The clinical course for patients with diffuse infiltrating low-grade gliomas (LGG) is often unpredictable. In such WHO grade II gliomas, negative prognostic factors for survival are advanced age, large tumor size, midline involvement, the presence of neurologic deficits and astrocytoma histopathology [1]. In long term survivors, health related quality of life (HRQL) is often reduced, even in patients with stable disease [2].

Surgical management of suspected LGG is controversial [3]–[7]. A key factor when deciding on the surgical strategy is often the tumors’ perceived relationship to so-called eloquent brain regions, meaning involvement of sensorimotor regions, language cortices, basal ganglia and/or larger white matter tracts. LGGs located within or in close proximity to these areas may be subject to a less aggressive surgical strategy to avoid acquired motor or verbal deficits, while hopefully preserving patients’ HRQL [7]. As radical resections are less often achieved in such regions, eloquence is perhaps also a negative prognostic factor with respect to survival [8]. Despite the key importance for clinical decision making, the association between lesion eloquence for survival and long-term HRQL has not been much explored in LGGs.

In a consecutive population based series of patients with supratentorial LGG treated at two centers we aimed to study if eloquence in tumor location has implications for survival or quality of life. Our secondary aim was to provide long-term data on HRQL in LGG patients.

After the central review of initial histopathology in all LGG, 153 adults with supratentorial LGG were identified and included in the study (figure 1). In 46 patients (31%) the tumor was located in an eloquent area. Among the 46 patients with LGG in eloquent locations, 22 (48%) underwent biopsy only as the initial surgical procedure, as compared to 17 (29%) in non-eloquent lesions. Baseline characteristics for the different groups are shown in table 1.

In the present study, we found impaired survival in patients with LGGs in eloquent locations compared to patients with tumors in other areas. The impact of eloquence on survival remained after adjusting for established prognostic factors that were skewed at baseline. In long-term survivors, reported HRQL was not statistically different in patients with eloquent and non-eloquent lesions.

In our study of 153 consecutive patients, 30% of all LGGs were defined as eloquent in location based on the Sawaya classification system [10]. However, to be remembered, eloquence as defined anatomically [10] does not always correlate to functional regions as characterized with various techniques, such as functional MRI or direct cortical stimulation. It was for example recently reported that presumed eloquence from imaging can be a modifiable risk factor for impaired survival since eloquent LGG can still be safely removed in many instances [8]. Perceived eloquence is still often of key importance when neurosurgeons decide on the surgical strategy with respect to aggressiveness and invasiveness of the procedure in addition to planning of which techniques or technology to utilize. This was demonstrated in our study by the declining percentage of resections with increasing eloquence of the tumor. However, is eloquence as important for the patients as it is for the surgeons? Neurosurgeons have tradition for a special respect for areas perceived of so-called eloquence with a traditional focus on the executive motor and language regions, even though there are presumably no non-functional regions in the brain. Much less attention and respect is given to brain regions that may affect various cognitive functions, personality functions or sensory neglect. Is the discrimination against other brain functions justified? In unselected patients with gliomas we earlier observed that new neurologic deficits have an immense effect on short-term HRQL [17]. Although a paresis may perhaps seem more important than the mild cognitive deficit in the short term, this may be different in the long term. How different surgically induced deficits affect HRQL over time is largely unknown, and how the response shift that may occur over time affects results remains speculative [18]. In a recent cross-sectional study of long term HRQL in LGGs, Aaronson et al found that most of the impairment in HRQL was attributed to the cancer diagnose per se, but with an additional burden in cases with neurocognitive symptoms and poor seizure control. While motor deficits were rare, approximately one quarter of patients reported serious problems with neurocognitive functioning, particularly memory and concentration [2]. This is supported by the findings in our study with a relatively high symptom burden in several assessed HRQL domains, especially for cancer related symptoms and less pronounced in specific brain symptoms including functions associated with eloquent location. Except from seizures, that are known to lower HRQL, [2] the disease specific symptom burden was largely similar to previous studies using the EORTC QLQ-BN20 questionnaire (table 4). However, concerning future uncertainty somewhat lower scores were noted in the LGG studies at long-term follow-up compared to high-grade gliomas recently diagnosed. If this reflects the difference in aggressiveness of the disease or the time since diagnose or both remain unknown. Seizures and use of antiepileptic drugs are well-known risk-factors for impaired HRQL and cognition [19]–[22]. It seems like ongoing seizure activity is related to impaired HRQL, while use of antiepileptic drugs have a stronger association with cognitive function [22]. In fact, the study from Klein et al suggest that patients with stable disease with grade II glioma and seizures have similar HRQL to epilepsy patients without glioma [22]. However, as only one patient had high symptom burden with respect to seizures in the present study, the impact or seizures were not explored in the HRQL analyses.

Several important aspects when caring for patients with LGG were illuminated in our study. First, eloquence affects the chosen surgical strategy and seems to have an independent and dose-response effect on survival. A direct biological effect of tumor location on survival cannot be out-ruled, but the finding may also be attributed to the prognostic importance of extensive resections [23]. Thus, more widespread use of technology to aid safe and extensive resections in eloquent lesions is perhaps beneficial. Second, our findings may indicate that our surgeons have been careful enough to avoid overly aggressive treatment since neurological deterioration was infrequent in eloquent locations and since HRQL was much alike in the two groups. More aggressive resections in eloquent locations could perhaps have been favorable with respect to survival, but how long-term HRQL could have been affected by more radical surgery remains speculative. This demonstrates the typical dilemma patients and their treating neurosurgeons regularly have to deal with in glioma surgery. Third, functions in eloquent brain regions may perhaps be of less importance for patients HRQL than perceived by surgeons. Unfortunately, a study with high-quality data on longitudinal HRQL in consecutive LGG patients is still lacking. In sum, our study may suggest that a surgical strategy advocating extensive resections may outweigh the risks in most LGG. With the use of modern technology such as 3D ultrasound, intraoperative MRI [24], or mapping techniques [25] quite safe resections are most often possible, even in eloquent locations. Further refinement of tools and techniques should be encouraged to safely enhance tumor removal.

The major strengths of this study is the high external validity due to the unselected population based inclusion, the review of histopathology for the survival analysis and the adjusted survival analysis with respect to known prognostic factors. Without this adjustment the worse prognosis seen in eloquent tumors could simply have been explained by patients having worse functional status and larger tumors more often crossing the midline. In addition, the long-term HRQL data is rare in the LGG literature and offer a more holistic perspective on the tolls of the disease and its management than the traditional surgical outcome measures such as extent of resection or complication rates. However, this study has limitations as well. Unfortunately we have no information on resection grades since early MRI was not routinely performed at both hospitals. Collection of data except for HRQL was done retrospectively. However, survival is a robust end-point unaffected by the collection of data. Further, the responding patients who provided HRQL data were pre-selected by their survivorship – and those responding seemed to in the best prognostic group at time of diagnose. Thus, the long-term findings in this study may best apply to patients with good prognostic factors at presentation. Perhaps also influencing the results was the rather low statistical power in the HRQL analyses.

We would like to thank Anne-Lise Furnes at University Hospital North Norway and Lisa M. Sagberg at St.Olavs University Hospital for facilitating this research project by helping in data collection. In addition we would like to thank Ole K. Losvik for help with figures.