ORIGINAL PAPER

Risk of second benign brain tumors among cancer survivorsin the surveillance, epidemiology, and end results program

Alina Kutsenko • Amy Berrington de Gonzalez •

Rochelle E. Curtis • Preetha Rajaraman

Received: 28 October 2013 / Accepted: 12 March 2014 / Published online: 30 March 2014

� Springer International Publishing Switzerland (outside the USA) 2014

Abstract

Purpose To assess risk of developing a second benign brain

tumor in a nationwide population of cancer survivors.

Methods We evaluated the risk of developing second

benign brain tumors among 2,038,074 1-year minimum can-

cer survivors compared to expected risk in the general popu-

lation between 1973 and 2007 in nine population-based cancer

registries in the NCI’s surveillance, epidemiology, and end

results program. Excess risk was estimated using standardized

incidence ratios (SIRs) for all second benign brain tumors and

specifically for second meningiomas and acoustic neuromas

diagnosed during 2004–2008.

Results 1,025 patients were diagnosed with a second pri-

mary benign brain tumor, of which second meningiomas

composed the majority (n = 745). Statistically significant

increases in risk of developing a second meningioma com-

pared to the general population were observed following first

cancers of the brain [SIR = 19.82; 95 % confidence interval

(CI) 13.88–27.44], other central nervous system (CNS)

(SIR = 9.54; CI 3.10–22.27), thyroid (SIR = 2.05; CI

1.47–2.79), prostate (SIR = 1.21; CI 1.02–1.43), and acute

lymphocytic leukemia (ALL) (SIR = 42.4; CI 23.18–

71.13). Statistically significant decreases in risk were

observed following first cancers of the uterine corpus

(SIR = 0.63; CI 0.42–0.91) and colon (SIR = 0.56; CI

0.37–0.82). Differences in risk between patients initially

treated with radiotherapy versus non-irradiated patients were

statistically significant for second meningioma after primary

cancers of the brain (pHet \ 0.001) and ALL (pHet = 0.02).

No statistically significant increased risks were detected for

second acoustic neuromas (n = 114) following any first

primary tumor.

Conclusions Risk of second benign brain tumors, partic-

ularly meningioma, is increased following first primary

cancers of the brain/CNS, thyroid, prostate, and ALL.

Radiation exposure likely contributes to these excess risks.

Keywords Meningioma � Radiotherapy � SEER � Brain

neoplasm � Second primary neoplasm

Introduction

The number of cancer survivors in the United States has

increased rapidly during the past decade. In January 2008,

there were approximately 12 million people alive with a

history of cancer [1]. Cancer survivors are at higher risk for

a number of morbidities, one of the most serious being

increased incidence of new malignancies, which account

for about 16 % of all cancers reported to the National

Cancer Institute’s (NCI) Surveillance, Epidemiology, and

End Results (SEER) Program [2]. A previous examination

of malignant brain tumors in cancer survivors found excess

risks following first cancers of the brain and central

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10552-014-0367-5) contains supplementarymaterial, which is available to authorized users.

A. Kutsenko (&) � A. Berrington de Gonzalez �R. E. Curtis � P. Rajaraman

Radiation Epidemiology Branch, Division of Cancer

Epidemiology and Genetics, NCI/NIH, 9609 Medical Center

Drive, MSC 9778, Bethesda, MD 20892, USA

e-mail: alk2022@med.cornell.edu

A. Berrington de Gonzalez

e-mail: berringtona@mail.nih.gov

R. E. Curtis

e-mail: rcurtis@mail.nih.gov

P. Rajaraman

e-mail: rajarama@mail.nih.gov

123

Cancer Causes Control (2014) 25:659–668

DOI 10.1007/s10552-014-0367-5

nervous system, prostate, and acute lymphoblastic leuke-

mia (ALL) [3]. In this analysis, we focus solely on second

benign malignancies of the brain and central nervous sys-

tem. Data on benign brain malignancies began to be

comprehensively collected starting in 2004 by the SEER

Program of population-based cancer registries. Almost

200,000 brain tumors were diagnosed in the United States

between 2004 and 2007. Approximately two-thirds of these

were tumors of benign and borderline malignancy [4].

Although histologically benign, these tumors can cause

serious morbidity and have the potential to cause cognitive

changes, seizures, and focal neurologic deficits [5]. The

two most common benign brain tumor subtypes are

meningiomas and acoustic neuromas, which together make

up approximately 23 % of all intracranial tumors [6]. The

only identified risk factors for benign brain tumors to date

are moderate to high-dose cranial irradiation; a history of

prior cancers of the brain, central nervous system (CNS),

and acute lymphocytic leukemia (ALL); and possession of

a few rare hereditary syndromes such as neurofibromatosis

[7, 8]. Cranial irradiation has been shown to significantly

increase the incidence of meningiomas and acoustic neu-

romas even at moderate doses [9–12].

