In recent decades, the percentage of children who can be cured from cancer has increased steadily, resulting in a growing number of childhood cancer survivors worldwide.1 However, many of these childhood cancer survivors develop chronic health conditions emerging years to decades later as a consequence of cancer therapy.2 Compared with chemo- or immunotherapy, late effects of radiation often occur in the former treated field, leading to subsequent neoplasms.3 The cumulative radiation dose correlates with rates of subsequent tumors in the central nervous system (CNS) that include mostly meningiomas or gliomas.4
Furthermore, cranial radiotherapy is known to increase the risk of de novo formation of cerebral cavernomas (
Brain magnetic resonance imaging (MRI) is the modality of choice for the detection and follow-up imaging of cavernomas.11, 12 In 1994, Zabramski
MRI classification of cerebral cavernomas according to Zabramski
Lesion type | MRI signal characteristics | Pathological characteristics |
---|---|---|
T1: hyperintense core |
Subacute hemorrhage, surrounded by a rim of hemosiderinstained macrophages and gliotic brain | |
T1: reticulated mixed-signal core hypointense rim | Loculated areas of hemorrhage and thrombosis of varying ages, surrounded by gliotic, hemosiderin-stained brain; in large lesions, areas of calcification may be seen | |
T2: reticulated mixed-signal core with surrounding | ||
T1: iso- or hypointense core | Chronic resolved hemorrhage, with hemosiderin staining within and around the lesion | |
T2: hypointense with a hypointense rim that magnifies the size of the lesion | ||
GE: hypointense with greater magnification than T2 | ||
T1: poorly seen or not visualized at all |
Two lesions in the category were pathologically documented as telangiectasias | |
T1 and T2: visible parts in the center of the actual cavernoma; the cavernoma is not fully distinguishable from hemorrhage |
GE = gradient echo sequence
Thus it remains unclear whether Nikoubashman’s interpretation of the MRI appearance of cavernomas based on the Zabramski classification might be helpful for estimation of the hemorrhage risk of RIC. We would like to help clarify this and therefore set our sights on assessing for the first time the risk of hemorrhage of RIC in the long-term follow-up of childhood cancer survivors with brain MRI in this case series.
This study was approved by the Institutional Review Board of the University of Luebeck (14– 180, 18–087).
We retrospectively analyzed 36 childhood cancer survivors out of 252 patients who were examined in the late effects clinic at the University Medical Center Schleswig Holstein in Luebeck over a period of 6 years (03/2014–02/2020). We limited the analysis to patients with acute leukemia or brain tumors who had been treated with cranial radiotherapy (alone or as part of total body irradiation) and had received cranial imaging as part of their follow-up. Additionally, at least 2 brain MRI examinations (1 at the time of the initial tumor diagnosis and at least 1 in the follow-up) were required for inclusion in the study. The patients at the late effects clinic (i) were younger than 18 at cancer diagnosis, (ii) were at least 18 at first follow-up in the clinic and iii) survived at least 5 years after the end of cancer therapy. Exclusion criteria for the study were (i) active malignancy and (ii) lack of consent. See the flowchart of the patient selection process in Figure 1.
All patients received cranial imaging with at least one follow-up MRI of the brain on 1.5 or 3 Tesla scanners. The MRI sequence protocol for detection and classification of RIC included a T1, T2 and T2*/susceptibility weighted imaging. Available brain MRI examinations were assessed and compared by two experienced neuroradiologists in consensual decisions. RIC were consensually detected and classified following the Zabramski classification and categorized into “high” (≥ 1 type I and/or II and/or type V, in accordance with the proposal of Nikoubashman
Clinical and imaging data were collected in a standardized pseudonymized data file. Most data were analyzed in a descriptive manner. For statistical analysis we used the software IBM® SPSS® (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp.). Categorical variables were analyzed in contingency tables using chi-squared test, or, if applicable, with the Fisher exact test. Mann-Whitney U test was used to compare continuous variables.
For the calculation of a possible association between the age at the initial tumor diagnosis (acute leukemia or brain tumor) and the occurrence of RIC the patients were dichotomized into the two groups “younger age” (≤ 8 years) and “older age” (> 8 years) based on the median age calculated in this collective.
Statistical significance was accepted at p < 0.05.
