Low(er) Grade Gliomas: Surgical Treatment

Introduction

Low-grade gliomas are a group of intrinsic brain tumors, mainly occurring with seizures in young patients, appearing on conventional magnetic resonance imaging (MRI) as highly infiltrative nonenhancing masses, well visible in fluid-attenuated inversion recovery (FLAIR) images, involving one to multiple lobes, occasionally presenting with small enhancing nodules inside the tumor mass. More than 90% of these tumors have IDH1 mutation and share a common biological behavior and a similar clinical prognosis, less influenced by the histologic grade. ^, They are comprehensive of diffuse low-grade (grade II) and intermediate-grade gliomas (grade III), and have been recently defined as lower grade gliomas (LGGs), a term that has replaced “low-grade” in the current clinical practice. Less than 10% of these infiltrative gliomas do not have an IDH1 mutation, but they share with the earlier similar clinical and radiologic presentation, and do not differ in the method of surgical treatment.

Surgical treatment for LGGs is the topic of the present chapter.

LGGs have become a major focus in neurooncology. (1) Their incidence in the global population is increasing due to improved diagnosis and higher exposure to several risk factors, arising as a side effect of socioeconomic and technological growth. (2) In contrast to glioblastomas, LGGs usually develop in the younger population and are typically associated with seizures; their occurrence predominantly in the more active portion of the population strongly impairs the patients’ ability to maintain a normal social and working life, and they have important economic and social impacts. (3) LGGs invariably progress toward a more malignant phenotype. (4) Their natural history is long and quite variable; some are almost indolent and progress very slowly; others quickly progress to glioblastomas despite a good molecular profile. (5) Many therapeutic advances have been achieved through the use of maximal surgical resection and upfront chemotherapy (CHT) eventually associated with radiotherapy, with the aim in low-grade gliomas to postpone the onset of recurrence and malignant transformation (progression), and in intermediate-grade gliomas to reach long-term tumor control. Nevertheless, although these important advances have significantly affected the natural history of the disease, LGGs ultimately recur and progress. ^,

Little is currently known about the clinical and molecular factors influencing the tendency of LGGs to recur, progress, or respond to available therapies.

Clinical determinants of LGG behavior are age at diagnosis, tumor volume and extension at diagnosis, speed of growth, histology, and residual tumor after surgery. The rate of recurrence is lower in the case of younger age, small initial tumor volume, and oligodendroglial—1p/19q codeletion features. The speed of growth has been recently identified as an independent prognostic factor. The extent of resection (EOR) recently has been suggested as an important factor, able to change the natural history of the tumor, and is the first significant step of treatment. ^, Extensive resection (GTR, gross tumor resection) is usually associated with a better prognosis and a lower rate of malignant transformation in low grades. ^, EOR (GTR) is used to stratify patients as at low risk (those who received a GTR) and at high risk (those in whom a GTR was not achieved). GTR is also associated with seizure control, another parameter included in the definition of low-risk (seizure-controlled) or high-risk (seizure-uncontrolled) tumors. Generally, low-risk patients are submitted to clinical and radiologic follow-up in case of grade II gliomas, or to adjuvant therapies in case of intermediate grade, whereas high-risk patients are always treated (according to molecular profile), usually at least initially with chemotherapy, or when malignant transformation has occurred, with adjuvant concomitant radio- and chemotherapy. ^{, ,}

Relatively little is known about the biological factors influencing the natural history of LGGs, their invasive patterns, or their tendency to recur or respond to therapy. Generally, histology seems to be predictive: tumors with astrocytic features recur earlier than those with oligodendroglial features. The main flaw of histologic classification is the consistent degree of intraobserver variability. ^, In addition to histologic characteristics, several molecular markers for LGGs have been identified and recently introduced in clinical practice. ^, The Cancer Genome Atlas Network has proposed a molecular classification of LGGs. They performed genome-wide analyses of 293 LGGs from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. The integration of genome-wide data from multiple platforms delineated three molecular classes of LGGs that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Grade II and III gliomas were subdivided in three prognostic categories according to the IDH1/2 and 1p19q status: 1p19q codeleted gliomas have the best outcome, the IDH1/2 mutated/non-1p19q codeleted gliomas have an intermediate survival (most of them are mutated for p53), and the gliomas nonmutated for IDH1/2 (none of which are codeleted for 1p19q and very few are mutated for p53) have the worst survival and were molecularly and clinically similar to glioblastoma, with which they shared aggressive biological behavior.

