Metastases and Paraneoplastic Syndromes

Main Text

Preamble

Brain metastases are the most common type of intracranial neoplasm in adults. Between 20-45% of all patients with advanced cancers (particularly lung and breast) will eventually develop CNS involvement. Brain metastases are often ultimately responsible for patient mortality, even in the face of controlled systemic disease.

We begin this chapter with a brief overview of CNS metastases, then follow with a discussion of cranial metastases by anatomic location, beginning with the brain parenchyma (the most common overall CNS location). We conclude with remote effects of cancer on the CNS, so-called paraneoplastic syndromes.

Metastatic Lesions

Preamble

Metastases are secondary tumors that arise from primary neoplasms at another site. As a group, metastases are now the most common CNS neoplasm in adults.

Overview

Etiology

Routes of Spread

CNS metastases can arise from both extra- and intracranial primary tumors. Metastases from extracranial primary neoplasms (“body-to-brain metastases”) most commonly spread via hematogenous dissemination.

Direct geographic extension from a lesion in an adjacent structure (such as squamous cell carcinoma in the nasopharynx) also occurs but is much less common than hematogenous spread. Invasion is usually through natural foramina and fissures where bone is thin or absent. Perineural and perivascular spread are less common but important direct geographic routes by which head and neck tumors gain access to the CNS.

Primary intracranial neoplasms sometimes spread from one CNS site to another, causing brain-to-brain or brain-to-spine metastases. Spread occurs preferentially along compact white matter tracts, such as the corpus callosum and internal capsule, but can also involve the ventricular ependyma, pia, and perivascular spaces.

CSF dissemination with “carcinomatous meningitis” occurs with both extra- and intracranial primary neoplasms.

Origin of CNS Metastases

Both the source and location of metastases vary significantly with patient age. Approximately 10% of all brain metastases (BMs) originate from an unknown primary neoplasm at the time of initial diagnosis.

Children

Metastases are rare in children, accounting for only 2% of all pediatric CNS tumors. The most common sources of cranial metastases in children are hematologic malignancies, such as leukemia and lymphoma. The preferential locations are the skull and dura. Parenchymal metastases are much less common in children compared with adults.

Adults

Lung, breast, and melanoma account for at least 2/3 of all BMs in adults. The most common primary tumor that metastasizes to the brain is lung cancer. Breast is the second most common primary tumor source followed by melanoma, renal carcinoma, and colorectal cancer. In ~ 10% of cases, no primary tumor is found at initial presentation.

Skull, dura, and spine metastases are typically caused by prostate, breast, or lung cancer followed by renal cancers and hematologic malignancies, such as non-Hodgkin lymphoma and multiple myeloma.

Pathology

Location

The brain parenchyma is the most common site (80%) followed by the skull and dura (15%) and leptomeninges (pia)/subarachnoid space (5%).

The vast majority of parenchymal metastases are located in the cerebral hemispheres, especially at the junction between the cortex and subcortical white matter (31-1)(31-2). While only 15% of metastases are found in the cerebellum, a solitary cerebellar mass in a middle-aged or older adult is more likely to be metastasis than a primary neoplasm!

Uncommon sites include the pons and midbrain, choroid plexus, ventricular ependyma, pituitary gland/stalk, and retinal choroid. Rarely, tumor cells diffusely infiltrate the brain perivascular spaces, a process termed carcinomatous encephalitis.

Size and Number

Most parenchymal metastases are between a few millimeters and 1.5 cm (31-3). Large hemispheric metastases are rare. In contrast, skull and dural metastases can become very large.

Approximately 50% of metastases are solitary while 50% are multiple. About 20% of patients have two lesions, 30% have three or more, and only 5% have more than five lesions.

Gross Pathology

Parenchymal Metastases

Parenchymal metastases are focal, round, relatively circumscribed, grayish-white or tan lesions that exhibit sharp borders with the adjacent brain (31-3). Melanoma metastases are often brown to black in color. Peritumoral edema, necrosis, hemorrhage, and mass effect range from none to striking.

Diffusely infiltrating parenchymal metastases are rare, and when they do occur, they typically extend along perivascular spaces.

Skull/Dural Metastases

Calvarial and skull base metastases are typically destructive, poorly marginated lesions (31-4)(31-5).

