Gliomatosis Cerebri

Definition

In the 1979 World Health Organization (WHO) classification of brain tumors, GC is considered as a undifferentiated and embryonic tumor^[7]. In the 1993 and 1999 WHO classifications, GC is defined as a diffuse glial tumor that extensively infiltrates the brain, involving more than two lobes (frequently bilaterally), and occasionally extending to infratentorial structures, or the spine, with the preservation of the structure of the normal surrounding tissues. It is listed as a subgroup of neuroepithelial neoplasm of unknown origin^[8,9]. According to the newest 2007 (4th edition) WHO classification of tumors of the Central Nervous System, GC is listed as a subtype of astrocytic tumors^[10].

Classification

GC can be subdivided into two forms based on descriptive neuropathologic grounds, Type I and Type II. Type I is a diffusely infiltrating glioma without formation of an obvious tumor mass, whereas Type II denotes the coexistence of a diffuse infiltrating low-grade glioma with associated tumor mass formation, usually showing features of a malignant glioma. Patients who have a solitary mass that later disseminates should not be considered as GC^[1,6,11].

Pathogenesis

The pathogenesis of GC is still quite controversial. The widespread nature of GC has led to the formation of two different hypotheses regarding its origin, i.e., i) GC arises from simultaneous neoplastic transformation of cells in different regions of the brain (oligoclonal origin hypothesis) or ii) GC arises from a single clone of cells and then spreads widely (monoclonal origin hypothesis)^[1-3]. Recent genetic analyses have not resolved this problem^[12-14].

Clinical manifestations

There is a wide range in age at presentation of GC (a range of 1 month to 85 years)^[3,15]. The majority of patients are male (as true in all gliomas) and comparatively young. Artigas et al. ^[16] described a bimodal distribution of age at initial GC diagnosis, peaking in the second and fifth decades of life. Armstrong et al.^[3] observed that 62% of patients with childhood GC were diagnosed in the second decade of life, and the median age at presentation was 12 years, confirming an increase in the incidence of GC during the second decade. The duration of sympotoms before diagnosis was remarkably variable, ranging from 1 week to 22 years^[2,3,16].

Clinical findings for patients with GC are usually subtle and nonspecific, mainly determined by the anatomic site involved. Patients most often show an insidiously evolving syndrome comprised of progressive headache, mental status changes, hemiparesis, and seizures (partial with or without secondary generalization). Findings on neurologic examination include evidence of raised intracranial pressure (papilledema, ophthalmoplegia, gait disturbance), neurobehavioral changes, and corticospinal deficits^[1,3,4,14].

Vates et al.^[1] made a retrospective review of the 22 cases. The most common complaints included mental status changes (77%), seizures (50%) and headaches (41%). The most common neurological manifestations included dementia (68%), corticospinal deficits (36%), gait abnormalities (36%), and papilledema (27%). Taillibert et al.^[2] studied the information from 296 cases (90 patients in the French Neuro-Oncology registry database ANOCEF and 206 cases reported in the literature). They observed the usual symptoms including seizures (92 cases), intracranial hypertension (58 cases), changes in mental status (55 cases), or focal neurological deficits (50 cases). Cecocentral scotoma, disorientation, stroke attack, atypical parkinsonian syndrome^[17-19], even preudo-subarachnoid and cortical visual impairment also were reported as symptoms of GC^[20]. In general, the majority of patients with GC show the same symptoms as patients with low-grade astrocytoma.

Radiographic features

Pathology

Histological examination of GC reveals the widespread infiltration of neoplastic glial cells with minimal destruction of pre-existing structures, and frequently a preferential infiltration of the white matter. In the affected white matter, neoplastic cells are often arranged parallel to the fiber tracts, and myelin sheaths may be destroyed, but axons are only slightly or even not destroyed. Perineuronal, perivascular, and subpial spread of tumor infiltration can be observed. There is an absence of demarcation between normal and affected areas. Areas of high mitotic activity and microvascular proliferation may be observed, and secondary malignant tumor areas can arise at different sites within the previous low-grade tumor, but necrosis is rare ^[1-4,11].