In this study, we use data from the SEER Program to

examine the standardized incidence ratio (SIR) of second

benign brain tumors among 1-year minimum cancer survi-

vors diagnosed with a first primary malignant tumor from

1973 to 2007 compared to risk of benign brain tumors in the

general population. We further assess the potential role of

cranial radiotherapy in this risk. While studies have evalu-

ated risk factors for second malignant brain tumors in SEER,

this is the first study to our knowledge to assess population-

based risk estimates of second benign brain tumors.

Methods

We used SEER Program data to examine 2,038,074 1-year

minimum cancer survivors, of whom 1,025 were diagnosed

with a second primary benign brain tumor between the

years of 2004 and 2007. The SEER program, which col-

lects population-based data on cancer incidence and sur-

vival in the United States, covers approximately 28 % of

the US population and accrues data on demographics,

tumor morphology and topography, and initial cancer

treatment. SEER added non-malignant CNS tumors to its

case definitions starting on January 1, 2004, thus only

recently allowing investigators the opportunity to analyze

comprehensive nationwide data on benign brain cancers

[13].

Patients eligible for inclusion in this study were reported

to one of nine SEER population-based cancer registries

(San Francisco-Oakland SMSA, Connecticut, Detroit,

Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta)

between the years of 1973 and 2008. Race was specified as

white (including white, other unspecified [1991?], and

unknown patients), black, or other (including American

Indian/AK Native, Asian/Pacific Islander patients). Data

analyses were restricted to patients who survived a mini-

mum of 12 months after their primary cancer diagnosis (to

minimize the probability of including primary metastases

or recurrence) and had an attained age of \85 years. Per-

son-years (PY) of observation were cumulated during the

calendar years 2004–2008 from 12 months after initial

cancer diagnosis until date of death, date last known alive,

or end of the study (12/21/2008), whichever occurred first.

We examined the risk of developing any second benign

brain tumor, as well as risk of the two most common

subtypes: meningioma and acoustic neuroma. Second

benign brain tumors were defined as benign/borderline

tumors in the brain or CNS with ICD-O-3 topography

codes for meninges, brain, and spinal cord, cranial nerves,

and other parts of the CNS (C70, C71, and C72). Intra-

cranial meningiomas were tumors with ICDO-3 morphol-

ogy codes 9,530–9,539 and ICDO-3 topography codes for

cerebral and unspecified meninges (C70.0 and C70.9)

excluding the spinal meninges (C70.1). Second acoustic

neuromas were defined by ICD-O-3 morphology code

9,560 and ICDO-3 topography codes for acoustic nerve and

unspecified cranial nerves (C72.4 and C72.5). Over 98 %

of the data for the second cancers were microscopically

confirmed, indicating the high reliability of the SEER

database and the low likelihood that metastases would be

reported as new primary tumors.

Standardized incidence ratios (SIRs) were calculated for

all benign brain tumors, meningioma and acoustic neuroma

using the MP-SIR SEER*Stat Program [14]. Expected

numbers of new benign brain tumors were calculated based

on the accumulated PYR and on gender, age, race, and

calendar time-specific SEER incidence rates in the general

reference population for 2004–2008. SIRs were calculated

as the observed (O) divided by the expected (E) number of

second cancers. Exact two-sided 95 % confidence intervals

(CIs) were calculated based on the assumption that the

observed number of subsequent tumors followed a Poisson

random distribution. Tests of heterogeneity (pHet) were

conducted as described by Breslow [15].

In addition to overall SIRs, we also calculated SIRs

stratified by time since and age at first primary diagnosis,

gender, and race. In order to evaluate the effects of treat-

ment with cranial irradiation on the risk of second benign

brain tumors, we stratified risk for first primary sites (oral

cavity and pharynx, eye and orbit, brain, other CNS, and

ALL) that were likely to receive cranial radiotherapy based

on standard treatment practices by reported initial radio-

therapy use and latency (time since first cancer diagnosis)

660 Cancer Causes Control (2014) 25:659–668

123

[16]. Of note, SEER Program does not specify location of

radiation given as first course of cancer-directed therapy

(total brain irradiation for hematopoietic stem cell trans-

plantation is not distinguished separately). The SEER

Program separately captured prophylactic cranial irradia-

tion from 1988 to 1997 for patients with leukemia and lung

cancer only (included in first course of radiotherapy from

1998 onwards). Evaluation of the effects of initial radio-

therapy was restricted to patients who survived at least

5 years, under the typical assumption of a minimum 5-year

latent period for radiation-related solid cancers [17]. For

first primary tumors, which indicated a significant SIR with

second benign brain tumor and radiotherapy, we stratified

by histology where applicable.

