Download The Burden of Radiation-Induced Central Nervous System Tumors

J Neuropathol Exp Neurol
Copyright Ó 2006 by the American Association of Neuropathologists, Inc.
Vol. 65, No. 3
March 2006
pp. 204Y216
REVIEW ARTICLE
The Burden of Radiation-Induced Central Nervous System
Tumors: A Single Institution’s Experience
B. K. Kleinschmidt-DeMasters, MD, Jennifer S. Kang, MD, and Kevin O. Lillehei, MD
Abstract
Radiation-induced tumors of the central and peripheral nervous
systems are becoming a noticeable subset of tumors seen at referral
institutions. This paper outlines a single institution’s experience with
22 examples of secondary meningiomas, gliomas, and sarcomas that
developed in adults. These tumors are being increasingly encountered by physicians, but the greatest burden is on the patients
themselves, who not only experience the life-altering effects of the
original tumor and the subsequent delayed cognitive effects of
radiotherapy, but later develop a second intracranial neoplasm. We
detail a particularly poignant example of a 34-year-old man who
developed a high-grade sarcoma with rhabdomyosarcomatous and
osteogenic elements. Local control was difficult over the next year,
and he eventually developed cerebrospinal fluid dissemination and
succumbed. Although radiation-induced neoplasm remain relatively
infrequent numerically, each case reminds us of the need for new,
less toxic, and more targeted therapies for brain neoplasms.
Key Words: Radiation-induced glioblastoma, Radiation-induced
glioma, Radiation-induced meningioma, Radiation-induced sarcoma, Rhabdomyosarcoma.
INTRODUCTION
Radium, when discovered by Marie and Pierre Curie at
the turn of the last century, showed such promise for
alleviating human suffering from disease. The world
applauded the discovery of radium and polonium, awarding
the Curies half the 1903 Nobel Prize for Physics (shared
with Henri Becquerel who discovered radioactivity in 1896)
and Madame Curie (after her husband’s death) the 1911
Nobel Prize for Chemistry for the characterization of radium
(1). Radiation therapy was soon embraced by physicians as a
treatment for tuberculosis and a variety of benign and
From the Departments of Neurosurgery (BKK-D, JSK, KOL),
Neurology (BKK-D), and Pathology (BKK-D), University of
Colorado Health Sciences Center, Denver, Colorado.
Send correspondence and reprint requests to: B. K. KleinschmidtDeMasters, MD, Department of Pathology, Box B216, University of
Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver,
CO 80262; E-mail: [email protected]
204
malignant conditions. Almost immediately, however, animal
experiments in 1910 and 1929 established the link between
irradiation and sarcoma development, and case reports of
sarcoma induction in humans began appearing by 1922 (2).
Another early indication of the potential deleterious effects
of radiation exposure was the deaths of both Curies as a
result of its side effects, with Madame Curie dying of
leukemia in 1934.
It took until 1948, however, for Cahan et al to formally
establish criteria for tumors deemed to be Bradiationinduced^ (2). Since he originally outlined his findings for
sarcomas arising in patients radiated for benign bone lesions,
his criteria have since been modified slightly (3, 4). First, the
new tumor has to arise within the field of irradiation.
Second, there has to be a histologically proven difference
between the initial and the second tumor. Third, a sufficient
latency period must exist between the irradiation and the
development of the second tumor, usually cited as greater
than 5 years (2, 4). Recently suggested criteria have included
the need for a significantly higher incidence of a tumor type
in an irradiated cohort than in an adequate control group (3);
Badditional support is found if an animal model exists and a
doseYresponse relationship exists^ (3).
In the intervening 50 years, the central and peripheral
nervous systems (CNS, PNS) have become well-recognized
sites for a significant percentage of radiation-induced
tumors. Nevertheless, until recently, the number of cases of
radiation-induced CNS/PNS tumors that any one institution
encountered was generally low (3).
In 2004, we saw an unprecedented number of patients
at our adult referral hospital with radiation-induced brain
tumors, prompting this review. In that year, seven patients
were seen for radiation-induced meningiomas, five of whom
underwent resection; these represented 13% of the meningiomas operated on that year at our institution. A search of
our Pathology and Neurosurgery Department files from
1991Y2005 disclosed 22 patients with radiation-induced
CNS tumors, including 15 meningiomas, four high-grade
gliomas, and three sarcomas. Three of the gliomas and 2 of
the sarcomas were also seen recently (Table 1). Although
these numbers are obviously influenced by referral patterns,
the number of cases we have encountered in the last 5 years
has certainly gotten our attention.