Dural metastases usually occur in combination with adjacent skull lesions, appearing as focal nodules (31-6) or more diffuse, plaque-like sheets of tumor. Dural metastasis without skull involvement is much less common.

Leptomeningeal Metastases

The term leptomeningeal metastases actually describes metastases to the subarachnoid spaces and pia (31-7). Diffuse sugar-like coating of the pia is typical (31-8). Multiple nodular deposits and infiltration of the perivascular (Virchow-Robin) spaces with extension into the adjacent cortex may occur (31-9)(31-20).

Microscopic Features

Although metastases may display more marked mitoses and elevated labeling indices compared with their primary systemic source, they generally preserve the same cellular features.

Clinical Issues

Demographics

Up to 40% of patients with treated systemic cancers eventually develop BMs. Peak prevalence is in patients older than 65 years of age. Only 6-10% of children with extracranial malignancies develop BMs.

Presentation

Seizure and focal neurologic deficit are the most common presenting symptoms of parenchymal metastases. 1/2 of all patients with skull/dural metastases present with headache. Seizure, sensory or motor deficit, cranial neuropathy, or a palpable mass under the scalp are other common symptoms.

Natural History

Although gross total resection of BMs improves symptoms and survival in selected patients, the natural history of parenchymal metastases is grim. Relentless, progressive increase in both number and size of metastases is typical. Median survival after diagnosis is short, generally averaging between 3 and 6 months, although in patients with gross total resection of a solitary metastasis, survival averages 13 months.

Imaging

Imaging findings and differential diagnosis vary with metastasis location. Each anatomic site has special features; each is discussed separately in this chapter.

Parenchymal Metastases

Imaging

Recent analyses indicate nearly 1/2 of systemic cancer therapy trials do not require mandatory cerebral imaging at baseline and only rare trials require continued surveillance imaging for patients without BMs at baseline. Despite this, there is increasing evidence supporting screening for BMs in many common cancers, such as advanced breast cancer, melanoma, and non-small cell lung cancer (NSCLC), both at diagnosis and after initiation of palliative systemic therapy.

Early detection of metastases improves the impact of treatments and increases patient survival rates. Contrast-enhanced MR is the preferred modality for diagnosing BMs and is more sensitive than either CT or nonenhanced MR. Because manual detection and delineation of BMs is time consuming, a variety of artificial intelligence (AI) methods have been utilized to detect brain tumors in their initial stages. Computer-aided deep learning using MR may be increasingly utilized in the future to detect BMs in patients with systemic cancers.

In this section, we review the findings of parenchymal BMs on standard imaging studies used in typical clinical practices.

CT Findings

Parenchymal metastases can be iso-, hypo- or hyperdense on NECT with variable surrounding hypodense vasogenic edema (31-11A)(31-12). With the exception of treated metastases, calcification is rare. Occasionally, the first manifestation of an intracranial metastasis is a brain bleed.

The vast majority of parenchymal metastases enhance strongly following contrast administration (31-11B). Double-dose delayed scans may increase lesion conspicuity. Solid, punctate, nodular, or ring patterns can be seen.

MR Findings

T1WI

Most metastases are iso- to mildly hypointense on T1WI. The exception is melanoma metastasis, which has intrinsic T1 shortening and thus appears moderately hyperintense (31-15). Subacute hemorrhagic metastases show disordered, heterogeneous signal intensity, often with bizarre-appearing intermixed foci of T1 hyper- and hypointensities (31-31).

T2/FLAIR

Signal intensity on T2WI varies widely depending on tumor type, lesion cellularity, presence of hemorrhagic residua, and amount of peritumoral edema. In contrast to high-grade gliomas, peritumoral hyperintense T2/FLAIR signal in metastases generally represents pure vasogenic edema, not tumor infiltration (31-14A). Many metastases are hypointense on T2WI and FLAIR. Exceptions are mucinous tumors, cystic metastases, and tumors with large amounts of central necrosis, all of which can appear moderately hyperintense.

Some hyperintense metastases show little or no surrounding edema. Multiple small hyperintense metastases (“miliary metastases”) can be mistaken for small vessel vascular disease unless contrast is administered.

T2*

Both subacute hemorrhage and melanin cause prominent signal intensity loss (“blooming”) on T2* (GRE, SWI) images (31-31A).