The neoplastic glial cells consist of different degrees of maturation (ranging from Grade I to Grade IV, predominately low-grade). Tumors with multiple grades may coexistence in an individual. The cellular morphology is variable, most are astrocytic, others oligodendroglial, and others can be mixed or unclassified^[1-6,40]. In the series of Peretti-Viton et al.^[11] there were 2 cases of oligodendroglioma, 1 case of anaplastic oligodendroglioma, 2 cases of anaplastic mixed oligoastrocytoma, 1 case of anaplastic astrocytoma, 2 cases of glioblastoma and 1 case of astrocytic proliferation. In the study by Taillibert et al.^[2], tumors were identified as astrocytic in 108 cases, oligodendroglial in 54 cases, mixed in 17 cases, with 117 cases classified as undetermined or non-specified.

Diagnosis and differential diagnosis

Before 1986, pathological diagnosis of GC was based on autopsy data. The first antemortem diagnosis was reported by Troost et al.^[41] in 1986 on the basis of MRI and biopsy results. Since then, in the English literature, close to 180 cases received intravitam pathological diagnosis based on biopsy, and of those cases, about 40 patients underwent a stereotactic biopsy^{[1-6,14-18,42]}. In the Chinese literature, there have been nearly 210 cases which received an intravitam pathological diagnosis, and about 30 patients underwent a stereotactic biopsy^[43-51].

When patients have symptoms such as headache, personality changes, or focal neurological deficits, and when neuroimaging provides MRI evidence of a diffuse infiltrative process involving more than two cerebral lobes often extending to infratentorial structures, a diagnosis of GC should be considered. But it must be kept in mind that GC may be misinterpreted not only as an ischemic, or infectious disease, but also as a demyelinating disease such as leukoencephalopathy or multiple scerosis. Their changes on CT and MRI images are similar to GC. Other tumor entities, such as diffusely infiltrating astrocytomas and multicentric gliomas, must be considered in the differential diagnosis as well^[4,11].

Imaging features of MRS (a “neoplastic” spectral pattern of elevated Cho/NAA) and PET may be helpful to distinguish GC from non-neoplastic diseases^{[25-27,36-39]}. Additionallaboratory findings are helpful in excluding infectious or inflammatory diseases. The acute onset of clinical symptoms in ischemia plays a determing role in differentiating GC from ischemic disorders. The differential diagnosis of leukoencephalopathy is uncommon if the deep or superficial gray matter is involved. The large plaques in multiple sclerosis are usually more circumscribed than changes in GC^[10]. When non-tumoral white matter diseases are excluded, multicentric gliomas should be considered^[52-54]. Multicentric gliomas consist of scattered neoplastic foci with no detectable microscopic continuity between them. The MRI characteristics of multicentric gliomas are different from those of GC. In multicentric gliomas, tumor masses occur at different sites with strong contrast enhancement (often either heterogeneous or ring-like). Centro-tumoral necrosis, perifocal vasogenic edema, mass effect on ventricles and sulci, and centrifugal extension that follows white matter tracts often can be observed. The most conflicting differential diagnosis includes low and high-grade diffuse astrocytomas and oligodendrogliomas. These tumors differ from GC in that astrocytomas and oligodendrogliomas are usually limited tumors, supratentorial, with an “all in one piece” extension. The brainstem is rarely involved in those cases except when the tumor arising from basal ganglia follows the cortico-spinal tract and thus infiltrates the brainstem. Also the hypothalamus is rarely involved. The clinical symptomatology predominately includes seizures in low-grade gliomas and focal deficits in high-grade gliomas^[11]. Because gliomas are not sharply delineated tumors, the differences between GC, diffuse astrocytomas, glioblastoma multiforme and oligodendrogliomas are ambiguous.