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Year First
Seen at
UCHSC/
Year of
Surgery(s)
Age of
Initial
Radiation
Exposure,
Gender
Time
Interval
to
Diagnosis
of RIN
Radiation-Induced Meningiomas
1992/1992,
Child, M
~30Y35
1992, 2002
years
Current
Age,
Karnofsky
Score (KS)
Previously Treated
Condition
Location and Type
of Initial
Radiation
Exposure
54 years,
KS 60
Left otitis media
XRT to left ear
Hard/soft
palate, maxillary sinus, L
middle fossa,
orbit
WHO grade I,
meningothelial*
WHO grade I,
meningothelial*
WHO grade I
meningothelial
44 X,-Y, -22
(17) WHO II,
atypical
WHO grade I,
with focal myxoid change
(small biopsy)
Size and Location
of RIN at
Diagnosis
Pathologic
Findings (each
resection listed
separately)
41 years, M
11 years
53 years,
KS
60Y70
Craniopharyngioma
(slides reviewed)
XRT to
suprasellar space
L frontal L
parietal
4 x 2.5 cm
1999/1999
2 weeks, F
39 years
45 years,
KS 100
Scalp hemangioma
over torcular region
XRT scalp
hemangioma
Torcular region
2001/2000,
2001, 2003
12 years, F
45 years
KS 0 Died
Recurrent R optic
nerve glioma (first
resected at age 3,
no XRT)
XRT to right
orbit
Right frontal
lobe
WHO grade II,
atypical WHO
grade III, anaplastic WHO
grade III, anaplastic
2003/2004
8 years, M
41 years
49 years,
KS
70Y80
Large facial
hemangioma
XRT to face
Dural-based,
bifrontal, invading ethmoids
WHO grade I,
transitional
(small biopsy)
1998/2004
multiple
meningiomas
3 years, F
31 years
40 years,
KS 50
WHO II cerebellar
astrocytoma (slides not
obtainable)
XRT to
cerebellum
Left occipital
parasagittal
WHO grade I,
transitional*
2004/1997,
2004
Child, M
~20Y25
years
35 years,
KS
60Y70
Left temporal
ganglioglioma
XRT to left
temporal lobe
L frontal
parasagittal
First meningioma in
same site (1997)
unavailable for
review WHO
grade I, meningothelial complex karyotype,
including abnormalities of 1p
Tumor resections 3, XRT, and
temozolomide; recurrent L
temporal lesions, abscess,
focal seizures; cognitive
delay, cranial neuropathies,
gait disturbance
As of 8/04, improving aphasia
Tumor resection 1999, SRS;
posttherapy venous hypertension treated with steroids and
acetazolamide; good recovery, now works full-time; no
residual
Tumor resections in 2000 and
2001, the last followed by
SRS to two residual nodules,
XRT total 6000 cGy in 30
fractions with concomitant
hydroxyurea; another recurrence in 2002 treated again
with SRS; continued tumor
growth, additional resection,
and death in 2003
Multiple social and psychiatric
problems, including mental
health admissions; persistent
headache, chronic narcotic use
Multiple meningiomas
followed since 1998, one
resected in 2004 residual
mental disability, ataxia, retinal necrosis, poor healing of
scalp wound
Works part-time as a cashier,
back to his preoperative
baseline, which includes
decreased cognitive function
and short-term memory; he
lives alone, but is assisted by
his parents for major tasks
Radiation-Induced CNS Tumors
205
1999/2000,
2004 multiple meningiomas
Interval Follow Up
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TABLE 1. Twenty-Two Radiation-Induced Neoplasms Seen at UCHSC
Year First
Seen at
UCHSC/
Year of
Surgery(s)
Age of
Initial
Radiation
Exposure,
Gender
2003/1999,
2004 multiple meningiomas
10 years, F
2002/2002,
2003
2002/1996,
2002, 2003
meningioma +
glioma
Time
Interval
to
Diagnosis
of RIN
Pathologic
Pathologic
Location and Type
Size and Location
Findings (each
Findingsresection
(each listed
Size and Location
of Initial
of RIN at
resection listed
of RINDiagnosis
at
Radiation
separately)
Interval Follow Up
separately)
Interval Follow Up
Diagnosis
Exposure
Current
Age,
Karnofsky
Score (KS)
Previously Treated
Condition
23 years
39 years,
KS 70
Acute lymphocytic
leukemia (ALL)
XRT to skull
base
Right orbit
First meningioma
in same site
(1999) unavailable for review
WHO grade I,
meningothelial*
20 mo, F
24 years
26 years,
unknown
ALL
Whole brain
radiation therapy, 18 Gy XRT
in 10 fractions
Midline falx
and bilateral
frontal lobes
WHO grade III,
anaplastic meningioma WHO
grade III, anaplastic meningioma
3 years, M
12 years
and 18
years
24 years,
KS 70
WHO grade II
posterior fossa ependymoma (slides reviewed)
Cranio spinal
XRT
At age 15, left
frontal lobe, at
age 21, two
lesions in left
cerebellum
Age 15, Btypical^
meningioma (not
reviewed) Age
21,WHO IV
glioma
2 years, F
35 years
37 years,
KS 70
Posterior fossa tumor
(original slides and
report not obtainable)
XRT to
posterior fossa
R temporalY
parietal lobe, 9
cm in greatest
diameter
WHO grade I,
transitional*
Deletion 1p36 by
FISH
2004
8 years, F
55 years
63 years,
KS 90
Scalp ringworm
XRT to scalp
No tissue available
(not biopsied)
1991/1993
Multiple
meningiomas
5 years, F
63 years
Unknown
Right cerebellar
tumor
XRT to skin
and cerebellum,
calculated to be
3240 cGy and
4000 cGy,
respectively
3 lesions: L
sphenoid,
2 cm, L cavernous sinus, 4.5
cm, and L clivus,
2 cm
3 lesions: large,
L occipital
region tentorium, along R
tentorial edge, 1
cm, and R falx,
2 cm
WHO grade II,
atypical Translocations 1q21,
3q21, 7q, 12q22
-24, 16p11,
absence of
monosomy 22
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2005/2005
Multiple
meningiomas
Residual right proptosis and V1
hypersensitivity; stable residual right skull base and cavernous sinus mass, with two
new enhancing dural nodules
being followed radiographically
Lost to follow up; as of 9/04, s/p
resection 2 and XRT, 5040
cGy in 28 doses, to growing
parafalcine lesion; refused
adjuvant chemotherapy; neurologically stable but cognitively delayed
L frontal mass resected
in 1996; cerebellar lesions
incidentally found on MRI,
resected in 2002 and 2003;
Gliadel wafers placed at second resection, followed by
XRT and concurrent BCNU;
currently on Iressa with episodic bouts of diarrhea;
attends college part-time, no
