Author(s): Cherry Junn, MD, Ny-Ying Lam, MD
Originally published: November 16, 2011 Last updated: May 24, 2021
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Disease/ Disorder

Definition

Primary brain tumors are anomalous masses of tissue in the brain due to an abnormal proliferation of cells that can be malignant or benign but are not due to metastatic disease.

Etiology

Brain tumors are a heterogenous group of lesions, and no underlying cause is identified for the majority of primary brain tumors.

The exact cause of gliomas, which include astrocytomas, ependymomas, glioblastomas, and oligodendrogliomas, is unknown.  Histologic heterogeneity is also noted with these glial tumors. Regarding genetic mutations, the Cancer Genome Atlas (TCGA) has published predominant genomic alteration patterns that lead to tumorigenesis1.  

Molecular etiology or tumor cell of origin for meningioma cells is thought to be related to arachnoid cap cells since they resemble each other.  Epidemiology studies focus on multiple genetic mutations associated with meningiomas.  However, meningioma’s slow growth poses challenges as it makes it difficult to identify the sources and timings of these mutations. 

Epidemiology including risk factors and primary prevention

The National Cancer Institute estimates that there are more than 24,500 new diagnoses of brain and central nervous system (CNS) cancers causing more than 18,600 deaths each year in the United States2,3.

Primary brain tumors account for 85% to 90% of all primary CNS tumors4,5.  Anaplastic astrocytomas and glioblastomas tumors comprise about 30% of primary brain tumors6.

Meningiomas comprise about another 30% of primary brain tumors, followed by pituitary tumors, schwannomas and CNS lymphomas2. Those with the human immunodeficiency virus, autoimmune disorders, and individuals who are on immunosuppressive agents such as transplant patients are at an increased risk for primary CNS lymphoma7. Incidence rates are higher in industrialized countries with men having slightly higher rates than women8.  Meningioma and other specific tumors are more common in women.

Exposure to ionizing radiation is one of the few known risk factors for development of primary brain tumors. Currently there is no clear evidence that cell phone usage or exposure to electromagnetic/radiofrequency radiation usage correlates with the development of cerebral neoplasms9.

Patho-anatomy/physiology

In 2016, the World Health Organization (WHO) revised CNS tumor classification to incorporate molecular parameters in addition to prior principle of diagnosis based on microscopy10.  Other major changes include the incorporation of genetically defined entities into the classification.  This new classification of the CNS primary brain tumors as:

  • Diffuse gliomas: all diffusely infiltrating gliomas have been grouped together based on growth pattern, behavior, and shared genetic driver mutations.
    • Diffuse astrocytoma and anaplastic astrocytoma: the WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytoma are each divided into:
      • Isocitrate dehydrogenase (IDH)-mutant: majority of both grade II and grade II tumors fall into this category
      • IDH-wildtype
      • Not otherwise specified (NOS): for some tumor types that lack access to molecular diagnostic testing, a diagnostic designation of NOS is allowed.
    • Glioblastomas (GBM):
      • Glioblastoma, IDH-wildtype
      • Glioblastoma, IDH-mutant
      • Glioblastoma, NOS
    • Oligodendrogliomas
    • Oligiodendrocytomas: These tumors account for less than 10% of primary central nervous system (CNS) tumors and are typically sensitive to chemotherapy.  Diagnosis of oligodendroglioma and anaplastic oligodendroglioma requires the demonstration of both an IDH gene family mutation and combined whole-arm loss of 1p and 19q (1p/19q codeletion).
    • Oligoastrocytomas: As per the 2016 WHO CNS classification scheme, this diagnosis is strongly discouraged. This change was made since almost all tumors with histological features suggesting both an astrocytic and an oligodendroglial component can now be classified as either astrocytoma or oligodendroglioma through genetic testing.
    • Pediatric diffuse gliomas: no longer grouped with adult gliomas since distinct underlying genetic abnormalities have been identified
  • Other astrocytomas: now includes pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, and anaplastic pleomorphic xanthoastrocytoma
  • Ependymomas
  • Neuronal and mixed neuronal-glial tumors
  • Medulloblastomas
  • Other embryonal tumors
  • Nerve sheath tumors
  • Meningiomas
  • Solitary fibrous tumor hemangiopericytoma
  • Lymphomas and histiocytic tumors

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Grading and staging of tumors is specific for tumor types. Grading of tumors is used to provide prognostication. A standardized grading system developed by the WHO is listed below:

  • Grade I: The tissue is benign. The cells look nearly like normal brain cells, and they grow slowly.  Better prognostic lesions.
  • Grade II: The tissue is generally nonmalignant but can be malignant. The cells look less like normal cells than the cells in a grade I tumor.  Higher likelihood of recurrence than grade I tumors.
  • Grade III: The malignant tissue has cells that look very different from normal cells. The abnormal cells are actively growing and have a distinctly abnormal appearance (anaplastic).  Often recur as higher grade lesions.
  • Grade IV: The malignant tissue has cells that look most abnormal and tend to grow quickly.  Most aggressive typically with a high recurrence rate. 

The prognosis will be determined by tumor type, molecular characterization and tumor grade. In general, GBM has the most grave prognosis with median survival of about 14 months for those who receive treatment11,12. Prognostic factors in patients with GBM include age, Methylguanine-DNA Methyltransferase (MGMT) methylationand IDH mutation status, performance status, and extent of surgical resection.

Specific secondary or associated conditions and complications

Brain tumor specific potential complications include vasogenic edema, SIADH, hydrocephalus, DVT, seizure, headache, fatigue, cognitive impairment, reactive mood and adjustment disorders, sleep disturbance, spasticity, dysphagia, and other focal neurological deficits.

Surgical intervention can have potential complications including infection, delayed wound healing, and pain at the surgical site.

Radiation effects are varied depending on the type of radiation used. Radiation therapy can lead to both demyelinating and axonal damage, leading to white matter damage.  Radiation-related complications may occur acutely or in a delayed fashion (months to years). Acute symptoms may include headache, nausea, vomiting, focal neurologic signs and skin changes. Early and late delayed radiation effects may include fatigue, cognitive changes, incontinence, and focal neurologic signs.  Impairment of memory and processing have been noted after partial brain radiotherapy13.  Encephalopathy can occur acutely within several days, early delayed occurring weeks to months after treatment, or delayed occurring 6 months to a year after initial therapy14.

Chemotherapy side effects have reduced with newer agents but are still significant. Fatigue, nausea, and vomiting are the most commonly reported symptoms; thrombocytopenia and neutropenia are also common. Other side effects include peripheral neuropathy and “chemo brain”15 which is thought to be due to white matter damage that is particularly vulnerable to the effects of chemotherapy, leading to deficits in concentration, memory, reasoning, and attention.  Other complications from chemotherapy including cytopenia, cardiotoxicity, myelotoxicity, alopecia, and seizures should also be considered. 

Other treatment side effects from steroids such as immunosuppression, hypertension, glucose intolerance, gastrointestinal bleeding, osteoporosis, and more can also be seen. 

Risk for venous thromboembolic disease is increased in patients with primary brain tumor.  Prophylaxis should be considered after surgery but routine prophylaxis in outpatient setting is not recommended.  

Essentials of Assessment

History

The presentation can be varied. Symptoms may be generalized due to increased intracranial pressure (headache with nausea or vomiting, personality changes, impaired gait) or focal. Focal presentations depend on the site of the tumor and can include hemiparesis, visual field defects, or speech impairment. In addition to location, size and mass effect will affect clinical presentation and history.  Headache, nausea/vomiting, or seizures are common presenting symptoms.  Lesions within the occipital lobe can affect vision while lesions within the temporal lobe can lead to changes in memory, hearing, and speech.  Personality changes, mood changes, sleep disturbance, hallucination and psychosis have also been reported.  Differential diagnosis includes stroke, epilepsy, abscess, and hydrocephalus. History should include onset, associated symptoms, and inquiry about risk factors.

Physical examination

A physical exam may help determine localization. A careful, comprehensive neurological examination including cranial nerve exam, motor/sensory testing, reflexes, and cerebellar examination must be performed.  Weakness, sensory abnormalities, and cognitive impairment may be found.

Functional assessment

Functional assessment should evaluate effects of the disease as well as those of cancer treatment. This should include assessment of pain, fatigue, seizures, neurologic impairments, and psychological status as well as the effects of impairments in the areas of cognitive functioning, mobility, self-care, safety, and general well-being. 

Laboratory studies

Laboratory studies may help detect and monitor secondary conditions and complications such as SIADH or neuro-endocrine dysfunction.