The study group of childhood cancer survivors consisted of 36 patients with the diagnosis of acute leukemia or brain tumor. At the time of the initial cancer diagnosis their age ranged from 1 to 25 years (median 8 years, interquartile range [IQR] 5–14 years). There were 19 female (median 7 years, IQR 3–14 years) and 17 male (median 10 years, IQR 6–15 years). We found no significant difference in the age profile between the two gender groups (p = 0.505).
In particular, initial childhood cancer diagnoses were acute lymphoblastic leukemia (ALL) (n = 13), acute myeloid leukemia (AML) (n = 5), pilocytic astrocytoma (n = 2), intracranial germinoma (n = 3), medulloblastoma (n = 9) and ependymoma (n = 3) with need for cranial radiotherapy and polychemotherapy.
The median period of the last long-term followup examination in our late effects clinics after initial tumor diagnosis was 18 years (IQR 13–29).
Cranial radiotherapy was applied in conventional fractionation for patients with ALL, AML, pilocytic astrocytoma and germinoma. However, in patients with medulloblastoma, cranial radiotherapy was given in conventional fractionation or as hyperfractionated treatment. Moreover, one patient with craniopharyngeoma was treated with proton therapy. The exact cumulative radiation dose to the brain could not be evaluated in this case. In patients with acute leukemia, total body irradiation consisted of 2 x 2.0 Gray (Gy) daily in three consecutive days. See Table 2 for scheme of cranial radiotherapy according to treatment protocols.
Cranial radiotherapy according to treatment protocols
Tumor entity | Dose/day | Number of fractions |
---|---|---|
ALL | 1.5 Gy | 8, 12, 16, 20 or 26 |
AML | 1.5 Gy | 8 or 10 |
Pilocytic Astrocytoma | 1.8 Gy | 28 or 30 |
Germinoma | 1.6 Gy | 15 or 25 |
1.8 Gy | 30 or 34 | |
Medulloblastoma | 2 x 1.0 Gy (hyperfractionated) | 30 or 34 |
ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; Gy = Gray
The median cumulative radiation dose in the 35 patients analyzed was 30.6 Gy (IQR 12–55 Gy). In all patients, no serious radiation-induced toxicities were reported. Individual`s cumulative radiation doses to the brain are listed in Table 3.
Patient characteristics, therapy data, findings of radiation-induced cavernomas and other comorbidities
No. | Gender (F=female; M=male) | Initial tumor diagnosis | Age at diagnosis (years) | Cumulative radiation dose to the brain (Gy) | Total number of brain MRI | Detection of RIC | Latency between CR and RIC (years) | Zabramski classification | RIC localization (1=supratentorial; 2=infratentorial; 3=both) | RIC dynamic | Other benign tumors in follow-up brain MRI | Leukoencephalopathy (mild; moderate; extensive) | Brain atrophy (mild; mode-rate; severe) | Other comorbidities in the long term | Period of follow-up (years) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | F | ALL | 17 | 24 | 9 | Meningioma | moderate | - | COPD, hyperparathyroidism, hypercholesterolemia, migraine | 44 | |||||
2 | F | ALL | 1 | 12 | 2 | mild | - | Lipedema, fibroepithelioma | 26 | ||||||
3 | F | ALL | 3 | 12 | 2 | - | - | Class I obesity | 22 | ||||||
4 | F | ALL | 7 | 8 | 2 | mild | - | CRF, class II obesity, hypercholesterolemia, hypopituitarism, thyroid nodules | 37 | ||||||
5 | F | ALL | 3 | 24 | 4 | + | 40 | II | 3 | + | Meningioma | extensive | mild | Hypercholesterolemia, class I obesity, thyroid nodules, scoliosis, myoma uteri | 44 |
6 | F | ALL | 21 | 24 | 2 | + | 10 | IV | 1 | mild | - | Reduced left ventricular ejection fraction, class III obesity, multiple vein thrombosis | 13 | ||
7 | M | ALL | 5 | 12 | 2 | - | - | Hypercholesterolemia | 19 | ||||||
8 | F | ALL | 9 | 12 | 2 | mild | - | Hypercholesterolemia | 28 | ||||||
9 | M | ALL | 11 | 30 | 9 | mild | - | Hypogonadism, hypercholesterolemia, | 13 | ||||||
10 | F | ALL | 7 | 30.6 | 3 | + | 29 | IV | 1 | Meningioma | moderate | - | Basalioma, hyperparathyroidism, class II obesity, thyroid nodules | 33 | |