neurologic deficits
Multiple meningiomas
along tentorium increasing in
size; mentally disabled but
without focal neurologic deficits; unemployed and living
with parents; she suffers from
mild headaches
History of Bmigraine^
headaches for 45 years; otherwise neurologically intact;
three meningiomas were incidentally found after an auto
accident in which she was
driving
Lost to follow up; as of
1995, she suffered from gait
difficulties and imbalance;
she had an uneventful postoperative course; at 4 months
after resection of the large left
tentorial lesion, there was no
growth of the remaining
lesions
Kleinschmidt-DeMasters et al
206
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Table 1. (continued)
33 years
55 years,
KS 90
2005/2005
17, F
34 years
49 years,
KS 80
Radiation-Induced Gliomas
2002/1996,
3 years, M
2002, 2003
meningioma +
glioma
12 years
and 18
years
2002/2002
22 years, M
1993/1993
2004/2004
207
XRT to right
neck
R foramen
magnum to C1,
intradural
No tissue available
(not biopsied)
ALL
Craniospinal
XRT
7 cm right
sphenoid wing
WHO I,
meningothelial*
Deletion 1p36 by
FISH
24 years,
KS 70
WHO grade II
posterior fossa ependymoma (slides
reviewed)
Cranio spinal
XRT
At age 15, left
frontal lobe, at
age 21, 2
lesions in left
cerebellum
1996, age 15,
Btypical^ meningioma;
2002, 2003
age 21,
WHO IV glioma
No EGFR amp;
3Y10 copies of
Ch. 7
5 years
KS 0
Died
(tumor at
age
27
years)
ALL
Craniospinal
XRT, thought
to be on the
order of 18Y24
Gy, but records
are not
available
3-cm right
cerebellar
enhancing
lesion with
smaller satellite lesions in
the right pons
and cerebellum
WHO IV,
glioblastoma
27 years, M
60 years
Pilocytic astrocytoma
XRT to
cerebellum
Cerebellum
WHO IV
glioblastoma
MIB-1: 14.7%.
TP 53: G5%. No
EGFR amp; no
gain of Ch. 7
54 years, M
20 years
KS 0
Died
(tumor at
age
87
years)
KS 0
Died
(tumor at
age
74
years)
XRT to neck
Enhancing,
6-cm-long
mass in the
spinal cord
from C3 to C7
WHO III,
anaplastic astrocytoma
Underwent XRT to cervical
spine with concomitant temozolomide; as of 4/05, there
was no residual tumor on
MRI; he died in 5/05 in home
hospice
Radiation-Induced Sarcomas
2001/2001,
23 years, M
2001, 2002
11 years
XRT to left
parietooccipital
lesion
Solid L
parietooccipital
region mass
Grade IV sarcoma,
fibrosarcoma
with osteogenic
Resection of sarcoma in 2/01,
wound infection and abscess
7/01; no follow-up tumor
KS 0
Died
(tum-
Non-Hodgkin
lymphoma
BThroat cancer,^ path
unavailable
Diagnosed as
glioblastoma in 1990
(on review found to be
Stable radiographic
appearance of shape and size
of mass; no focal neurologic
deficits; intermittent R arm
pain
Loss of vision in right
eye; residual tumor in resection cavity, possible SRS in
future
L frontal mass resected
in 1996; cerebellar lesions
incidentally found on MRI,
resected in 2002 and 2003;
Gliadel wafers placed at second resection, followed by
XRT and concurrent BCNU;
currently on Iressa with episodic bouts of diarrhea;
attends college part-time, no
neurologic deficits
Underwent tumor
debulking in 2002 complicated by postoperative cerebrospinal fluid leak; the
residual was treated with
temozolomide 14/28 days and
XRT 50.4 Gy in 28 fractions;
subsequently received SRS
boost to the brainstem lesion
and BCNU; he suffered mild
imbalance and coordination
problems with a gradual
decline until death in 10/03
Experienced a rapid decline in
clinical status and died in 12/
93, 2 months after presenting
to our hospital
Radiation-Induced CNS Tumors
21, F
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2004
Year First
Seen at
UCHSC/
Year of
Surgery(s)
Current
Age of Initial
Age,
Time Interval Karnofsky
Radiation
to Diagnosis Score
Exposure,
of RIN
Gender
(KS)
or at
age
34
years)
22 years, F
15 years
KS 0
Died
(tumor at
age
37
years)
2001/2001
26 years, F
19 years
KS 0
Died
(tumor at
age
45
years)
pleomorphic xanthoastrocytoma with
anaplastic features)
Diagnosed as
malignant astrocytoma
with focal oligodendroglioma, 1976 (on
review, thought to be
ganglioglioma with
anaplastic oligodendroglial or neurocytic
component)
Diagnosed as
oligodendroglioma,
1983 (slides unavailable for review, but
residual, low-grade
heavily calcified neoplasm adjacent to sarcoma in 2001
resection)
Size and
Location of
RIN at
Diagnosis
extending into
the adjacent
lateral
ventricle.
XRT to right
frontal resection
cavity
R frontal
subcutaneous
tissues, bone,
and dura with
lymphovascular
and venous
sinus invasion
XRT to L
parietooccipital
resection cavity,
5940 rads in 33
fractions
L parietooccipital
resection cavity
Pathologic
Findings (each
resection listed
separately)
sarcoma and
rhabdomyosarcoma elements
Grade IV sarcoma,
malignant
fibrous histiocytoma
(undifferentiated
high-grade pleomorphic sarcoma)
with focal myxoid
features
Grade IV sarcoma,
malignant
fibrous histiocytoma (undifferentiated highgrade pleomorphic sarcoma)
with extensive
myxoid features
Interval Follow Up
therapy until referral to our
institution in 10/01 at which
point he had repeat resection
and I-131 treatment through
gliaSite balloon; subsequently
had SRS and chemotherapy
with ifosfamide and mesna;
global aphasia, decreased
attention, and right hemiparesis; he died in 8/02
Following diagnosis of the
radiation-induced sarcoma,
she had two resections and
reconstruction procedures of
her scalp and cranium; she
suffered a rapid decline (2
months) in her neurologic and
overall clinical state; she died
in 3/98
Patient did reasonably well
postoperatively; she went
home and led a relatively
independent lifestyle (~KS
70) until a more rapid decline
near the time of death in
11/03
*, Meningioma with 1Y2 Batypical features^ such as small cell formation, prominent nucleoli, hypercellularity, or loss of architectural pattern, but insufficient to meet criteria for WHO grade II atypical meningioma.
