Non-Uniform Distribution of Metastatic Intracranial Tumors in Cancer Patients

Keywords

brain metastases, distribution, lung cancer, breast cancer, pathogenesis, neuroimaging, brain vulnerability/resistance

Outline
Introduction 37
- Epidemiology and Clinical Presentation of Brain Metastases 37
- Intra-axial Metastases: Pathogenesis and Neuroimaging 38
- Extra-axial Metastases: Pathogenesis and Neuroimaging 41
  - Pachymeningeal Metastases 41
  - Leptomeningeal Metastases 41
Brain Spatial Distribution of Metastases 43
- Role of the Primary Tumor on the Distribution 45
- Brain Local Vulnerability/Resistance to Metastases 46
- Recurrent Metastases 46
Discussion 48
References

Introduction

Epidemiology and Clinical Presentation of Brain Metastases

Brain metastases (BMs) occur in 20–40% of adult cancer patients with an incidence of>170 000 new cases per year in the USA ( ) and become symptomatic during life in 60–75% of the patients. Thus, they represent the most common tumors of the central nervous system (CNS).

Although the exact incidence is unknown because some brain metastatic patients are neurologically asymptomatic, the frequency of the diagnosis of BMs has increased in recent years probably due to an increased sensitivity of imaging techniques ( ), particularly when lesions are located in the posterior cranial fossa or they are very small. Other explanations may be the increase of the overall survival in oncologic patients due to the advent of more effective systemic treatments and an acquired resistance of metastatic tumor cells in the brain to escape the effects of those chemotherapeutic agents that, although partially, pass the blood–brain barrier.

The most common primary tumors responsible for BMs are lung cancer in men and breast cancer in women. Other primary tumors include melanoma, renal cell cancer, colon cancer, pelvic tumors and unknown primary tumors ( ). In addition to the cerebral and cerebellar parenchyma, other sites of intracranial metastases include the meninges, the pituitary and pineal glands and the choroid plexus ( ).

Brain metastases are more often diagnosed in patients with known malignancy (metachronous presentation). Less frequently (up to 30%), brain metastases are diagnosed either at the time of the diagnosis of the primary tumor (synchronous presentation) or before the discovery of the primary tumor (precocious presentation). The primary site is unknown in up to 15% of patients. Neoplastic disease prognosis worsens tremendously when a patient receives the diagnosis of brain metastasis. Median survival of patients after the identification of symptomatic brain metastases is, in fact, generally short from about 4 months in breast cancer ( ) to 4–12 months in lung cancer ( ) patients.

Intra-axial Metastases: Pathogenesis and Neuroimaging

Two main biological mechanisms have been considered to explain the occurrence of brain intra-axial metastases in the last 120 years: mechanical trapping of tumor emboli and the “seed and soil” hypothesis. The “seed and soil” hypothesis is the dominant current explanation of metastasis ( ). This hypothesis states that successful outgrowth of metastatic tumors depends on the cross-talk and permissible interactions between the tumor cells and the site-specific microenvironment in the host organs. Currently, this hypothesis is based on the principle that neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. On this basis, the process of metastasis is selective for cells that succeed in promoting angiogenesis, invasion, embolization, survival in the circulation, arrest in distant capillary beds, extravasation and multiplication within the brain tissue. An emerging paradigm is that tumors are able to produce factors that induce the formation of pre-metastatic niches in organs where metastases will ultimately develop ( ). The interaction with metastatic tumor cells in the brain is largely based on the neoplastic angiogenesis/vascular remodeling as in other organs and on three other unique properties that differentiate the brain from other organs.

1.

Angiogenesis/vascular remodeling: the potent angiogenesis/permeability factor, vascular endothelial growth factor (VEGF) plays a crucial role in the development of pathological neovascularization and in the increase of microvessel density. Whether tumor-associated blood vessels are formed by new vessel formation or by co-option of existing highly dense vessels is not yet clear. In murine models, metastases did not show an increase of vessel density, but microvessel luminal dilation as a form of vascular remodeling in which the division of endothelial cells increases the surface and the size of the vessels ( ).
2.

