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Cranial Nerve Surgery Disease:Glial Tumor (Glioma)

Brain Cancer article

Brain Tumor is divided into two major groups, the one where brain cancer is developed from brain itself (cerebral parenchyma), and the other where it is developed from tissue outside of the brain. Tumor developed in cerebral parenchyma is called as neuronal epithelial tumors, and there are glioma and neuronal cell tumors. WHO Brain Tumor Pathology Classification has been revised for the first time in 10 years in 2016. Major change is that gene diagnosis becomes necessary, but the detail is withheld here since the explanation of it requires too much space. General matters regarding brain tumor is described here.
Surgical case, which writer has experienced during 1994 to 2008, is described here.

Firstly, glioma which is the most common brain tumor is explained.

Glioma takes 25% of primary brain tumor.

Development of Glioma is said to be more or less 20 persons out of 100,000. The most common brain tumor is meningioma and glioma, and both take around 25% of primary brain tumor. In the WHO Definition 2016, Diffuse Glioma is called as glioma. They include five tumors as listed below.;

  1. Diffuse astrocytoma
  2. Degenerate glioma
  3. Glioblastoma
  4. Oligodendroglia tumors
  5. Degenerate oligodendroglioma

To diagnose this glioma, deletion of gene called as IDH and 1p/19q chromosome were described as inevitable.

Grade IV of high-grade astrocytic tumor

Astrocytic tumor is developed from stellate cell astroglia which is the typical brain tumor representing glioma and is the brain structural components. They are grouped in three, which are Diffuse astrocytoma (Grade II), Degenerate glioma (Grade III) and Glioblastoma (Grade IV). Among these three, grade III and grade IV is designated as malignity, and grade IV is the highest malignancy and high in development frequency (aboPeak development age of diffuse astrocytoma (grade II) is in the age of 30s and 40s. The same of Degenerate glioma (Grade III) is in the age of 50s through 60s. Glioblastoma (Grade IV) are common in the age of 60s. Malignant diffuse astrocytoma is progressed along nerve fiber so that as nerve fiber in the cerebral hemisphere spread to brain structure like spider’s thread, it grown up like an island. It originally advances invasively to the opposite side through callosum (butterfly pattern), invade through the wall of brain ventricle (sub ependymal extension), or sowing transition in the cerebrospinal cavity (leptomeningeal carcinomatosis), which tissues spread around in the spinal fluid surrounding the brain surface, can be seen. It grows like sword (spinal cord) casing as dissemination reaches to spinal cavity and covers spinal cord. The least common case, diffuse astrocytoma infiltrate in venosus cavity adherent to brain surface and forms metastatic lesion in lung. In pediatric cancer, leukemia is the most common then brain tumor, and brain tumor is the most common one in solid tumor. Development frequency of brain tumor under age of 15, 3.6 person per year in 100,000 child population. Glioma takes 1/3 of pediatric brain tumor, but frequency of neuroblastoma is less in comparison to adult (1.5%), but frequency of astroglioma (18.6%), then medulloblastoma (12%), embryonic cell tumors (10%) are getting high.

Symptoms are focal symptoms, like increased intracranial pressure symptoms (nausea and vomiting, headache) or paralysis. Pathogeny by epileptic attack takes 30 to 50%, and 10% to 30% may cause a stroke in the course.
For the treatment, administration of preventive ant-epilepsy drug is not recommended except for the special case like perioperative period. As for the treatment for tumor peripheral Edema, it is recommended to administrate Dexamethasone or Betamesazone, which has less mineralocorticoid effect.

Pilocytic astrocytoma (Grade I)
Diffuse astrocytoma (Grade II)

In the Diffuse astrocytoma, there are;

  1. Fibrillary astrocytoma
  2. Gemistocytic astrocytoma (Fig.3)
  3. Protoplasmic astrocytoma (Fig.4)

Above 3 types exist.

Fibrillary astrocytoma appears more commonly in adult cerebral hemisphere white matter and children’s brain-stem area. Obese cellular stellate cell swelling appears only in cerebral hemisphere. Protoplasmic astrocytoma appears in Cerebral hemisphere gray matter. It is said that mutated obese cellular stellate cell swelling is easy to malignantly change.

Age, size of tumor, existence or non-existence of Symptoms of Neurosis, removal degree of the surgery, and tissue type are considered as prognosis factor. In general, complete removal is tried but it is better not to overdo. When there is no problem at biopsy and in case it grows further in the course, delivery of radiation is conducted. It is said that the radiation exposure is ineffective. It is also said that the removal degree and prognosis has no correlative relationship. Chemo treatment, in general, is hard to expect the effect. It is said that almost all have IDH mutations, but treatment method does not been decided by these.