Results

A total of 2,038,074 1-year minimum cancer survivors

were diagnosed with a first primary cancer between 1973

and 2007, at ages \85 years in the SEER data (Table 1).

The majority of patients were white (85 %) and between

the ages of 65–84 (46 %) at first cancer diagnosis. Patients

had a mean age at diagnosis of 61.8 years and were

followed up for an average of 8.0 years. Approximately

32 % of 1-year minimum cancer survivors were treated

with radiotherapy.

Table 2 describes the risk of developing a second benign

brain tumor compared to expected risk in the general

population according to various risk factors for all benign

brain tumors (n = 1,025), meningioma (n = 745), and

acoustic neuroma (n = 114). Risk of developing any sec-

ond benign brain tumor was higher for cancer survivors

compared to the expected rates in the general population

(SIR = 1.13). Risks were higher in males than in females

for all benign brain tumors (SIR = 1.25 vs. 1.06) and for

second meningiomas (SIR = 1.29 vs. 1.07) (pHet = 0.01).

SIRs for all second benign brain tumors appeared to differ

by race with higher increases in risk seen for blacks and

other races (pHet = 0.02). Young age at initial diagnosis

(age \25 years) was associated with markedly increased

risks for all benign tumors combined (SIR = 7.57) and

meningioma (SIR = 13.17) compared to diagnosis at older

ages (pHet \ 0.001). Reported initial radiotherapy was

associated with a higher risk of developing a second benign

brain tumor (SIR RT = 1.21, SIR noRT = 1.09), and this

difference was statistically significant for second menin-

gioma (SIRRT = 1.36, SIRnoRT = 1.05, p \ 0.001). In

contrast, there was no overall evidence of a risk associated

with reported radiation for acoustic neuroma in these data

but statistical power was limited.

Observed SIRs for all second benign brain tumors

combined by first primary sites were in general very similar

to those for meningioma. Table 3 therefore presents

detailed results for the risk of second meningioma alone by

time since first primary cancer diagnosis and by type of

first primary site. Statistically significant increases in risk

of second meningioma compared to expected rates in the

general population were observed following first cancers of

the brain (SIR = 19.82; 95 % CI 13.88–27.44), other CNS

(SIR = 9.54; 95 % CI 3.10–22.27), thyroid (SIR = 2.05;

95 % CI 1.47–2.79), prostate (SIR = 1.21; 95 % CI

1.02–1.43), and ALL (SIR = 42.4; 95 % CI 23.18–71.13).

SIRs were also increased (but nonsignificantly) following a

number of other first sites, including cancers of the salivary

gland, nasopharynx, esophagus, stomach, liver, gallblad-

der, eye, and acute non-lymphocytic leukemia. Where

increased risk of developing a second meningioma was

observed, this risk generally increased with time since

initial cancer diagnosis. Increased risk of developing a

second meningioma compared to the general population

was first observed in the period ten or more years following

initial diagnosis with ALL (SIR = 66.75; 95 % CI

36.49–112.00). A modest increased SIR of meningioma

after prostate cancer was observed overall, but risks were

statistically significant only after a 10-year latency period.

Risk of developing a second meningioma following first

Table 1 Selected characteristics of 1-year cancer survivors

Characteristic No. of patients (%)

# 1-year survivors 2,038,074 –

Average age 61.8 years –

Average follow-up 8.0 years –

Sex

Male 1,024,578 50.3

Female 1,013,496 49.7

Race

White 1,734,508 85.1

Black 172,546 8.5

Other 131,020 6.4

Age at primary diagnosis

\25 years 52,425 2.6

25–44 years 241,310 11.9

45–64 years 810,161 39.7

65–84 years 934,178 45.8

Calendar year of diagnosis

1973–84 493,194 24.2

1985–94 595,578 29.2

1995–03 642,175 31.5

2004–2008 307,127 15.1

Radiotherapy treatment

Yes RT 664,033 68.3

No RT 1,391,227 31.6

Unknown RT 2,822 0.1

Cancer Causes Control (2014) 25:659–668 661

123

cancers of the uterine corpus (SIR = 0.63; 95 % CI

0.42–0.91) and colon (SIR = 0.56; 95 % CI 0.37–0.82)

was significantly lower than expected rates based on the

general population. Observed SIRs for all second benign

brain tumors combined were very similar to those for

meningioma, with the exception of increased SIRs for all

benign brain tumors following cancers of the nasopharynx

(SIR = 3.87; 95 % CI 1.05–9.91) and kidney (SIR = 1.72;

95 % CI 1.17–2.43).

