Gliomatosis cerebri is a diffuse infiltration of the brain by atypical glial cells, covering more than two brain lobes. Typical clinical symptoms are spastic paresis, progressive cognitive decline, epileptic seizures, cephalgia, cerebellar syndrome, cranial nerve dysfunction. The necessary diagnostic tests include brain MRI, electroencephalography and cerebral biopsy. Treatment is carried out by combining courses of chemotherapy and diffuse irradiation of the brain. In parallel, symptomatic therapy is carried out.
ICD 10
C71.9 Malignant neoplasm of the brain of unspecified localization
General information
The term “gliomatosis cerebri” was first introduced in 1938. According to the 2007 WHO classification, gliomatosis of the brain refers to astrocytic neuroepithelial tumors, neoplasms with grade III malignancy. In the new classification of CNS tumors (WHO, 2016), gliomatosis cerebri is considered as a variant of the spread of diffuse glioma.
Neoplasia refers to rare brain tumors. In the literature on neurology, morbidity data range from 0.6-8 cases per year. Pathology affects all age categories, most often people aged 40-60 years get sick. Men suffer from gliomatosis somewhat more often than women, the ratio is 1.3:1.
Causes
Histochemical and genetic studies of tumors, which have been attempted since the beginning of the XXI century, have revealed genetic changes in tumor cells compared to normal gliocytes. The most well-known gene mutations are IDH1, IDH2, occurring in 70% of cases. Mutations cause a change in biochemical processes inside a healthy cell and its transformation into a tumor cell. The etiofactors provoking mutations and triggering oncogenesis have not been precisely established. A multifactorial mechanism of the occurrence of the oncological process is possible, including the following components:
- Oncogenic factors. Presumably, radioactive radiation, oncogenic viruses (cytomegalovirus, polyomavirus, herpes infection), harmful chemicals contained in some food products (preservatives, dyes, emulsifiers), polluted air play a mutagenic role. These effects can cause changes in the genetic apparatus of cells, leading to the transformation of the latter into cancer cells.
- Immunosuppression. The immunosuppressive state of the body develops against the background of therapy with corticosteroids, cytostatics, and a long course of chronic diseases. It leads to the absence of active activation of antitumor mechanisms responsible for the elimination of cells that have undergone oncotransformation. The result is an unhindered increase in the number of tumor cells, the progressive development of the oncoprocess.
- Genetic susceptibility. A genetically determined tendency to various oncopathologies of the central nervous system can be traced in a number of hereditary diseases (neurofibromatosis, Hippel-Lindau disease, Lee-Fraumeni syndrome). The mechanisms of realization of the predisposition inherent in the genome have not yet been determined.
Pathogenesis
The IDH1/2 genes encode enzymes that catalyze the synthesis of alpha-ketoglutarate (pentose) and its carboxylation into isocitrate. Mutations of these genes lead to the blocking of these biochemical reactions, the transfer of pentose to the oncometabolite 2-hydroxyglutarate. Intracellular dysmetabolic processes cause a change in the parameters of normal gliocytes, their acquisition of characteristics characteristic of cancer cells: cellular atypism, a tendency to uncontrolled division. In the presence of other mutations of the cellular genome, similar pathogenetic mechanisms are implemented.
Gliomatosis cerebri is characterized by diffuse spread of cancer cells through brain tissues without the formation of tumor nodes. The lesion captures at least two lobes, spreads to both hemispheres. Most often (76%) the large brain, the corpus callosum, is infiltrated. In half of the cases, the involvement of the bridge, the midbrain is noted.
Gliomatosis of thalamus tissues is observed in 43% of cases, subcortical ganglia — in 34%, cerebellum — in 29%. Damage to the cerebral cortex is noted in 19% of patients. Microscopically, foci of gliomatosis are represented by atypical glial cells, mostly similar to astrocytes. In some cases, cancer cells that are phenotypically identical to oligodendrogliocytes predominate.
Classification
Since gliomatosis cerebri is classified by WHO as a form of diffuse glioma, its division by phenotypic morphology features becomes relevant. Information about the type of cells that make up the gliomatosis zones is of paramount prognostic importance. In this regard, there are three main options:
- Astrocytic. Gliomatous zones are represented by atypical astrocytes. The most common type of gliomatosis has grade II-III malignancy. Over time, it can transform into a more malignant glioblastoma variant.
- Oligodendroglial. Gliomatous sites consist of atypical oligodendrogliocytes. The degree of malignancy is II-III. Subsequently, glioblastoma degeneration of the tumor is possible.
- Glioblastoma. Morphologically it is represented by low-differentiated atypical cells. Occurs primarily or as a result of the transformation of previous variants. The most aggressive cerebral oncoprocess, grade IV malignancy.
Thanks to the introduction of genetic testing of tumor cells into medical practice, gliomas were divided according to the presence of an IDH mutation. If a defect in the IDH1/IDH2 genes is detected, the tumor is classified as having an IDH mutation. With a negative result of genetic analysis, the neoplasm is regarded as IDH-wild type. In cases of unavailability of IDH testing, the tumor is classified as NOS.
Symptoms
The symptoms are extremely nonspecific, at the initial stages of the disease does not reflect the massiveness of the lesion. Typical pyramidal movement disorders, dementia. The predominance of the lesion of one hemisphere leads to the development of hemiparesis of the contralateral extremities, bilateral gliomatosis manifests itself with tetraparesis of varying severity. Muscle weakness is accompanied by an increase in tendon reflexes, spastic hypertonicity, giving the limbs a semi-bent position.