The importance of adding molecular data to histology to better stratify tumor patients has been also proposed by the WHO tumor classification assembly ^, ; an integrated diagnosis has been recommended for routine pathologic practice, in which molecular data obtained from the most representative area of the tumor are associated to histologic appearance; this helps in the classification of the tumor. ^, Accordingly, oligodendrogliomas are the tumors characterized by the presence of 1p19q codeletion. The presence of 1p19q codeletion is always associated with IDH1 mutation. Astrocytomas are characterized by the absence of 1p19q codeletion and presence of ATRX mutation. ATRX mutation, often associated with p53 mutation, is not exclusively associated with IDH1 mutation, and IDH1 wild-type tumors with the histologic grade of low-grade gliomas may be present. Integrated diagnosis seems to better correlate with biological behavior, and helps also in the decision-to-treat process.

The optimal treatment for low(er)-grade gliomas has yet to be determined. Watchful observation, needle biopsy, open biopsy, as well as surgical resection have all been advocated by different authors. ^{, , ,} No evidence concerning class I or II exists regarding the optimal management of these patients, even if the more modern tendency is to obtain at least some type of tissue diagnosis, ^, advocating a maximal resection whenever possible. ^,

The rationale behind the observational or “wait and see” policy was the occasionally indolent or very slow progress of these tumors. ^, On the other hand, following modern oncologic concepts, and the recent advances in molecular classification of these tumors, most authors recommended a biopsy, in order to have a histopathologic and molecular confirmation of the nature of the neoplasm. ^{, ,} Surgical resection of low-grade gliomas is still a matter of debate, although recent studies are increasingly supporting this choice. ^{, , ,} Surgery can in fact achieve multiple aims: it allows a more reliable histologic diagnosis and eventually yields the molecular profile (e.g., IDH1 mutation, 1p/19q codeletion, and O(6)-Methylguanine-DNA methyltransferase [MGMT] status); it relieves symptoms; when a GTR has been achieved, it has a beneficial effect on seizure control; in addition, GTR could decrease the rate of recurrence and of malignant transformation. ^{, ,} In addition, surgery may change the natural history of the tumor, even when this is considered within the molecular stratification. ^{, ,} Furthermore, the response to adjuvant treatment is influenced by the EOR, being generally higher in patients in whom a GTR has been reached. Nevertheless, surgery carries unavoidable risks, which can potentially and permanently affect the patient’s quality of life.

Given this general information on lower-grade glioma behavior and the possibility of treatment, it is clear that a modern surgical approach to these tumors seeks to maximally resect the mass, minimizing postoperative morbidity to preserve a patient’s functional integrity. ^{, , , , , ,} Since the natural history of the tumor can be relatively long (with or without surgery), the conservation of simple and complex neurologic functions of the patient is mandatory. To achieve the goal of a satisfactory tumor resection associated with the full preservation of the patient’s abilities, a series of neuropsychological, neurophysiologic, neuroradiologic, and intraoperative investigations have to be performed.

In this chapter, we will describe the rationale, the indications, and the modality for performing a safe and rewarding surgical removal of low(er)-grade gliomas.

Rationale of Surgical Treatment

The major aims of surgical treatment are: (1) obtaining adequate specimens and representative tissue to reach a correct histologic and molecular diagnosis; (2) achieving a cytoreduction to decrease the rate of recurrence and malignant transformation, possibly prolonging survival; (3) improving the neurologic symptoms of the patients; (4) obtaining a better seizure control.