Degenerate glioma (Grade III)

In Japan, treatment in accordance with glioma is conducted for degenerate glioma. In 2012, the report of long-term result of EORTC and RTOG randomized comparison test regarding anaplastic oligodendroglioma, and the report shows the effectiveness of radiation + chemo treatment(PCV;procarbazine + CCNU + vincristine), especially indicated in co-lost group of chromosomes 1p/19g. In Japan ACNU is used instead of CCNU, but there are many cases where TMZ which has less adverse effect than PCV are used.

Glioblastoma (Grade IV)

This disease can be divided into secondary glioblastoma which low-grade glioma becomes malignant, and primary glioblastoma which does not become malignant. This is very much intercorrelated with the existence of mutation of IDH1 and IDH2, and secondary GBM which has IDH1/2 malignancy, in general, good in prognosis but rare in glioblastoma (about 10%).

It is listed as prognosis factor of malignant glioma that age, entire body condition before surgery, removal degree of surgery and prognosis condition (whether or not workable). Standard treatment for glioblastoma is the extended local radiation therapy with TMZ after expeditious removal. Radiation exposure (local 60Gy) after expeditious removal is conducted, administrate TMZ during the period, and continue administrated after exposure completed.
In the O6-methylguanine-DNA methyltransferase(MGMT)Promoter Region methylation cases, significant extension of survival period is indicated. TMZ with radiation therapy combined has shown the effect which is greater than radiation only treatment. But in the case of without MGMT promoter region methylation, effect can not be identified. Methylation, i.e. the case where gene expression is suppressed, effect becomes better.

Standard treatment for glioblastoma with 70 years or much older person, even nowadays, is postoperative radiation therapy. Regarding the methylation case, even with TMZ single treatment can show effect which is not inferior to radiation therapy only treatment. Carmustine wafer as intraoperative topical chemotherapy agents starts to be used from 2013 against the malignant glioma. Because of the Carmustine wafer usage, not all of the case though, there is a case where shrinkage of tumor is clearly recognized.
Two random comparison tests are conducted to anti-VEGF bevacizumab, and there is no extension in overall survival time (OS), and in regard to the evaluation of progression-free survival (PFS) extension, conflicting results are shown. With Carmustine wafer usage, better result in the image (MRI) is certainly recognized, and deduction of increased efficacy by contrast agent, and also the decrease in peripheral high signal are seen are seen, but in regard to the extension of overall survival time, no effect is recognized.

Diagnosis of Glioma

At diagnosis, several patterns are taken with using the followings

MRI-T1WI, T2WI, Flair, Gd-enhanced MRI (Contrast MRI), DSA, MR-spectroscopy (MRS), TL scintigraphy, MR spectroscopy-Cho/NAA ratio, Cho/Cr ratio

Peripheral part receives the increased efficacy strongly and necrotic zone at center part shows low signal. (fig.7)

As same as Anaplastic Astrocytoma, infiltration is strong so that it invades and advances to the opposite side, and is commonly showing the butterfly pattern.

There are quite a lot of creating solitary focus at the separated part along the fiber from primary tumor site. (Fig.9)

Occasionally, a multi-center glioblastoma image is shown, and also there is a case showing the image of multiple metastatic brain tumors. (Fig.10)

Dissemination by cerebrospinal fluid is easy to be developed, and in case when it is developed at brain room proximal, progress to sub ependymal extension or brain room becomes also easy so that it forms solitary focus at the part on spinal flow. (Fig.11)

Also, at very rare case, glioblastoma may be developed at pineal region.

Other than these, gliomatosis cerebri is a special disease which infiltrate extraordinarily wide area through the way of normal tissue. This name is deleted from WHO classification 2016, but it is grouped in diffuse glioma so that this is extremely malignant clinically and pursuant to Grade IV. Its characteristics are; no tumor mass can be seen, no increased efficacy by contrast agent, and indicate broader high-signal by T2WI, but sometimes there is a case where tumor mass is recognized. Chemo therapy has no effect so that survival period has barely extended by radiation exposure. Duration from diagnosis to death is similar to glioblastoma, roughly about one and half years.

Radiation and chemotherapy treatment after the tumor removal is a common treatment.

Treatment for malignant glioma is common for the treatment to intraparenchymal hemorrhage. Meningeal carcinomatosis spilt over it becomes an issue in the late stage through the course. Therefore, countermeasure treatment is necessary from early stage, but there is no set treatment at this moment.