T1 C+

Virtually all nonhemorrhagic metastases enhance following contrast administration (31-14B). Patterns vary from solid, uniform enhancement to nodular, “cyst + nodule,” and ring-like lesions. Multiple metastases in the same patient may exhibit different patterns.

DWI, MRS

DWI is variable, but metastases generally do not exhibit restricted diffusion. Some highly cellular tumors show low ADC values. MRS may show a prominent lipid peak.

Differential Diagnosis

The major differential diagnosis for punctate and ring-enhancing metastases is abscess. Abscesses and septic emboli typically restrict on DWI. Primary neoplasms like glioblastoma tend to be infiltrating, whereas metastases are almost always round and relatively well demarcated.

Both metastases and multiple embolic infarcts share a predilection for arterial “border zones” and the gray matter-white matter interfaces. Most acute infarcts restrict strongly on DWI and rarely demonstrate a ring-enhancing pattern on T1 C+ scans. Chronic infarcts and age-related microvascular disease are hyperintense on T2WI and do not enhance following contrast administration.

Multiple cavernous malformations can mimic hemorrhagic metastases but are typically surrounded by a complete hemosiderin rim. Multiple sclerosis occurs in younger patients and is preferentially located in the deep periventricular white matter, not the gray matter-white matter interface.

Primary infratentorial parenchymal brain tumors in adults are rare. No matter what the imaging findings are, a solitary cerebellar mass in a middle-aged or older adult should be considered a metastasis until proven otherwise!

Skull and Dural Metastases

Terminology

The term “skull” refers both to the calvarium and to the skull base. As one cannot distinguish neoplastic involvement of the periosteal vs. meningeal dural layers, we refer to these layers collectively as the “dura.” In actuality, the arachnoid—the outermost layer of the leptomeninges—adheres to the dura, so it, too, is almost always involved any time tumor invades the dura.

Overview

The skull and dura are the second most common sites of CNS metastases from extracranial primary tumors. Calvarial and skull base metastases can occur either with or without dural involvement.

In contrast, dural metastases without coexisting calvarial lesions are less common. Between 8-10% of patients with advanced systemic cancer have dural metastases. Breast (35%) and prostate (15-20%) cancers are the most frequent sources. Single lesions are slightly more common than multiple dural metastases.

Imaging

General Features

Solitary or multiple focal lesions involve the skull, dura (and underlying arachnoid), or both. A less common pattern is diffuse neoplastic dura-arachnoid thickening, seen as a curvilinear layer of tumor that follows the inner table of the calvarium.

CT Findings

Complete evaluation requires both soft tissue and bone algorithm reconstructions of the imaging data (31-16). The most common finding on NECT is a focal soft tissue mass centered on the diploic space. A biconvex shape with both subgaleal and dural extension is typical. Most dural metastases enhance strongly on CECT.

Bone CT usually demonstrates one or more relatively circumscribed intraosseous lesions (31-19). Permeative, diffusely destructive lesions are the second most common pattern (31-16). A few osseous metastases—mostly those from prostate and treated breast cancer—can be blastic and sclerotic.

Large dural metastases displace the brain inward, buckling the gray matter-white matter interface medially (31-17). Hypodensities in the underlying brain suggest parenchymal invasion or venous ischemia.

MR Findings

Hyperintense fat in the diploic space provides excellent, naturally occurring demarcation from skull metastases on T1WIs. Metastases replace hyperintense yellow marrow and appear as hypointense infiltrating foci. Dural metastases thicken the dura-arachnoid and are typically iso- or hypointense to underlying cortex.

Most skull metastases are hyperintense to marrow on T2WI, but the signal intensity of dural metastases varies. FLAIR hyperintensity in the underlying sulci suggests pia-subarachnoid tumor spread. Hyperintensity in the underlying brain is present in 1/2 of all cases and suggests either tumor invasion along the perivascular spaces or compromise of venous drainage.

Nearly 70% of dural metastases are accompanied by metastases in the overlying skull. Involvement of the adjacent scalp is also common. Contrast-enhanced T1WI should be performed with fat saturation (T1 C+ FS) for optimal delineation, as some calvarial lesions may enhance just enough to become isointense with fat.

