnic backgrounds (OR = 0.61; 95% CI: 0.41–0.93). While we detected a decrease in incidence of childhood OPGs among Latinos/as, Abadin et al., did not identify a significant difference in the odds of developing a childhood OPG among Latino/a children with NF1 (OR = 0.71; 95% CI: 0.43–1.18) [22]. This could be explained in part by the fact that their study compared Latinos/as to all non-Latinos/as. It is reasonable to infer that a large portion of those who identified as Latino/a may have been of European ancestry, and that due to this racial distribution among Latinos/as, the findings may have been attenuated through genetic admixture. However, since SEER does not collect information on NF1 diagnoses, we are unable to generalize the patterns observed among those with an NF1-associated OPG to this SEER study; at best, we can note similarities between the findings.

Our study must be considered in light of specific limitations. As with most registry sources, SEER data do not provide patient history of co-morbidities, including NF1, such that we are unable to determine how these factors may modify the current investigation. This is a drawback of the study that should be taken into consideration when considering the reported results and limits result generalizability. Related to missing NF1 status, approximately 50–60% of OPGs [1, 23] are estimated to be NF1-positive, and NF1-related OPGs are almost always low-grade, may not have “malignant” behavior, and diagnoses are not made based on tumor histology since most all are followed by MRI and not resected [24, 25]. Therefore, the number of NF1-associated OPGs may be underrepresented in the current study since it is unusual to surgically resect even symptomatic OPGs in NF1. Diagnostic bias cannot be fully ruled out since OPGs require ophthalmologic examination or MRI for diagnosis, and therefore differences in access to care across racial/ethnic groups may have impacted the reported results. To evaluate this potential, first, we assessed any difference in insurance status according to method of OPG diagnostic confirmation (data not shown) and found that mode of OPG diagnostic confirmation did not differ according to insurance status (P-value = 0.81). Second, we evaluated if method of OPG diagnostic confirmation differed according to race/ethnicity and found no difference by race/ethnicity (P-value = 0.27). To see if disparities in treatment existed by race/ethnicity in this study population as a proxy for access to care, we evaluated if treatment/recommendation for surgery differed by race/ethnicity and again found no difference (P-value = 0.38). It is important to emphasize that the SEER program captures nearly 100% of all cancer cases diagnosed within each of the 18 participating registries and has been methodologically arranged to over-represent racial and ethnic minorities [26, 27]. As history of other potential confounding factors (e.g., health behaviors or environmental risk factors) are unavailable in the SEER database, we cannot account for how our results may have differed by these covariates. We also acknowledge that we were limited in our ability to investigate any heterogeneity in OPG presentation across other minority groups, including American Indians, due to small sample size.

Despite these limitations, our study has notable strengths. The SEER program is the most comprehensive cancer registry in the United States, and represents a substantial portion of the population across racial/ethnic groups to accurately provide a comprehensive and longitudinal perspective of cancer history in the US [19, 28]. This study represents one of the first to analyze childhood OPG incidence rates across a joint race/ethnicity variable, as opposed to by race or ethnicity singularly. Our ability to assess differences in risk of OPGs across race/ethnicity with a moderately large case series is an added study strength, as is the fact that this study contributes to a gap in the literature regarding racial/ethnic risk disparities in OPG incidence. Lastly, using the most up-to-date SEER data has helped to clarify and more adequately identify differences by racial/ethnic background on OPG incidence rates in the US through a population-based approach.

5.1. Conclusion

These data suggest that incidence of OPGs vary significantly across racial/ethnic groups in the United States. These differences could be explained by true differences in underlying genetics, environmental exposures, or social factors with the potential to introduce ascertainment bias. Future studies investigating how genetic differences or social factors across racial/ethnic groups influence the clinical presentations associated with this tumor may help further elucidate clinical factors for the prevention and management of this malignancy, especially if these studies are able to incorporate NFI data. Comparative molecular and genetic analyses of these tumors between both NF-1 affected and non-affected children stratified by race/ethnicity may highlight modifiable factors influencing OPG risk.

Abbreviations

OPG

Optic Pathway Glioma

NF1

Neurofibromatosis Type 1

SEER

Surveillance, Epidemiology, and End Results Program

US

United States

IR

Incidence Rate

IRR

Age-Adjusted Incidence Rate Ratio

CIs

Confidence Intervals

OR

Odds Ratio