General treatment for malignant glioma in Japan is to conduct radiation and chemotherapy (Temozolomide: Temodar) after the removal. However, the tumor reappearance rate is still high and when reappeared, in general, re-operation, radiation re-exposure, administration of bevacizumab (molecularly targeted drug, vascular endothelial growth factor inhibitor) are considered. Regarding bevacizumab, VEGF is oozed out from the tissue named as astrocyte to create blood vessel, but plasma component is easy to leak out than normal tiny vessel so that this causes the angioedema. Therefore, molecularly targeted drug, bevacizumab which prevent from vessel formation by VEGF, becomes effective, but when it is administrated actually, on image, only relief of edema and tumor shrinkage are seen, no effect on survival time are reported. There is an adaptation in the initial case only in Japan, but in overseas there is no such case, adaptation only at recurrence case. Too much burden is a disadvantage since it requires few hundred thousand yen as cost. Also, be aware of the side effect. As the other method, there is a case where Gliadel wafer which is a Nitrosourea Anti-Cancer medicine and alkylating agent of BCNU (Carmustine) sustained preparation is used. There is a case where epidemic effect is confirmed depend on the symptom.

Report says that the effect of neutron capture therapy is expected.

At the removal of tumor, it is said that the border of tumor area is indicated by aminolaevulinic acid so that the isolation degree becomes high, but there exist false positive and false negative. There is vaccine, lymphocyte activation therapy and immune therapy like own dendritic cells available, but there is no multimodality data available regarding their effect so that effect is unknown. Regarding the Boron Neutron Capture Therapy, writer has been collaborate researched with Teikyo University Professor Hatanaka and Osaka University professor Mogami, with making mouse brain tumor model in Kanto and Kinki Nuclear Reactor Facility, but at that time, Boron intake ratio to tumor cells was low so that my experience indicated that the effect is seen only for superficial cancer. Recent report says that the intake ratio is getting high so that the effect is expected.

NovoTTF-100A system which inhibit the growth of neoplastic cell by electric field.

NovoTTF-100A system (Novocure’s OPTUNE) is authorized as new treatment equipment for glioma at first in Japan on December 2016 for first and reappeared glioma treatment. But it is not subject to the Health Insurance, so that it takes extremely high charge, 3 million yen per month. This system is a treatment equipment where adhesive sheet which create electric field is pasted on brain skin, then electric field so called Tumor Treating Fields (TT field) is excited to hold neoplastic cell proliferation. TTF is a middle frequency alternate electric field, is broadly classified as electromagnetic wave and grouped into the same frame with radiation. Novocure, USA corporation announced that NovoTTF is listed as new treatment equipment in NCCN (National Comprehensive Cancer Network) Central nervous system Cancer clinical guideline on January 22, 2013

Radiation necrosis is difficult to differentiate with recurrence.

Radiation necrosis is developed in few months to 10 years range after the radiation treatment. But it is very much difficult to differentiate with reappearance of tumor, also there is no assured differential method. When intake is recognized by methionine Met-PET, it can likely diagnose as reappearance. Substance of radiation necrosis is coagulation necrosis, but large amount of VEGF, which is supplied from reactive astrocyte produced in accompany with necrosis, renews the vascular permeability and produces the advanced inter-organizational edema. This is the cause of massive edema brought by radiation necrosis. In the past, steroid is the main treatment drugs but vascular endothelial growth factor inhibitor, Bevacizumab used for the treatment of glioblastoma, becomes known as effective. However, high cost is still the problem.

Treatment trial for initial treatment resistance or recurrent malignant glioma.

For the case, first stage radiation therapy does not effect for malignant glioma so that it indicate early increase tendency, or the case which reappearance has occurred, effective treatment method has clearly not yet established. Especially for the treatment to brain is limited since excess treatment to brain directory connected to impair activities of daily living. In such kinds of circumstances, several treatment methods are developed. Some of them are described as below.

  1. Super-selective Arterial Injection Therapy using Etoposide and Cisplatin
    • Nakagawa H., et al. Surg Neurol 41:19-27, 1994
    • Nakagawa H., et al Cancer Clinical 39:1715-1720, 1993
    • Nakagawa H., et al Cranial Nerve Surgery 22:35-42, 1994

    The method is; first insert microcatheter to the peripheral vascular nutrition, administrate etoposide to modify blood-brain barrier so that water-soluble anticancer agents becomes easy to take into the brain, then administrate CDDP. With interdependent combinational effect of both agents, and as the treatment for no curable recurrent malignant glioma, loss of the initial tumor is gained.