The Concept of Functional Neuro-Oncology: Resection According to Functional Boundaries

Surgery for LGGs aimed at maximal tumor resection, associated with full patient functional integrity. ^{, ,} Various strategies have been developed to achieve this result. In the recent past, different intraoperative imaging techniques, including those (such as intraoperative MR) that have led to an increase in maximal resection, have been implemented, without contributing to a significant impact on the maintenance of patient functional integrity. The most relevant oncologic impact, both in terms of amount of tissue removal and preservation of function, has been produced by the introduction of brain-mapping techniques. ^{, , , ,} This term refers to a group of techniques, which allow safe and effective lesion removal from eloquent or functional areas, preserving the functional integrity of the patients. They allow the identification and preservation at time of surgery of cortical and subcortical sites involved in specific functions. The concept of detecting and preserving the essential functional cortical and subcortical sites has been recently defined as “surgery according to functional boundaries,” and it is summarized with the term “functional neuro-oncologic approach.”

The shift of the paradigm from image-based surgery to surgery based on functions finds its rationale in various considerations: most LGGs are located in areas of the brain traditionally defined as eloquent (language and motor areas); therefore, resection of tumors within these areas have to be necessarily associated with function preservation. ^{, , , ,} LGGs are highly infiltrative tumors, in which cells could be found beyond the borders of the tumors as visualized in FLAIR images, which makes approaches based on pure images quite limited in terms of oncologic results ; LGGs are characterized by a slow rate of growth, which induces a progressive reorganization of surrounding brain areas, modifying and reshaping brain functional organization in a way that is patient-specific and that cannot be fully depicted by functional imaging techniques (e.g., functional magnetic resonance imaging [fMRI]). ^{, ,} The functional approach exploits the functional reorganization reached by the patient’s brain, allowing the surgeon to remove as much of the tumor as is feasible, possibly extending resection far beyond the tumor margins visible and detectable by conventional MR images, preserving functional integrity. ^{, ,} The new paradigm (or philosophy) stands in looking for functional brain boundaries independently from where they are located in respect to tumor borders.

How to Manage a Patient with a Presumptive Diagnosis of a Lower-Grade Glioma

Using a functional approach, the management of the patient entering the outpatient clinic with a diagnosis of a presumptive low(er)-grade glioma must be aimed at defining the degree of functional reorganization achieved by the patient brain surrounding the tumor. ^{, ,} This information defines the feasibility of resection and the possible degree of tumor removal that can be achieved in the individual patient. The management must therefore arrange a careful interview of the patient, associated with a detailed neuropsychological evaluation; data obtained from these analyses have to be integrated with those obtained from imaging, to design a comprehensive map of patient brain functional reorganization. This information is used for making the eventual decision to treat, and for planning the resection ( Fig. 8.1 ).