Blood–brain and blood–tumor barriers: the microvasculature of the brain parenchyma is lined with a continuous, non-fenestrated endothelium with tight junctions and little pinocytic vesicle activity. This structure, known as the blood–brain barrier (BBB), limits the entrance of circulating macromolecules into the brain parenchyma. Experiments on transgenic and knockout mice clearly demonstrated that the pericytes surrounding the brain blood vessels play an intimate role in the formation and maintenance of BBB integrity, challenging the conventional view that astroglial cells play the major role in regulating the BBB. Activation of adhesion molecules, such as tumor cell integrin aVb3, seems to control brain metastases through the regulation of VEGF expression ( ). Also, the role of the basement membrane proteins such as collagen, laminins and integrins have been demonstrated ( ).
3.

High energy consumption: the dense network of blood vessels in the brain provides it with an abundant supply of oxygen and nutrients. High-throughput proteomic analysis of experimental models of brain metastatic cells has shown profiles towards the elevated expression of proteins involved in promoting energy utilization. Moreover, microarray expression profiles on laser-captured tumor cells from surgically resected human breast cancer brain metastasis samples showed hexokinase 2 (HK2), (an enzyme that mediates the first step in glucose metabolism by phosphorylating glucose to produce glucose-6-phosphate), as a candidate gene upregulated in brain metastasis ( ).
4.

Immune-privileged site: despite the brain being considered an immune privileged sanctuary, glial cells play immune functions in the brain. Microglia are a specialized population of glial cells that are regarded as the resident macrophages in the brain. Like macrophages, under proper conditions, microglia are phagocytic, able to present antigens and seem constantly to remodel their processes in apparent attempts to survey the brain parenchymal environment ( ). Also astroglial cells may be involved in defense of the cellular infiltration. Immunohistochemistry studies have shown that both microglia and astrocytes are activated even at the early stages of the metastatic cascade in response to the arrival and migration of cancer cells in the brain, indicating that the surveillance system of glial cells is very sensitive in detecting metastatic tumor cells ( ).

The most common primary sites of cancer for intra-axial metastases are lung cancer, breast cancer and melanoma. Other primary tumors include colon cancer, kidney cancer and pelvic malignancies.

In the current clinical setting, intra-axial metastases are identified by conventional magnetic resonance imaging (MRI) with a 3 mm spatial resolution. Gadolinium-enhanced MRI is superior to contrast-enhanced computed tomography (CT) in the diagnosis of brain metastases, because of higher spatial resolution, higher contrast resolution, higher sensitivity with paramagnetic contrast agents, no bone artifacts in the images and less partial-volume artifacts for the detection of lesions adjacent to bones. In this context, contrast-enhanced MRI is known to be more sensitive than contrast-enhanced CT (including double-dose delayed contrast) or than unenhanced MRI in detecting brain metastases, particularly when located in the posterior fossa or very small ( ). Double or triple doses of gadolinium-based contrast agents are, in this respect, better than single doses, but increasing the dose may lead to an increased number of false-positive findings ( ).

On MRI T1-weighted images, lesions are isointense to mildly hypointense and are hyperintense on T2-weighted and fluid attenuation inversion recovery (FLAIR) images. In cases of a mucinous content, the lesions may be hypointense on T2-weighted images. Hemorrhagic metastases are hyperintense on T1-weighted images and may also show hypointensity on turbo spin echo and gradient echo T2-weighted images, owing to the extravasation and/or deposition of blood products, respectively. Usually metastatic lesions show marked vasogenic edema and mass effect. Surrounding edema is hyperintense on FLAIR and relatively hypointense on T1-weighted images and is usually wide in comparison to the size of the lesion. Following administration of a gadolinium-based contrast agent, solid, nodular, or irregular ring patterns of enhancement are seen ( Figure 4.1 ).

Extra-axial Metastases: Pathogenesis and Neuroimaging

Extra-axial metastases include lesions that directly do not involve the brain parenchyma; thus, lesions may be located in the skull, in the pachymeningeal (dural) and in the leptomeningeal compartments. Here, we discuss the lesions that primarily develop in the meningeal compartments.

Pachymeningeal Metastases

Dural metastases may occupy the epidural space, usually by direct extension from skull metastases, or the subdural space either by direct extension from an epidural metastasis or by hematogenous spread. Dural metastases occur in up to 9–10% of all patients with cancer, as based on autopsy reports, and represent the only site of intracranial metastases in about 4% of cases ( ). The most common primary sites of cancer are the breast, prostate, lung (small cell and non-small cell), head and neck and hematologic malignancies such as lymphoma and leukemia. Other tumor types include renal cell cancer, neuroblastoma, thyroid cancer, thymic cancer, leiomyosarcoma, carcinoid, melanoma, squamous cell cancer of skin, and adenocarcinoma of unknown primary origin. The most common locations are parietal and frontal whereas the infratentorial location is most commonly affected through perineural dissemination from head and neck tumors with intracranial extension. When large in size, lesions may cause vasogenic intra-axial edema and, at times, may invade the intra-axial structures. If lesions are located proximal to dural venous sinuses, patients may experience symptoms from occlusion of the sinuses or from compression of cranial nerves, such as III, IV and VI in the cavernous sinus.

