Racial/ethnic disparities and incidence of malignant peripheral nerve sheath tumors: results from the Surveillance, Epidemiology, and End Results program, 2000–2014

Abstract

Background:

Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors, generally high-grade, and comprise ~5–10% of soft tissue sarcomas. Over two-thirds of MPNSTs metastasize, and upwards of 40% clinically recur. Etiologic risk factors for MPNSTs are historically understudied. There is evidence to suggest MPNST incidence differs across racial/ethnic groups in pediatric populations. Therefore, we sought to estimate differences in MPNST incidence by race/ethnicity among all ages in the United States.

Methods:

Incidence 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 rate ratios (IRR) and 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4). We estimated incidence rates among all ages, and among those diagnosed <25 years and ≥25 years.

Results:

MPNST cases were abstracted from SEER-18 (n=1,047). Among all age groups, Blacks experienced an elevated incidence of MPNSTs compared to Whites (IRR_Blacks=1.26, 95% CI: 1.04–1.50). Asian and Latinos/as experienced lower incidences compared to Whites (IRR_Asians=0.78, 95% CI: 0.61–0.99; IRR_Latinos/as=0.84, 95% CI: 0.69–1.02). In subgroup analyses, no statistically significant associations with MPNSTs were identified among cases diagnosed <25 years of age, whereas the associations observed among all age groups were prominent among those diagnosed ≥25 years of age.

Conclusions:

Incidence rates of MPNSTs were highest in Blacks compared to Whites and other minority groups. This study suggests specific patterns exist in terms of race/ethnicity and age at diagnosis of MPNSTs.

Introduction

Malignant peripheral nerve sheath tumors (MPNST) comprise 5–10% of soft tissue sarcomas across all age groups and originate from peripheral nerve sheath-derived cells [1,2]. Most diagnoses of this extremely rare phenotype occur in adults 20–50 years of age [3], with an estimated overall incidence of 1.46 cases per 1,000,000 person-years [4]. Prognosis is generally poor, especially as these tumors are high-grade with a strong potential to metastasize. In fact, over 67% of tumors metastasize, and upwards of 40% recur [5,2]. Moreover, 5-year survival remains poor despite increased screening measures, and ranges between 26–60% [6,7]. Two main factors contribute to this range in 5-year survival, namely type of MPNST (i.e., whether the MPNST is radiation-induced or associated with neurofibromatosis type 1 [NFI]) [6], and age at diagnosis (i.e. survival of pediatric MPNSTs is influenced by sex, race and therapy, whereas tumor characteristics such as size and site impact survival rates in adult MPNSTs) [1]

A diagnosis of a MPNST often will trigger evaluation for a clinical diagnosis of NF1 and/or genetic testing for NF1 germline mutations [8,9]. This is because approximately 50% of MPNSTs are associated with NF1 [10]. Apart from NF1 and high-dose radiation therapy, few epidemiologic risk factors have been identified that strongly influence MPNST risk [11,12]. A Surveillance, Epidemiology, and End Results (SEER) program database study evaluating MPNST incidence with data through 2009 in the pediatric population suggested an increased incidence among Blacks when compared to Whites, and decreased incidence of MPNSTs among Asians compared to Whites, albeit not at a statistically significant level [4]. Racial/ethnic differences in similar tumor types [13] have been used to identify at-risk populations for these tumors with high rates of recurrence and low overall survival rates. To more fully elucidate if racial/ethnic disparities exist in relation to MPNST incidence, we abstracted data from the SEER 18 program database that represents the most up-to-date and comprehensive collection of population-based cancer registries in the United States (US).

Materials and Methods

Study population

MPNST data were obtained from the SEER 18 database (April 2017 release) [14,15]. The SEER program provides population-based cancer incidence and survival data for nearly 30% of the US population and a large proportion (38%) of the US Latino/a population [16]. 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/a 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 [17], we will use the term Latino/a to reflect the geographical origins of a large proportion of this ethnic group.

SEER registries represent the following states and geographic areas: 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 are obtained by these regional SEER registries from medical records [16]. MPNST case listing and incidence data were procured from SEER 18 for the time period 2000–2014, as these represent the available years for the SEER 18.