We further examined the patterns of the SIRs for second

meningioma according to the age at first cancer diagnosis,

gender, and race (Table 4). Excess risk of developing a second

meningioma compared to the general population following

cancers of the brain (SIR = 114.06; 95 % CI 74.51–167.13),

other CNS tumors (SIR = 73.86; 95 % CI 8.95–266.82), and

ALL (SIR = 90.16; 95 % CI 48.01–154.18) was greatest in

patients diagnosed with a primary tumor at age 25 years or

younger. The highest risk of meningioma occurred after

prostate cancers diagnosed in the youngest age group for this

cancer site of 45–64 years (SIR = 1.46; 95 % CI 1.12–1.88).

Analyses stratified by gender indicated higher risks of devel-

oping second meningioma compared to general population

expected rates among male patients as compared to female

patients following primary cancers of the brain, other CNS,

ALL, and thyroid, although the differences were only statis-

tically significant after a first other CNS cancer (pHet = 0.01).

In general, risk of second meningioma was more increased

among black patients, particularly following primary malig-

nant cancers of the brain (pHet = 0.001). SIR deficits were

observed for second meningioma following primary cancers

of the uterine corpus and colon regardless of age, race, or

gender.

In order to assess the effects of cranial irradiation on risk

of second benign brain tumors, we further examined pri-

mary sites that were likely to receive cranial radiotherapy

(oral cavity and pharynx, eye and orbit, brain, other CNS,

and ALL), stratified by reported use of radiotherapy

(Table 5). Increased risk of developing a second menin-

gioma compared to the general population was increased

for all of these sites. A higher magnitude of excess risk for

individuals reporting use of radiotherapy was generally

observed for each of the included primary sites, but this

difference was only statistically significant for meningioma

after first primary cancers of the brain (SIRRT = 41.81;

95 % CI 28.21–59.69, SIRnoRT = 3.57; 95 % CI

0.43–12.90, pHet \ 0.001) and ALL (SIRRT = 93.18; 95 %

Table 2 Risk of developing second benign brain tumors during 2004–2008 among 2,038,074 SEER 1-year cancer survivors

Characteristics All benign brain Meningioma Acoustic neuroma

No. of patients % SIR pHet No. of patients % SIR pHet No. of patients % SIR pHet

All patients 1,025 100 1.13* 745 72.7 1.14* 114 11.1 1.05

Gender

Male 412 40.2 1.25* 0.01 279 37.4 1.29* 0.01 59 51.8 1.07 0.85

Female 613 59.8 1.06 466 62.6 1.07 55 48.2 1.03

Race

White 861 84 1.10* 0.02 618 83 1.13* 0.03 96 84.2 0.97 \0.001

Black 88 8.6 1.24 74 9.9 1.23 3 2.6 0.99

Other 76 7.4 1.44* 53 7.1 1.36* 15 13.2 2.36*

Latency

12–35 mo 169 13.7 1.11 \0.001 120 13.3 1.13 \0.001 21 16 1.03 0.51

36–59 mo 134 10.9 1.03 93 10.3 1.01 14 10.7 0.82

60–119 mo 298 24.1 1.17* 208 23 1.14 37 28.2 1.18

120? mo 424 34.4 1.15* 324 35.8 1.20* 42 32.1 1.06

Age at primary diagnosis

\25 years 62 6 7.57* \0.001 49 6.6 13.17* \0.001 2 1.8 1.26 0.37

25–44 years 129 12.6 1.23* 71 9.5 1.07 25 21.9 1.39

45–64 years 482 47 1.09 351 47.1 1.13* 57 50 0.94

65–84 years 352 34.3 1 274 36.8 1.02 30 26.3 1.05

Radiotherapy

Yes 356 34.7 1.21* 0.12 287 38.5 1.36* \0.001 28 24.6 0.81 0.09

No 669 65.3 1.09* 458 61.5 1.05 86 75.4 1.17

pHet = p value for heterogeneity

* Statistically significant (p \ 0.05)

662 Cancer Causes Control (2014) 25:659–668

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Table 3 Standardized incidence ratios for second meningiomas by primary site and time since first cancer diagnosis

