Gliomatosis cerebri

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2],nabeel ahmed

Gliomatosis cerebri is a rare primary brain carcinoma. It is a diffusely infiltrating neuroepithelial tumor, which involves at least three cerebral lobes and occasionally infratentorial structures or the spinal cord. The brain architecture is commonly preserved, with neurons being spared. Gliomatosis cerebri is classified as glial tumors of the central nervous system. Recent data does not classify this tumor growth as a primary diagnosis, instead its name is used to describe a special pattern of diffuse and extensive growth of glioma cells, involving multiple lobes of the brain. Microscopic histopathological examination may reveal diffuse proliferation of immature glial elements resembling astrocytes, oligodendroglia, or undifferentiated cells with cytologic and nuclear atypia, calcifications, microcysts, and mitotic figures without the presence of any necrosis or microvascular proliferation. Gross pathology of gliomatosis cerebri is characterized by a diffuse astrocytic growth pattern involving at least three cerebral lobes and bilateral involvement of the cerebral hemispheres, deep gray matter, brainstem, or cerebellum. Symptoms include: headache, nausea, vomiting, seizure, loss of balance, memory loss, personality changes, cognitive problems, confusion, diplopia, difficulty in swallowing, difficulty in speech, motor weakness, and facial numbness. Imaging through a head CT scan can show an isodense and hypoattenuated mass with ill-defined asymmetry and lack of mass effect. While on brain MRI, gliomatosis cerebri is characterized by bilateral and diffuse infiltrative tumor which is isointense or hypointense on T1-weighted images and hyperintense on T2-weighted and FLAIR images. Other imaging studies for gliomatosis cerebri include MR spectroscopy, MR perfusion, PET scan, and bone scan. Radiotherapy and chemotherapy are recommended among all patients who develop gliomatosis cerebri. Temozolomide and PCV 3 combination chemotherapy are the preferred drugs for the treatment of high-grade and low-grade gliomatosis cerebri, respectively. Supportive therapy for gliomatosis cerebri includes anticonvulsants and corticosteroids. Surgery is not the first-line treatment option for patients with gliomatosis cerebri.

Gliomatosis cerebri was first reported by Landau in 1910. Since then, several physicians published isolated cases of gliomatosis cerebri and only later in 1938, it was completely studied and described by Nevin.

Gliomatosis cerebri may be classified into several sub types based on the origin (primary and secondary) and the type of tumor cell (astrocytic, oligodendroglial, and mixed). Recent data does not classify this tumor growth as a primary diagnosis, its name is used to describe a special pattern of diffuse and extensive growth of glioma cells, involving multiple lobes of the brain.

Genes involved in pathogenesis of gliomatosis cerebri include p53, OLIG-2, Ki-67, EGFR, PTEN, VCAM1, VEGF, and gene on chromosomes 7q, 10q, and 13q. Gliomatosis cerebri may be associated with neurofibromatosis type 1 and pilomatricoma. Gliomatosis cerebri is demonstrated by positivity to tumor markers such as GFAP, S-100, and Ki-67.

Common causes of gliomatosis cerebri include genetic mutations. The genes associated with the etiology of gliomatosis cerebri include p53,OLIG2, Ki-67, EGFR, PTEN, VCAM1, VEGF, and genes on chromosome 7q, 10q, and 13q. Astrocytic gliomatosis cerebri, which is the most common histologic form of GC demonstrated mutations in p53 and (isocitrate dehydrogenase) IDH1.

Gliomatosis cerebri must be differentiated from the following: Progressive multifocal leukoencephalopathy, multiple sclerosis, Marburg disease, multicentric glioblastoma, primary CNS lymphoma, viral encephalitis, acute disseminated encephalomyelitis, CNS vasculitis, Behçet’s disease, venous sinus thrombosis, stroke, Gerstmann syndrome, leptomeningeal gliomatosis, Alzheimer’s disease, Lewy body dementia, parkinsonism

Gliomatosis cerebri is a rare brain tumor. The incidence of gliomatosis cerebri is estimated to be around 40 cases per year in the United States. It tends to affect the late teens to middle-aged population, affecting people 15 years old and above. The peak incidence for gliomatosis cerebri is 20-40 years. The median age at diagnosis is 34 years. Males are more commonly affected with gliomatosis cerebri than females. The male to female ratio is approximately 1.5 to 1.

