Brain metastasis

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Micrograph showing a colorectal carcinoma metastasis to the cerebellum. HPS stain. Metastatic adenocarcinoma - cerebellum - very low mag.jpg
Micrograph showing a colorectal carcinoma metastasis to the cerebellum. HPS stain.

A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body and is therefore considered a secondary brain tumor. [1] [2] The metastasis typically shares a cancer cell type with the original site of the cancer. [3] Metastasis is the most common cause of brain cancer, as primary tumors that originate in the brain are less common. [4] The most common sites of primary cancer which metastasize to the brain are lung, breast, colon, kidney, and skin cancer. Brain metastases can occur months or even years after the original or primary cancer is treated. Brain metastases have a poor prognosis for cure, but modern treatments allow patients to live months and sometimes years after the diagnosis. [5]

Contents

Symptoms and signs

Brain metastasis in the right cerebral hemisphere from lung cancer shown on T1-weighted magnetic resonance imaging with intravenous contrast. Hirnmetastase MRT-T1 KM.jpg
Brain metastasis in the right cerebral hemisphere from lung cancer shown on T1-weighted magnetic resonance imaging with intravenous contrast.

Because different parts of the brain are responsible for different functions, symptoms vary depending on the site of metastasis within the brain. However, brain metastases should be considered in any cancer patient who presents with neurological or behavioral changes. [6]

Brain metastases can cause a wide variety of symptoms which can also be present in minor, more common conditions. Neurological symptoms are often caused by increased intracranial pressure, [7] with severe cases resulting in coma. [8] The most common neurological symptoms include:

Causes

The most common primary tumors causing brain metastases are, in order of decreasing frequency: Lung, breast, kidney, gastrointestinal, and melanoma. Lung and breast cancers account for over half of brain metastases. [11]

The most common sources of brain metastases in a case series of 2,700 patients undergoing treatment at the Memorial Sloan–Kettering Cancer Center were: [12]

Lung cancer and melanoma are most likely to present with multiple metastasis, whereas breast, colon, and renal cancers are more likely to present with a single metastasis. [3]

Pathophysiology

Metastatic spread to the brain is usually hematogenous. Metastatic cells often lodge at the interface between gray mater and white mater as arteries narrow in caliber at this site. Spread to the meninges may result in leptomeningeal cancer. [11]

Diagnosis

Resected fragments of a brain tumor, and in this case the very dark appearance supports a diagnosis of metastatic pigment-forming melanoma. Gross pathology of melanoma metastasis.jpg
Resected fragments of a brain tumor, and in this case the very dark appearance supports a diagnosis of metastatic pigment-forming melanoma.

Brain imaging (neuroimaging such as CT or MRI) is needed to determine the presence of brain metastases. [6] In particular, contrast-enhanced MRI is the best method of diagnosing brain metastases, although primary detection may be done using CT. [10] Positron emission tomography (PET) is usually not considered suitable for imaging of brain metastases, because the most frequently used PET-radiotracer, 18F-FDG, does not only accumulate in the tumor but is naturally taken up by normal brain tissue, usually resulting in insufficient tumor-to-background contrast. PET-imaging of brain metastases is however feasible using alternative radiotracers, such as the Gallium-68 labeled peptide 68Ga-Trivehexin, [13] a tracer targeting the tumor cell surface protein αvβ6-integrin. 68Ga-Trivehexin demonstrated high uptake in a brain metastasis of tonsil carcinoma but no uptake in the surrounding healthy brain tissue, enabling a delineation of the brain metastasis. [14] In addition to imaging, biopsy is often recommended to confirm diagnosis. [6]

The diagnosis of brain metastases typically follows a diagnosis of a primary cancer. [10] Occasionally, brain metastases will be diagnosed concurrently with a primary tumor or before the primary tumor is found.

In the setting of brain metastasis due to malignant melanoma, MRI imaging showed high T1 and low T2 intensity due to the deposition of melanin in the brain. In susceptibility weighted imaging (SWI), it usually shows abnormal SWI hypointensity in larger proportion than brain metastasis caused by breast carcinoma. [15]

Treatment

Treatment for brain metastases is primarily palliative, with the goals of therapy being reduction of symptoms and prolongation of life. However, brain metastases harboring a mutation in the BRAF kinase at position V600 are effectively druggable with small molecule inhibitors such as dabrafenib. Unfortunately, drug resistance is observed within 4-6 months after treatment. [16] Recently, expression of NGFR was associated with progressive intracranial disease in melanoma patients [17] Additionally, there is limited evidence that the treatments that are offered takes account of patient-focused comparative effectiveness. [1] However, in some patients, particularly younger, healthier patients, aggressive therapy consisting of open craniotomy with maximal excision, chemotherapy, and radiosurgical intervention (Gamma Knife therapy) may be attempted. [1]