11 | F | ALL | 5 | 39 | 6 | Vestibular schwannoma, DD aneurysmal bone cyst | mild | - | Diabetes mellitus type 2, hypercholesterolemia, steatosis hepatis, congestive heart failure, restrictive lung disease, thyroid nodules, deep vein thrombosis, basalioma, CRF, vestibular schwannoma | 39 | |||||
12 | M | ALL | 2 | 30 | 2 | moderate | - | Thyroid Nodules, hypopituitarism, diabetes mellitus type 2, CRF, steatosis hepatis, cataract | 35 | ||||||
13 | F | ALL | 2 | 12 | 4 | moderate | - | Intellectual disabiliy | 17 | ||||||
14 | F | AML | 14 | 12 | 2 | + | 21 | IV | 1 | mild | - | Thyroid nodules, hypercholesterolemia, hypertension, spondyloarthritis | 26 | ||
15 | M | AML | 15 | 12 | 2 | - | - | Thyroid nodules, restrictive lung type disease, 1, hypogonadism, diabetes mellitus hypercholesterolemia | 31 | ||||||
16 | F | AML | 16 | 12 | 3 | + | 28 | IV | 3 | moderate | - | Thyroiditis | 18 | ||
17 | F | AML | 2 | 15 | 2 | + | 21 | IV | 3 | - | - | Cataract, hypercholesterolemia, depression | 24 | ||
18 | F | AML | 8 | 12 | 3 | - | - | CRF, class ii obesity, chronic pain, visual impairment | 14 | ||||||
19 | M | PA | 1 | 54 | 28 | + | 23 | IV | 3 | moderate | moderate | Hypopituitarism, stroke, epilepsia, hearing loss, hypercholesterolemia, gallstones | 29 | ||
20 | M | PA | 17 | 50.4 | 24 | moderate | - | Hypercholesterolemia | 11 | ||||||
21 | M | Germinoma | 17 | 40 | 16 | mild | - | Hypopituitarism, chronic renal failure | 5 | ||||||
22 | M | Germinoma | 14 | 24 | 20 | mild | - | Hypopituitarism, class I obesity, depression, hypercholesterolemia | 9 | ||||||
23 | M | Germinoma | 10 | 40 | 21 | + | 5 | IV | 1 | moderate | - | Depression, hypercholesterolemia, hypopituitarism | 12 | ||
24 | M | CP | 17 | n.a. | 15 | mild | - | Hypopituitarism, class I obesity, hypercholesterolemia, autoimmune polyendocrine syndrome type 2 with diabetes mellitus type 1, vitiligo, thyroiditis | 13 | ||||||
25 | F | Medulloblastoma | 7 | 55 | 3 | + | 27 | IV | 2 | Meningioma | - | mild | Hypothyroidism, thyroid nodules, hearing loss,asthma | 28 | |
26 | M | Medulloblastoma | 8 | 54 | 25 | + | 5 | IV | 3 | + | mild | - | Hypopituitarism, hearing loss | 14 | |
27 | M | Medulloblastoma | 8 | 54 | 21 | + | 2 | I | 3 | + | moderate | moderate | Hypopituitarism, hearing loss | 10 | |
28 | M | Medulloblastoma | 13 | 54 | 24 | + | 5 | IV | 2 | + | moderate | - | Hypopituitarism, loss, class I obesity, epilepsy, tetraparesis hearing | 10 | |
29 | M | Medulloblastoma | 11 | 68.6 | 24 | + | 2 | IV | 3 | + | - | mild | Spinal hygroma, hypothyrodism, growth hormone deficiency | 14 | |
30 | M | Medulloblastoma | 6 | 68.6 | 18 | + | 7 | IV | 3 | + | - | - | Hypopituitarism, hearing loss, intellectual disability | 19 | |
31 | M | Medulloblastoma | 9 | 60 | 3 | + | 29 | II | 2 | mild | - | Basalioma, hearing loss, intellectual disability | 30 | ||
32 | F | Medulloblastoma | 25 | 60 | 6 | + | 18 | IV | 3 | extensive | moderate | Coxarthrosis with total endoprothesis, gonarthrosis | 18 | ||
33 | M | Medullo- blastoma | 2 | 60 | 13 | + | 7 | IV | 3 | moderate | mild | Visual Impairment, groth hormone deficiency, hypothyroidism, intelectual disability, hearing loss, steatosis hepatis | 17 | ||
34 | F | Ependy-moma | 12 | 68 | 31 | + | 13 | IV | 3 | moderate | mild | Hypopituitarism, chronic renal failure | 13 | ||
35 | F | Ependy-moma | 6 | 72 | 28 | extensive | - | - | 13 | ||||||
36 | F | Ependy-moma | 7 | 68 | 10 | mild | - | Asthma bronchiale | 13 |
ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CRF = cancer related fatigue; COPD = chronic obstructive pulmonary disease; CP = craniopharyngeoma; CR = cranial radiotherapy; DD = differential diagnosis; MRI = magnetic resonance imaging; n.a. = not available; PA = pilocytic astrocytoma; PCHT = polychemotherapy; RIC = radiation-induced cavernomas