  2. FdUrd Administration treatment for tumor cavity or resection cavity.
    • Nakagawa H., et al. Jpn J Clin Oncol 31: 251-258, 2001

    The report says that the FdUrd administration, for which writer acquire a US Patent through Ommaya reservoir indwelling in tumor resection cavity, is effective

  3. Combined treatment of rIL2 selective arterial injection and water-soluble anticancer agents
    • Nakagawa H., et al. 97th AACR, 2006

    Anticancer efficacy by administrating recombinant IL2 against the Rat’s ENU triggered tumor is indicated as below using animal CT. With having this result, Ethical Committee has authorized and is used in clinical application. Epidemical tumor loss effect has recognized but currently this treatment has ceased its continuation due to financial reason.

  4. Micro Multileaf Treatment (Stereotactic Radiotherapy)
    • Nakagawa H., et al. 96th AACR, 2005; ICACT,2006,Paris; ECCO 15/ESMO 34,2009、Berlin
  5. Sodium Butyrate (NaB) administrated to sustained tumor cavity or Intrathecal therapy
    • Nakagawa H., et al. 97th AACR, 2006

    Sodium Butyrate (NaB) is a natural single chain fatty acid, and it indicates concentration dependence in vitro and cell killing effect. Also, Infiltration restraint efficacy is shown at Walker 256 cell or Human A-172 neuroblastoma cells. In addition, it shows extremely low toxicity in primary neuron culture and stellate cell culture.
    Same effect is indicated at NaB Sustained cerebrospinal cavity administration in Normal Rat and Rat Cancerous Meningitis Model. From these results, NaB administration in medullary cavity or tumor cavity becomes a good treatment for malignant glioma and Cancer meningitis. Ethical Committee authorization is attained with these data, then sustained spinal cavity therapy is performed to progressive malignant glioma which has a resistance against the reappearance and initial treatment. For 27 cases, 78% in the image of response rate and epidemic extension of the duration of survival lifetime (PFS, OS) are recognized. At this moment, this treatment is to re-submit to Tokushukai Ethical Committee, and with having the outcome from the Committee, we plan to perform treatment again.

  6. Combination effect with infiltration control of cerebrospinal sowing cancer cells by Y-27632 cerebrospinal cavity administration – cerebrospinal treatment by anti-cancer agent
    • Nakagawa H., et al. Mo Cancer Res 3:425-33,2005

    This is to see the combination effect of Y-27632 administration for inhibitory effect of cancer cell infiltration and chemotherapy in the cerebrospinal cavity. Soon, this clinical application will be submitted to Tokushukai Ethical Committee.

At this moment, 5th case: “Sodium Butyrate (NaB) dosage therapy to sustained tumor cavity or intrathecally” is very much promising treatment, and in the judgement of the effect of suppressing progress for tumor, 78% out from 27 persons, who are indicating reappearance or showing the resistance to the initial treatment, have recognized an effect, and even histologically, degeneration at tumor is clearly seen. With advancing the improvement, enough effect can be expected.


Gliosarcoma is a mixed tumor of glioma and sarcoma. It means that the glioma is having the component of sarcoma, thus it is very rare case. It often develops at temporal cortex, and treatment for Gliosarcoma is the same as glioma so that the size of tumor resection affects to the prognosis. Treatment effect is inferior than glioma.

Low-grade glioma (Grade I, II)

Astroglioma, Depletion projection glioma and oligoastrocytoma of Grade 1 and II are used to be jointly referred to as low-grade glioma (LGG). Recently, this expression is said to be an incorrect definition but it is currently common word so that here we refer it as LGG.

In LGG, age, size of tumor, existence or non-existence of neurological deficit, surgically isolated degree, histological type are prognosis factors.

Postoperative radiation Therapy PFS against the LGG is 5.3 years, in radiation stand-by group is 3.4 years so that the postoperative radiation therapy may significantly extend PFS. But overall survival time (7.2 years and 7.4 years) has no difference in between. From the view point of the complicated disease of radiation therapy, exposure timing is not yet consented.

Brainstem glioma is appeared more commonly at pediatric pontine, and 1 year survival rate is less 50%. Even in oligodendroglioma with low degree of differentiation, 5 years survival rate of 70 to 80% can be expected.
Surgery plus radiation therapy is the standard treatment (spot 50 to 56Gy) for diffuse astrocytoma. 5 years survival rate is 50 to 70% and 90% of them will become tumor death.Ependymoma is common in childhood, and completely removal and radiation therapy is the basis. Receptivity of chemotherapy is low.