Because diffuse pontine glioma (DPG) is rare among young children, the outcome of affected patients is unknown.
Because diffuse pontine glioma (DPG) is rare among young children, the outcome of affected patients is unknown.
The authors reviewed clinical and radiologic characteristics of all children aged <3 years with DPG who were evaluated at their institution. Inclusion followed standard magnetic resonance imaging criteria for the diagnosis of DPG.
The median age at diagnosis in 10 patients was 2.2 years (range, 0.8–2.7 years). The median interval between the onset of symptoms and diagnosis was 2.5 months. All patients presented with cranial nerve palsy with (n = 7) or without (n = 3) other neurologic deficits attributable to brainstem involvement. All patients had pons-based tumors involving >50% of this brainstem segment. Histologic confirmation was attempted in 2 patients who had atypical radiologic features at diagnosis. Four patients initially were observed only. All patients received therapy, which consisted of radiation therapy (RT) (n = 2), RT and chemotherapy (n = 6), or chemotherapy only (n = 2). Four patients died of tumor progression after a median of 0.7 years (range, 0.5–3.7 years). Six patients have survived for a median of 2.3 years (range, 0.9–8 years). The 3-year progression-free and overall survival rates were 45% ± 19% and 69% ± 19%, respectively.
Children aged <3 years with DPG potentially may fare better than older patients with the same diagnosis despite the use of similar therapy. The current results suggested that DPG in younger children may be distinct biologically from similar tumors in older age groups. Cancer 2008. © 2008 American Cancer Society.
Brainstem gliomas constitute 10% to 15% of all brain tumors in children,1 and diffuse pontine gliomas account for 80% of all brainstem tumors in childhood. Although magnetic resonance imaging (MRI) has revolutionized the diagnosis of diffuse pontine glioma,2 no progress has been reached in the treatment of children with such tumors for the last 20 years.3 The long-term survival of children with diffuse pontine glioma has remained <10% despite the use of radiation therapy (RT), which is the mainstay of therapy, and several different regimens of chemotherapy.3
Although diffuse pontine glioma in children portends a poor prognosis, a few prognostic factors associated with improved outcome have been recognized and consist of prolonged latency between onset of symptoms and diagnosis,4, 5 lack of cranial nerve palsies,6 presence of atypical radiologic characteristics,7 and concurrent diagnosis of neurofibromatosis type 1.4, 8, 9
Diffuse pontine glioma usually affects school-aged children.5 However, these tumors can affect patients of any age, including adults10 as well as infants and toddlers.11–13 Because diffuse pontine gliomas rarely affect children <3 years, little is known about their outcome. In addition, most contemporary clinical trials for children with diffuse pontine glioma are restricted to patients aged ≥3 years.
We reviewed our institutional experience in the treatment of young children with diffuse pontine glioma. To our knowledge, unlike other reports in which patients were evaluated by MRI or computed tomography,11–13 the current study represents the largest series to date of children aged <3 years with diffuse pontine glioma evaluated exclusively by MRI.
Once Institutional Review Board approval was obtained, we reviewed the medical records and MRI studies at diagnosis of all children aged <3 years with diffuse pontine glioma who were evaluated at our institution between October 1, 1992 and May 1, 2007. The study period was established to encompass all patients who had their MRI studies reviewed centrally to confirm the diagnosis of diffuse pontine glioma.
Diffuse pontine gliomas were defined either as poorly demarcated tumors originating within the pons and involving >50% of this brainstem segment as assessed by T2-weighted MRI sequence or as any infiltrative tumor originating in the pons but involving other contiguous segments of the brainstem.14, 15 Exclusion criteria consisted of nonpontine primary tumors, focal tumors (ie, well marginated tumors involving <50% of the pons), concurrent diagnosis of neurofibromatosis type 1, or histologic diagnosis other than glioma. Clinical information and treatment data were ascertained from chart review.
