Optic pathway gliomas (OPGs) are considered benign tumors when diagnosed in pediatric patients. OPGs associated with neurofibromatosis 1 (NF1) generally have an even more favorable course.1 These tumors usually present within the first 7 years of life; 90% present within the first 2 decades.2 Late-onset OPG (after 8 years of age) is a rarer entity that is not very well characterized.3 Tumor progression is documented in 15% to 30% of OPG cases and leads to visual impairment in approximately 30%.4 A meta-analysis by Opocher et al5 found only a few risk factors for progression emerging clearly from the literature, including young age at presentation (age <1 year), no NF1 comorbidity, and posterior location of the tumor. Management of pediatric patients with OPG must be individualized because of the heterogeneity of the patient population and chaotic tumor behavior. Currently, there is no consensus regarding long-term follow-up protocols for OPG patients. Some authors advocate 10 to 25 years of follow-up, whereas others have proposed that those patients who do not deteriorate during puberty will remain stable and therefore do not require an intense follow-up protocol.6,7 Follow-up data from most of the relevant series available is focused on the first 2 decades. Publications dealing with OPG in adults are rare, and consist mainly of case reports and small case series 8-11. In the present study, we present a series of OPG patients that have been under our follow-up as adults. We discuss the different sub-groups, risk factors for deterioration, and management options.
PATIENTS AND METHODS
We conducted a retrospective study that was approved by the institutional ethics committee at the Tel-Aviv Sourasky Medical Center. Data from patient medical records was accrued between 1990 and 2012. Inclusion criteria were age >18 years at last follow-up and sufficient follow-up data to determine the course of the disease. The only reason for exclusion of adult OPG patients was lack of sufficient follow-up data.
During the selected follow-up period, 24 patients >18 years of age who either were diagnosed with OPG as adults or were currently being monitored after diagnosis during childhood were identified. We divided the patient population into 2 groups. Group A included patients diagnosed with OPG as children and followed into adulthood. Group B included patients whose first diagnosis of OPG was in adulthood. Within group B, 2 subgroups of patients were identified: patients with characteristically “pediatric-like” tumors that were only diagnosed at adulthood and patients with characteristically “adult-like” tumors. Radiological progression was determined on the basis of magnetic resonance (MR) imaging (MRI) interpretation by a senior neuroradiologist (L.B.S.) according to accepted criteria (MacDonald criteria12,13 and volumetric measurements when available14,15). Visual deterioration was determined from statements in the patient’s neuro-ophthalmological follow-up records. Visual deterioration was defined as a drop of >2 lines in the Snellen test or a worsening in the Humphrey visual field test. Visual decline refers to visual deterioration inflicted directly by or related to the tumor, after examining with best refraction correction and ruling out other unrelated causes like aging and cataracts.
For each patient, we analyzed the course of the disease (both visual and radiological) during childhood and during adulthood.
A total of 24 adult OPG patients were followed up at the Gilbert Israeli Neurofibromatosis Center, the Division of Neurosurgery, the neuro-ophthalmology unit, and the neuro-oncology service at the Tel-Aviv Sourasky Medical Center. Two patients were excluded because of insufficient follow-up data. Twenty-two patients were included in this study.
Group A: Patients Diagnosed as Children
Twelve patients were diagnosed at childhood (<18 years of age). Seven patients were male, and 5 female. Seven patients had NF1, 2 patients with familial disease. The average age at diagnosis with OPG was 8.3 ± 5.4 years, ranging from 6 months to 17 years. Median follow-up time in this group was 9.5 years (range, 4 months-21 years). Anatomically, 3 patients in this group had Dodge I tumors, 6 patients had Dodge II tumors, and 3 patients had Dodge III tumors 16 (Table).
TABLE Demographics a...Image Tools
Group A During Childhood
Within this group (n = 12), 1 patient presented with bilateral blindness. Two of the remaining 11 patients suffered from worsening of their visual function during childhood. Five patients (of the 12) had radiological progression of their tumor during childhood. Two patients experienced some spontaneous regression of their tumors; both of these patients had NF1 and did not require any treatment. The remaining 5 patients remained stable during childhood.
Group A During Adulthood
At adulthood, 3 patients (of 11) suffered from worsening of their visual function. One of these patients had concomitant radiological progression.
