1. GENERAL INFORMATION
2. PATHOLOGY AND BIOLOGY
7. LATE SEQUELAE
Low-grade astrocytomas (LGAs), also defined as grade II astrocytomas, are primary brain tumours arising from glial tissue. In this overview only the diffusely growing LGA of the cerebral hemispheres occurring in adults will be discussed. The pilocytic astrocytoma [mainly occurring in children in the posterior fossa), and the optic nerve glioma, both regarded as LGA, should be treated differently from the adult hemispheric LGA, and have a different prognosis. Also, relatively rare tumours such as gangliocytoma, and the dysembroplastic neuro-ectodermal tumour (DNET), considered to belong to the group of LGA, will not be discussed here due to their different behaviour and prognosi. The same holds true for brainstem astrocytomas and gliomatosis cerebri, both of which may show low-grade features on histopathological examination.
LGA, defined by the International Classification of Disease for Oncology [ICD-O) with morphology code as 9400/3 (ICD-O 2000) which include also astrocytoma not otherwise specified (NOS), is one of the most common primary malignant brain tumour. In Europe, the annual incidence is slighlty less than 1 per 100,000 [RARECARE, web site]. In population-based registries LGA constitutes about 11% of all malignant nervous system tumours (ICD-O 191,192). Most patients diagnosed with LGA are between 30-69 years of age, and in this age group the annual incidence rate is between 1 and 1.7 per 100.000 (EUROCARE 2004). LGA is about 1.4 times more common in men (Curado 2007) and occurs about 2 times more often in caucasians (Curado 2007, Deorah 2006). A study on the trends in incidence of adult primary intracerebral tumours in Denmark, Finland, Norway, and Sweden found an increase in the overall incidence during the period 1969-98 with a peak around the late 1970s and early 1980s (Lonn 2004). Since 1984, the incidence has been stable or has even shown a slightly decreasing trend. On analysing specific histological types during the period 1969-98, the incidence of astrocytoma remained stable. In the US incidence of brain tumours increased until 1987, when the annual percentage of change reversed direction. Falling trend was observed for astrocytoma (Deorah 2006).
From the RARECARE project (EUROCARE 2004) survival data from LGA was analysed from 70 population-based cancer registries in 18 European countries. The survival analysis covered 11,885 adults with a diagnosis of LGA during the period 1995-2002 with a follow-up until 31st of December 2003.
The causes of astrocytoma are largely unknown, but genetic factors and a variety of environmental factors have been implicated at different levels. Furthermore, given the lower incidence rate of astrocytoma in women than men (see Figure 1), it has been hypotesized that reproductive and hormonal factors may be involved in the etiology of astrocytoma.
Familarity and genetic factors
Inherited syndromes may account for 5% of cases. Certain inherited syndromes with germ-line mutations, like neurofibromatosis type 1 and 2, tuberous sclerosis, and Li-Fraumeni syndrome predispose to develop astrocytoma or other tumours. Mutations in p53 are found in two-thirds of patients affected by low grade diffuse astrocytomas (WHO grade II) (Chawengchao 2001). Many studies on the familial risk of astrocytoma were conducted through the nationwide Swedish Family Cancer Database. Among adults, close to 11,000 patients with CNS tumours were identified, out of whom about 200 had parents with a CNS tumour. The standardised incidence ratio (SIR) was twice as high for astrocytoma for individuals with parents diagnosed with astrocytoma, and tripled if siblings had astrocytoma (Hemminki 2003a). Another Swedish study, which studied the risk of first-degree relatives (FDR) of glioma patients to develop LGG, showed a SIR of 3.65 for all FDR. The risk was even higher for FDR of probands < 40 year (SIR 4.75). The risk for siblings showed a SIR of 9.0 for patients younger and 7.0 for patients older than 40 years of age (Malmer 2002). A genetic cause of the increased risk, especially in sibpairs, seems likely because of observations of a very young average age of onset (22.6 years) as compared to 39.9 years among all LGG cases. Recently a study on Utah Population Data Base (UPDB), a genealogy representing the Utah pioneers and their descendants showed significantly increased risks to first- and second degree relatives for astrocytomas for relatives of astrocytomas but not of glioblastoma (Blumenthal 2008).