Central review of all pertinent MRI studies was conducted by a neuroradiologist (F.H.L.) who was blinded to the patients' clinical characteristics. For part of this review, we assessed tumor characteristics, including involved brainstem segments, tumor dimensions, presence of atypical radiologic features, and pattern of enhancement. Pathologic review of available tumor samples was undertaken by a neuropathologist (D.W.E.) who was blinded to the patients' clinical characteristics.
Ten of 114 patients (8.8%) with diffuse pontine glioma who were evaluated at our institution during the study period met our inclusion criteria (Table 1). Their median age at diagnosis was 2.2 years (range, 0.8–2.7 years). The median latency between onset of symptoms and diagnosis was 2.5 months in 8 patients, and this interval was indeterminate for Patient 1 because of unreliable history obtained from his parents. Diffuse pontine glioma was diagnosed incidentally in Patient 7.
|Patient no.||Age at diagnosis, y||Sex||Interval between onset of symptoms and diagnosis||Clinical findings at diagnosis||Treatment||Overall survival, y|
|Cranial nerve palsy||Pyramidal deficit||Cerebellar signs|
All patients presented with cranial nerve palsy. Pyramidal deficits and cerebellar signs and symptoms were observed in 6 patients and 4 patients, respectively (Table 1). One patient (Patient 2) presented with severe apneic spells requiring surgical decompression of cerebellar tonsils before the start of additional therapy. Patient 7, whose tumor was diagnosed incidentally, underwent brain computed tomography for a skull fracture, which prompted the diagnosis of diffuse pontine glioma.
All patients harbored primary, intrinsic, diffuse pontine tumors with characteristic mass effect on surrounding structures according to standard radiologic criteria. Table 2 summarizes some of the characteristics of these tumors. It is noteworthy that atypical characteristics were detected in only 2 patients at diagnosis (Patients 5 and 6). The tumor in both patients had a diffuse, infiltrative, T2-hyperintense area and well circumscribed, enhancing nodules (Fig. 1a). Both Patients 5 and 6 underwent stereotactic biopsy of the enhancing nodules. Their tumors were diagnosed originally as well differentiated astrocytoma and low-grade infiltrative astrocytoma, respectively.
|Patient no.||Tumor location||Dimensions, cm||Enhancement (pattern)||Atypical characteristics|
|1||Pons and medulla||2.8×2.7||Yes (focal, small nodules)||None|
|2||Pons, medulla, and midbrain||4×5||Yes (marked, heterogeneous)||None|
|3||Pons and midbrain||4.4×3.6||Yes (minimal, punctate)||None|
|4||Pons, medulla, and midbrain||2.6×2.7||No||None|
|5||Pons and midbrain||4.5×3.5||Yes (focal in nodule)||Enhancing nodule|
|6||Pons and medulla||3.2×2.6||Yes (minimal in nodule)||2 nodules with minimal enhancement|
|7||Pons, medulla, and midbrain||4.1×3.2||No||None|
|8||Pons and midbrain||3.6×2.6||Yes (focal in necrotic areas)||None|
|9||Pons and midbrain||4.1×3.9||No||None|
|10||Pons and midbrain||4.8×4.1||No||None|
Pathologic review of the tumor from Patient 5 revealed an unusual histopathology that was not typical for a diffuse pontine glioma. Tumor cells with spindle-cell morphology and bipolar fibrillary processes or oval nuclei and poorly defined cytoplasmic borders were arranged in a vague fascicular or storiform pattern (Fig. 2a). Nuclear pleomorphism was mild. Although a few mitotic figures were detected, the mitotic count did not exceed 2 per 10 high-power fields (Fig. 2b). The Ki-67 immunolabeling index was <5%. All tumor cells showed strong immunoreactivity for glial fibrillary acidic protein (Fig. 2c). No tumor cells were immunoreactive for neuronal markers, but an antineurofilament protein antibody demonstrated entrapped axons, which were distributed irregularly among the fascicles of tumor cells (Fig. 2d). Neither angiogenesis nor necrosis was observed. These features were considered to be similar to those in some types of pilocytic astrocytoma. We believed that the tumor biopsy from Patient 6 was nondiagnostic, essentially yielding normal tissue.