Relationship Between Changes Occurring During Childhood and Adulthood Outcome
When looking at the long-term status of the 12 members of group A, that were diagnosed in childhood, we see the following within the sub-group of 6 patients who experienced progression in childhood:
* Of the 2 patients who suffered radiological progression and visual decline as children, 1 patient had further progression of the tumor and associated visual decline during adulthood, undergoing surgery for subtotal resection. The other patient's tumor and vision remained stable as an adult with no need for treatment during adulthood.
* Two other patients who had progressive tumors with no associated visual decline during childhood experienced de novo visual decline as adults.
* A third patient who had progressive tumor with no associated visual decline during childhood remained stable as an adult with no need for treatment during adulthood.
* The patient who presented with bilateral blindness experienced tumor progression as a child, but the tumor remained stable as an adult with no need for treatment during adulthood.
In comparison, within the sub-group of 6 patients whose tumors remained stable (or regressed) in childhood, all 6 remained stable as adults with no visual decline and no need for treatment during adulthood.
To summarize, of the 6 patients who were totally stable (or improved) radiologically during childhood, none experienced any progression during adulthood. Of the 6 patients who progressed radiologically during childhood, 1 patient had both radiological progression and visual decline and 2 other patients had isolated visual decline during adulthood. We found that 3 of 6 patients (50%) had progression at adulthood after tumor activity during childhood.
Three of the patients with progressive OPGs had other central nervous system tumors as well (cerebellopontine angle meningioma, brainstem glioma, and cystic hamartoma). Three patients in group A required surgery. Two patients underwent subtotal resection and the third underwent cyst fenestration. Two of these patients required ventriculoperitoneal shunting to relieve tumor-associated hydrocephalus. Pathology in both cases was consistent with pilocytic astrocytoma. Two of 12 patients received chemotherapy, 1 for radiological progression in a blind patient and 1 for visual deterioration. The first treated patient experienced peritoneal tumor seeding associated with the ventriculoperitoneal shunt. The main bulk of his tumor stabilized after treatment with vincristine and carboplatin, and the metastasis responded to treatment with a multiagent protocol (etoposide, carboplatin, vincristine, cytoxan). The second patient stabilized both visually and radiologically after chemotherapy. Two patients received radiation therapy, 1 for a concomitant brainstem glioma and 1 for a malignant peripheral nerve sheath tumor.
Group B: Patients Diagnosed as Adults
Ten patients were diagnosed at adulthood. Five patients were male and 5 were female. Four patients had NF1. Median follow-up time was 13.75 years (range, 4-11 years). Mean age at diagnosis was 39 ± 21 years, ranging between 20 and 68 years.
Of this group, 2 patients suffered from high-grade tumors (World Health Organization grades III and IV). These patients presented at a relatively older age (64 and 68 years) with signs and symptoms mimicking optic neuritis or central retinal vein occlusion. Both of these patients initially experienced rapid visual deterioration and tumor progression and then exhibited good short-term responses to the accepted glioblastoma treatment protocol (combined temozolomide and radiation therapy). Nevertheless, both of these patients died as a result of their high-grade OPG (within 4 and 7 years from diagnosis).
The remaining 8 patients had radiologically appearing low-grade tumors (only 2 with verified histology: 1 with juvenile pilocytic astrocytoma and 1 with World Health Organization grade II astrocytoma). Four patients of this adult low-grade glioma group (50%) experienced visual decline, 3 with concomitant radiological progression. The fourth patient had visual decline with no apparent radiological change. Two patients underwent surgery, 1 for an open biopsy and 1 for insertion of a ventriculoperitoneal shunt and a biopsy. The patient who underwent the open biopsy lost the vision in the affected eye and has not had any recurrence since then. The patient who had a ventriculoperitoneal shunt inserted developed dissemination of his tumor and seeding in the frontal horn. He was treated with a combination of vincristine and carboplatin followed by vinblastine and later stabilized both visually and radiologically. Two demonstrative MRIs are presented in Figures 1 and 2. Figure 3 demonstrates the outcome of the patients in this series.
