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Selected References

Extracranial Tumors and Tumor-Like Conditions

Fibrous Dysplasia

Couturier A et al: Craniofacial fibrous dysplasia: a 10-case series. Eur Ann Otorhinolaryngol Head Neck Dis. ePub, 2017

Kwee TC et al: Benign bone conditions that may be FDG-avid and mimic malignancy. Semin Nucl Med. 47(4):322-351, 2017

Yang L et al: Prevalence of different forms and involved bones of craniofacial fibrous dysplasia. J Craniofac Surg. 28(1):21-25, 2017

Zreik RT et al: Malignant transformation of polyostotic fibrous dysplasia with aberrant keratin expression. Hum Pathol. 62:170174, 2017

Benhamou J et al: Prognostic factors from an epidemiologic evaluation of fibrous dysplasia of bone in a modern cohort: the FRANCEDYS Study. J Bone Miner Res. 31(12):2167-2172, 2016

Rossi DC et al: Extensive fibrous dysplasia of skull base: case report. Neurol Sci. 36(7):1287-9, 2015

Tehli O et al: Computer-based surgical planning and custom-made titanium implants for cranial fibrous dysplasia. Neurosurgery. 11 Suppl 2:213-9, 2015

Unal Erzurumlu Z et al: CT imaging of craniofacial fibrous dysplasia. Case Rep Dent. 2015:134123, 2015

Neelakantan A et al: Benign and malignant diseases of the clivus. Clin Radiol. 69(12):1295-303, 2014

Zhou SH et al: Gene expression profiling of craniofacial fibrous dysplasia reveals ADAMTS2 overexpression as a potential marker. Int J Clin Exp Pathol. 7(12):8532-41, 2014

Paget Disease

Cucchi F et al: 18F-sodium fluoride PET/CT in Paget disease. Clin Nucl Med. 42(7):553-554, 2017

Kwee TC et al: Benign bone conditions that may be FDG-avid and mimic malignancy. Semin Nucl Med. 47(4):322-351, 2017

Qi X et al: Familial early-onset Paget's disease of bone associated with a novel hnRNPA2B1 mutation. Calcif Tissue Int. ePub, 2017

Lalam RK et al: Paget disease of bone. Semin Musculoskelet Radiol. 20(3):287-299, 2016

Rai NP et al: Paget's disease with craniofacial and skeletal bone involvement. BMJ Case Rep. 2016:bcr2016216173, 2016

Aneurysmal Bone Cyst

Sodhi HB et al: Temporal aneurysmal bone cyst: cost-effective method to achieve gross total resection. Acta Neurochir (Wien). 158(8):1633-5, 2016

Motamedi MH et al: Assessment of 120 maxillofacial aneurysmal bone cysts: a nationwide quest to understand this enigma. J Oral Maxillofac Surg. 72(8):1523-30, 2014

Chordoma

Guler E et al: The added value of diffusion magnetic resonance imaging in the diagnosis and posttreatment evaluation of skull base chordomas. J Neurol Surg B Skull Base. 78(3):256-265, 2017

Kitamura Y et al: Genetic aberrations and molecular biology of skull base chordoma and chondrosarcoma. Brain Tumor Pathol. 34(2):78-90, 2017

Rassi MS et al: Pediatric clival shordoma: a curable disease that conforms to Collins' Law. Neurosurgery. ePub, 2017

Tian K et al: MR Imaging grading system for skull base chordoma. AJNR Am J Neuroradiol. 38(6):1206-1211, 2017

Zhai Y et al: Clinical features and prognostic factors of children and adolescent patients with clival chordomas. World Neurosurg. 98:323-32, 2017

Gulluoglu S et al: The molecular aspects of chordoma. Neurosurg Rev. 39(2):185-96; discussion 196, 2016

Hasselblatt M et al: Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis. Acta Neuropathol. 132(1):149-51, 2016

Wang AC et al: STAT3 inhibition as a therapeutic strategy for chordoma. J Neurol Surg B Skull Base. 77(6):510-520, 2016