Ionising radiation is the only established cause. A study in a Finnish populationshowed that second primary brain tumours occur more frequently than expected among patients treated previously for brain tumours with radiation therapy (Salminen 1999) The atomic bomb survivors have a high incidence of meningioma correlating with the dose of radiation to their brain. Also, they have a higher incidences of glioma, schwannoma, and pituitary tumours (Preston-Martin 1989). However, because exposure to high levels of ionizing radiation is rare, these exposures account for only a small percentage of brain tumours. In a case-controlled study conducted in Los Angeles county, detailed job histories and information about risk factors were obtained from around 300 adult patients with CNS tumours and 300 matched controls (Preston-Martin 1996). Employment in jobs likely to involve high exposure to electrical and magnetic fields or jobs in the rubber and plastic industry. A case-controlled study of gliomas in adults in the San Francisco Bay area confirmed an association between increased risk and several occupations that had been reported previously. S pecifically, legal and social service workers, shippers, janitors, motor vehicle operators, and aircraft operators have odds ratio’s that increased with longer duration of employment. Physicians and surgeons, foundry and smelter workers, petroleum and gas workers, and painters showed an increased risk on both astrocytic and non-astrocytic tumours (Carozza 2000). Risks also increased with duration of exposure to a tenfold increase for those employed for over 20 years. An increased risk on astrocytoma [odd ratios 1.4 - 1.8) was found for workers exposed to organic chemicals in the petroleum-refining or chemical manufacturing industries in a case-referent study conducted in New Jersey (Thomas 1987).Associations of astrocytic brain cancer with possible exposure to carbon tetrachloride, methylene chloride, tetrachloroethylene, and trichloroethylene have been reported; the strongest being with methylene chloride (Heineman 1994). An association between astrocytoma and residential proximity to cranberr-bog cultivations was found in a population-based case-control study in Massachusetts (Aschengrau 1996 ). In a Swedish study based on the Swedish Cancer Enviroment Registry, pulp-mill workers were found to have more gliomas than expected (SIR 1.5) (Andersson 2002).A similar study reported also agricultural occupations like general farmers and farmworkers to have an increased incidence of gliomas: OR of 2.5 (95%CL: 1.4,4.7 ), whereas e.g childcare workers were associated with a decreased incidence of glioma [OR = 0.4; 95%CL: 0.2,0.9) (De Roos 2003).
Two cohort studies and 16 case-control studies have been considered to evaluate the risk among long-term users (>=10 years) of cellular telephones and brain tumour (Hardell 2008). For glioma, four case control showed increased risk (OR) and meta-analysis yielded OR = 2.0, 95% CI = 1.2-3.4.
Women have a lower astrocytoma risk (shown in Figure 1). Factors as age at first live birth, age at menarche, parity, menopausal status, use of oral contraceptive, and use of hormone replacement therapy have been studied. The results from a cohort of about 90,000 US women showed a positive association between age at menarche and risk. Compared with women with a relatively early age at menarche (<=12 years), women who were older than 14 years of age at menarche had 64% increased risk of glioma, and women who were older than 14years of age at menarche had 66% increased risk of glioma. This study also provide little support for associations between hormonal and reproductive factors and risk of glioma. ( Navarro Silvera 2006).
The authors would like to thank the cancer registries adhering to the RARECARE project for permitting use of the the incidence and survival analysis from the RARECARE dataset. The RARECARE project (Surveillance of rare cancers in Europe) is co-funded by the European Commission (EC) through its Public Health and Consumer Protection Directorate (DG SANCO). PHEA programme (grant agreement n° 2006113).