KS, Karnofsky score in 2005; current age is as of 2005; RIN, radiation-induced neoplasms; XRT, radiation therapy; WHO, World Health Organization; EGFR, epidermal growth factor receptor; Ch., chromosome; SRS,
stereotactic radiosurgery; MRI, magnetic resonance imaging; BCNU, carmustine; FISH, fluorescent in situ hybridization.
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1998/1997,
1998
Previously Treated
Condition
Location and
Type of Initial
Radiation
Exposure
Kleinschmidt-DeMasters et al
208
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Table 1. (continued)
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Radiation-Induced CNS Tumors
209
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Kleinschmidt-DeMasters et al
The recent literature also suggests that radiationinduced CNS/PNS tumors are becoming a more noticeable
subset of tumors seen at other referral centers, both in the
United States and Europe (4, 5). These tumors can be a
treatment challenge for radiation oncologists, given that
some of these patients have already received maximal doses
of radiation to that brain region at the time of their original
lesion. However, most importantly, these tumors are a
burden for the individual patient who with great relief
overcomes and survives the rigors of surgery, radiation
therapy, and often chemotherapy for their original tumor,
only to have inflicted on them, years later, another tumor of
iatrogenic, albeit currently nonpreventable, origin. In addition, many of these patients suffer from years’ worth of
severe cognitive deficits primarily as a result of the original
radiation therapy. We detail the unfortunate case history
from one such recent patient to underscore the suffering that
such patients experience.
Illustrative Case History
This 34-year-old man first presented in 1989 at the age
of 23 years with seizures and headaches. He was treated by
his primary care physician with phenytoin and no imaging
studies were acquired. One year later, he developed a right
visual field cut, prompting a visit to an ophthalmologist who
ordered a computed tomography scan and discovered a left
parietal tumor. The patient was referred to a neurosurgeon.
The left parietal tumor was resected on February 3, 1990,
and diagnosed as glioblastoma multiforme. He received
postoperative radiation therapy but no chemotherapy.
He underwent yearly serial magnetic resonance imaging (MRI) studies for approximately 4 years, which were
negative for recurrence. He was then lost to follow up but was
able to find work as a dishwasher. He experienced significant
cognitive deficits attributable to his cranial external beam
radiation therapy.
In October 2000, 10 years after his first tumor was
resected, the patient developed headaches and numbness on
the right side of his body. He did not seek medical attention
until he started having difficulty with speech, for which he
consulted a different neurosurgeon in January 2001. An MRI
scan revealed a recurrent enhancing mass in the same region
as his original tumor. The patient underwent surgical excision
of the mass on February 2, 2001; it was unclear from the
operative report whether this was a gross total or subtotal
resection. High-grade sarcoma with osteogenic differentiation
J Neuropathol Exp Neurol Volume 65, Number 3, March 2006
was documented (Fig. 1A, B). The patient received no
adjuvant therapy.
In July 2001, the patient experienced recurrent symptoms and MRI showed abnormalities in the site of the
resection bed. Surgery revealed an abscess in the region of
his previous operation. The abscess was drained, and blood
cultures grew out Staphylococcus aureus; he was treated with
6 weeks of antibiotics. He had persistent expressive aphasia
but did well until a follow-up scan on October 8, 2001,
showed recurrence of the tumor.
He was referred to our institution, the fourth hospital
and fourth neurosurgeon involved in his care. On admission,
MRI scan showed a very large parietooccipital tumor that
had rapidly regrown within the site of the operative bed,
extending from the dura to the left lateral ventricle. A
separate nodule was seen in the choroid plexus. A gross total
resection was performed on November 7, 2001.
Histologically, the tumor was a high-grade, complex
sarcoma with a predominantly herringbone fibrosarcomatous
pattern and focal osteogenic differentiation, similar to that
seen on the previous resection specimen from 2001 (Fig. 1A,
B). Additional rhabdomyosarcomatous differentiation was
present in the new specimen, evidenced by cells with
abundant eosinophilic cytoplasm (Fig. 1C) and vague
cross-striations (Fig. 1D). These cells were strongly immunoreactive for desmin (Fig. 1E), myo-D1 (Fig. 1F), and
myogenin. Mitotic activity was very brisk (Fig. 1A, C).
There was no immunoreactivity for S-100 protein and no
evidence of nerve sheath origin. No residual glioma was
found in material from either resection.
A GliaSite balloon was placed into the resection cavity
with delivery of 50 Gy to a depth of 1 cm over 72 hours using
radioactive iodine. After treatment, the radioactive iodine and
the balloon were removed. The resection bed on follow-up
MRI scanning appeared clean (Fig. 1G).
Unfortunately, several months after resection, he
developed a left cerebellopontine angle subarachnoid metastasis for which he received gamma knife therapy on March
14, 2002. A subcutaneous mass along his occipital incision
appeared and was excised on April 24, 2002. Over the ensuing
months, he developed cerebrospinal fluid dissemination of his
tumor with enhancing masses developing along the ependymal surfaces of the ventricle, within the subarachnoid space
overlying the frontal lobe (Fig. 1H) and adjacent to the pons
(Fig. 1I). Smaller lesions were found in the cerebellum, in
the left internal auditory canal, and along the spine. Several
cycles of chemotherapy with ifosfamide and mesna proved
ineffective and he died on August 18, 2002.