Intracranial Pseudotumors

Ecchordosis Physaliphora

Park HH et al: Ecchordosis physaliphora: typical and atypical radiologic features. Neurosurg Rev. 40(1):87-94, 2017

Ferguson C et al: A case study of symptomatic retroclival ecchordosis physaliphora: CT and MR imaging. Can J Neurol Sci. 43(1):210-2, 2016

Özgür A et al: Ecchordosis physaliphora: evaluation with precontrast and contrast-enhanced fast imaging employing steady-state acquisition MR imaging based on proposed new classification. Clin Neuroradiol. 26(3):347-53, 2016

Chihara C et al: Ecchordosis physaliphora and its variants: proposed new classification based on high-resolution fast MR imaging employing steady-state acquisition. Eur Radiol. 23(10):2854-60, 2013

Textiloma

Akpinar A et al: Textiloma (gossypiboma) mimicking recurrent intracranial abscess. BMC Res Notes. 8:390, 2015

Minks D et al: Suspected cerebral foreign body granuloma following endovascular treatment of intracranial aneurysm: imaging features. Neuroradiology. 57(1):71-3, 2015

Slater LA et al: Long-term MRI findings of muslin-induced foreign body granulomas after aneurysm wrapping. A report of two cases and literature review. Interv Neuroradiol. 20(1):67-73, 2014

Calcifying Pseudoneoplasm of the Neuraxis

Saha A et al: Calcifying pseudoneoplasm of the spine: imaging and pathological features. Neuroradiol J. ePub, 2017

Brain metastases are rapidly increasing in incidence and are major complications of common cancers. Up to 40% 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.

CNS metastatic disease arises from numerous sources and has many different imaging "faces." We begin this chapter with an overview that includes the brain as a "sanctuary site" for CNS metastases. We focus on general features, including how and from where cranial metastases arise, the role of highly site-specific microRNAs in the metastatic "cascade," the effect of age on primary tumor type and CNS location, symptomatology, treatment options, and prognosis.

We follow with a discussion of cranial metastases by anatomic location, beginning with the brain parenchyma (the most common overall CNS location) and concluding with perineural tumor extension from head and neck cancers. We include an updated discussion of how metastatic neoplasms of unknown origin are characterized in the era of targeted therapies for tumors such as non-small cell lung cancer and melanoma.

We conclude with a consideration of the remote effects of cancer on the CNS and the increasingly important group of so-called paraneoplastic syndromes.

Metastatic Lesions

The incidence of CNS metastases is increasing worldwide. Brain metastases are, not only a leading cause of cancer mortality, but also as a group have become the most common CNS neoplasm in adults. Brain metastases are now 10 times more common than primary malignant CNS tumors with at least 170,000 new cases reported in the USA each year. Population aging, improved imaging techniques, and new treatment regimens that allow patients with primary systemic cancers to survive longer all contribute to this striking increase.

Overview

Terminology

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Etiology

Routes of Spread. CNS metastases can arise from both extraand intracranial primary tumors. Metastases from extracranial primary neoplasms ("body-to-brain metastases") most commonly spread via hematogeneous 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 hematogeneous spread. Invasion usually proceeds along paths of least resistance, i.e., 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. One typical example is spread of a malignant astrocytoma (e.g., glioblastoma) to other CNS sites. 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" and "drop metastases" to the brain and spine occurs with both extraand intracranial primary neoplasms.

Metastasis Formation. Although vascular dissemination of systemic tumor cells occurs readily, the development of brain metastases is far more complex than simply delivering a tumor embolism to an end organ. The brain is a biologically relatively protected ("sanctuary") site because of the bloodbrain barrier. Most disseminated tumor cells do not immediately produce brain metastases.

The establishment, growth, and survival of metastases all depend on the interaction of tumor cells with multiple different host factors in the target organ microenvironment. Metastasis formation is a biologically complicated, genetically mediated process. A veritable cascade of events (the metastatic "cascade") is required before brain metastases develop. There is also increasing evidence that specific microRNAs in the primary tumor are metastasis locationspecific, including oncogenic microRNAs that seem to be specific for the CNS.