The diffusely growing gliomas are classified as astrocytomas, oligodendrogliomas or mixed gliomas, based on histopathological examinations. Astrocytomas account for about 80% of all gliomas. Histological variants of astrocytomas are fibrillary astrocytoma, gemistocytic astrocytoma, and protoplasmatic astrocytoma. The gemistocytic variant is particularly prone to dedifferentiation into anaplastic astrocytoma and glioblastoma multiforme. Pilocytic astrocytoma is mainly seen in children and may be regarded as a true benign tumour
(Kleihues 2000). Distinctions are made between low-grade and high-grade tumours. The absence of high-grade features such as mitoses, necrosis, nuclear atypia and microvascular proliferation implies a low-grade tumour. In the current WHO classification the previously applied grading system (grades I to IV for astrocytic tumours) has been abandoned. An LGA is now designated as "astrocytoma" (Kleihues 2000). Although a histopathology diagnosis of LGA has prognostic significance, it remains to some extent subjective as its is still being based on visual rather than genetic criteria.
3.1 Clinical presentation
LGA is a disease of young adults, and the majority of patients, up to 80 % (Grier 2005), presents with one or more (focal) seizures without other symptoms (Rees 2002; Ashby 2004). Typically, the clinical neurological examination does not show abnormalities; features of a rapidly growing tumour such as an HGG leading to neurological deficits and features of increased intracranial pressure are absent. Despite this, many patients with LGA (30%) may have problems with cognitive functioning that are already apparent at presentation (Pahlson 2003; Taphoorn 2004, Grier 2006). In some, the tumour may be detected by chance when imaging is performed for other reasons (e.g. head trauma, tension headache, dizziness). On imaging, LGAs appear on CT scans as hypodense lesions with relatively little mass effect and no contrast enhancement. On MRI, T2-weighted sequences or FLAIR images demonstrate a diffusely infiltrating high-signal lesion with slight mass effect. There is no contrast enhancement of this low-signal lesion on T1 sequences (DeAngelis 2001; Recht 1992; Franzini 1994). MRI is more sensitive in detecting LGA than CT. The presence of calcifications suggests an oligodendroglioma (about 20% of oligodendrogliomas show calcifications) rather than an astrocytoma. Both CT and MRI imaging have limitations in determining whether a lesion represents LGA, and an arachnoid cyst or infarction with atypical clinical presentation may be mistaken for an LGA. Additionally, ganglioglioma and DNET, which are rare tumours in adults, and which are most frequently located in the (medial) temporal lobe, may show features similar to LGA. However, these tumours are more sharply demarcated from the surrounding tissue than LGA and a ganglioglioma may show enhancement with contrast agent. More importantly, the distinction between a high-grade and a low-grade tumour may be difficult; in about 35% of cases diagnosed as "typical" LGA on imaging, subsequent histopathological examination has revealed high-grade features: this occurs most often in patients over 40 years of age ( Ginsberg 1998; Scott 2002; Henson 2005). The newer imaging modalities such as diffusion weighted imaging (DWI), MR spectroscopy (MRS) and functional positron emission tomography (PET) imaging may play an increasing role in tumor grading, together with (pre)surgical/functional mapping and follow-up after treatment in LGG, especially when conventional imaging fails to provide the necessary information.
A significant correlation between glioma grade and perfusion has been established (Hakyemez 2005, Ludemann 2005). Higher relative cerebral blood volumes are thought to be associated with microvascularity and be predictive of angiogenesis; in a recent study relative cerebral blood volume maps were shown to predict progression as an adjunct to histopathological findings (Fuss 2001).
Up to date, PET/SPECT has not been able to significantly improve the specificity of standard MRI ( Herholz 1998; Knopp 1999; Kono 2001; Vuori 2004). An integrated MRI/PET scanner for brain imaging may provide in the near future many better capabilities for defining the treatment and reliabale information during the follow-up of LGG (Minn 2005).
LGAs are confined to the cerebral hemispheres. They are mainly located in the subcortical structures of the frontal, temporal and parietal lobes, and less frequently in the occipital lobe (DeAngelis 2001). They are primarily located in "secondary" functional areas next to the so-called primary eloquent brain areas (Duffau 2004). Less frequent locations are the basal ganglia or the thalamus. However, these tumours may extend through the corpus callosum into the contralateral hemisphere.