Malignant cases diagnosed with cancer at one of the following sites and ICD-O-3 histologic codes were included from SEER 18: peripheral nerves and the autonomic nervous system (C47.0-C47.6, C47.8-C47.9); and ICD-O-3 codes 9540 (Malignant peripheral nerve sheath tumor); 9560 (Neurilemoma); 9561 (Triton tumor); and 9571 (Perineurioma). As MPNSTs occur throughout life, all cases, regardless of age, were included in the analysis [18,5]. Age at and year of diagnosis, sex, race/ethnicity, number of primary tumors, and diagnostic confirmation were abstracted for these analyses.

Statistical analyses

SEER 18 incidence data were used to estimate incidence rates (IR) and age-adjusted incidence rate-ratios (IRR) with 95% confidence intervals (CIs) to assess the association between race/ethnicity and incidence of MPNSTs during 2000–2014. IRs, IRRs and 95% CIs were estimated using SEER*Stat software version 8.3.4 (seer.cancer.gov/seerstat) [15]. Incidence rates were age-adjusted to the 2000 US standard population using single ages between 0 and 85+, and the Tiwari method was used to calculate confidence intervals [19]. We estimated IRs and age-adjusted IRRs for all cases ages 0–85. Most MPNSTs related to NF1 occur in those patients less than 25–30 years of age [18,6], while non-NF1 related MPNSTs are more likely to occur in those individuals above 25–30 years of age [10,20,7]. To identify differences in incidence by race/ethnicity between those cases that may be NF1-related versus non-NF1-related, we conducted subgroup analyses among those diagnosed under 25 years of age and those diagnosed above 25 years of age.

We created a merged “race/ethnicity” variable by combining the SEER variables “race recode” and “origin recode NHIA.” Race was defined as being White, Black or Other racial groups, whereas ethnicity was defined as being of Hispanic/Latino/a origin regardless of self-reported race (White, Black, or Other). This combined 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 small sample sizes. 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.

Results

A total of 1,047 incident MPNSTs were analyzed from SEER 18 for the period 2000–2014 (Table 1). During the period 2000–2014, 83% of MPNSTs occurred in those above 25 years of age, with the highest number of incident cases diagnosed in those 35–44 years of age. MPNSTs were most commonly diagnosed in Whites (62%). A higher proportion of males were diagnosed with MPNSTs compared to women (56 versus 44%, respectively). For the majority of these cases, this was the first primary tumor diagnosed (72%), and nearly all cases had histological confirmation (98%).

Table 1.

Select Demographic and Clinical Characteristics of Malignant Peripheral Nerve Sheath Tumors (Ages 0–85⁺), SEER 18 2000–2014.

Characteristic	Ages 0–85+ (n = 1,047)
Age at Diagnosis, n (%)
0–14 years	58 (5.54)
15–24 years	119 (11.37)
25–34 years	135 (12.89)
35–44 years	192 (18.34)
45–54 years	175 (16.71)
55–64 years	151 (14.42)
65–74 years	104 (9.93)
≥75 years	113 (10.79)
Sex, n (%)
Male	577 (55.11)
Female	470 (44.89)
Racial/Ethnic Group a, n (%)
White	644 (61.51)
Black	152 (14.52)
Asian	77 (7.35)
Other	10 (0.96)
Latino/a	164 (15.66)
Number of Primary Tumors, n (%)
1	757 (72.30)
≥2	290 (27.70)
Diagnostic Confirmation, n (%)
Positive Histology	1,028 (98.19)
Radiography-No Microscopic Confirmation	9 (0.86)
Positive Exfoliative Cytology-No Positive Histology	7 (0.67)
Direct Visualization-No Microscopic Confirmation	1 (0.10)
Unknown	2 (0.19)
Histology, n (%)
Malignant Peripheral Nerve Sheath Tumor	921 (87.97)
Neurilemoma	84 (8.02)
Triton Tumor	39 (3.72)
Perineurioma	3 (0.29)
Tumor Grade, n (%)
Grade I	57 (5.44)
Grade II	142 (13.56)
Grade III	181 (17.29)
Grade IV	239 (22.83)
Unknown	428 (40.88)
SEER Summary Stage 2000, n (%)
Blank(s)	815 (77.84)
Distant site(s)/node(s) involved	31 (2.96)
Localized only	100 (9.55)
Regional by both direct extension and	2 (0.19)
Regional by direct extension only	72 (6.88)
Regional lymph nodes involved only	4 (0.38)
Unknown/unstaged/unspecified	23 (2.20)
Time Period of Diagnosis, n (%)
2000–2006	507 (48.42)
2007–2014	540 (51.58)