Specific receptors mediate attachment and subsequent infiltration of circulating tumor cells into the CNS. Once tumor cells enter the brain, they are surrounded and infiltrated by activated astrocytes. These astrocytes upregulate "survival genes" in tumor cells, rendering them highly resistant to chemotherapy.

If metastatic cells manage to colonize the inhospitable brain habitat, upregulated matrix proteins, cytokines, and various growth factors may create a microenvironment that actually promotes tumor growth. Inactivation of tumor suppressor genes with simultaneous activation of protooncogenes is typical. Upregulation and amplification of some genes such as EGFR is also common.

Origin of CNS Metastases. Both the source and the intracranial location of metastases vary significantly with patient age. Approximately 10% of all brain metastases originate from an unknown primary neoplasm at the time of initial diagnosis. In 10% of patients, the brain is the only site involved.

Children. The most common sources of cranial metastases in children are hematologic malignancies. In descending order of frequency, they are leukemia, lymphoma, and sarcoma (osteogenic sarcoma, rhabdomyosarcoma, and Ewing sarcoma).

The preferential locations are the skull and dura. Parenchymal metastases are much less common in children compared with adults.

Adults. Metastases from lung, breast, and melanoma account for at least two-thirds of all brain metastases in adults. The overall most common extracranial primary tumor that metastasizes to the brain parenchyma is lung cancer (especially adenocarcinoma and small cell carcinoma).

Breast cancer is the second most common primary tumor source, followed by melanoma, renal carcinoma, and colorectal cancer. In between one-quarter and one-third of cases, the primary tumor is unknown at the time of neurosurgical intervention.

Skull, dura, and spine metastases are typically caused by prostate, breast, or lung cancer, followed by hematologic malignancies and renal cancers.

CNS METASTASES: EPIDEMIOLOGY AND ETIOLOGY

Epidemiology

•Adults > > children

○Metastases = most common CNS neoplasm in adults

○5x increase in past 50 years

○Brain metastases occur in > 30-40% of cancer patients

Routes of Spread

•Most common = extracranial primary to CNS via

○Hematogeneous dissemination

○Direct geographic extension (nasopharynx, sinuses)

○Perineural, perivascular spread

•Less common

○Brain-to-brain from CNS primary

○Brain-to-CSF from CNS primary

•Least common

○Tumor-to-tumor metastasis

○Sometimes called "collision tumor"

○Most common "donor" tumor = breast, lung

○Most common "recipient" tumor = meningioma

Origin

•10% unknown primary at initial diagnosis

○Children: leukemia, lymphoma, sarcoma

○Adults: lung, breast cancer, melanoma, renal carcinoma, colorectal cancer

Pathology

Location. The brain parenchyma is the most common site (80%), followed by the skull and dura (15%). Diffuse leptomeningeal (pial) and subarachnoid space infiltration is relatively uncommon, accounting for just 5% of all cases.

The vast majority of parenchymal metastases are located in the cerebral hemispheres. Hematogeneous metastases have a special predilection for arterial border zones and the junction between the cortex and subcortical white matter (27-1) (27- 2). Between 3-5% are found in the basal ganglia. Rarely, tumor cells diffusely infiltrate the brain perivascular spaces, a process termed "carcinomatous encephalitis" (27-4).

Only 15% of metastases are found in the cerebellum. The midbrain, pons, and medulla are uncommon sites (especially for solitary lesions) and account for less than 5% of metastases.

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Other rare sites include the choroid plexus, ventricular ependyma, pituitary gland/stalk, and retinal choroid.

Size and Number. Although parenchymal metastases vary in size from microscopic implants to a few centimeters in diameter, most are between a few millimeters and 1.5 cm. Large hemispheric metastases are rare. In contrast, skull and dural metastases can become very large.

Approximately half of all metastases are solitary lesions, and half are multiple. About 20% of patients have two lesions, 30% have three or more, and only 5% have more than five lesions. Approximately 1% have such widespread dissemination that they have a "miliary" appearance.