12–35 Months 36–59 Months 60–119 Months 120? Months Total

Observed SIR Observed SIR Observed SIR Observed SIR Observed SIR 95 % CI

120 1.13 93 1.01 208 1.14 324 1.20* 745 1.14* 1.06–1.23

Salivary gland 1 3.88 0 N/A 0 N/A 2 2.01 3 1.58 0.33–4.61

Nasopharynx 1 9.95 0 N/A 0 N/A 1 3.15 2 3.01 0.36–10.88

Esophagus 1 2.39 0 N/A 1 3.08 1 4.35 3 2.46 0.51–7.18

Stomach 2 2.22 1 1.68 3 3.19 0 N/A 6 1.63 0.6–3.55

Small intestine 0 N/A 0 0 1 2.03 1 1.84 2 1.12 0.14–4.05

Colon 5 0.59 2 0.29 12 0.94 7 0.39* 26 0.56* 0.37–0.82

Rectum and

rectosigmoid

3 0.92 6 2.14 4 0.72 5 0.62 18 0.92 0.54–1.45

Liver 2 4.84 0 N/A 1 5.4 0 N/A 3 3.37 0.7–9.86

Gallbladder 0 N/A 1 15.32 0 N/A 0 N/A 1 2.25 0.06–12.52

Nose, nasal cavity and

middle ear

0 N/A 0 N/A 0 N/A 0 N/A 0 N/A 0–5.07

Lung and bronchus 4 0.64 4 1.13 4 0.77 5 0.95 17 0.84 0.49–1.35

Bones and joints 0 N/A 0 N/A 1 4.67 0 N/A 1 1.04 0.03–5.8

Soft tissue including

heart

1 1.92 1 2.49 1 1.27 1 0.57 4 1.16 0.32–2.96

Melanoma of the skin 4 0.9 7 1.82 8 1 19 1.15 38 1.16 0.82–1.59

Female breast 37 1.37 22 0.86 52 0.93 85 0.96 196 1 0.86–1.14

Uterine cervix 1 1.21 0 N/A 2 0.93 13 1.44 16 1.25 0.72–2.04

Uterine corpus 6 1.12 2 0.41 10 0.93 10 0.43* 28 0.63* 0.42–0.91

Ovary 3 1.64 2 1.51 1 0.42 8 1.42 14 1.26 0.69–2.11

Prostate 21 1 21 1.03 53 1.27 47 1.38* 142 1.21* 1.02–1.43

Urinary bladder 1 0.22 4 1.05 10 1.39 14 1.29 29 1.1 0.73–1.57

Kidney 4 1.48 1 0.48 8 2.3 3 0.7 16 1.28 0.73–2.07

Eye and orbit 0 N/A 0 N/A 1 3.42 1 1.81 2 1.66 0.2–5.98

Brain 3 8.99* 1 5.01 3 7.72* 29 32.43* 36 19.82* 13.88–27.44

Other CNS 0 N/A 0 N/A 2 15.82* 3 11.65* 5 9.54* 3.1–22.27

Thyroid 3 1.23 5 2.39 10 2.44* 22 2.03* 40 2.05* 1.47–2.79

Hodgkin lymphoma 0 N/A 0 N/A 0 N/A 3 1.22 3 0.78 0.16–2.29

Non-hodgkin lymphoma 5 1.09 6 1.58 8 1.23 12 1.63 31 1.39 0.95–1.98

Myeloma 0 N/A 0 N/A 3 3.43 0 N/A 3 0.87 0.18–2.53

Acute lymphocytic

leukemia (ALL)

0 N/A 0 N/A 0 N/A 14 66.75* 14 42.40* 23.18–71.13

Chronic lymphocytic

leukemia (CLL)

3 2.1 3 2.62 4 2.27 1 0.59 11 1.82 0.91–3.26

Acute non-lymphocytic

leukemia (ANLL)

1 4.34 0 N/A 0 N/A 2 5.11 3 2.98 0.61–8.7

Acute myeloid leukemia

(AML)

1 4.75 0 N/A 0 N/A 0 N/A 1 1.1 0.03–6.13

Acute monocytic

leukemia

0 N/A 0 N/A 0 N/A 0 N/A 0 0 0–74.07

Chronic myeloid

leukemia (CML)

1 3.58 0 N/A 0 N/A 0 N/A 1 1.04 0.03–5.78

* Statistically significant (p \ 0.05)

Cancer Causes Control (2014) 25:659–668 663

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CI 44.68–171.35, SIRnoRT = 25.78; 95 % CI 7.02–66.01,

pHet = 0.02). Increased risks of second meningioma after

other central nervous system cancers, thyroid cancer, and

cancer of the oral cavity/pharynx were quite similar

regardless of reported radiotherapy.

Since primary cancers of the brain and CNS are a het-

erogeneous group characterized by distinct differences in

age of onset, invasiveness, and etiology, we stratified the

aforementioned sites at increased for cranial radiotherapy

in the brain and CNS by specific histology. When subdi-

vided by histology, increased risk of developing a second

meningioma compared to the general population was

observed after first primary diagnoses of malignant glioma,

astrocytoma NOS, gemistocytic astrocytoma, pilocytic

astrocytoma, oligodendroglioma, and medulloblastoma

(Online resource 1). Increased risk of meningioma was

greatest after a first diagnosis of medulloblastoma or pil-

ocytic astrocytoma, both of which are primarily childhood

tumors (SIR = 275.44; 95 % CI 142.32–481.14 and

SIR = 69.49; 95 % CI 8.42–251.03, respectively).