3.3 Diagnostic criteria
Histopathology is presently the most important tool for diagnosis of LGA (Kleihues 2000). However, because of the heterogeneous nature of gliomas, histopathological examinations may miss high-grade features, especially in small,stereotactically obtained, biopsy specimens (sampling error) (Jackson 2001). Therefore a definitive diagnosis should ideally be based on a combination of histopathological, clinical and radiological features.
Staging does not apply to LGA. Although LGA is a diffusely infiltrating tumour, metastasis outside the central nervous system hardly, if ever, occurs. Leptomeningeal spread of LGA may occur in a minority of patients, more frequently in children than in adults ( Perilongo 2003).
Surgery for LGA can be performed for two reasons. A tissue biopsy is necessary to make a histopathological diagnosis, and provide samples for molecular genetic analyses. Reduction of tumour mass may be crucial in order relieve neurological signs and symptoms and signs, to relieve increased intracranial pressure, and to improve survival. As gliomas may have a heterogeneous histopathological structure, small (stereotactic) biopsies may result in an underestimation of tumour grade
Several retrospective analyses in LGA patients have shown that (focal) external radiotherapy results in improved survival (Shaw 1989; Cairncross 1989). As other retrospective studies did not demonstrate a survival benefit of radiotherapy, selection bias was presumed to be a confounding factor (Piepmeier 1987; Cairncross 2000). Adversaries of radiation therapy in LGA have also pointed to irreversible long-term side-effects of radiation which may lead to severe cognitive deterioration (Choucair 1997). At present, the controversy on (early) radiation treatment in low grade gliomas has ended, largely based on the results of prospective randomised trials in both Europe and the US. Two trials comparing high-dose with low-dose radiation (59.4 versus 45 Gy; 64.8 versus 50.4 Gy) did not demonstrate a survival benefit for high-dose radiation
(Karim 1996; Shaw 2002). Moreover, the results of the European trial (EORTC 22844) showed that high-dose radiation resulted in a worse health-related quality of life (Kiebert 1998). Of even more importance is the EORTC 22845 randomised trial in > 300 patients with low grade gliomas, comparing early radiotherapy with observation only, following surgery or biopsy. Although progression-free survival was significantly longer in the radiotherapy group, overall survival was not different (Karim 2002). Based on these results, early radiotherapy in low grade glioma patients with favourable prognostic factors has largely been abandoned. However, patients with histologically proven low grade gliomas over 40 years of age or showing neurological deficits are likely to benefit from early radiation therapy, type 2 level of evidence (Pignatti 2002). Nowadays, focal radiation is employed with total doses ranging from 45 to 60 Gy in fractions of up to 2 Gy as a
standard option on a type C basis. Also, patients with epilepsy refractory to anticonvulsants may benefit from radiation of a LGA (Rogers 1993).
Currently, systemic chemotherapy is not a standard treatment for LGA patients. Drawing on the effective chemotherapeutic treatment of high-grade oligodendroglioma and high-grade oligoastrocytoma with PCV chemotherapy or temozolomide, these agents have also been employed in low-grade oligodendroglial tumours in several phase II studies (van den Bent 1998; van den Bent 2003; Mason 1996; Pace 2003; Buckner 2003; Quinn 2003). Objective responses on imaging have been reported but may be difficult to interpret due to the absence of contrast enhancement of LGA. Interestingly, MR spectroscopy may add to the evaluation of therapy (Murphy 2004). In a recent study in low-grade oligodendroglial tumours, an objective response was obtained in 29 to 52% of patients. In contrast to the relation between response to chemotherapy and loss of chromosome 1p and 19q in anaplastic oligodendrogliomas, no such relationship was observed in low-grade oligodendrogliomas (Buckner 2003). Since there are potential long-term adverse effects of radiation and LGA may respond to chemotherapy, randomized studies comparing radiation and chemotherapy in LGA with unfavorable prognostic factors are now on trial in the US and Europe.