The most potent risk factor associated with the development of gliomatosis cerebri is neurofibromatosis type 1.

There is insufficient evidence to recommend routine screening for gliomatosis cerebri.

Without treatment, patients may progress to develop focal neurological deficits, altered mental status, hydrocephalus, brain herniation, and ultimately death. Transformation into glioblastoma (grade 4) usually occurs in the later stages of the disease. Commonly documented complications of gliomatosis cerebri include brain herniation, hydrocephalus, coma, metastasis, recurrence, benign intracranial hypertension, and side effects of radiotherapy and chemotherapy. Prognosis is generally poor with a 5-year survival rate for patients undergoing treatment is approximately 17.7%. Median survival of patients who are treated with whole brain radiotherapy alone is 13.7 months (range 1–35), whereas those who are treated with combined whole brain radiation therapy and chemotherapy have a median survival of 26.14 months (range 6–42).

There is no established system for the staging of gliomatosis cerebri.

When evaluating a patient for gliomatosis cerebri, you should take a detailed history of the presenting symptom (onset, duration, and progression), other associated symptoms, and a thorough family and past medical history review. Other specific areas of focus when obtaining the history include review of common associated conditions such as neurofibromatosis type 1. Symptoms of gliomatosis cerebri include: Headache, nausea and vomiting, seizure, loss of balance, memory loss, personality changes, cognitive problems, confusion, diplopia, difficulty in swallowing, difficulty in speech, motor weakness, and facial numbness

Common physical examination findings of gliomatosis cerebri include dysphagia, dysarthria, nystagmus, papilledema, hemiparesis, facial paresthesia, vision loss, ataxia, mental status changes, aphasia, and focal neurological defects (corticospinal tract defects, spinocerebellar tract defects, and cranioneuropathies).

There are no diagnostic lab findings associated with gliomatosis cerebri.

Chest x-ray may be performed to detect metastases of gliomatosis cerebri to the lungs.

Head CT scan is helpful in the diagnosis of gliomatosis cerebri. On head CT scan, gliomatosis cerebri is characterized by an isodense and hypoattenuated mass with ill-defined asymmetry and lack of mass effect.

Brain MRI is helpful in the diagnosis of gliomatosis cerebri. On brain MRI, gliomatosis cerebri is characterized by bilateral and diffuse infiltrative tumor which is isointense or hypointense on T1-weighted images and hyperintense on T2-weighted and FLAIR images.

There are no ultrasound findings associated with gliomatosis cerebri.

Other imaging studies for gliomatosis cerebri include MR spectroscopy (decreased NAA/creatine ratio and elevated choline/creatine ratio, choline/NAA ratio, and myoinositol), MR perfusion (low/normal relative cerebral blood flow), PET scan (markedly decreased accumulation of [18F]-fluorodeoxyglucose on F-18 FDG PET, hypermetabolism on C-11 methionine PET, and marked increase in cerebral blood flow on 15(O)-water PET), and bone scan (metastasis to bones).

Other diagnostic studies for gliomatosis cerebri include biopsy, which demonstrates glial cells resembling astrocytes, oligodendrocytes, or undifferentiated cells with atypia and mitoses.

Radiotherapy and chemotherapy are recommended among all patients who develop gliomatosis cerebri. Temozolomide and PCV 3 combination chemotherapy are the preferred drugs for the treatment of high-grade and low-grade gliomatosis cerebri, respectively. Supportive therapy for gliomatosis cerebri includes anticonvulsants and corticosteroids.