Few significant associations or clear patterns were

observed for development of second acoustic neuromas in

cancer survivors compared to the general population except

for increased risks of acoustic neuroma following cancer of

the nasopharynx (all latencies combined, n = 2), but

numbers were small (Online resource 2).

Discussion

This report represents, to our knowledge, the first large-

scale population-based analysis of the risk of second

Table 4 Selected standardized

incidence ratios for second

meningioma stratified by age at

primary diagnosis, gender, and

race

* Statistically significant

(p \ 0.05)

Primary sites

Brain Other CNS ALL Prostate

O SIR PHet O SIR PHet O SIR PHet O SIR PHet

Age at primary diagnosis

\25 years 26 114.06* \0.001 2 73.86* 0.01 13 90.16* 0.04 0 N/A 0.07

25–44 years 4 5.76* 2 14.65* 1 14.07 0 N/A

45–64 yr 5 7.35* 1 4.15 0 N/A 61 1.46*

65–84 yrs 1 4.69 0 N/A 0 N/A 81 1.07

Gender

Male 14 25.26* 0.27 4 27.39* 0.01 7 60.65* 0.29 142 1.21* N/A

Female 22 17.43* 1 2.65 7 32.59* 0 N/A

Race

White 26 16.01* 0.001 4 8.96* 0.46 12 43.10* 0.25 111 1.18 0.64

Black 5 47.24* 1 21.52 2 121.41* 24 1.36

Other 5 57.75* 0 N/A 0 N/A 7 1.24

Primary sites

Thyroid Colon Uterine corpus All primary sites

O SIR PHet O SIR PHet O SIR PHet O SIR PHet

Age at primary diagnosis

\25 years 0 N/A 0.33 0 N/A 0.94 0 N/A 0.71 49 13.17* \0.001

25–44 years 14 1.97* 1 0.55 2 0.68 71 1.07

45–64 years 17 1.90* 11 0.56* 16 0.59* 351 1.13*

65–84 years 9 3.25* 14 0.57* 10 0.72 274 1.02

Gender

Male 7 2.99* 0.29 6 0.40* 0.31 0 N/A N/A 279 1.29* 0.01

Female 33 1.92* 20 0.64* 28 0.63* 466 1.07

Race

White 35 2.15* 0.35 19 0.51* 0.32 26 0.66* 0.67 618 1.13* 0.03

Black 3 2.4 4 0.74 2 0.91 74 1.23

Other 2 1 3 0.85 0 N/A 53 1.36*

664 Cancer Causes Control (2014) 25:659–668

123

benign brain tumors in the United States. Meningiomas

comprised the majority of subsequent benign brain tumors

and thus drove the observed associations. We noted sig-

nificant excess risk of second meningioma compared to

expected risk in the general population after primary can-

cers of the brain, other CNS, prostate, and ALL. Excess

risks for these sites were generally higher in individuals

diagnosed with a primary cancer at younger ages, in males,

and in blacks. We also observed associations between

second meningiomas and primary tumors of the breast,

thyroid, and significant deficits of benign brain cancers

after initial cancers of the uterine corpus and colon.

Previous studies have examined risk of second malig-

nant (as opposed to benign) brain tumors among cancer

survivors. A SEER-based analysis of subsequent new

malignant tumors of the brain and CNS observed an

increased risk of subsequent brain cancer compared to the

general population following first tumors of the brain,

other CNS, ALL, thyroid, and testis [3]. These results are

remarkably similar to the findings we observe for second

benign tumors, although the magnitude of risk was much

higher in our results for risk of second meningioma. The

higher excess risk we observe for meningioma following

these sites is consistent with prior studies, which have

reported higher risks for meningioma than for glioma (the

most common subtype for malignant brain tumors) fol-

lowing exposure to radiation [18–20]. This is expected

since malignant and benign brain tumors are considered to

be distinct in etiology. As with our results for second

meningioma, higher SIRs for second malignant brain

tumors were seen with earlier age at first diagnosis. Other

studies have separately linked second brain cancers to first

cancers of the brain, CNS, and ALL in childhood cancer

survivors and have observed greater risks after longer

latency periods [21–23]. The increased risk we detected

among patients\25 years of age at primary diagnosis and

with a long latency period is likely driven by the increased

risks observed in ALL and childhood brain tumors.

Genetic factors may also play an important role in the

development of multiple malignancies. The increased rates

of second cancers observed in younger patients may sug-

gest a genetic susceptibility to developing cancer. How-

ever, it is important to note that latency may be a

confounding factor in our data since we only analyzed

second benign brain tumors diagnosed between 2004 and

2007.