Gross Pathology. The gross pathologic appearance of metastases varies according to tumor site.

Parenchymal Metastases. Parenchymal metastases are generally round, relatively circumscribed lesions that exhibit

(27-1) Graphic shows parenchymal metastaseswith surrounding edema . The GM-WM junction is the most common location. Most metastases are round, not infiltrating. (27-2) Metastases from bronchogenic carcinoma show varied locations, appearances. GM-WM lesions show hemorrhage, midbrain lesions are gray-tan , and another parenchymal metastasis shows necrosis . (Courtesy R. Hewlett, MD.)

(27-3) Parenchymal metastases generally have sharp borders with adjacent brain . Necrosis is common and often extensive. (From DP: Brain, 3e.) (27- 4) Perivascular spread of this metastatic adenocarcinoma is striking. Note cuffs of tumor cells surrounding innumerable small arteries and arterioles . (From DP: Brain, 3e.)

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sharp borders with the adjacent brain (27-3). With the exception of melanotic melanoma, most are tan or grayish white. Some mucin-producing adenocarcinomas have a gelatinous appearance.

Inflammatory reactions to infiltrating tumor cells can alter the permeability and function of the brain neurovascular unit at the proliferating edge of the tumor. Peritumoral edema, necrosis, and mass effect range from none to striking.

The spatial distribution of parenchymal metastases is nonuniform, suggesting that vulnerability to metastases may differ among brain regions. For example, the parietooccipital lobes are the most common site for non-small cell lung cancers.

Hemorrhage varies with primary tumor type. Melanoma, renal cell carcinoma, and choriocarcinoma are especially prone to develop intratumoral hemorrhages. For example, compared

with lung cancer, metastatic melanoma is five times more likely to hemorrhage.

Diffusely infiltrating parenchymal metastases are rare. When they occur, they may be grossly indistinguishable from anaplastic astrocytoma or glioblastoma. Small cell lung carcinoma is the most common tumor that causes such "pseudogliomatous" infiltration.

Skull/Dural Metastases. Calvarial and skull base metastases can be relatively well circumscribed or diffusely destructive, poorly marginated lesions (27-5) (27-6). Head and neck tumors that extend intracranially by direct geographic invasion generally cause significant local bony destruction.

Dural metastases usually occur in combination with adjacent skull lesions, appearing as focal nodules or more diffuse, plaque-like sheets of tumor (27-8) (27-9) (27-10). Dural metastasis without skull involvement is much less common.

Most dural metastases also involve the subjacent arachnoid and are actually dura-arachnoid tumor deposits.

Leptomeningeal Metastases. The term "leptomeningeal metastases" actually describes metastases to the subarachnoid spaces and pia. Diffuse opacification of the leptomeninges with sugar-like coating of the pia is typical (27-11). Multiple nodular deposits (27-12) and infiltration of the perivascular (Virchow-Robin) spaces with extension into the adjacent cortex may occur (27-13). Rarely, metastatic tumor spreads under the pia (subpial spread).

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.

Some metastases are more difficult than others to characterize on standard histopathologic studies. Apart from their morphologic features, ancillary immunohistochemical (IHC) analysis is the most effective tool for characterizing a metastatic neoplasm of unknown origin.

Recent advances have enabled delineation of actionable, clinically relevant genomic alterations within metastases that help identify the primary source. IHC characterization and new microRNA-based tests can identify the tumor origin in the majority of such cases. Molecular analysis is a further step that can be helpful.

In some instances, metastases harbor relevant genetic alterations that are not present in primary tumor biopsies. Genomic heterogeneity and molecular discordance between primary tumors and brain metastases are additional factors complicating potential targeted treatment regimens.