FIGURE 1. (A–I) Thirty-four-year-old man (patient from the illustrated case history) with a postradiation complex sarcoma
manifesting a fibrosarcoma pattern and brisk mitotic activity ([A] and [H, E], 200), foci of osteogenic differentiation ([B] and
[H, E], 200), and rhabdomyosarcomatous differentiation (C–F). Note the large cells with abundant eosinophilic cytoplasm ([C]
and [H, E], 600) that contained ill-defined cross-striations at high power ([D, H], and [E], 1250) and were strongly
immunoreactive for desmin ([E], 600) and Myo-D1 ([F], 600). Neuroimaging studies (T1-weighted, with gadolinium)
chronicle the unfortunate progression of his tumor. Despite a relatively clean resection bed after his second resection (G), he
developed tumor regrowth, cerebrospinal fluid dissemination over the surface of the frontal lobe (H), and adjacent to pons (I),
as well as cerebellar lesions; he died shortly thereafter.
210
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Radiation-Induced CNS Tumors
211
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Kleinschmidt-DeMasters et al
DISCUSSION
This illustrative case represents one of the more graphic
examples of the 22 patients we have seen at our institution
with secondary, radiation-induced CNS neoplasms (Table 1).
The recurring left parietooccipital lesion in this patient was
diagnosed as a complex radiation-induced sarcoma, with
rhabdomyosarcomatous and osteogenic foci of differentiation, clearly arising in the site of his original tumor. We
obtained his original 1990 slides from the outside hospital
and, on review, discovered that the original resected tumor
diagnosed as glioblastoma was actually a pleomorphic
xanthoastrocytoma (PXA) with anaplastic features, a tumor
type that was not characterized until the late-1990s (6, 7).
This patient’s slides from 1990 showed pleomorphic tumor
cells and copious numbers of eosinophilic granular bodies
with more focal lymphocytic collections, xanthic cells,
Rosenthal fibers, and elongate spindle tumor cells, all features
of PXA, but with superimposed necrosis, microvascular
proliferation, and mitoses. PXA with anaplastic features is a
tumor with behavior similar to a grade 3 anaplastic astrocytoma. Long-term survival with glioblastoma is rare and slides
from the original resection should be rereviewed whenever
possible, because in over 40% of instances, an alternate
diagnosis explains the patient’s better outcome (8). Obtaining
old slides and records is becoming more of a challenge,
because patients are now often seen at multiple institutions
(as shown here) and slides from 20 years ago are often no
longer available. Nevertheless, we were able to review this
patient’s original surgical pathology material and the
alternate diagnosis likely accounts for his 11-year interval
before diagnosis of his radiation-induced sarcoma (8).
Radiation-induced brain sarcoma is one of several
radiation-induced tumors types that can be seen in the central
and peripheral nervous systems, along with meningiomas,
high-grade gliomas, schwannomas (9), and malignant peripheral nerve sheath tumors (Table 1). Kaschten et al, in their
1995 review of the literature on radiation-induced glial and
CNS sarcomatous tumors, found that of the sarcomas, 58%
were diagnosed as fibrosarcomas, 22% as meningeal
sarcomas, and 14% as osteogenic sarcomas (10). Case
reports of malignant fibrous histiocytomas, chondrosarcomas,
mesenchymal chondrosarcomas, Bfibrochondrosarcoma^
(11), and other unusual Bmixed^ forms have also appeared
(12Y14). Our other two radiation-induced sarcomas were
undifferentiated high-grade pleomorphic sarcomas (malig-
J Neuropathol Exp Neurol Volume 65, Number 3, March 2006
nant fibrous histiocytoma, myxoid type) (Fig. 2A). The
literature seems to suggest that radiation-induced sarcomas
are more likely to contain mixed mesenchymal elements
compared with spontaneous primary CNS sarcomas, but this
is difficult to prove because of the case-report nature and
relative rarity of all primary CNS sarcomas.
The life-altering effects of the original tumor, the
subsequent delayed effects of radiation therapy that resulted
in cognitive deficits, and the eventual development of a
second radiation-induced tumor illustrate the obvious
burden suffered by the patient we illustrate in the case
history, his family, and his physicians. We were acutely
aware that, as physicians, we were unwittingly responsible
for this scenario.
All three of the patients with radiation-induced
sarcoma seen at our institution have died from their tumors
(Table 1). However, on a more optimistic note, the patients
with radiation-induced meningioma treated at our institution
have generally had better clinical outcomes than much of the
literature on radiation-induced meningiomas would have led
us to believe. Indeed, many clinicians have taken the
message from the literature that all patients with radiationinduced meningiomas do poorly and are difficult to manage
surgically and medically.
In 2004, seven patients with radiation-induced meningiomas were seen by our neurosurgical service, five of whom
underwent surgical resection of their tumor. Two patients are
being followed expectantly with stable MRI scans (Table 1),
including one with multiple skull base meningiomas 6
decades after receiving radiation treatment for tinea capitis
(Fig. 2B, C). Several other of the 15 total patients with
meningiomas had been followed for 5 to 10 years before
their tumors required first excision or reresection, underscoring the fact that a significant percentage of radiationinduced meningiomas can be relatively indolent in their
behavior (Table 1).
In general, our patients with radiation-induced meningioma have been managed with individually tailored treatment regimens, including gross total resection whenever
possible, reresection when necessary, and occasionally
stereotactic radiosurgery. There has thus far been only one
known death among our meningioma patients (Table 1).