Most dural metastases enhance strongly, appearing as biconvex masses centered along the adjacent diploic space. Dural “tails” are present in ~ 1/2 of all cases. Frank tumor invasion into the underlying brain is seen in 1/3 of cases. Dural thickening can be smooth and diffuse or nodular and mass-like.

Hypercellular metastases with enlarged nuclei and reduced extracellular matrix may show diffusion restriction (hyperintense) and decreased ADC values (hypointense) on diffusion-weighted sequences.

Differential Diagnosis

The major differential diagnoses for skull metastases are surgical defects and normal structures. A surgical defect, such as a burr hole or craniotomy, can be distinguished from a metastasis by clinical history and the presence of defects in the overlying scalp. Venous lakes, vascular grooves, arachnoid granulations, and sometimes even sutures can mimic calvarial metastases. Normal structures are typically well corticated, and the underlying dura is normal.

Myeloma can be indistinguishable from multiple lytic skull metastases. Skull base osteomyelitis is a rare but life-threatening infection that can resemble diffuse skull base metastases. ADC values are generally higher in infection than in malignant neoplasms.

The major differential diagnosis for solitary or multifocal dura-arachnoid metastases is meningioma. Metastases, especially from breast cancer, can be virtually indistinguishable from solitary or multiple meningiomas on the basis of imaging studies alone.

The differential diagnosis of diffuse dura-arachnoid thickening is much broader. Nonneoplastic pachymeningopathies, such as meningitis, chronic subdural hematoma, and intracranial hypotension, can all cause diffuse dura-arachnoid thickening. Metastatic dural thickening is generally—although not invariably—more “lumpy-bumpy”(31-18).

Leptomeningeal Metastases

Terminology

The anatomic term leptomeninges refers to both the arachnoid and the pia. The widely used term leptomeningeal metastases (LMs) is technically incorrect, as it is employed to designate the imaging pattern seen when tumor involves the subarachnoid spaces and pia (31-9).

Synonyms for LMs include meningeal carcinomatosis, neoplastic meningitis, and carcinomatous meningitis.

Epidemiology and Etiology

LMs from systemic cancers (31-8) are rare, occurring in 5% of cases. The most common sources are breast and small cell lung cancers.

Intracranial primary tumors more commonly cause LM. In adults, the two most common are glioblastoma and lymphoma. The most common intracranial sources of childhood LM are medulloblastoma and other embryonal tumors, such as embryonal tumors with multilayered rosettes C19MC-altered, ependymoma, and germinoma.

Imaging

General Features

LMs follow the brain surfaces, curving along gyri and dipping into the sulci. The general appearance on contrast-enhanced scans is as though the CSF “turns white”(31-7).

CT Findings

NECT scans may be normal or show only mild hydrocephalus. Sulcal-cisternal enhancement, especially at the base of the brain, can sometimes be seen on CECT.

CECT scans may also be normal.

MR Findings

T1 scans may be normal or show only “dirty” CSF. Most LMs are hyperintense on T2WI and may be indistinguishable from normal CSF. Sulcal-cisternal hyperintensity on FLAIR is common (31-24A)(31-26A). If tumor has extended from the pia into the perivascular spaces, underlying brain parenchyma may show hyperintense vasogenic edema (31-18).

Postcontrast T1 scans show meningitis-like findings. Smooth or nodular enhancement seems to coat the brain surface, filling the sulci (31-26B) and sometimes almost the entire subarachnoid space, including the thecal sac (31-24). Cranial nerve thickening with linear, nodular, or focal mass-like enhancement may occur with or without disseminated disease (31-27).

Tiny enhancing miliary nodules or linear enhancing foci in the cortex and subcortical white matter indicate extension along the penetrating perivascular spaces (31-22).

Differential Diagnosis

The major differential diagnosis of LMs is infectious meningitis. It may be difficult or impossible to distinguish between carcinomatous and infectious meningitis on the basis of imaging findings alone. Other diagnostic considerations include neurosarcoid. Clinical history and laboratory features are essential elements in establishing the correct diagnosis.

LEPTOMENINGEAL METASTASES

General Features

• Pia + subarachnoid space metastases

• Uncommon

 5% of systemic cancers

 More common with primary tumors (e.g., glioblastoma, medulloblastoma, germinoma)

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