This is the first article focusing on long-term follow-up of adult patients with OPG in the MR era. We stratified our group into 2 subgroups: group A, consisting of pediatric patients with apparently low-grade tumors who were followed into adulthood, and Group B, consisting of patients diagnosed as adults. To our surprise, it became evident that OPG may continue to be an active disease during adulthood. This statement is true both for patients under surveillance from childhood and for those who are first diagnosed when as adults. In the first group (group A), we have not documented any malignant transformations. In patients diagnosed during adulthood (group B), high-grade astrocytomas seem to be more common. It is possible that the 2 adult patients who presented with high-grade gliomas of the optic pathway may represent the evolution of a previously unnoticed low-grade tumor rather than the de novo appearance of a glioblastoma. Unfortunately, the IDH1 mutation ratio was available for only 1 patient and was negative in this particular case.17-21
Our findings suggest that patients with OPG in both groups should be continuously followed up during adulthood. Effective patient follow-up should be handled by a multidisciplinary team, monitoring every patient individually with careful neuro-ophthalmological evaluation and MRI surveillance, preferably with volumetric analysis.14,15 Prompt responses to anatomic and or ophthalmological changes may lead to better preservation of visual function over time.22-25
In 1973, Hoyt et al11 described a series of 15 adult patients with OPG. This article, published in the pre-MRI era, focuses on malignant tumors of the nerve and chiasm leading to blindness and mortality. Hoyt et al describe them as common tumors occurring in an uncommon location. Similarly, in the modern MR era, there are only sporadic case reports dealing with adult OPG, all again focusing on the malignant subtype.8-10,26 Articles dealing with pediatric OPG patients followed up into adulthood are rare.27 A recent exception is an article by Chong et al28 describing 33 adolescents with OPG, demonstrating favorable results for chemotherapy in this group. This article, despite dealing with a relatively old group of patients (age ≥10 years), is not focused on long-term outcome and disease course during adulthood.
Group A: Patients Diagnosed at Childhood
This group consists of the typical OPG. These tumors present in pediatric patients, usually with NF1, and are considered relatively benign, requiring treatment or intervention in only approximately 30% of cases. Of this group, only 3 patients had verified histology, all defined as pilocytic astrocytoma. These tumors usually require prolonged follow-up, both radiologically and through clinical visual assessments. Current recommendations for the management of pediatric OPG patients suggest that if the tumor and vision are both stable, follow-up intervals can be slowly lengthened.
In our series, the pediatric group included 12 patients, all with radiologically typical low-grade gliomas of the optic pathway. Six of these patients had tumors that were radiologically stable or even experienced some regression during childhood, and none of them suffered any progression or further visual decline during adulthood. Of the 6 patients whose tumors progressed radiologically during childhood, 3 patients (50%) suffered some level of additional tumor progression and/or visual decline in adulthood. We found that patients with radiological progression during childhood are at risk of further progression as adults, even after temporary stabilization.
Of the 6 patients whose tumors progressed radiologically during childhood, 1 patient had further radiological progression during adulthood accompanied by visual decline, and 2 other patients had isolated visual decline. Of the 10 patients who had stable vision during childhood, 2 patients had visual deterioration as adults. Of the 2 patients who had visual deterioration during childhood, 1 patient had further visual deterioration as an adult, accounting for a total of 3 patients (out of 12, all 3 of them with radiological progression at childhood) who had visual decline as adults. This leads us to the conclusion that patients with radiological progression during childhood are at risk of further progression as adults, even after temporary stabilization. Even patients whose vision was initially stable may still suffer visual impairment during adulthood as a result of the tumor.
Group B: Patients Diagnosed at Adulthood
The second group includes 2 subgroups (B1 and B2). Group B1 consists of 8 patients with late-onset, low-grade tumors diagnosed at adulthood. Only 1 patient in group B1 had verified pathology, consistent with fibrillary astrocytoma. Of group B2, both patients were diagnosed with high-grade glioma, one with glioblastoma multiforme and the other with an anaplastic astrocytoma. Of this group, 4 (50%) had visual decline, and 3 of those 4 patients (37%) had radiological progression. These percentages are consistent with or a bit higher than the accepted numbers for clinical behavior of pediatric patients with OPG (and NF1).2,4,29 For this group, a monitoring protocol similar to that of pediatric patients is recommended. On progression, chemotherapy may be less of an option, and more liberal use of radiation therapy should be considered.
Forty percent of the NF1 patients in our series were diagnosed at adulthood. In the current paradigm, it is possible that these patients actually belong to the first group but were not screened at childhood. The advantage of MR surveillance for asymptomatic patients with NF1 is that those with diagnosed OPG could be provided with a more focused and visually oriented follow-up.