However, several patients live with significant cognitive
disabilities primarily related to their original radiation
therapy. Hence, although an inordinately high number of
FIGURE 2. (A) The other two radiation-induced sarcomas were undifferentiated high-grade pleomorphic sarcomas, with focal
myxoid features, and did not contain mesenchymal elements (hematoxylin and eosin [H&E], 200). (B, C) Neuroimaging
studies (coronal views, T1-weighted, with gadolinium) from one of our postradiation meningioma cases in which the woman had
received low-dose radiation for tinea capitis decades earlier; note the multiplicity of lesions. (D–F) Neuroimaging studies (coronal
views, T1-weighted, with gadolinium) from a woman who had received high-dose therapeutic radiation for a posterior fossa
tumor (unknown type) decades earlier; again note multiplicity of lesions. Although the ominous-appearing, largest lesion was
aggressively resected ([D], preoperative scan; [E], postoperative scan), it was a World Health Organization grade I meningioma
([F], H&E, 100), albeit with loss of chromosome 1p. (G–I) Radiation-induced gliomas can occur in unusual locations and at
unusual ages, as illustrated by an anaplastic astrocytoma occurring in the cervical spinal cord of a 74-year-old man ([G], H&E,
600), a glioblastoma in the cerebellum of an 87-year-old man ([H], H&E, 200), and a glioblastoma in the cerebellum of a
21-year-old man ([I], H&E, 200).
212
Ó 2006 American Association of Neuropathologists, Inc.
Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.
J Neuropathol Exp Neurol Volume 65, Number 3, March 2006
patients with radiation-induced meningiomas indeed Bdo not
do well,^ confirming some clinicians` impression, the
patients` problems are not solely the result of their
radiation-induced meningioma(s). Our experience has been
that even with recurrence, many of the tumors can be
controlled effectively.
The link between radiation and meningioma development is a strong one. Meningiomas were the most frequent
cranial tumor type to develop in the atomic bomb survivors of
Hiroshima and Nagasaki. The most recent Life Span Study
(LSS), published in Cancer in 2004, demonstrated a doserelated excess of tumors of the CNS and pituitary gland
among a cohort of 80, 160 survivors (15). All examples were
reviewed by pathologists to verify diagnoses. Meningiomas
were followed in frequency by neuroepithelial tumors,
schwannomas, and pituitary tumors. The overall incidence
of tumors increased steadily with age and was stable over
time. Tumors were histologically similar to their spontaneously occurring counterparts.
Recent studies have confirmed earlier work showing
that persons who underwent six or more full mouth dental
x-rays over a lifetime also have a significantly increased risk
of meningioma (16). Other types of dental x-rays, i.e.
posterior bitewings, lateral cephalometric, and panoramic
radiographs, are not statistically associated with increased
risk. The risk is especially pronounced in patients who had
full-mouth series 15 to 40 years ago, at a time when radiation
exposure was much greater that it currently is today in dental
practice (16).
The majority of meningiomas in the past have been
attributable to low-dose irradiation to the scalp for tinea
capitis. Recently, more examples of meningiomas arising
after moderate (1000Y2000 rads) to high-dose therapeutic
radiation (>2000 rads) have been reported (3). Generally, the
lower the dosage of radiation the patient receives, the longer
the interval to development of the meningioma.
Radiation-induced meningiomas in patients previously
treated with low-dose radiation for tinea capitis (mean
1.4Y1.8 Gy [17]) have been recognized for decades and
show a strong doseYresponse relationship, with the relative
risk approaching 20 after doses of approximately 2.5 Gy
(18). Treatment of large numbers of immigrants between
1948 and 1960 subsequently lead to BAn Iatrogenic
Epidemic of Benign Meningioma^ in Israel (19). Sadetzki
et al, in a large study of 253 radiation-induced meningiomas
developing after tinea capitis treatment, found a mean
latency period of 36 years (range, 12Y49 years), multiplicity
in 16% of cases, calvarial location in 59%, and a nonsignificant higher recurrence rate compared with the control
meningioma group (17). Other recent studies have shown
similar figures for multiplicity (15%) and a relatively low
recurrence rate, but have additionally shown a high
percentage of malignant meningiomas (29%) and second
neoplasms other than meningioma (28%) (20).
Radiation-induced meningiomas occurring after therapeutic moderate- or high-dose cranial radiation therapy
(XRT) often occur in patients who received their therapy
in childhood and develop their tumors after a shorter latency
period (5Y20 years) than those who received low-dose scalp
Ó 2006 American Association of Neuropathologists, Inc.
Radiation-Induced CNS Tumors
irradiation for tinea capitis. An inverse relationship exists
between radiation dose and interval to second tumor
development and supports a doseYresponse relationship
(21). Younger children treated with high-dose radiotherapy
may be particularly vulnerable to chromosomal injury and
occasionally have developed radiation-induced meningiomas
at intervals as short as 12 and 14 months after therapy
(reviewed in [21]).
The patients we have encountered at our institution
received their radiation in childhood for a potpourri of
benign and malignant conditions and all have developed
tumors many years after therapy (Table 1). This assortment
of background conditions, including facial hemangioma
(22), parallels that found in several other series (23, 24)
and reinforces the idea that the original condition for which
the patient received radiation therapy has little or no
influence on the host’s tendency to develop a radiationinduced neoplasm.
Children with acute lymphoblastic leukemia (ALL) are
another group well known to be at risk for secondary brain
tumors as a result of the administration of prophylactic
cranial irradiation (20, 22, 25). One group of authors felt the
problem was significant enough to suggest that BBecause of
the possibility of benign, potentially curable brain tumors
occurring after cranial irradiation, it may be wise to carry
out occasional cranial imaging in the follow-up of these
patients. No routine imaging follow-up is needed after
chemotherapy alone^ (26).