However, the diagnosis of GC should be confirmed by a histopathological examination. Stereotactic biopsy has evolved as a powerful and safe method to provide a tissue diagnosis with minimal disruption of normal brain function. It plays a significant role in the management of malignant brain tumors. Many other authors have pointed out that stereotactic biopsy is preferred over surgical biopsy in the diagnosis of cranial lesions. In comparing common open biopsies with the stereotactic method, the following advantages are noted: only a small hole is made in the skull (no trepanation), deep targets can be easily reached without significant brain damage, the precise location of the biopsy can be achieved, and multiple biopsies can be taken at intervals along one or several tracks in order to determine the various aspects of the lesions in respect to size, limits, anaplastic foci, and local variations, etc.^[55,56] Thus far, about 40 cases with GC have been pathologically confirmed through stereotactic biopsy. In the study by Peretti-Viton et al.^[11], the pathological data were obtained by stereotactic biopsy in 4 cases, and by surgical biopsy in 5 cases. In the study by Taillibert et al.^[2], 12 patients underwent stereotactic biopsy, compared to 5 patients who underwent open biopsy. No statistical analyses comparing surgical biopsy with stereotactic biopsy in GC have been reported. The advantages of stereotactic biopsy may also apply for the pathological diagnosis of GC.

A definite diagnosis of GC should be arrived at on the basis of a combination of clinical, radiological and pathological data. However, there have been no precise diagnotic criteria established for GC, and the differences between GC, diffuse astrocytomas, glioblastoma multiforme and oligodendrogliomas remains unclear. Therefore, valid diagnosis criteria should be established and further studies focusing on the difference between GC and common gliomas should be performed. We recommend the criteria proposed by Peretti-Viton et al.^[11], that is MRI evidence of a diffuse tumor infiltration in the brain (with or without small enhancing nodules) consistent with the WHO definition of GC (a diffuse tumor with extensive infiltration of more than two lobes of the brain, frequently bilateral, and often extending to basal ganglia, thalamus, corpus callosum, brain stem, hypothalamus and spinal cord).There should be confirmation of astrocytic or oligodendrocytic proliferation by biopsy according to the WHO classification of tumors. That may be helpful in making a diagnosis of GC in clinical work.

Therapy

Although there has been considerable progress in the initiation of clinical trials to establish treatment regimes specifically designed for GC, an optimal therapeutic strategy is still not well established. Most studies argue that surgery is not a viable option because there is widespread dissemination of neoplastic glia. It is limited mainly for primary biopsy and determination of tumor histology. However, Zheng et al.^[49] and Zhang et al.^[50] propose that surgery is an optional therapy for GC, and the degree of operational incision is an important factor affecting the prognosis.

Radiotherapy may be useful. Brain irradiation can stabilize or improve neurologic function. In 4 published retrospective studies^[4,57-59], 58% (24/41) of evaluable patients had a clinical response, and 31% (13/41) had a radiologic response, with a median survival time ranging from 11 to 38 months. The optimal configuration of the radiation field cannot be determined at present, but extensive involved-field therapy, or whole-brain radiotherapy (WBRT) appears to be the most appropriate forms of radiotherapy for most patients. However, large field or whole brain radiotherapy may carry considerable risk of severe delayed toxicity such as delayed leukoencephalopathy, which was reported in 28% and 12% of patients, respectively, in a large retrospective study ^[60].