Overall, racial/ethnic differences in incidence of MPNSTs were identified. Among Blacks, the incidence rate was significantly higher (P<0.05) compared to Whites (IR_Blacks=0.11 per 100,000 person-years and IR_Whites=0.08 per 100,000 person-years, respectively; Table 2), resulting in a 26% higher incidence among Blacks compared to Whites (IRR_Blacks=1.26, 95% CI: 1.04–1.50). Conversely, Asians experienced a significantly lower incidence rate compared to Whites (IR_Asians=0.07 per 100,000 person-years and IR_Whites=0.08 per 100,000 person-years, respectively; IRR_Asians=0.78, 95% CI: 0.61–0.99). Latinos/as were also suggested to experience a lower incidence of MPNSTs compared to Whites, with borderline statistical significance (IRR_Latinos/as=0.84, 95% CI: 0.69–1.02).

Table 2.

Age-Adjusted Malignant Peripheral Nerve Sheath Tumor Incidence Rates by Race/Ethnicity, Ages 0–85⁺, SEER 18 2000–2014.

Race/Ethnicitya	Rateb	SE	Lower CIc	Upper CI	Count	Rate Ratio (95% CI)	Population
White	0.08	0.00	0.08	0.09	644	Reference (1.00)	714,204,429
Black	0.11*	0.01	0.09	0.12	152	1.26 (1.04–1.50)	147,820,072
Asian	0.07*	0.01	0.05	0.08	77	0.78 (0.61–0.99)	116,483,699
Latino/a	0.07	0.01	0.06	0.08	164	0.84 (0.69–1.02)	268,708,762

^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 person-years 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.

In subgroup analyses by age at diagnosis, racial/ethnic disparities in incidence of MPNSTs across age categories were evident (Table 3). Specifically, no statistically significant differences were observed for any racial/ethnic group and incidence of MPNSTs among cases diagnosed under the age of 25. However, when analysis was restricted to those ages 25 and above (those most likely to be non-NF1 patients), it became clear that the associations observed among all age groups were driven by those cases greater than 25 years of age. Specifically, Blacks experienced higher incidence rates than all other racial/ethnic groups in this higher age category (IR_Blacks=0.14 per 100,000 person-years), and were significantly more likely than Whites to develop a MPNST (IR_Whites=0.11 per 100,000 person-years; IRR_Blacks=1.24, 95% CI: 1.01–1.52). Asians experienced a significantly lower incidence rate of MPNSTs (IR_Asians=0.08 per 100,000 person-years and IR_Whites=0.11 per 100,000 person-years, respectively), and were ~25% less likely to develop an incident MPNST compared to Whites. Latinos/as ages 25 years and above were significantly less likely to develop an incidence MPNST compared to Whites (IR_Latinos/as=0.09 per 100,000 person-years; IRR_Latinos/as=0.77, 95% CI: 0.61–0.96); an association that emerged as statistically significant when estimating IRs and IRRs among these older cases.

Table 3.

Age-Adjusted Malignant Peripheral Nerve Sheath Tumor Incidence Rates by Race/Ethnicity, Ages 0–24 and 25⁺, SEER 18 2000–2014.

	Ages 0–24							Ages 25+
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	0.04	0.00	0.03	0.04	79	1.00 (Reference)	213,488,438	0.11	0.00	0.10	0.12	565	1.00 (Reference)	500,715,991
Black	0.05	0.01	0.03	0.07	29	1.34 (0.84–2.08)	60,182,679	0.14*	0.01	0.11	0.16	123	1.24 (1.01–1.52)	87, 637, 393
Asian	0.04	0.01	0.02	0.06	14	0.99 (0.52–1.78)	38,417,708	0.08*	0.01	0.06	0.11	63	0.74 (0.56–0.97)	78,065,992
Latino/a	0.04	0.01	0.03	0.06	54	1.24 (0.86–1.78)	125,664,633	0.09*	0.01	0.07	0.11	110	0.77 (0.61–0.96)	143,044,129

^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 person-years 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.

Discussion

In this study, we identified differences in the incidence rates of MPNSTs by race/ethnicity through the SEER Program. The incidence rate of MPNSTs was higher in Blacks compared to Whites, while other minority groups experienced lower MPNST incidence rates compared to their White counterparts. Our case series of MPNSTs was distributed similarly to other reports in the literature with respect to age and sex. As with previous reports, MPNSTs were diagnosed most predominately among those between the ages of 30–50 [3,20,4], and a slight preponderance of male MPNST cases was evident [20,4,21].