Surgery is not the first-line treatment option for patients with gliomatosis cerebri. CSF shunting is usually reserved for patients with hydrocephalus.

There is no established method for prevention of gliomatosis cerebri.

There are no secondary preventive measures available for gliomatosis cerebri.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Gliomatosis cerebri was first reported by Landau in 1910. Several physicians published isolated cases of gliomatosis cerebri and only later in 1938, it was extensively studied and described by Nevin.

• The earliest mention of gliomatosis cerebri in the literature dates back to the early 20th century.
• Gliomatosis cerebri was first reported by Landau in 1910. Several physicians published isolated cases of gliomatosis cerebri and only later in 1938, it was extensively studied and described by Nevin.
• Since then, just over 300 cases have been reported in the literature.^[1]
• The largest case series was by Taillibert et al, who analyzed 90 cases from the French neuro-oncology network between 1993 and 2004 and more than 206 cases described in the literature between 1938 and 2004.
• The first international gliomatosis cerebri group meeting was help in Paris, France in 2015.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Gliomatosis cerebri may be classified into several subtypes based on the origin (primary and secondary) and the type of tumor cell (astrocytic, oligodendroglial, and mixed).

Gliomatosis cerebri may be classified based on the origin into two subtypes:^[1][2][3][4]

Type of gliomatosis cerebri	Characteristic features
Type 1 (Primary)	No pre-existing primary cerebral neoplastic lesion (de novo) No discrete mass Diffuse spread of tumor More common Median age at diagnosis is 56 years Mean survival time was longer than type 2 (24 months) Predominantly low-grade
Type 2 (Secondary)	Results from a pre-existing cerebral glioma Discrete mass with diffuse CNS involvement Less common Median age at diagnosis is 44 years Mean survival time was shorter than type 1 (21 months) Predominantly high-grade IDH1 mutation is more common

Gliomatosis cerebri may be classified based on the predominant tumor cell type into three sub-types:^[4]

• Astrocytic – it is considered a distinct entity of astrocytic glioma as per the latest WHO classification for CNS tumors.^[5]

• Oligodendroglial – very few cases of isolated oligodendroglial GC has been reported. No difference in the signs and symptoms are noted.^[6]
• Mixed – more common than isolated oligodendroglial GC.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2], nabeel ahmed

Genes involved in pathogenesis of gliomatosis cerebri include p53, OLIG-2, Ki-67, EGFR, PTEN, VCAM1, VEGF, and gene on chromosomes 7q, 10q, and 13q. Gliomatosis cerebri may be associated with neurofibromatosis type 1 and pilomatricoma. The most common form of GC which is astrocytic involves mutation in p53 and (isocitrate dehydrogenase) IDH1. On gross pathology, gliomatosis cerebri is characterized by a diffuse astrocytic growth pattern involving at least three cerebral lobes and bilateral involvement of the cerebral hemispheres, deep gray matter, brainstem, or cerebellum. On microscopic histopathological examination, gliomatosis cerebri is characterized by diffuse proliferation of immature glial elements resembling astrocytes, oligodendroglia, or undifferentiated cells with cytologic and nuclear atypia, calcifications, microcysts, and mitotic figures without the presence of any necrosis or microvascular proliferation. Gliomatosis cerebri is demonstrated by positivity to tumor markers such as GFAP, S-100, and Ki-67.

Genes involved in pathogenesis of gliomatosis cerebri include:^[1][2][3][4]

• P53
• Isocitrate dehydrogenase (IDH1)
• OLIG-2
• Ki-67
• EGFR
• PTEN
• VCAM1
• VEGF
• Gene on chromosome 7q
• Gene on chromosome 10q
• Gene on chromosome 13q

Gliomatosis cerebri may be associated with:^[5][6][7]

• Neurofibromatosis type 1
• Pilomatricoma

On gross pathology, gliomatosis cerebri is characterized by:^[3][6][8]