It is noteworthy that Patient 5 experienced local tumor progression within the diffuse component of the tumor and leptomeningeal spread (Fig. 1b). A third patient (Patient 2) had a diffuse tumor with marked, heterogeneous enhancement.
Four patients underwent observation only at first. Patients 1 and 7 were followed for 5 months and 9 months, respectively, until neuroimaging showed clear progression. Then, they received RT only (Patient 1) or RT with concurrent and subsequent erlotinib (Patient 7; Tarceva; OSI Pharmaceuticals, Melville, NY; Roche, Basel, Switzerland; Genentech, South San Francisco, Calif). Patient 4 was started electively on chemotherapy after 3 months of observation using carboplatin and vincristine followed by temozolomide (Temodar; Schering-Plough, Kenilworth, NJ) and thalidomide. Patient 6, who had a tumor with atypical radiologic characteristics, was observed for 4 months until disease progression was established on neuroimaging studies. This patient experienced disease stabilization after receiving 18 months of chemotherapy, which consisted of carboplatin and vincristine.
The 2 initial patients in this series (Patients 8 and 9) were started on chemotherapy, which consisted of cyclophosphamide and vincristine, and carboplatin and vincristine, respectively, but treatment was switched to RT within 3 months because of clinical progression. Two patients (Patients 2 and 3) received RT followed by the 5-day schedule of temozolomide for up to 6 courses. Patient 10 received erlotinib concurrently with and after RT.
The median dose of local RT in 8 patients was 54 grays (Gy) (range, 50.4-55.8 Gy). Three patients (Patients 1, 2, and 3) were aged <2 years at the time they started RT.
Patient 9 has experienced multiple tumor progressions (local and leptomeningeal). This patient received several investigational chemotherapy and biologic agents and has had disease stabilization for >3 years since she completed treatment with lonafarnib, an oral farnesyl transferase inhibitor (SCH66336, sarasar; Schering-Plough).16 Patient 7 is currently receiving palliative chemotherapy after clinical and radiologic progression. Four patients have died of tumor progression after a median interval of 0.7 years from diagnosis (range, 0.5–3.7 years) (Table 1), and 6 patients have survived for a median of 2.3 years (range, 0.9-8 years). Of 5 patients who survived for >2 years, only 1 patient (Patient 2) has experienced a good partial response to therapy. All other surviving patients had disease stabilization as their best radiologic response.
Long-term sequelae have been investigated in only 2 patients. Patient 2 has hearing loss and speech problems. He also experienced primary hypothyroidism, which required hormone supplementation and poor growth associated with growth hormone deficiency. Patient 9 has significant osteopenia because of prolonged exposure to corticosteroids and poor growth associated with growth hormone deficiency. The 3-year progression-free and overall survival rates for all patients were 45% ± 19% and 69% ± 19%, respectively.