Imaging

Magnetic resonance imaging (MRI) is the preferred modality for tumor characterization via T1 and T2 weighted imaging and should be performed with gadolinium contrast. Malignant brain tumors often enhance with gadolinium and may have central necrosis and surrounding edema. Other imaging studies including positron emission tomography (PET) scans, magnetic resonance spectroscopy (MRS), and computed tomography angiography (CTA) may aid in diagnosis and treatment. CT imaging with contrast may reveal a mass with surrounding vasogenic edema if an MRI is not feasible.

Specific testing may also be warranted based on symptoms and exam findings: these include audiology for acoustic neuroma, lumbar puncture for abnormal tumor cells, endocrine workup for hormonal abnormalities, and electroencephalogram for suspected seizure activity.

Supplemental assessment tools

Functional Scales

Both the Functional Independence Measure (FIM) and Disability Rating Scale (DRS) are frequently used to evaluate function in patients with acquired brain injuries such as brain tumors. The Karnofsky Performance Scale (KPS) is commonly used in oncology to evaluate an individual’s performance status with daily activities16. The scale is a 0 to 100 scale in which 100 indicates no disease effects, 50 indicates a requirement for help and frequent medical care, and 10 indicates rapidly progressive fatal disease. The Eastern Cooperative Oncology Group (ECOG) Scale is also often used to describe functional ability in cancer patients. It is a 0 to 5 scale in which 0 represents the patient being asymptomatic and 5 represents death. Both KPS and ECOG scales were developed to assess constitutional performance status and are used to evaluate if a patient may tolerate aggressive treatment options. However, both scales have limitations when used to describe patients with neurological impairments from brain tumor since grading is affected by the level of assistance needed to ambulate or perform self-care. 

Several measures have been validated specifically in brain tumor patients to assess quality of life and function including the Functional Assessment of Cancer Therapy – Brain (FACT-Br)17 and MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)18. Mayo-Portland Adaptability Inventory has been used to assess functional status after an acquired brain injury19. Neuropsychological evaluation can be used to assess and monitor “chemo brain” or Cancer and Treatment-Related Neurocognitive Degeneration (CRND)15.

Early predictions of outcomes

Prognosis may be determined by clinical and pathological staging of the tumor, knowledge of the typical course of the specific type of tumor, and treatment options available. The physiological reserve of the patient is also important in determining ability to tolerate therapy and functional outcomes.

Environmental

An assessment of the living environment may be helpful in planning management of fatigue, pain, and cognitive or motor impairments. Seizures may raise safety concerns and affect the patient’s ability to drive.

Social role and social support system

A plan and goal for treatment is best determined via communication with the patient, family, and team. An assessment of the patient’s support system and life role is important in formulating a management plan. Treatment options should be weighed in the setting of prognosis and reasonable goals of care. The importance of providing support in the form of psychological aide, counseling, palliative care, and symptom management cannot be understated.

It is important to listen to the patient’s wishes and not to provide false hope. Rehabilitation units can be ideal locations for achieving functional gains prior to discharge home, even for patients with advanced disease. Hospice programs focus specifically on end-of-life care in addition to incorporating palliative measures that prioritize quality of life.

Professional Issues

Rehabilitation of patients with primary brain tumor should be approached in the same manner as in noncancerous neurologic disease, with emphasis on restoring or maximizing independence with mobility, activities of daily living, cognition, and communication.  Unique to this population is a need to carefully consider any anticipated disease progression and accordingly adjust time frame to reach rehabilitation goals.  With improvement in cancer treatments, more patients are living longer and needing rehabilitation during the survivorship period. A partnership with neuro-oncologists, neurosurgeons, radiation oncologists, and other providers is needed to help provide rehabilitation care for these patients. This collaboration may occur during multidisciplinary tumor board meetings, multidisciplinary clinical settings, or through carefully coordinated consultations.

The National Cancer Act in 1971 helped to develop training, demonstration, and research projects in rehabilitation. More recently, cancer rehabilitation fellowships have been developed at select institutions to help physiatrists gain knowledge and experience managing rehabilitation in all types of cancer diagnoses.  Although the American College of Surgeons Commission20 on Cancer identifies rehabilitation services as a key resource for cancer patients, clear guidelines on how and when patients receive rehabilitation services are lacking.  Cancer Rehabilitation Medicine is a developing field and has been identified as a key area for growth within AAPM&R’s Bold Vision.