CNS METASTASES: PATHOLOGY

Location

•Adults

○Brain (80%, cerebral hemispheres > > cerebellum)

○Skull/dura (15%)

○Pia ("leptomeningeal"), CSF (5%)

○Other (1%)

•Children

○Skull/dura > > brain parenchyma

Size

•Parenchymal metastases

○Microscopic to a few centimeters (most 0.5-1.5 cm)

•Skull/dura metastases

○Variable; can become very large

Number

•Solitary (50%)

•2 lesions (20%)

•≥ 3 lesions (30%)

○Only 5% have > 5 lesions

Gross Pathology

•Round, well-circumscribed > > > infiltrating

•Variable edema, necrosis, hemorrhage

Microscopic Features

•Preserves general features of primary tumor

•May have more mitoses, elevated labeling indices

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(27-8) Solitary dural metastasis indents the brain and appears identical to a meningioma. (Courtesy R. Hewlett, MD.)

(27-9) Multiple dural metastases from breast carcinoma are shown. (Courtesy B. Horten, MD.)

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(27-11) Pia-subarachnoid ("leptomeningeal") metastases coat the brain, fill the subarachnoid cisterns . (Courtesy R. Hewlett, MD.)

(27-12) Metastatic carcinoma shows many discrete tumor deposits on pia. (Courtesy P. Burger, MD, DP: Neuropathology, 2e.)

(27-13) Mets fill space between the arachnoid and pia and extend along perivascular spaces into cortex . (Courtesy P. Burger, MD.)

Clinical Issues

Demographics. As treatments for primary systemic cancers improve, patients live longer, and the incidence of brain metastasis continues to increase.

Currently, up to 40% of patients with treated systemic cancers eventually develop brain metastases. The incidence is strongly age-related, ranging from less than 1:100,000 in patients younger than 25 years to more than 30:100,000 at age 60 years.

Peak prevalence is in patients over 65 years of age. Only 6-10% of children with extracranial malignancies develop brain metastases.

Skull/dura metastases have a bimodal distribution. There is a smaller peak in children and a much larger peak in middle-aged and older adults. Overall average age is 50 years, skewed by pediatric cases and young women with aggressive breast cancers.

Presentation. Symptoms vary with tumor site. Seizure and focal neurologic deficit are the most common presenting symptoms of parenchymal metastases. Half of all patients with skull/durae metastases present with headache. Seizure, sensory or motor deficit, cranial neuropathy, or a palpable mass under the scalp are other common symptoms.

Natural History. 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. Median survival in patients with untreated metastases from lung cancer is around 1 month. Longer survival is associated with younger patient age, higher performance status, low systemic tumor activity, primary site, and presence of a solitary lesion.

Treatment Options. Treatment choice varies with the histologic type and number and location of metastases. General treatment aims are symptom prevention/palliation, improvement in quality of life, and—when possible—prolonged survival. Surgical resection, fractionated stereotactic radiosurgery, whole-brain radiation, and immunoor chemotherapy are the most widely available options although many chemotherapeutic agents have limited blood-brain barrier penetration.

Recent advances in tumor immunology such as the discovery of monoclonal antibodies targeting immune checkpoints (immune checkpoint blockade, ICB) have opened promising new frontiers in the fight against cancer. Significant improvements in survival of patients with CNS metastases from metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma have been reported using ICB in combination with radiation therapy.

Imaging

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

Determining tumor response to therapy and then differentiating response from recurrence or treatment-related changes on imaging studies can be challenging. Radiological guidelines such as RECIST and Macdonald criteria for response assessment in solid tumors are inadequate for the CNS. The updated Response Assessment in Neuro-Oncology (RANO) criteria are often used but remain controversial, particularly for assessing neuroinflammatory processes and the impact of vascular targeting agents.

Parenchymal Metastases

Terminology

Parenchymal metastases are secondary tumor implants that involve the brain parenchyma. Tumor in the perivascular (Virchow-Robin) spaces is included in our discussion of parenchymal metastases; intraventricular (ependymal and choroid plexus) metastases are discussed as miscellaneous metastases (see below).

Imaging

Conventional CT and MR are the most commonly used techniques for detecting brain metastases and monitoring treatment response.

CT Findings. Both soft tissue and bone algorithm reconstructions that should be performed as subtle calvarial lesions can easily be overlooked. Soft tissue reconstructions

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should be viewed with both narrow and intermediate ("subdural") window widths.