• Diffuse, usually astrocytic growth pattern
• Involvement of at least three lobes of the brain ^[9]
• Bilateral involvement of the cerebral hemispheres, deep gray matter, brainstem, or cerebellum

Common intracranial sites involved in gliomatosis cerebri include:^[10]

• Basal and thalamic nuclei (75%)
• Corpus callosum (50%)
• Brainstem and spinal cord (10-15%)
• Cerebellum (10%)
  • Two or more sites generally affected at the same time

On microscopic histopathological examination, gliomatosis cerebri is characterized by:^[11]

• Diffuse proliferation of immature glial elements resembling astrocytes, oligodendroglia, or undifferentiated cells
• Cytologic and nuclear atypia
• Calcification
• Microcysts
• Mitotic figures
• No necrosis or microvascular proliferation

According to WHO classification of brain tumors, gliomatosis cerebri is classified into grade 2 or grade 3 tumors.

Gliomatosis cerebri is demonstrated by positivity to tumor markers such as GFAP, S-100, and Ki-67.^[12][13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2](

Common causes of gliomatosis cerebri include genetic mutations. The genes associated with the etiology of gliomatosis cerebri include p53, (Isocitrate dehydrogenase 1) IDH1, OLIG2, Ki-67, EGFR, PTEN, VCAM1, VEGF, and genes on chromosome 7q, 10q, and 13q.

Common causes of gliomatosis cerebri include genetic mutations. The genes associated with the etiology of gliomatosis cerebri include:^[1][2][3][4]

• P53
• Isocitrate dehydrogenase 1 (IDH1)^[5]
• OLIG2
• Ki-67
• EGFR
• PTEN
• VCAM1
• VEGF
• Gene on chromosome 7q
• Gene on chromosome 10q
• Gene on chromosome 13q

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Gliomatosis cerebri must be differentiated from progressive multifocal leukoencephalopathy, multiple sclerosis, Marburg disease, multicentric glioblastoma, primary CNS lymphoma, viral encephalitis, acute disseminated encephalomyelitis, CNS vasculitis, Behçet’s disease, venous sinus thrombosis, stroke, Gerstmann syndrome, leptomeningeal gliomatosis, Alzheimer’s disease, Lewy body dementia, and parkinsonism.

Gliomatosis cerebri must be differentiated from:^[1][2][3][4]

• Gliomatosis cerebri must be differentiated from other diseases that cause clumsiness, progressive weakness, visual and speech changes and personality changes such as progressive multifocal leukoencephalopathy and leptomeningeal gliomatosis. Gliomatosis cerebri has more prominent long tract signs commonly involving corticospinal and spinocerebellar defects.
• Gliomatosis cerebri must be differentiated from other diseases that cause memory loss, visuospatial defects, loss of executive function including cognitive and functional impairment such as alzheimers disease, lewy body dementia and parkinsonism. Gliomatosis cerebri may have the same exact features but are more subacute than the mentioned diseases.
• Gliomatosis cerebri must be differentiated from other diseases that causes acute focal neurological deficits including hemiparesis, diplopia, aphasia and sensory changes such as a stroke, Gerstman syndrome, primary CNS lymphoma, multicentric glioblastoma and venous sinus thrombosis. Gliomatosis cerebri may have the same features but may not point to a single localizing area of affectation on brain imaging as it involves the brain diffusely (more than three lobes).
• Gliomatosis cerebri must be differentiated from other diseases that cause headaches, malaise, weight loss and other constitutional symptoms such as CNS vasculitis and Behcets disease. Gliomatosis cerebri rarely present with inflammatory signs and symptoms.
• Gliomatosis cerebri must be differentiated from other diseases that cause optic neuritis and other symptoms dessiminated in time and space such as multiple scleosis. Gliomatosis cerebri have a subacutely declining course rather than the typical relapsing-remitting course seen in majority of the case of multiple sclerosis.
• Gliomatosis cerebri must be differentiated from other diseases that cause headaches, blurred vision, still neck, vomiting and nausea such asviral enchephalitis, meningitis and acute disseminated encephalomyelitis. These diseases are inflammatory in nature and they present acutely while gliomatosis cerebri present subacutely.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

Gliomatosis cerebri is a rare brain tumor. The incidence of gliomatosis cerebri is estimated to be less than 100 cases per year in the United States. Gliomatosis cerebri is a disease that tends to affect the middle-aged population. The peak incidence for gliomatosis cerebri is 20-40 years. The median age at diagnosis is 34 years. Males are more commonly affected with gliomatosis cerebri than females. The male to female ratio is approximately 1.5 to 1.