Childhood cancer survivors received between 2 and 31 MRI examinations of the brain and we analyzed in total 383 MRI examinations. Radiation-induced meningiomas were found in four patients (11%), one of whom had 2 and another had 5 meningiomas. Furthermore, in one patient we found a possible vestibular schwannoma, which, however, could not be reliably distinguished from an aneurysmal bone cyst via imaging. Gliomas were not detected in long-term follow-up. Leukoencephalopathies were found in 28 patients (78%), while 12 of those 28 (43%) were mild, 10 were moderate (36%) and 6 extensive (21%). According to semi-quantitatively analysis we found brain atrophy in 8 patients (22%): Five of them mild (62.5%) and three moderate (36.5%), but detected no cases of severe brain atrophy.
For further long-term comorbidities see Table 3.
In long-term follow-up 162 of 383 brain MRI examinations (42%) did not meet inclusion criteria because of lacking T2*/susceptibility weighted imaging sequences or movement or other artifacts. Thus, we were able to analyze 221 brain MRI examinations (58%) concerning RIC.
18/36 patients (50%) showed RIC. We found a significant relation of existing RIC to the original tumor entity (p = 0.023) and to the cumulative radiation dose to the brain (p = 0.016).
The occurrence of RIC was equal in female (n = 9) and male patients (n = 9) (p = 0.500). There was no significant association between the occurrence of RIC with the age at initial tumor diagnosis respectively start of cranial radiotherapy. Furthermore, we found no significant differences of RIC in the dichotomized patient groups “younger age” (≤ 8 years, RIC n = 8) and “older age” (> 8 years, RIC n=10) (p = 0.370).
The cumulative radiation dose differed significantly between childhood cancer survivors with RIC (median 54 Gy [IQR 24–60 Gy]) and childhood cancer survivors without RIC (median 24 Gy [IQR 12–40 Gy]) (p = 0.019).
All 9 childhood cancer survivors with treated medulloblastoma developed RIC (100%). Occurrences of RIC dependent on the other tumor entities were: ALL 3/13 (23%), AML 3/5 (60%), pilocytic astrocytoma 1/2 (50%), germinoma 1/3 (33%) and ependymoma 1/3 (33%). One patient with craniopharyngeoma did not develop RIC. We classified RIC only in 1 patient (3%) with ALL (Zabramski type II) and in 2 patients (6%) with medulloblastoma (Zabramski type I and type II) as high risk for hemorrhage while all other detected RIC were classified as Zabramski type IV with low risk for hemorrhage. We did not find any statistically significant difference between RCI with low and high risk for hemorrhage depending on the original tumor entity (p = 0.737). We did not categorize RIC as Zabramski type III or V, in accordance with the proposal of Nikoubashman
The aim of this study was to describe for the first time the course of RIC during long-term follow-up of childhood cancer survivors, those formerly treated with cranial radiotherapy in connection with the initial diagnosis of leukemia or brain tumor. We thus assessed the hemorrhage risk of RIC following Nikoubashman’s interpretation of the MRI appearance of cavernomas based on the Zabramski classification and examined the question of how to deal with RIC that frequently appear in MRI follow-up examinations of childhood cancer survivors. In our experience to date this seems to be distinctly more difficult than providing recommendations regarding extraaxial or intraaxial neoplasms (especially meningiomas or gliomas), which have already been the subject of extensive discussion in relevant literature as long-term consequences.4 Several guidelines, often based on a risk stratification system mainly taking into account the initial cancer diagnosis and the treatment received, recommend specific follow-up examinations to facilitate early diagnosis and treatment of these sequelae.15
Besides neoplasms, neurocognitive deficits in connection with pathological findings in brain MRI, such as leukoencephalopathy or brain atrophy, are reported in connection with childhood cancer survivors.16 Also our results showed 4 radiation-induced meningiomas, but no gliomas. There were variable findings of leukoencephalopathy, brain atrophy and several other comorbidities, though this was not a focal point of our studies.