Chemotherapy represents another alternative therapy regimen. Beside some reports about the value of temozolomide (TMZ) treatment in individual cases, 2 larger prospective studies have recently established that a significant proportion of patients will benefit from an initial chemotherapy treatment with PCV (procarbazine, lomustine, vincristine), or TMZ. Sanson et al.^[61] treated 63 consecutive GC patients with initial chemotherapy consisting of either PCV (procarbazine, 60 mg/m² on days 8 to 21; CCNU, 110 mg/m² on day 1; and vincristine, 1.4 mg/m² on days 8 and 29), or temozolomide (TMZ; 150 to 200 mg/m² for 5 days every 4 weeks). Seventeen patients received 1 to 6 cycles (median, 5) of PCV, and 46 received 2 to 24 courses (median, 13) of TMZ. Clinical objective responses were observed in 21 of 63 (33%) patients, and radiologic responses were seen in 16 of 62 (26%). Overall survival of patients treated with either therapy was 29 months, with no statistical differences between the two groups. However, in the study, there were 14 cases which presented as a circumscribed glioma at onset, and later spread in a diffuse manner. Those cases cannot strictly be classified as GC according the WHO classification, so treatment in this group may not be fully applicable to other dense GC. In the study of Levin et al.^[62], 11 radiotherapy patients who had not received prior radiotherapy received a median number of 10 treatment cycles of TMZ. A positive response was noted in 5 patients (45%), and the median time to tumor progression was 13 months with a progression-free survival of 55% at 12 months. Interestingly, it was found that there was high proportion of oligodendroglial tumors in the two studies, and oligodendroglial tumors are known to be chemosensitive. The inherent sensitivity of oligodendroglial tumors was elegantly shown to have a molecular correlation (i.e., 1p or 19q chromosomal loss).

It is important to select the most appropriate treatment (or combination) according to the tumor characteristics. Because it is necessary, in general to limit the neurotoxicity of large-field radiotherapy when treating a wide-spread infiltrative tumor, the current approach is to treat GC, in particular oligodendroglioma, with primary chemotherapy. The choice of a primary chemotherapy regimen for GC includes PCV and TMZ, the latter demonstrating similar efficacy with reduced toxicity. If the disease progresses despite first-line chemotherapy, 25% to 50% of the patients can be expected to respond to second-line chemotherapy (most often with one of the above 2 regimens not previously used). When tumors progress despite first and second-line chemotherapy, radiotherapy should be used as a salvage therapy ^[13,15].

Prognosis

Despite aggressive and often multimodal therapeutic intervention, prognosis of GC is still poor^[1-11,13,15]. Of the 22 cases reported by Vates et al.^[1], the median length of survival was as follows: no treatment, 1 month (n = 4); radiotherapy alone, 28 months (95% confidence interval, 5~51 months; n = 13); radiotherapy followed by chemotherapy, 2 patients, alive at 28 and 104 months; radiotherapy and chemotherapy simultaneously, 3 patients, one alive at 18 months and the others died at 7 and 9 months. In the study by Taillibert et al.^[2] analyzing 296 individual cases, the median survival time (MST) was 14.5 months. In the study by Herrlinger et al.^[6], the MST was 14 months (ranging from 4~91 months) after detection of T2 hyperintensities by MRI indicating for GC, and 16 months after histological diagnosis (ranging from 2 to 96 months). Armstrong et al.^[3] studied 13 pediatric patients who were diagnosed as GC and were treated at the Children’s Hospital of Philadelphia. They found the overall survival rate was 64% after 2 years (range, 6.5 to 67 months).

There are perhaps, some factors which may effect the length of survival. Vates et al.^[1] found that the Karnofsky Performance Scale scores and grade were directly related to length of survival. In the study by Taillibert et al.^[2], the MST was higher for patients with a performance status ≥ 80 (27 months vs. 9 months), low grade gliomatosis (Grade II = 20 months, Grade III = 11.5 months, Grade IV = 8.5 months), oligodendroglial subtype (36 months compared to 14 months for mixed GC and 11 months for astrocytic GC). Kim et al.^[4] pointed out that a Ki-67 labelling index greater than 1.0 had a significantly unfavourable impact on survival. In their series, the MST and one-year survival rates of the 6 patients with a Ki-67 labelling index greater than 1.0 were 9 months and 37.5%, whereas no deaths occurred among the 5 patients whose labeling index was 1.0 or less. Armstrong et al.^[3] found that an age of < 10 years and contrast enhancement on MRI at diagnosis may be risk factors indicating a shorter survival in pediatric patients with GC.

Controversial issues