Late effects of radiotherapy exposure may contribute to

the aforementioned associations observed between primary

cancers and second meningiomas. Increased SIRs for

meningioma compared to the general population were

observed following all sites with potential exposure to

cranial radiotherapy, and the magnitude of excess risk was

generally higher in those with reported radiotherapyTa

ble

5R

isk

of

men

ing

iom

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llo

win

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ania

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60

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20?

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nth

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ota

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serv

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har

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–5

.09

31

.56

0.3

2–

4.5

55

1.4

90

.49

–3

.49

0.4

5

No

RT

00

.00

N/A

41

.32

0.3

6–

3.3

74

0.9

00

.25

–2

.31

Ey

ean

do

rbit

Yes

RT

17

.48

0.1

9–

41

.68

17

.40

0.1

9–

41

.22

27

.44

0.9

0–

26

.87

No

RT

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N/A

N/A

0N

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/A

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esR

T1

4.8

00

.12

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6.7

62

95

6.9

5*

34

.18

–8

1.7

83

04

1.8

1*

28

.21

–5

9.6

9\

0.0

01

No

RT

21

1.1

3*

1.3

5–

40

.19

0N

/AN

/A2

3.5

70

.43

–1

2.9

0

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ssy

stem

Yes

RT

12

3.1

00

.58

–1

28

.71

10

.32

0.2

6–

57

.47

21

4.2

6*

1.7

3–

51

.52

0.8

8

No

RT

11

2.1

40

.31

–6

7.6

22

12

.46

*1

.51

–4

53

12

.35

*2

.55

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6.0

9

Acu

tely

mp

ho

cyti

cle

uk

emia

(AL

L)

Yes

RT

0N

/AN

/A1

01

08

.13

*5

1.8

5–

19

8.8

61

09

3.1

8*

44

.68

–1

71

.35

0.0

2

No

RT

0N

/AN

/A4

34

.18

*9

.31

–8

7.5

14

25

.78

*7

.02

–6

6.0

1

PH

et

was

calc

ula

ted

for

the

tota

lla

ten

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erio

d

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tati

stic

ally

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nifi

can

t(p

\0

.05

)

Cancer Causes Control (2014) 25:659–668 665

123

exposure compared to those without reported radiotherapy

(although the difference was only statistically significant

following primary diagnoses of the brain and ALL). 94 %

of primary brain, 40 % of primary other CNS, and 71 % of

primary ALL cases were reported to have received radio-

therapy treatment; however, reporting of prophylactic RT

for ALL is known to be incomplete in SEER before 1988.

These cases had a significantly increased risk of developing

a subsequent meningioma in our data. Our observed

increased risk of second meningioma following exposure to

radiotherapy is consistent with previous studies that have

noted increased risk of meningioma in children therapeu-

tically irradiated for treatment of tinea capitis [9, 19] and in

childhood cancer survivors treated with radiotherapy [9,

18, 20]. In a cohort study of 10,834 Israeli patients irra-

diated for tinea capitis from 1948 to 1960, the relative risk

and excess relative risk per gray (ERR/Gy) of developing

meningiomas were 9.5 (95 % CI 3.5–25.7) and 4.63,

respectively. Studies of childhood cancer survivors in

Britain and the US have reported a strong linear relation-

ship between radiation dose and risk of subsequent

meningioma and radiation dose, with ERRs/Gy of 1.06 and

2.2, respectively [18, 20]. Although none of the three

studies detected an effect of age at exposure on risk of

meningioma following exposure to radiation, these studies

were conducted on childhood cancer survivors and may

have missed an age at exposure effect over a wider interval

of age.

Sporadic and radiation-induced meningiomas are dis-

tinct entities. Genes implicated in sporadic meningiomas

include NF2, TP53, and PTEN, while radiation-induced

meningiomas are characterized by genetic losses of parts of

chromosome 22q [24]. It has been proposed that radiation-

associated tumors may occur later than their sporadic

counterparts. In our data, we observed a significantly

increased risk of second meningiomas following radio-

therapy treatment 12–35 months (SIR = 1.44; 95 % CI

1.08–1.87) and 120? months (SIR = 1.75; 95 % CI

1.45–2.08) after primary cancer diagnosis. Increased risk of

second meningioma was observed in non-irradiated

patients 60–119 months (SIR = 1.21; 95 % CI 1.01–1.42)

after primary cancer diagnosis. Given that the increased

risk of second meningioma detected in irradiated patients

12–35 months after primary cancer diagnosis may be

attributable to surveillance bias, these data are difficult to

interpret with respect to genetic disposition.