Our study focuses on RIC. An assumed correlation between cranial radiotherapy and cavernomas in children was primarily described in 1994.17 In the following years this phenomenon was investigated extensively in several studies and summarized in review articles with a visible predominance in young patients treated for cancer.18, 19, 20, 21, 22, 23, 24 Furthermore, researchers also looked into the question of whether RIC differ from other, sporadically or familially occurring cavernomas regarding their natural course. Baumgartner
Concerning RIC, our results include a significant relation to the initial tumor entity and the cumulative radiation dose to the brain, as reflected by the occurrence of RIC without exception in patients treated for medulloblastoma with high cumulative radiation doses. In 2007 Lew
With regard to the correlation between RIC and cranial radiotherapy, data on the time lag of the occurrence after radiation are additionally available. Following examination of 5 patients with cavernomas after cranial or craniospinal irradiation, Jain
Due to possible hemorrhage complications of RIC, the two latter studies very explicitly advocated imaging monitoring and Singla
A number of studies have examined the hemorrhage risk of cavernomas in general. Flemming
It is certainly more difficult, however, to deal with lesions classified as Zabramski type I or II. As a reminder: type I is a (sub-)acute hemorrhage while type II as a “popcorn lesion” shows multiple hemorrhages. Here we again refer to data on the generally increased bleeding risk of cavernomas with already existing hemorrhage.7 Among others, Jeon
As regards our results, we classified RIC as high risk for hemorrhage (Zabramski type I and II) in only 3 of 36 childhood cancer survivors (8%) and all other RIC were classified as low-risk lesions (Zabramski type IV [microhemorrhagic]). In this risk assessment we orient ourselves to the proposal made by Nikoubashman
It must be emphasized that in this retrospective case series half of the childhood cancer survivors examined in long-term follow-up showed RIC in follow-up brain MRI. Thus, our study supports the development of cavernomas after cranial radiotherapy as a common side effect in childhood cancer survivors, though most RIC are not likely to hemorrhage and are detected incidentally. Our results therefore suggest a mainly benign course of RIC. Consequently we conclude that the complication risk of RIC can definitely be described in good conscience as low in communication with childhood cancer survivors as long as one applies assessments of existing classifications.13, 14 This ensures an advantageous aspect in dealing with patients who might feel anxious as a result of their prior cancer history. Studies with larger groups of patients and stronger study designs may possibly clarify whether dealing with RIC should be included and defined in the guidelines in connection with childhood cancer survivors.
Thus, we conclude that RIC are common late effects in childhood cancer survivors treated with cranial radiotherapy affecting half of the patients. However, only a few RIC (occurring in 8% of all reviewed childhood cancer survivors) were classified as high risk for hemorrhage and the majority of RIC follow a benign course. None of the childhood cancer survivors with RIC developed symptomatic hemorrhages. These results augment accurate risk assessment in individualized long-term follow-up also in order to reduce morbidity in childhood cancer survivors. In this context we are addressing an important point in the communication with childhood cancer survivors.
A retrospective approach with a relatively small sample size is a limitation of the present analysis. But, in particular, the accumulation of data concerning childhood cancer survivors also in the long-term follow-up, focused on here, is extremely rare, also in university hospitals. Nevertheless we strongly believe that this to our knowledge first study of this specific topic is valuable to assess the clinical relevance of radiation-induced cavernomas in brain MRI and add to be clear about their low risk for hemorrhage (with importance for patients and for physicians).
We are also restricted by the selection bias concerning inconsistent brain MRI data with lack of standardized imaging protocols in many MRI examinations conducted abroad and in some cases only a single follow-up examination with an extensive time lag until radiation. Furthermore, we did not focus on a detailed description of the irradiated fields, in particular, and the localization of RIC in our patient group, but we propose that this topic should be assessed after examination of larger collectives. The correlation between RIC and cranial radiotherapy that we assume in our results naturally remains unproven, also histologically, in the end (in this connection, the differential diagnoses cerebral microhemorrhages or teleangiectasias also have to be considered). The extent to which hemorrhages from cavernomas correlate with clinical symptoms is a complex issue of its own that this study cannot resolve on the basis of a relatively small group without symptomatic hemorrhages.