Although diffuse pontine gliomas uncommonly affect young children, the current study demonstrates that young age at diagnosis (<3 years) may be associated with a better outcome. Six of our patients have survived for at least 2 years despite the use of therapy that is ineffective in older children with similar tumors. Conversely, 3 patients experienced short survival, which is typical for older children with diffuse pontine glioma. Only 3 of our patients (Patients 5, 6, and 9) had other prognostic factors associated with improved outcome, consisting of atypical radiologic characteristics at diagnosis and long latency between onset of symptoms and diagnosis. One patient, whose tumor was diagnosed incidentally, had typical radiologic characteristics and already has experienced clinical and neuroimaging progression after completing RT. Marked tumor enhancement, an uncommon radiologic characteristic that has not been associated with the outcome of patients with diffuse pontine glioma, was observed in 1 patient (Patient 2).15, 17 All but 3 of our patients had cerebellar signs and/or pyramidal deficits in addition to cranial nerve palsy at presentation, which are clinical features associated with a poor prognosis.18
One strength of the current study was our central radiologic review, which selected only patients who had MRI studies at diagnosis that fulfilled established criteria for diffuse pontine glioma.14, 15 Diffuse pontine gliomas have a highly infiltrative behavior, producing a histopathologic phenotype reminiscent of gliomatosis cerebri. This accounts for the diffuse expansion of the pons without the formation of a distinct mass until late in the course of the disease, when progression to glioblastoma usually is associated with foci of pleomorphic glial tumor cells, a high mitotic count, angiogenesis, and necrosis with circumferential palisading of tumor cells. Two of our patients had atypical neuroimaging features, and histopathologic assessment of 1 of those tumors was possible. That tumor was unusual for demonstrating a mass of cells unlike those normally observed in diffuse pontine glioma. Instead, its phenotype, including a variable degree of infiltration (as assessed by axon entrapment), was reminiscent of some optic pathway gliomas, which are classified as pilocytic astrocytomas. In addition, it did not have the histopathologic characteristics of some low-grade brainstem gliomas that usually present as relatively circumscribed tumors in the tectum and medulla with features of a fibrillary astrocytoma or pilocytic astrocytoma, respectively.
Very few reports have described the outcome of children aged <3 years with diffuse pontine gliomas. Two multi-institutional studies in patients aged <3 years with malignant brain tumors included 28 children with brainstem glioma.11, 12 Both studies used upfront combination chemotherapy followed by RT at the time of progression or at the completion of chemotherapy, depending on whether or not residual tumor was present.11, 12 Because some patients were evaluated by computed tomography and not MRI in both studies, it is unclear what percentage of patients truly harbored a diffuse pontine glioma. Neither report provided details about clinical and radiologic characteristics of these patients and their treatment.11, 12 The 2-year progression-free and overall survival rates for the 14 patients who were treated by Duffner et al. (Baby Pediatric Oncology Group) were 28% ± 17% and 42% ± 14%, respectively.11 The 3-year progression-free and overall survival rates were 7% ± 7% and 29% ± 12%, respectively, in the second study.12
Lenard et al. have described 1 patient with diffuse pontine glioma diagnosed at age 23 months who experienced complete resolution of his tumor at age 6.6 years.19 This patient presented with signs and symptoms for 12 months. Stereotactic biopsy of the tumor yielded a diagnosis of fibrillary astrocytoma (World Health Organization grade 2). This patient received a combination of homeopathic medications only without RT. Thompson and Kosnik reported 2 neonates who experienced clinical signs attributable to brainstem involvement shortly after birth.20 Brain MRI demonstrated typical diffuse pontine glioma in both patients, and pathologic confirmation was not obtained. Both patients were observed only and remained well with regression of clinical and imaging findings 4 years and 10 years after diagnosis.
One recent report described an improved outcome in 13 children aged <4 years with pontine glioma diagnosed between 1983 and 2001.13 Their 2-year overall survival rate was 27.7% ± 13.6%. However, in that study, no central radiologic review was performed to distinguish between focal and diffuse tumors, and no information was provided about the number of patients evaluated exclusively by MRI.
The reason for the difference in outcome between our patients aged <3 years and older children with diffuse pontine glioma is unclear but probably is unrelated to therapy. It is possible that early diagnosis in the minority of our patients may have influenced their longer survival; however, only 3 of our patients (Patients 4, 6, and 7) had subtle neurologic involvement at diagnosis.
We hypothesize that the improved outcome of children aged <3 years with diffuse pontine glioma may be a consequence of different biologic characteristics of tumors in this age group compared with older children. Likewise, high-grade gliomas originating outside the brainstem that affect very young children have distinct biologic characteristics and improved prognosis compared with older children.11, 21, 22 Because very little is known about the biology of diffuse pontine gliomas,23 we have started a prospective study to collect tumor samples and perform extensive molecular analysis in such tumors.24 By better understanding the biology of diffuse pontine gliomas, we may be able to design appropriate and more efficacious therapies for affected patients of all ages.
We thank Mehmet Kocak, MSc, for his help in the statistical analysis.