Numerous reports document adults with radiationinduced meningiomas after cranial irradiation for pituitary
adenomas and craniopharyngiomas (although radiationinduced meningiomas are only one of several adverse side
effects attributable to radiotherapy in this cohort such
as visual deterioration and pituitary dysfunction) (27, 28).
Follow-up studies of patients with pituitary adenoma suggest
that the risk for a given patient receiving radiation is
relatively low. No secondary brain tumors were found in
one study of 325 pituitary tumor patients in Sweden (29),
and one malignant brain tumor (expected 0.3) and one
meningioma were encountered in 296 patients with pituitary
tumors in Edinburgh from 1962 to 1990 (30).
However, the actual numbers of patients with radiation-induced meningiomas, especially following high-dose
radiation therapy, seen at a given institution is starting to
increase, as we have illustrated. A British group recently
cited radiation-induced meningiomas occurring after highdose irradiation as accounting for 3.7% of the meningiomas
seen at their institution over a 10-year time period (5). AlMefti et al last year published his findings on 16 radiationinduced meningiomas seen from 1992 to 2001 at his
institution; 14 of these were secondary to high-dose
radiation the patients had received (4).
No signature histologic features of radiation-induced
meningiomas have been identified thus far. Although early
studies suggested that radiation-induced meningiomas were
Ba recognizable entity^ (31) as a result of their cytological
atypia, the majority of tumors meet current criteria for
World Health Organization (WHO) grade I (32). Al Mefti
et al noted the lack of correlation between histologic features
213
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Kleinschmidt-DeMasters et al
and tumor behavior (4). His series was comprised entirely of
referral cases, and hence 100% had had a first recurrence
after initial resection elsewhere by the time they were seen at
his institution (4). Of this already recurrent group, 62% went
on to have a second and 17% a third recurrence, but only
38% were either WHO grade II atypical or WHO grade III
anaplastic meningiomas. Progesterone receptor status and
low proliferation index did not correlate with benign tumor
behavior in his study. He attributed the aggressive behavior in
his cohort to the presence of multiple clonal aberrations in all
tumors studied with chromosomal alterations on 1p (89% of
cases) and 6q (67% of cases) (4). Others have also noted loss
of 1p, 7p, and 6q by CGH (33) and a gene on 1p13 has been
implicated (34). Although loss of 1p is the most common
alteration in radiation-induced meningiomas, it is also found
in approximately 30% of spontaneous meningiomas (35, 36)
and hence is not a signature genetic hallmark of radiationinduced lesions. Mutations in NF2 gene, seen in up to 50%
of spontaneous meningiomas, are generally not observed in
radiation-induced meningiomas (37, 38), nor are mutations
in the PTEN, TP53, HRAS, KRAS, and NRAS genes (38).
On review, many of our meningiomas possessed one or
two of the cytologic features seen in WHO grade II atypical
meningiomas (i.e. small cell formation, hypercellularity,
macronucleoli, or sheeting architecture) but fell short of
diagnostic criteria for atypical meningioma; these cases are
denoted by an asterisk (*) in Table 1. This finding may well
reflect the increased genetic aberrations in these tumors.
Location and size are also problems with radiationinduced tumors. Al Mefti et al noted that skull base location
might preclude gross total removal (4). We concur with this
interpretation and note the increasing number of patients
who originally received radiation therapy for posterior fossa
tumors and later developed skull base meningiomas compared with the predominance of more surgically accessible
calvarial tumors in patients radiated for tinea capitis (17).
This, along with multiplicity (Fig. 2B, C) and enormous size
(Fig. 2D), further add to the difficulties in surgical management. Aggressive surgical resection can be performed in
some patients (Fig. 2E postoperative scan from patient
illustrated in Fig. 2D). Despite the ominous preoperative
neuroimaging features, this was a grade I meningioma
(Fig. 2F). Fluorescence in situ hybridization studies showed
deletion of 1p36. On occasion, we have been able to
supplement surgical resection or biopsy with postoperative
radiosurgery for tumor residual with successful control on
short-term follow up (Table 1).
Like radiation-induced meningiomas, radiation-induced
gliomas may occur after low-dose irradiation for tinea capitis
or after high-dose therapeutic cranial radiation therapy for
pituitary adenomas, acute lymphoblastic leukemia, or various
types of brain tumors such as ependymoma, medulloblastoma,
and astrocytomas. Tsang et al estimated the relative risk for
glioma arising after radiation therapy for patients with pituitary
adenomas to be 16 times greater than the general population in
Ontario, with secondary glioma occurring at a risk of 1.7% at
10 years and 2.7% at 15 years (39).
Radiation-induced gliomas are usually glioblastomas or
anaplastic astrocytomas, although radiation-induced gliosar-
214
J Neuropathol Exp Neurol Volume 65, Number 3, March 2006
comas, low-grade astrocytomas (40), primitive neuroectodermal tumors (41, 42), and oligodendroglioma (43) have
been reported. Tumors develop 5 to 25 years postradiation,
with an average of 9.6 years (40). Similar to the situation
with radiation-induced meningiomas, there are no signature
histologic features unique to radiation-induced gliomas.
Brat et al recently assessed radiation-induced highgrade gliomas for possible alterations in p53, PTEN, KRAS,
EGFR, and p16 and found molecular alterations similar to
those seen in spontaneously arising, primary (de novo) highgrade astrocytomas, with the possible exception of an absence
of PTEN mutations in the radiation-induced group (44).