• Gliomatosis cerebri is a rare brain tumor. The incidence of gliomatosis cerebri is estimated to be less than 100 cases per year in the United States.^[1]

• Gliomatosis cerebri is a disease that tends to affect the middle-aged population. The peak incidence for gliomatosis cerebri is 20-40 years.^[2]
• The median age at diagnosis is 34 years.^[3]

• Males are slightly more affected than females. The male to female ratio is approximately 1.5 to 1.^[2]

• The annual incidence rate of gliomatosis cerebri is approximately 0.1 per 1,000,000 individuals worldwide.^[4]

• There is no data on racial predilection for gliomatosis cerebri.

• There is no data on regional and geographical predilection for gliomatosis cerebri.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

The most potent risk factor associated with the development of gliomatosis cerebri is neurofibromatosis type 1.

The most potent risk factor associated with the development of gliomatosis cerebri is neurofibromatosis type 1.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

There is insufficient evidence to recommend routine screening for gliomatosis cerebri.

There is insufficient evidence to recommend routine screening for gliomatosis cerebri.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]

If left untreated, patients with gliomatosis cerebri may progress to develop focal neurological deficits, altered mental status, hydrocephalus, brain herniation, and ultimately death. Transformation into glioblastoma (grade 4) may occur a few years later. Common complications of gliomatosis cerebri include brain herniation, hydrocephalus, coma, metastasis, recurrence, benign intracranial hypertension, and side effects of radiotherapy and chemotherapy. Prognosis of gliomatosis cerebri is generally poor, and the 5-year survival rate of patients with treatment is approximately 17.7%. Median survival of patients who are treated with whole brain radiotherapy alone is 13.7 months (range 1–35), whereas those who are treated with combined whole brain radiation therapy and chemotherapy have a median survival of 26.14 months (range 6–42). Median survival without any form of treatment is reported raging from 7 to 18.5 months.

• If left untreated, patients with gliomatosis cerebri may progress to develop focal neurological deficits, altered mental status, hydrocephalus, brain herniation, and ultimately death.
• Transformation into glioblastoma (grade 4) may occur a few years later.^[1][2]

Common complications of gliomatosis cerebri include:^[3][1][4][2]

• Brain herniation
• Hydrocephalus
• Coma
• Metastasis
• Recurrence
• Benign intracranial hypertension
• Side effects of radiation therapy
• Side effects of chemotherapy

Prognosis of gliomatosis cerebri is generally poor, and the 5-year survival rate of patients with treatment is approximately 17.7%.^[5][6]

Median survival of patients who are treated with whole brain radiotherapy alone is 13.7 months (range 1–35), whereas those who are treated with combined whole brain radiation therapy and chemotherapy have a median survival of 26.14 months (range 6–42).^[7] Median survival without any form of treatment is reported raging from 7 to 18.5 months. ^[8]

The prognosis of gliomatosis cerebri depends on the following:^[9][10]

• Resectibility of the tumor mass
• Age of the patient
  • Age < 10 year is associated with worse prognosis.
• Gender of the patient
  • Males have better prognosis than females.
• Predominant type of cell
  • Oligodendroglial type of gliomatosis cerebri have a better prognosis.
• Location of tumor
  • Infratentorial tumor is associated with shorter survival.
• Size of the tumor
• Stage of the cancer
• Primary diagnosis vs. recurrence

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