6.4 Treatment of recurrent disease
During the course of a "wait and see" policy, suspected LGA progression of tumour should warrant surgical intervention or at least a biopsy for making a histopathological diagnosis. Subsequent treatment should be based on a firm histopathological diagnosis. The choice of treatment of recurrent disease of LGA (i.e., following initial treatment) depends partly on the initially given treatment. Surgery for recurrent tumour growth can be advocated for both a second histopathological diagnosis and for removal of tumour mass. Not only can high-grade tumours be diagnosed, but a different subtype of glioma is frequently observed as well. For example, a pure astrocytic tumour may develop into a mixed glioma, which has consequences for the subsequent treatment of choice (Kleihues 2000). Another reason to advocate surgery for recurrent disease is to differentiate between recurrent tumour and radiation necrosis (Henze 2004). In cases where neither radiotherapy nor chemotherapy has been administered initially, patients with recurrent LGA should preferably be treated with focal radiotherapy (with or without a preceding re-operation). However, patients with a diffuse regrowth, in whom the radiation field is judged too large by the radiation oncologist, systemic chemotherapy may be the standard treatment option on a type C basis.
6.5 New Therapeutic options
Molecular analysis will hopefully soon be able to predict which subsets of low-grade gliomas are responsive to existing therapies or to new treatments. These new therapies, including anti-angiogenic treatment or immune modulation agents, have mainly been developed for recurrent high-grade gliomas, but some data in LGA have emerged (Watanabe 2003). To date, these agents have been of only limited value in the treatment of recurrent astrocytomas. Recently developed biologically-targeted therapies such as small molecule tyrosine kinase inhibitors are currently under study.
Cognitive and focal neurological deficits may have a great impact on long term survivors of brain tumors, regardless of the histology and grade of the tumors. Memory loss, apathy, concentration difficulties and personality changes may have a profound effect even in those patients who appear to have a Karnofsky performance status of 100. Surgery in so-called silent areas may contribute to cognitive deficits. Less clear are the late effects of radiation therapy on cognitive function. Radiotherapy is known to cause an early somnolence syndrome, but may also cause late sequelae, in particular a delayed leuko-encephalopathy with cognitive dysfunction and radiation necrosis
(Corn 1994; Crossen 1994; Kumar 2000). In individual patients it is difficult, however, to dissect the direct effects of the tumor on cognition from late effects of treatment. A recent survey on cognitive deficits in progression free survivors of low grade gliomas failed to confirm the generally assumed relationship between radiotherapy and cognitive deficits (Klein 2002). Only in those patients who had been treated with fraction of more than 2 Gy evidence of increased cognitive dysfunction was observed. The only other association with cognitive deficits was treatment with anti-epileptic drugs. Prior studies have suggested that whole brain radiotherapy may be associated with more cognitive deficits than involved field irradiation, but today involved field radiotherapy is standard practice (Gregor 1996). Radiation therapy may also affect cranial nerves, or induce endocrine dysfunction even in case of tumors distant from the hypothalamus-pituary region
(Brandes 2000). Seizures may have a great impact on the quality of life, even in patients with well controlled tumors. Newer anti-epileptic drugs may have less side-effects and should be considered, especially in those patients that are on a multi-drug regimen (van Breemen et. 2007). Apart from cognitive deficits, a risk of death of 2.5% at 2 years has been reported for doses of 50.4 Gy. A 5% risk of radionecrosis in 5 years may occur after 60 Gy to one third or 50 Gy to two thirds of the brain volume or with 50-53 Gy to brain stem. A similar risk for blindness is associated to irradiation with 50 Gy on the optic chiasm.
No general guidelines for the follow-up of LGA can be given, and these should be tailored to the individual patient, taking tumor grade, previous treatments and remaining treatment options into account. Follow-up in patients with low grade glioma should continue, even if with lesions which have been stable for many years. At some point in time, progression will occur, and treatment should be installed before irreversible deficits develop.
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Dr. Marica Eoli (Author)
Fondazione IRCCS Istituto Neurologico Besta - Milan, Italy
Dr. Gaetano Finocchiaro (Author)
Fondazione IRCCS Istituto Neurologico Besta - Milan, Italy
Dr. Gemma Gatta (Consultant)
Dr. Michele Reni (Associate Editor)
Dr. Marry Siegersma (Author)
Prof. Martin J.B. Taphoorn (Author)
Prof. Charles Vecht (Reviewer)