Patients usually complain of headache and/or cranial neuropathy at onset, followed by visual changes, alterations in mental status, and seizures. About one-tenth of patients are asymptomatic and are diagnosed incidentally by neuroimaging. At the first diagnosis, patients have progressive and systemic neoplastic disease with bone, lymph nodes, liver and lungs as the most commonly involved sites. The median survival of patients with dural metastases is about 10 months, which is favorable compared to the 4–6 months of patients with intra-axial metastases and to the 2 months of those with leptomeningeal metastases.

Gadolinium-enhanced brain MRI is the study of choice for the diagnosis of dural metastases, especially using 3D high resolution T1-weighted imaging with isotropic voxels. The lesions may appear as focal meningeal plaques with or without an enhancing dural tail or as lenticular nodules ( Figure 4.2 ). The lesions may be single or multiple, sometimes appearing as diffuse dural thickening with nodular areas. Sometimes, in women with breast cancer, it is a true diagnostic challenge to establish the differential diagnosis between a dural metastasis and a meningioma ( ). Diffuse dural enhancement may also be challenging: differentials include a reactive response following a lumbar puncture, a reactive response to skull metastases, infectious or inflammatory etiologies and idiopathic pachymeningeal thickening.

Leptomeningeal Metastases

Leptomeningeal metastases are the result of the seeding of tumor cells to the leptomeninges (the pia and the arachnoid) via the cerebrospinal fluid, represent the third most common metastatic complication of the central nervous system and are increasingly common as cancer patients live longer. Leptomeningeal metastases are found in 1–5% of patients with solid tumors (carcinomatous meningitis), 5–15% of patients with leukemia (leukemic meningitis) and lymphoma (lymphomatous meningitis), and 1–2% of patients with primary brain tumors ( ).

Autopsy studies revealed that 19% of patients with cancer and neurologic signs and symptoms have evidence of leptomeningeal involvement. Breast, lung, and melanoma are the most common primary tumors to metastasize to the leptomeninges. Similarly to dural metastases, leptomeningeal metastases most often present in patients with disseminated and progressive systemic neoplastic disease (>70%), but can present after a disease-free interval (20%) and even be the first manifestation of cancer (5–10%). Leptomeninges may be reached by cancer cells through: (1) hematogenous spread; (2) direct extension from contiguous tumor; or (3) centripetal migration along perineural or perivascular spaces ( ). Once cancer cells have entered the subarachnoid space, they are passively transported by the CSF bulk flow resulting in the often observed multifocal seeding (see Figure 4.2 ). The most common sites are the base of the brain, the dorsal surface of the spinal cord, and the cauda equina ( ). Hydrocephalus may occur at any level of the neuraxis and is due to obstruction of the CSF outflow, either dependent on compression or on traction of the ventricular foramina/sylvian aqueduct. Clinical manifestations depend on the involvement of the cerebral hemispheres, the cranial nerves, and the spinal cord and roots. Signs on examination generally exceed symptoms reported by the patient.

The most useful laboratory test in the diagnosis of leptomeningeal metastasis is the lumbar puncture. The presence of malignant cells in the CSF is diagnostic of leptomeningeal metastasis but the diagnosis of primary tumor, especially if it is occult, is often not possible.

Magnetic resonance imaging with gadolinium enhancement is the technique of choice to evaluate patients with suspected leptomeningeal metastasis. Because leptomeningeal metastasis involves the entire neuraxis, imaging of the entire CNS is required. FLAIR images may show inhomogeneous CSF signal saturation that leads to the suspicion of CSF bulk flow alterations in the subarachnoid spaces. Cranial nerve enhancement and subarachnoid enhancing nodules can be considered diagnostic of leptomeningeal metastasis in patients with cancer ( Figure 4.3 ). Nonetheless, gadolinium-enhanced imaging has a more than 30% incidence of false-negative results so that a normal study does not exclude the diagnosis of leptomeningeal metastases. Due to the dural–arachnoid enhancement that may be observed after lumbar puncture, imaging should be obtained prior to the procedure.