Overall survival rates from MPNSTs have been historically lower among Blacks compared to other racial/ethnic groups [21], and a higher risk of death due to MPNSTs has been identified in both Black and Latino/a children compared to Whites [21]. In terms of differences in incidence rates across racial/ethnic groups, few studies exist that have investigated this potential risk factor. One recent study using SEER data through 2009 reported that among all ages, MPNSTs occurred at a lower incidence among Asians compared to Whites (IRR=0.61; 95% CI: 0.47–0.79) [4]. This result supports our current finding that Asians have significantly lower rates of MPNSTs compared to Whites. We further suggest that Latinos/as also experience lower MPNST incidence rates than Whites, especially those diagnosed in Latinos/as above 25 years of age. This observation was not reported in the assessment by Bates, et al., as IRRs were not estimated in Latinos/as separately (i.e., race categories included: White, Black and Other) [4]. Our study also reported a significantly elevated rate of MPNSTs in Blacks compared to Whites; an association eluded to by Bates, et al. (IRR=1.18; 95% CI: 0.99–1.40) [4].

As with the current study, Bates, et al., [4] opted to conduct a subgroup analysis among younger cases. While they restricted to those in the pediatric population (ages 0–19), their findings remained similar to our results among those under 25 years of age. Specifically, like us, they reported that no statistically significant differences in MPNST incidence across racial/ethnic groups existed in that age group. Of note, NF1-related MPNSTs are most frequent among those under the ages of 25–30 [6,20,7]. Therefore, in conjunction with the findings presented by Bates, et al., our findings suggest that racial/ethnic disparities in MPNST incidence are more prominent in higher age categories, and thus may reflect racial/ethnic disparities that are unique to non-NF1-related MPNSTs rather than those MPNSTs diagnosed in younger cases that are more likely associated with NF1. However, as we do not have NF1 data available in SEER, these results remain suggestive in nature.

This study must be considered in light of specific limitations. Similar to other registry sources, SEER data does not provide patient history of co-morbidities, including NF1. As up to 50% of MPNSTs occur in those with NF1 [10,22], our study was limited in the ability to a) ascertain which MPNST cases had an underlying NF1 diagnosis; and b) determine incidence rates across racial/ethnic groups stratified by NF1-diagnosis. To date, incidence of NF1 is not considered to vary across racial/ethnic groups, however without NF1 status, we are unable to conclude whether the racial/ethnic MPNST incidence differences observed herein are specific to those with or without NF1. This limits generalizability of study results since racial/ethnic disparities in incidence occurred most strikingly among those 25⁺ years of age. This result may reflect differences in non-NF1-related MPNST incidence by race/ethnicity as most non-NF1-related cases occur in those greater than 25–30 years of age, although we emphasize that without NF1 data we are unable to conclude this definitively [6]. We also note that the race/ethnicity risk estimates among those ages 0–24 are limited in sample size compared to those 25 years and above, which could influence some statistical significance achieved. Further, we understand that premalignant lesions may be managed differently in those older than 20 years, but history of other potential confounding factors (e.g., health behaviors or environmental risk factors) are unavailable in the SEER Program database, therefore we cannot account for how these covariates may have influenced our results. A potential limitation could be that tumor characteristics in SEER do not undergo central pathologic review and therefore misclassification of tumor types is unable to be ruled out.

Despite these limitations, our study has several important strengths. The SEER program is a collection of the most comprehensive cancer registries in the United States, and represents a substantial portion of the diverse US population across racial/ethnic groups to accurately provide a longitudinal perspective of cancer history in the US [23,16]. Our ability to assess differences in risk of MPNSTs across race/ethnicity with a moderately large case series among all ages is an additional study strength. Using the most up-to-date SEER data helped to clarify and more adequately define differences in MPNST incidence rates by race and ethnicity in the US through a population-based approach. Our ability to access data from a collection of cancer registries with a racially/ethnically diverse population as opposed to those conducted in more homogenous (e.g., European [2], Chinese [24]) populations, allowed for the distinction between incidence rates across racial/ethnic groups to be made.

These data suggest that incidence of MPNSTs vary significantly across racial/ethnic groups in the United States, and that racial/ethnic differences in MPNST incidence may occur most predominately among those ages 25 years and above. Future studies investigating how differences in underlying genetics or environmental exposures across racial/ethnic groups influence the clinical presentations and prognostic factors associated with these tumors may help further elucidate factors for overall prevention and management.