Symptomatic care

Symptomatic care should be given to all patients with brain metastases, as they often cause severe, debilitating symptoms. Treatment consists mainly of:

Radiotherapy

Radiotherapy plays a critical role in the treatment of brain metastases, and includes whole-brain irradiation, fractionated radiotherapy, and radiosurgery. [6] Whole-brain irradiation is used as a primary treatment method in patients with multiple lesions and is also used alongside surgical resection when patients have single and accessible tumors. [6] However, it often causes severe side effects, including radiation necrosis, dementia, toxic leukoencephalopathy, partial to complete hair loss, nausea, headaches, and otitis media. [20] In children this treatment may cause intellectual impairment, psychiatric disturbances, and other neuropsychiatric effects. [21] Results from a 2021 systematic review on radiation therapy for brain metastases found that despite much research on radiation therapy, there is little evidence to inform comparative effectiveness and such patient-centered outcomes as quality of life, functional status, or cognitive effects. [1] In addition, whole-brain irradiation in combination with surgery showed no effect on overall survival when compared to whole-brain irradiation alone as demonstrated by a systematic review by the Agency for Healthcare Research and Quality. [1]

Surgery

Brain metastases are often managed surgically if they are accessible. Surgical resection followed by stereotactic radiosurgery or whole-brain irradiation deliver superior survival compared to whole brain irradiation alone. [6] Therefore, in patients with only one metastatic brain lesion and controlled or limited systemic disease, a life expectancy of at least 3 months with maintenance of performance status might be expected. [22]

Chemotherapy

Chemotherapy is rarely used for the treatment of brain metastases, as chemotherapeutic agents penetrate the blood brain barrier poorly. [2] However, some cancers such as lymphomas, small cell lung carcinomas (SCLC) and breast cancer may be highly chemosensitive and chemotherapy may be used to treat extracranial sites of metastatic disease in these cancers. [2] The effectiveness and safety of using chemotherapy to treat a brain metastasis that came from a SCLC is not clear. [23] An experimental treatment for brain metastases is intrathecal chemotherapy, a technique in which a chemotherapeutic drug is delivered via intralumbar injection into the cerebrospinal fluid. [24] Current research on the treatment of brain metastases includes creating new drug molecules to effectively target the blood-brain barrier and studying the relationship between tumors and various genes. [25] In 2015, the United States FDA approved Alecensa (alectinib) for use in patients with a specific type of non-small cell lung cancer (NSCLC; ALK-positive), a type of cancer which often metastasizes to the brain, whose condition worsened after use or were unable to take another medication, Xalkori (crizotinib). [26]

Immunotherapy

Immunotherapy, for instance Anti-PD-1 alone or in combination with anti-CTLA-4, appears to be effective in some patients with brain metastases especially when these are asymptomatic, stable and not previously treated. [27] In 2022, OMICs-based approaches such as single-cell and bulk RNA-sequencing revealed molecular subgroups in melanoma brain metastases (MBM) that may explain the variable response of MBM to therapeutic interventions. [28] [29] Moreover, methylome and transcriptome profiling of MBM revealed immune cell and microglia-enriched tumor subsets showing favorable outcome. [30]

Prognosis

The prognosis for brain metastases is variable; it depends on the type of primary cancer, the age of the patient, the absence or presence of extracranial metastases, and the number of metastatic sites in the brain. [6] For patients who do not undergo treatment the average survival is between one and two months. [6] However, in some patients, such as those with no extracranial metastases, those who are younger than 65, and those with a single site of metastasis in the brain only, prognosis is much better, with median survival rates of up to 13.5 months. [2] Because brain metastasis can originate from various different primary cancers, the Karnofsky performance score is used for a more specific prognosis. [6]

Epidemiology

It is estimated that the worldwide incidence rate for brain metastases lies around 9% to 17%, based on the region of diagnosis. [31] [32] However, the baseline incidence rate of brain metastases were found to increase with improvements to brain imaging technology. [33] Approximately 5-11% of brain metastasis were found to be deadly at 30 days, and 14 - 23% were found to be deadly at three months. [34]

More cases of brain metastases were found in adults, compared to children. [35] 67% to 80% of all cancer patients were found to develop brain metastases, as of 2012. Lung cancer, breast cancer and melanoma patients were found to be at the highest risk of developing brain metastases. [36] [37] [38] [39] [40] However, recent trends in brain metastasis epidemiology have shown an increase in incidence for patients with renal, colorectal, or ovarian cancers. [41] Brain metastases are most commonly diagnosed within multiple intracranial areas within the context of extracranial diseases.