Group B2 includes the 2 adult patients with adult-type tumors (high-grade gliomas, World Health Organization grades III and IV). Overall survival reported in the literature is usually <1 year,8 although most of these numbers were reported in the pre-MRI era and current numbers may be different. In our series, this group includes 2 adult men diagnosed in their sixth decade of life, with a surprisingly extended long-term survival. Their overall survival (7 and 4 years) was much longer than the numbers reported in the literature, both for high-grade gliomas in general and specifically for optic pathway high-grade gliomas. Both of them suffered rapid radiological progression and visual decline and received radiochemotherapy.
We are aware of the possible biases in this study such as a selection bias toward more difficult cases in both groups because data were collected from a tertiary referral center for neurosurgery. In addition, this is a retrospective study that may suffer from the known shortcomings of such a design. Our relatively small and heterogeneous group of patients makes solid conclusion making difficult. We believe, however, that there is an advantage that these patients are followed up by a program that treats and follows up both adults and children. Additional prospective studies with long-term radiological and visual end points are needed to verify our findings.
Patients with radiologically stable tumors diagnosed during childhood did not suffer progression during the follow-up period. Prolonged follow-up should be considered in patients who suffered visual decline or radiological progression during childhood and adult patients with late-onset OPG. OPG is a possible cause for visual decline in adult NF1 patients.
Several practical implications arise from our data. Our series leads us to recommend prolonged follow-up for pediatric OPG patients who suffered visual decline or radiological progression at childhood, even after a period of stability. Adults with high-grade gliomas of the optic pathway demonstrated more favorable prognosis than their counterparts with more commonly located tumors in our limited series.
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
We thank Dr David Curzon for his assistance with the manuscript.
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The authors present a retrospective follow-up of 22 patients with optic pathway glioma (OPG) diagnosed between 1990 and 2012. Despite the limited number of cases, the length of follow-up led to significant observations, especially in the group diagnosed in adulthood. Especially because of late development of visual impairments, the authors recommend lifelong follow-up. Prospective studies with a larger number of patients are needed to learn whether this is required for all patients. In most centers, it is difficult to accumulate a large series of OPGs. Significant new information has, however, been accumulated, for instance, through prospective multicenter studies on pediatric patients with low-grade gliomas that also included OPGs. Thus, the French Society of Pediatric Oncology explored multiagent chemotherapy as an alternative to radiotherapy in 85 pediatric patients with progressive OPG,1 the German Speaking Society of Pediatric Oncology and Hematology2 described the risk factors of progression in 231 patients with OPG, and a nationwide British prospective cohort study analyzed the risk factors for progression in 195 patients with OPG.3 Such studies demonstrate the importance of interinstitutional collaborations for establishing more reliable data for prognostic evaluation and clinical decisions in rare neurosurgical diseases.
Einar O. Vik-Mo
Iver A. Langmoen
1. Laithier V, Grill J, Le Deley MC, et al.; French Society of Pediatric Oncology. Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy: results of the first French prospective study of the French Society of Pediatric Oncology. J Clin Oncol. 2003;21(24):4572–4578. View Full Text | PubMed | CrossRef Cited Here... |
2. Gnekow AK, Falkenstein F, von Hornstein S, et al.. Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol. 2012;14(10):1265–1284. View Full Text | PubMed | CrossRef Cited Here... |
3. Stokland T, Liu JF, Ironside JW, et al.. A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702). Neuro Oncol. 2010;12(12):1257–1268. View Full Text | PubMed Cited Here... |
1. A 51 year old male presents to the clinic complaining of blurred vision and has evidence of an optic chiasm neoplasm on MRI. Biopsy of the lesion reveals a low grade astrocytoma. What is the most appropriate next course of action?
A. Repeat imaging in 2 years
B. Treatment at time of progression
C. Immediate chemotherapy and radiation
D. Immediate radiotherapy only
2. A 16 year old male with NF1 presents for follow-up 4 years after a diagnosis of Dodge II low-grade optic pathway glioma. After initial progression during early puberty, the tumor has been radiographically stable with no visual decline. What is this patient’s visual prognosis and need for follow-up?
A. Vision will likely remain stable; no need for continued follow-up.
B. Vision will likely decline until tumor stabilizes, monitor until stabilization is confirmed.
C. Vision will likely decline until end of adolescence; monitor until age 18.
D. Vision will continuously decline in adulthood; long-term follow-up is needed.
3. In patients with optic pathway gliomas, what age has been shown to be an independent prognostic factor for a worse progression free survival?
A. ≤ 1 year old
B. 2-5 years old
C. 6-9 years old
D. ≥ 10 years old