Our large population-based sample of second meningi-

omas allowed us, unlike previous studies, to examine the

risk of developing second meningiomas by specific his-

tology of first primary brain tumor. Excess risk of second

meningioma compared to the general population was

highest after first primary medulloblastoma and pilocytic

astrocytoma. This is consistent with particularly high

excess risks of malignant brain/CNS tumors compared to

the general population after medulloblastoma (SIR = 18.9)

[3], and high risks of second malignant tumors of any type

observed after a first diagnosis medulloblastoma and

astrocytoma or pilocytic astrocytoma in two other studies

[3, 22, 25]. Both cancers mainly occur during childhood

with the mean age at exposure being 14.1 and 18.8 years,

respectively. Possible explanations for the particularly high

observed increased risk of second neoplasms following

these particular tumors could be young age of radiotherapy

exposure, or an intrinsic quality of the tumor itself.

Unlike primary diagnoses of meningioma, which is

approximately twice as common in women compared with

men [4], the excess risk of developing second meningioma

compared to the general population was higher among

male cancer survivors than female cancer survivors, sug-

gesting that the sex difference in second meningioma rates

is lower than in primary meningioma rates. A possible

explanation for this difference is that a larger fraction of

second meningioma cases in cancer survivors could be

attributable to radiotherapy exposure, compared to

meningiomas in the general population which may be

attributable to a number of different factors, including

hormonal influences [26].

Our finding of an association between thyroid cancer

and meningioma has been reported in several studies,

including a recent large case–control study of meningioma

by Claus et al. [26–29]. While the mechanism underlying

this association is not clear, one possible explanation is that

the two cancers may be linked by common hormonal risk

factors.

Several previous studies report an association between

meningioma and female breast carcinoma, while other

studies found either no or only weak associations [26, 30,

31]. The cumulative observed rate of meningioma in

female breast patients was 58 times the expected rate in a

recent study conducted by Rao et al. [31]. In our analysis of

1-year minimum cancer survivors, breast cancer survivors

did not have higher rates of meningioma than the general

population beyond the first 12 months after primary diag-

nosis. This indicates a possible screening bias underlying

the association, at least within our data.

We observed significant deficits of second meningiomas

after first cancers of the colon and uterine corpus. The

deficits occurred in a small number of white males and

females at later latencies. The etiology behind these asso-

ciations is unclear, and these findings need to be replicated

in other studies.

Few primary sites were associated with an increased risk

of developing a second acoustic neuroma compared to

expected population risk. Previous studies have observed

increased sensitivity to radiotherapy for acoustic neuroma

compared with other benign brain tumors [9, 32]. In a study

666 Cancer Causes Control (2014) 25:659–668

123

of 93,000 atomic bomb survivors, Preston et al. reported

ERR per Sievert of 4.5 (95 % CI 1.9–9.2) for acoustic

neuromas and 0.64 (95 % CI -0.01 to 1.8) for meningio-

mas [32]. It is possible that with our smaller numbers of

acoustic neuroma, we had insufficient statistical power

with which to detect underlying associations with radio-

therapy for this tumor.

Limitations of our study include the lack of detailed

information regarding dose or location of radiation, che-

motherapeutic agents, genetic conditions, or environmental

factors that could be related to the development of second

benign brain tumors. Although this is one of the largest

studies to date of second benign brain tumors, these tumors

were only comprehensively collected starting in 2004,

resulting in a relatively small number of cases to date. The

incidence rates of all benign brain and CNS tumors in the

general population between the years of 2005–2008 were

stable, thus making increased capture over calendar time

unlikely [6]. However, the recent reporting date of second

benign brain tumors adds a latency bias. Long-term sur-

vivors were primarily diagnosed in the earlier calendar

years, and the increased risk observed in the first 5 years

since primary diagnosis is only from the most recent dec-

ade. Further, this study may have overestimated the rates of

second benign brain tumors compared to the rates in the

general population. Given that most benign brain tumors

are asymptomatic, more second benign brain tumors may

have been detected in this study due to increased surveil-

lance after the patient’s primary malignancy or CNS irra-

diation. Cancer survivors are also more likely to undergo

imaging in the setting of vague symptoms when compared

to the general population. Although some misclassification

of race may have occurred in our data given that self-

reported race can incorrectly describe or simplify a

patient’s complex genetic background [33], this is unlikely

to account for all of the risk differences between races in

our data given the strong correlation between self-reported

race/ethnicity and genetic cluster categories [34–36].

Additionally, reported race takes social factors into account

that may be influencing the patient’s health outcomes.

Despite these limitations, our study has the strength of a

large-scale, population-based design. Despite the rarity of

benign brain tumors, use of the nationwide SEER registry

allowed us to assess an extensive number of cases repre-

sentative of the United States. Additionally, we were able

to extend previous literature on second benign brain tumors

in childhood cancer survivors to include adults. Future

studies will be needed to reassess possible associations and

risk factors for second benign brain tumors once more data

are collected.

Conflict of interest The authors declare that they have no conflict

of interest.

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