Both population studies and autopsy studies have historically been used to calculate the incidence of brain metastases. However, many researchers have stated that population studies may express inaccurate data for brain metastases, given that surgeons have, in the past, been hesitant to take in patients with the condition. As a result, population studies regarding brain metastases have historically been inaccurate and incomplete. [42] [43]

Advances in systemic treatments of brain metastases, such as radiosurgery, whole-brain radiotherapy and surgical resection has led to an increase in median survival rate of brain metastases patients. [44]

See also

Related Research Articles

<span class="mw-page-title-main">Brain tumor</span> Neoplasm in the brain

A brain tumor occurs when a group of cells within the brain turn cancerous and grow out of control, creating a mass. There are two main types of tumors: malignant (cancerous) tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondary tumors, which most commonly have spread from tumors located outside the brain, known as brain metastasis tumors. All types of brain tumors may produce symptoms that vary depending on the size of the tumor and the part of the brain that is involved. Where symptoms exist, they may include headaches, seizures, problems with vision, vomiting and mental changes. Other symptoms may include difficulty walking, speaking, with sensations, or unconsciousness.

<span class="mw-page-title-main">Metastasis</span> Spread of a disease inside a body

Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases (mets). It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.

<span class="mw-page-title-main">Bone tumor</span> Abnormal growth of tissue within bone

A bone tumor is an abnormal growth of tissue in bone, traditionally classified as noncancerous (benign) or cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body such as from lung, breast, thyroid, kidney and prostate. There may be a lump, pain, or neurological signs from pressure. A bone tumor might present with a pathologic fracture. Other symptoms may include fatigue, fever, weight loss, anemia and nausea. Sometimes there are no symptoms and the tumour is found when investigating another problem.

<span class="mw-page-title-main">Melanoma</span> Skin cancer originating in melanocytes

Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye.

Spinal tumors are neoplasms located in either the vertebral column or the spinal cord. There are three main types of spinal tumors classified based on their location: extradural and intradural. Extradural tumors are located outside the dura mater lining and are most commonly metastatic. Intradural tumors are located inside the dura mater lining and are further subdivided into intramedullary and extramedullary tumors. Intradural-intramedullary tumors are located within the dura and spinal cord parenchyma, while intradural-extramedullary tumors are located within the dura but outside the spinal cord parenchyma. The most common presenting symptom of spinal tumors is nocturnal back pain. Other common symptoms include muscle weakness, sensory loss, and difficulty walking. Loss of bowel and bladder control may occur during the later stages of the disease.

<span class="mw-page-title-main">Angiosarcoma</span> Cancer of the lining of the blood or lymphatic vessels

Angiosarcoma is a rare and aggressive cancer that starts in the endothelial cells that line the walls of blood vessels or lymphatic vessels. Since they are made from vascular lining, they can appear anywhere and at any age, but older people are more commonly affected, and the skin is the most affected area, with approximately 60% of cases being cutaneous (skin). Specifically, the scalp makes up ~50% of angiosarcoma cases, but this is still <0.1% of all head and neck tumors. Since angiosarcoma is an umbrella term for many types of tumor that vary greatly in origin and location, many symptoms may occur, from completely asymptomatic to non-specific symptoms like skin lesions, ulceration, shortness of breath and abdominal pain. Multiple-organ involvement at time of diagnosis is common and makes it difficult to ascertain origin and how to treat it.

<span class="mw-page-title-main">Invasive carcinoma of no special type</span> Medical condition

Invasive carcinoma of no special type, invasive breast carcinoma of no special type (IBC-NST), invasive ductal carcinoma (IDC), infiltrating ductal carcinoma (IDC) or invasive ductal carcinoma, not otherwise specified (NOS) is a disease. For international audiences this article will use "invasive carcinoma NST" because it is the preferred term of the World Health Organization (WHO).

Adjuvant therapy, also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. The surgeries and complex treatment regimens used in cancer therapy have led the term to be used mainly to describe adjuvant cancer treatments. An example of such adjuvant therapy is the additional treatment usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to the presence of undetected disease. If known disease is left behind following surgery, then further treatment is not technically adjuvant.

<span class="mw-page-title-main">Blastoma</span> Type of cancer arising from precursor cells

A blastoma is a type of cancer, more common in children, that is caused by malignancies in precursor cells, often called blasts. Examples are nephroblastoma, medulloblastoma, and retinoblastoma. The suffix -blastoma is used to imply a tumor of primitive, incompletely differentiated cells, e.g., chondroblastoma is composed of cells resembling the precursor of chondrocytes.