Rehabilitation Management and Treatments

At different disease stages

Definitive brain tumor treatments are based on the tumor type and extent of disease. Current treatment protocols for primary brain tumors combine surgical resection (if possible) with radiation therapy and adjuvant chemotherapy. Glucocorticoids, such as dexamethasone, are administered to reduce cerebral edema and may also contribute to improved neurologic function. Venous thrombo-embolism is common, so anticoagulant prophylaxis should be considered in nonambulatory patients. Reversible causes of symptoms should be sought and treated.

Rehabilitation services can support the patient from diagnosis to surgery, adjuvant therapy, survivorship, and terminal or end-of-life care. Dietz described adaptive rehabilitation to be preventive, restorative, supportive, or palliative depending on a cancer patient’s disease stage21.  Rehabilitation management should address the effects of the disease as well as side effects of cancer therapies. This may include addressing delirium, neurogenic bladder, neurogenic bowel, spasticity, neuropathic pain, adjustment to disability, and sleep disturbance.

Coordination of care

Rehabilitation treatments are individualized for the patient. Rehabilitation specialists should be part of a multidisciplinary team that may include neuro-oncologists, neurosurgeons, radiation oncologists, and others, as appropriate. A neuro-rehabilitation team comprised of physical therapy, occupational therapy, speech therapy, vocational rehabilitation, neuropsychology, and rehab psychology is crucial to adequately addressing the needs of brain tumor patients. Treatments should address cognitive/communication strategies, emotional and behavioral aspects, as well as physical functioning. Appropriate therapies should be initiated to address the effects of the neoplasm or treatment on speech, cognition, vision, strength, balance, coordination, or gait. Memory, concentration, and processing speed may affect rehabilitation strategies. Fatigue may require incorporation of energy conservation techniques, adjustment of therapy timings, and addressing sleep impairment. Nutritional impairments should be addressed.  Spasticity may benefit from neurolytic or chemodenervation procedures. Antiepileptic medications are indicated for seizure onset, though routine prophylaxis is not indicated in the absence of seizure activity. Counseling and supportive communication of the patient and family may help reduce anxiety and depression.

Serial imaging is used to assess the response to cancer treatment and provide evidence of response to treatment or disease progression.

Patient & family education

Quality of life issues must be addressed in addition to maximizing cognitive and physical function. The rehabilitation medicine physician is equipped to address these issues via supportive care and pain control at all stages of cancer treatment in concert with other treating specialists. This includes not only care of the patient but also addressing family concerns and providing education.

Emerging/unique Interventions

Use of advanced imaging techniques, such as diffusion tensor imaging (DTI) or functional MRI have started to be used to reduce functional damage incurred during surgical resection.  Recent studies have demonstrated functional mapping-guided resection reduces functional damage and also can be used intraoperatively22,23. 

Tumor treating fields delivered via transducer arrays over the scalp are being used in conjunction with maintenance chemotherapy in glioma patients and have demonstrated prolonged survival in patients with supratentorial disease.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Knowledge of the potential acute and delayed complications after surgery, radiation, and/or chemotherapy is important when assessing functional changes or new symptoms in brain tumor patients.

Rehabilitation management of the brain tumor patient requires a dedicated neuro-rehabilitation team led by a physiatrist who understands the medical and prognostic factors that may affect functional trajectory and outcome in this unique patient population.

Cutting Edge/ Emerging and Unique Concepts and Practice

 Immunotherapeutic agents are in clinical trials and allow the body’s inherent immune system to reduce the tumor burden.  With increased understanding of the molecular criteria such as genetic mutations, clinical trials are now looking at molecular-targeted therapies and gene therapy24.

Gaps in the Evidence- Based Knowledge

There is a need for well-designed studies to demonstrate the role and value of rehabilitation in the care of patients with primary brain tumors.   There is a lack of understanding of the role of rehabilitation in survivorship21.  As new developments in neuro-oncology treatment continue, the role of rehabilitation should continue to be examined to minimize disability and maximize quality of life. 25 