Violations of the intellectual sphere manifest themselves by a decrease in memory, attention, slowing down thinking. The steadily progressive nature of cognitive dysfunction leads to the development of elements of amnesia, acalculia, agnosia, apraxia, followed by a transition to deep organic dementia. Mental disorders are possible: behavior change, aggressiveness, psychomotor agitation, euphoria.
40% of patients complain of diffuse cephalgia. Symptoms of intracranial hypertension (nausea without food, vomiting at the height of cephalgia, a feeling of pressure on the eyeballs) occur in 34% of patients. In 38% of cases, epileptic paroxysms are observed. Dysfunction of various cranial nerves is noted with the same frequency.
In 33% of cases, gliomatosis cerebri occurs with cerebellar syndrome. Signs of cerebellar ataxia include large-scale nystagmus, instability of walking, accompanied by deviations of the body to the sides, discoordination, hypermetry of movements, chanted speech, macrography. Sensory disorders are noted in 18% of cases, represented by superficial and deep hypesthesia, paresthesia.
Complications
The defeat of the cranial nerves of the bulbar group is accompanied by swallowing disorders. Choking may be complicated by ingestion of food/liquid into the respiratory system with the development of aspiration pneumonia. Pronounced pyramidal, cerebellar disorders make the patient bed sick. Restriction of motor activity without appropriate care is fraught with the occurrence of pressure sores, congestive pneumonia. Spastic paresis leads to the formation of joint contractures. The most severe life-threatening complications are possible with damage to the cerebral trunk, where the vascular and respiratory centers are located.
Diagnostics
Diagnostic difficulties are associated with the non-specificity of the clinical picture. In the neurological status, a diverse neurological deficit is determined, indicating the diffuse nature of brain tissue damage. Before the era of neuroimaging, gliomatosis cerebri was diagnosed exclusively by pathologists. Modern lifetime diagnosis of the disease is possible only based on the results of brain MRI and biopsy. The list of examinations prescribed by a neurologist during diagnosis includes:
- Electroencephalography. EEG is performed at the initial diagnostic stage. Registers diffuse changes in bioelectric activity. Paroxysmal epileptogenic adhesions are observed in the case of convulsive syndrome.
- Magnetic resonance imaging. In T1 mode, the tumor is iso- or hypodensive, which makes it difficult to assess its prevalence. The gold standard of diagnosis is MRI in T2 mode, which gives hyperdensive visualization of gliomatous zones. CT of the brain may not reveal the tumor process, since in this study gliomatosis turns out to be isodensive in relation to normal brain tissues.
- Stereotactic biopsy. Despite the heterogeneity of the structure of various gliomatous sites, most clinicians are inclined to the need for a biopsy. The resulting cerebral material is subject to histological examination, which makes it possible to establish the morphological affiliation of the tumor, to assess the degree of malignancy.
- IDH-typing. A new diagnostic method, gradually being introduced into neuro-oncological practice. It is carried out using the technology of genetic PCR diagnostics. The results of typing are taken into account when choosing therapeutic tactics, allow you to make more accurate prognostic assumptions.
Differential diagnosis
Gliomatosis cerebri must be differentiated from:
- multiple lymphomas of the central nervous system;
- multifocal glioblastoma;
- encephalitis;
- progressive leukoencephalopathy.
Encephalitis is characterized by an appropriate epidemiological history, for leukoencephalopathy — development against the background of HIV, detection of JC virus DNA in the study of cerebrospinal fluid. MRI allows to distinguish gliomatosis from multi-focal lesions (lymphomas, glioblastomas).
Treatment
The diffuse nature of the tumor process does not allow radical surgical treatment. The operation is possible with a combination of gliomatosis with a single large focal lesion. In such cases, neurosurgical intervention is aimed at removing the focus. The main methods of conservative therapy are:
- Radiological treatment. A series of radiotherapy sessions with total cerebral irradiation is performed. The best results are obtained by using IMRT irradiation using computerized X—ray accelerators. The method allows you to regulate the intensity of exposure in various parts of the brain: direct radiation to large areas of gliomatosis, minimize the dose of radiation to critically important cerebral structures.
- Chemotherapy. Combined with radiotherapy. It is carried out by a phased course of treatment with cytostatics: temozolomide, carmustine, carboplatin. The most effective is the use of several drugs with different mechanisms of action. The break between courses of chemotherapy is due to the pronounced side effect of chemotherapy drugs, the need to restore the body.
- Symptomatic treatment. It is aimed at relieving the main symptoms of the disease, side effects of cytostatic and radiation therapy. Antiemetic, analgesic, decongestant, psychotropic, antiepileptic pharmaceuticals are used.
Attempts are continuously being made to develop new effective methods of treatment. Two areas look the most promising – genetics and biochemistry. Research in the field of genetic engineering is aimed at finding methods for changing the genome of a tumor cell that can cause its apoptosis. The study of the biochemical features of cancer cells implies the search for radically new ways of pharmacological effects on the tumor process.
Prognosis and prevention
Gliomatosis cerebri is a serious disease with a fatal outcome. The life expectancy of patients after diagnosis is on average 2-3 years, in some cases exceeds 10 years. The prognosis depends on the morphological variant, the prevalence of the tumor. Studies show a significant increase in the life expectancy of patients with gliomas with IDH1/IDH2 mutations in comparison with patients whose tumors are free from IDH defects. Measures to prevent gliomatosis are the exclusion of oncogenic effects, the correct treatment of viral infections prone to persistence, and the maintenance of an adequate level of immunity.