Cancer of unknown primary origin (CUP) is a cancer that is determined to be at the metastatic stage at the time of diagnosis, but a primary tumor cannot be identified. A diagnosis of CUP requires a clinical picture consistent with metastatic disease and one or more biopsy results inconsistent with a tumor cancer.

A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.

<span class="mw-page-title-main">Leptomeningeal cancer</span> Medical condition

Leptomeningeal cancer is a rare complication of cancer in which the disease spreads from the original tumor site to the meninges surrounding the brain and spinal cord. This leads to an inflammatory response, hence the alternative names neoplastic meningitis (NM), malignant meningitis, or carcinomatous meningitis. The term leptomeningeal describes the thin meninges, the arachnoid and the pia mater, between which the cerebrospinal fluid is located. The disorder was originally reported by Eberth in 1870. It is also known as leptomeningeal carcinomatosis, leptomeningeal disease (LMD), leptomeningeal metastasis, meningeal metastasis and meningeal carcinomatosis.

<span class="mw-page-title-main">Liver metastasis</span> Medical condition

A liver metastasis is a malignant tumor in the liver that has spread from another organ that is affected by cancer. The liver is a common site for metastatic disease because of its rich, dual blood supply. Metastatic tumors in the liver are 20 times more common than primary liver tumors (tumors that originate in the liver(. In 50% of all cases the primary tumor is of the gastrointestinal tract; other common sites include the breast, ovaries, bronchus and kidney. Patients with colorectal cancer may also develop liver metastases.

In oncology, metastasectomy is the surgical removal of metastases, which are secondary cancerous growths that have spread from cancer originating in another organ in the body.

<span class="mw-page-title-main">Bone metastasis</span> Medical condition

Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that result from primary tumor invasions into bones. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing sarcoma are rare; the most common bone tumor is a metastasis. Bone metastases can be classified as osteolytic, osteoblastic, or both. Unlike hematologic malignancies which originate in the blood and form non-solid tumors, bone metastases generally arise from epithelial tumors and form a solid mass inside the bone. Primary breast cancer patients are particularly vulnerable to develop bone metastases. Bone metastases, especially in a state of advanced disease, can cause severe pain, characterized by a dull, constant ache with periodic spikes of incident pain.

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

Neuro-oncology is the study of brain and spinal cord neoplasms, many of which are very dangerous and life-threatening. Among the malignant brain cancers, gliomas of the brainstem and pons, glioblastoma multiforme, and high-grade astrocytoma/oligodendroglioma are among the worst. In these cases, untreated survival usually amounts to only a few months, and survival with current radiation and chemotherapy treatments may extend that time from around a year to a year and a half, possibly two or more, depending on the patient's condition, immune function, treatments used, and the specific type of malignant brain neoplasm. Surgery may in some cases be curative, but, as a general rule, malignant brain cancers tend to regenerate and emerge from remission easily, especially highly malignant cases. In such cases, the goal is to excise as much of the mass and as much of the tumor margin as possible without endangering vital functions or other important cognitive abilities. The Journal of Neuro-Oncology is the longest continuously published journal in the field and serves as a leading reference to those practicing in the area of neuro-oncology.

<span class="mw-page-title-main">Abscopal effect</span> Hypothesis in the treatment of metastatic cancer

The abscopal effect is a hypothesis in the treatment of metastatic cancer whereby shrinkage of untreated tumors occurs concurrently with shrinkage of tumors within the scope of the localized treatment. R.H. Mole proposed the term "abscopal" in 1953 to refer to effects of ionizing radiation "at a distance from the irradiated volume but within the same organism".

Prophylactic cranial irradiation (PCI) is a technique used to combat the occurrence of metastasis to the brain in highly aggressive cancers that commonly metastasize to brain, most notably small-cell lung cancer. Radiation therapy is commonly used to treat known tumor occurrence in the brain, either with highly precise stereotactic radiation or therapeutic cranial irradiation. By contrast, PCI is intended as preemptive treatment in patients with no known current intracranial tumor, but with high likelihood for harboring occult microscopic disease and eventual occurrence. For small-cell lung cancer with limited and select cases of extensive disease, PCI has shown to reduce recurrence of brain metastases and improve overall survival in complete remission.

<span class="mw-page-title-main">CNS metastasis</span> Spreading of cancer cells

CNS metastasis is the spread and proliferation of cancer cells from their original tumour to form secondary tumours in portions of the central nervous system.

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