References

  1. Weathers S-P, O’Brien B, de Groot J, Mahajan A, Prabhu SS. Tumors of the Central Nervous System. In: Kantarjian H, Wolff R, eds. The MD Anderson Manual of Medical Oncology. 3e ed. The McGraw-Hill Companies, Inc.; 2016. Accessed March 24, 2021. https://accessmedicine-mhmedical-com.offcampus.lib.washington.edu/content.aspx?bookid=1772&sectionid=121901618#1126744830
  2. Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017. Neuro-Oncology. 2020;22(Supplement_1):IV1-IV96. doi:10.1093/neuonc/noaa200
  3. Cancer Facts and Figures 2021.; 2021. Accessed March 24, 2021. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf
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  7. Grommes C, Deangelis LM. Journal of Clinical Oncology Primary CNS Lymphoma. J Clin Oncol. 2017;35:2410-2418. doi:10.1200/JCO.2017
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  9. Kan P, Simonsen SE, Lyon JL, Kestle JRW. Cellular phone use and brain tumor: a meta-analysis. Journal of Neuro-Oncology. 2008;86(1):71-78. doi:10.1007/s11060-007-9432-1
  10. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathologica. 2016;131(6):803-820. doi:10.1007/s00401-016-1545-1
  11. Johnson DR, O’Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. Journal of neuro-oncology. 2012;107(2):359-364. doi:10.1007/s11060-011-0749-4
  12. Koshy M, Villano JL, Dolecek TA, et al. Improved survival time trends for glioblastoma using the SEER 17 population-based registries. Journal of neuro-oncology. 2012;107(1):207-212. doi:10.1007/s11060-011-0738-7
  13. Khan S, Patel K, Gonzalo AVC. Cognitive deficits in brain cancer. Central Nervous System Cancer Rehabilitation. Published online 2018:49-61. doi:10.1016/B978-0-323-54829-8.00006-8
  14. Thakkar P, Greenwald BD, Patel P. Rehabilitation of adult patients with primary brain tumors: A narrative review. Brain Sciences. 2020;10(8):1-18. doi:10.3390/brainsci10080492
  15. Jean-Pierre P, Johnson-Greene D, Burish TG. Neuropsychological care and rehabilitation of cancer patients with chemobrain: Strategies for evaluation and intervention development. Supportive Care in Cancer. 2014;22(8):2251-2260. doi:10.1007/s00520-014-2162-y
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  17. Weitzner MA, Meyers CA, Gelke CK, Byrne KS, Levin VA, Cella DF. The functional assessment of cancer therapy (FACT) scale. Development of a brain subscale and revalidation of the general version (FACT-G) in patients with primary brain tumors. Cancer. 1995;75(5):1151-1161. doi:10.1002/1097-0142(19950301)75:5<1151::AID-CNCR2820750515>3.0.CO;2-Q
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  19. Bellon K, Malec JF, Kolakowsky-Hayner SA. Mayo-Portland Adaptability Inventory-4. Journal of Head Trauma Rehabilitation. 2012;27(4). doi:10.1097/HTR.0b013e3182562f04
  20. American College of Surgeons Commission on Cancer. (2019). Optimal Resources for Cancer Care: 2020 Standards. [Online] Chicago: American College of Surgeons. [Accessed 10 May 2021]. Available from: https://www.facs.org/-/media/files/quality-programs/cancer/coc/optimal_resources_for_cancer_care_2020_standards.ashx
  21. Dietz JH. Adaptive rehabilitation in cancer: a program to improve quality of survival. Postgraduate medicine. 1980;68(1):145-147, 150-151, 153. doi:10.1080/00325481.1980.11715495
  22. Chang EF, Clark A, Smith JS, et al. Functional mapping–guided resection of low-grade gliomas in eloquent areas of the brain: improvement of long-term survival. Journal of Neurosurgery. 2011;114(3):566-573. doi:10.3171/2010.6.JNS091246
  23. Ferracci F-X, Duffau H. Improving surgical outcome for gliomas with intraoperative mapping. Expert Review of Neurotherapeutics. 2018;18(4):333-341. doi:10.1080/14737175.2018.1451329
  24. Delgado-López PD, Corrales-García EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clinical and Translational Oncology. 2016;18(11):1062-1071. doi:10.1007/s12094-016-1497-x
  25. Shahpar S, Mhatre P V., Huang ME. Update on Brain Tumors: New Developments in Neuro-oncologic Diagnosis and Treatment, and Impact on Rehabilitation Strategies. PM and R. 2016;8(7):678-689. doi:10.1016/j.pmrj.2015.10.012

Original Version of Topic

Christian Shenouda, MD. Cerebral Neoplasms. 11/16/2011.

Previous Revision(s) of Topic

Christian Shenouda, MD. Cerebral Neoplasms. 9/17/2015.

Author Disclosures

Cherry Junn, MD
Nothing to Disclose

Ny-Ying Lam, MD
Nothing to Disclose