Young age is a distinctive feature in some radiationinduced gliomas (40, 44). All but one of the nine patients
reported by Brat et al were less than 34 years of age,
whereas the 10 patients in the series by Salvati et al ranged
in age from 18 to 63 years (40). Two of our four gliomas
were very old and developed tumors in unusual locations,
including a 74-year-old man with anaplastic astrocytoma of
the cervical spinal cord after radiation therapy for Bthroat
cancer^ (Fig. 2G) and an 87-year-old man with a glioblastoma of the cerebellum after radiation therapy for a pilocytic
astrocytoma decades previously (Fig. 2H). The latter patient
with a 52-year interval and one of our meningiomas with a
63-year latency period have been previously reported
(45, 46). These two patients illustrate the disquieting fact
that some radiated patients may never outlive the risk for
developing secondary neoplasms. Unusual locations are, of
course, a byproduct of which area of brain was originally
radiated. Our other two patients with gliomas were young
and also had cerebellar glioblastomas (Fig. 2I). Interestingly,
one of our patients with radiation-induced glioblastoma
multiforme (GBM) still survives, paralleling a recently
reported case report citing response to chemotherapy in a
radiation-induced GBM who survived 44 months (47).
Recent animal studies provide the strongest evidence
that gliomas are directly radiation-induced (48, 49). In a
recent study of 3-year-old male primates that received
fractionated WBRT (350 cGy for 5 days per week for
2 weeks to a total dose of 3500 cGy), nine of 11 animals
developed glioblastomas. Tumors occurred at intervals of
2.9 to 8.3 years after radiation and comparative genomic
hybridization showed deletions in the primate chromosome
(Ch.) corresponding to human Ch. 9 (50).
Thus far, at least five cases of radiation-induced
neoplasms have been reported after stereotactic radiosurgery (39, 51, 53), although the risks for these appear
lower after radiosurgery than after fractionated radiation
therapy (54). Loeffler et al have suggested that the proper
term for new, histologically different tumors arising in
previously irradiated resection cavities is Bradiationassociated^ because there is Bno definitive evidence at a
molecular level that radiation [was] the causative factor.
Such information is simply not available in [these] patients^
(52). Given the track record with external beam cranial
radiation therapy and the number of years it took to
appreciate the full oncogenic effects of radiation, it will
take time before the long-term effects of radiosurgery as a
carcinogen are fully realized. It should be noted, however,
Ó 2006 American Association of Neuropathologists, Inc.
Copyright @ 2006 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.
J Neuropathol Exp Neurol Volume 65, Number 3, March 2006
that the types of tumors thus far anecdotally reported after
stereotactic radiosurgery are identical in type to those
reported after inadvertent radiation exposure (atomic bomb
survivors, people receiving dental x-rays), after low-dose
radiation therapy for tinea capitis, and after high-dose
therapeutic radiation doses. Hence, it is highly likely that
CNS/PNS tumors occurring after stereotactic radiosurgery
are radiation-induced as well.
Many thousands of patients around the world have
received efficacious treatment with either external beam
cranial XRT or stereotactic radiosurgery (>200,000 patients
over the past 30 years [54])Vtherapy that undoubtedly saved
numerous lives or prolonged survival. Fortunately, a very
small number of such individuals have had the burden of
developing a second, radiation-induced CNS/PNS neoplasm.
Currently, we know little about what individual host factors
might influence such an occurrence (except for children with
neurofibromatosis or Li-Fraumeni syndrome who appear to
be at increased risk for developing their second malignancies
within the radiation portals [55]). The suffering of even one
patient as a result of an iatrogenic therapy regimen
should prompt us to seek safer, equally efficacious therapeutic alternatives.
Neuropathologists play an important role as Bwatchdogs^ for a variety of new and innovative treatment regimens,
especially for gliomas. We need to continue to advocate for
full autopsies to be performed on each and every patient who
dies after a new treatment protocol and we strongly believe
that provision for autopsy follow up should be written into
every clinical trial. We need to continue to document the
adverseVand favorableVeffects of each new variation in
therapy bravely attempted by our clinical colleagues. This
documentation, of course, needs to be made in nonjudgmental fashion, recognizing that for many desperate patients with
brain tumors, we have little else to currently offer them
except experimental therapy. Most patients enter these trials
fully cognizant of the risks they are taking and know that
they will most assuredly die if no therapy is given. Nevertheless, neuropathologists Bstand in the gap^ and must
provide autopsy or surgical pathology feedback in a timely
fashion, so that treatment regimens can be modified, improved, and in rare cases, discarded, to optimize care for the
next patient who comes along.
There is little doubt that in the future, radiation therapy
will be of historic interest only and replaced entirely by safer
and more effective alternatives. At that time, young
physicians may shake their heads (as we do today when
recalling some of the early treatments used for multiple
sclerosis or syphilis) and ask how in the world we physicians
in the year 2006 could have ever used the best-known
carcinogenVradiationVas a therapy for cancer.
ACKNOWLEDGMENTS
The authors thank Dr. Arie Perry for helpful comments
and gratefully acknowledge Ms. Susan Peth for expert
manuscript preparation, Ms. Amy Kendall in the University
of Colorado Tumor Registry for obtaining survival data, and
Ms. Lisa Litzenberger for photographic assistance. This study
Ó 2006 American Association of Neuropathologists, Inc.
Radiation-Induced CNS Tumors
was supported in part by funds from the Michele PlachyRubin Foundation for Brain Tumor Research at UCHSC. The
epidemic continues: in the 4 months since submission of this
manuscript we have seen 2 more examples at our weekly
Brain Tumor Board: a probable radiation-induced meningioma (non-resected) in a 63-year-old woman overlying her
recurrent oligoastrocytoma (with LOH 1p, 19q), first diagnosed and radiated in 1990; and a WHO grade II atypical
meningioma (resected) with complex karyotype in a 48-yearold female who had received her radiation therapy at age 14
years for a pituitary adenoma.
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