Patient Interview

This must take into account the symptoms and the duration of the clinical history. Most patients report a history of epileptic seizures. A careful anamnesis shows that seizures are often preceded by minor manifestations, generally abortive seizures. In addition, patients with a long history of seizures often describe a progressive increase in their frequency, and in those who are already taking antiepileptic drugs (AEDs), a progressive increase in dosage and number of drugs that are taken, with the development of drug-resistant epilepsy. ^, The cases of patients with tumors affecting the insular region, or the region of the ventral premotor or of the supplementary motor area, are typical. The careful analysis of the semiology of the seizures provides information on the progression of the neoplasm and its temporal and current extension, as well as important information on the degree of functional reorganization achieved by the surrounding brain due to the presence, growth, and extension of the neoplasm itself. In case of dominant insular tumors, the onset of focal seizures with speech arrest indicates the activity of the ventral premotor and of the underlying connection bundles, indicative of a partial or not complete language reorganization; on the contrary, in the same tumors, the appearance of generalized seizures in the absence of focal symptoms or focal sensorimotor seizures indicates the reorganization of the language circuits; similarly, the onset of mesial temporal seizures suggests both the extension of the tumor to the temporal region and a high degree of reorganization of the circuits. In the first case a subtotal or partial removal may be expected; in the latter, a complete resection can be predicted. A careful interview must also be aimed at highlighting the appearance of signs and symptoms of involvement of deep associative circuits, such as the occurrence of mood changes in the case of frontal or limbic tumors. The presence of such disturbances highlight the need to extend the intra-operative mapping with appropriate tests capable of identifying and sparing such networks. ^{, , ,} The patient’s interview is associated with the neurologic examination, which is often completely normal. The percentage of patients with motor and/or language deficits varies between 2% and 15% according to the various series. ^, Other additional data to be evaluated are patient educational level, job and future career development, current hobbies, and future pregnancy in the case of female patients. These data (referred to as patient needs) have to be carefully discussed with the patient for the elaboration of a tailored surgical strategy, particularly in the context of the permanent effects that surgery may exert on the quality of life. ^,

Neuropsychologic Evaluation and Psycho-Oncological Interview

Psychological evaluation consists of two components: neuropsychological and psycho-oncologic evaluation.

The neuropsychological evaluation evaluates the degree of functional reorganization achieved by the individual patient, and prepares the patient for intraoperative testing. Extensive testing is used and explores all functional domains. ^, The types of tests vary according to language and population, taking also into account the age and level of education. In our institute we have developed, and have been using for many years, a battery that explores five main functional domains: memory, language, praxis, executive functions, and fluid intelligence ( Table 8.1 ). The duration of the evaluation takes about 1 hour and 30 minutes, and it is generally well tolerated. During the preoperative evaluation, the battery, administered by a neuropsychologist, shows some degree of impairment in several functional domains in most patients , even when the complete neurologil examination is normal. Executive function is the domain most frequently affected. ^{, ,} The neuropsychological evaluation allows staff to prepare and select, for the individual patient a series of tests to be carried out at the time of surgery, selecting among the available items those that the patient performs in a more constant and stable way. ^{, , ,} The reproducibility of the selected items must be repeated in a further evaluation carried out the day immediately before the procedure, to carefully calibrate them to the individual patient condition.

Table 8.1

Neuropsychological Tests Included in the Milano-Bicocca Battery

Preoperative Neuropsychological Test
Functional Domains	Test
Memory	Digit forward and backward, Corsi forward and backward, Rey auditory, verbal words learning test (RAVLT) immediate and delayed recall, Rey complex figure recall
Language	Token, pictures naming words and sentences comprehension, actions naming, semantic and phonemic fluencies, words and nonwords and sentences repetition
Praxis	Rey complex figure copy, ideomotor apraxia test, oral-motor apraxia test
Attentive and executive functions	Attentive matrices test, trail-making test, Stroop test

The tests exploring the five large functional domains are reported.

The psycho-oncologic evaluation is a complementary investigation and assesses the patient’s needs, the presence of anxiety disorders, the understanding of the state of the disease and of the therapeutic process to which the patients will go through, along with the ability to perform part of the procedure in awake anesthesia if needed. ^{, , ,} The assessment consists of a psychological interview and the administration of welfare questionnaires. In our institute, a psychotherapist generally carries out the psychological interview and administers the well-being questionnaires (see EORTC questionnaire for brain tumors) or those for assessing anxiety and depression (see Hospital Anxiety and Depression Scale). Patients with normal or slightly impaired neuropsychological assessment scores often show important changes in the psycho-oncologic assessment scales, which result in the development of discomfort in the conduct of normal daily activities, which could significantly affect quality of life.

Data generated during patient interviews and neuropsychological and psycho-oncologic evaluations are then matched with those obtained by imaging.

Imaging Work-Up

The imaging methods are divided into basic and advanced methods.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here