NECT. Most metastases are isoto slightly hypodense relative to gray matter (27-14A). Sometimes, edema is the most striking manifestation of metastases on NECT (27-15). In the absence of edema or intratumoral hemorrhage, even moderately large metastases may be virtually invisible on NECT scans (27-16). With the exception of treated metastases, calcification is rare.

Occasionally, the first manifestation of an intracranial metastasis is catastrophic brain bleeding. An underlying metastasis is a not uncommon cause of spontaneous intracranial hemorrhage in older adults (27-17).

CECT. The vast majority of parenchymal metastases enhance strongly following contrast administration (27-14B) (27-16B). Double-dose delayed scans may increase lesion conspicuity. Solid, punctate, nodular, or ring patterns can be seen.

(27-14A) Axial NECT in a

63y woman with known breast carcinoma shows a few scattered bifrontal hyperdensities . (2714B) CECT scan shows "too numerous to count" enhancing metastases, most of which were isodense and completely invisible on the precontrast study.

(27-15A) NECT in a 57y woman in the ER with seizure and altered mental status shows multiple patchy and confluent hypodensitiesin the subcortical and deep white matter of both hemispheres. (27-15B) A CECT was declined and emergency MR obtained to "look for stroke." T1 C+ FS shows multiple enhancing nodules as the cause for the edema. Chest, abdomen, and pelvis CT was normal. Biopsy disclosed adenocarcinoma.

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MR Findings

T1WI. Most metastases are isoto mildly hypointense on T1WI (27-18A). The exception is melanoma metastasis, which has intrinsic T1 shortening and thus appears moderately hyperintense (27-19). Subacute hemorrhagic metastases show disordered, heterogeneous signal intensity, often with bizarre-appearing intermixed foci of T1 hyperand hypointensities (27-20).

T2/FLAIR. Signal intensity on T2WI varies widely depending on tumor type, lesion cellularity, presence of hemorrhagic residua, and amount of peritumoral edema. Many metastases are very cellular neoplasms with high nuclear:cytoplasmic ratios and thus appear hypointense on T2WI and FLAIR (2718B) (27-18C). Exceptions are mucinous tumors, cystic metastases, and tumors with large amounts of central necrosis, all of which can appear moderately hyperintense.

(27-16A) Axial NECT in a patient with headaches and nonfocal neurological symptoms appears almost normal except for anatomic distortion and asymmetry in the white matter of both temporal lobes caused by a nearly isodense parenchymal mass . (27-16B) CECT in the same case shows that the mass enhances strongly . Peritumoral edema is almost absent. Biopsy disclosed metastasis, primary unknown.

(27-17A) An 80y man was in the emergency department for "brain attack." NECT shows a large heterogeneously hyperdense left parietooccipital hematoma. (27-17B) CTA shows a "spot" sign of contrast accumulation within the expanding hematoma . Actively bleeding metastatic adenocarcinoma, unknown primary, was found at surgery.

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*. Blood products and melanin contain metal ions including iron, copper, manganese, and zinc. Both subacute hemorrhage and melanin cause prominent signal intensity loss ("blooming") on T2* (GRE, SWI) images (27-20) (27-23). Nearly 75% of melanoma metastases have either T1 hyperintensity or demonstrate susceptibility effect; 25% demonstrate both. Nonhemorrhagic nonmelanotic metastases do not become hypointense on T2* (27-19).

T1 C+. Virtually all nonhemorrhagic metastases enhance following contrast administration (27-15B) (27-18D). Patterns vary from solid, uniform enhancement to nodular, "cyst + nodule," and ring-like lesions (27-21) (27-22). Multiple metastases in the same patient may exhibit different patterns

(27-20).

(27-22) A 63y man presented with severe headaches and papilledema. NECT scan shows a solitary posterior fossa mass with hemorrhage . MR scans show a "cyst + nodule" pattern. This was adenocarcinoma, unknown primary.

Longitudinal studies have demonstrated that, in older patients, multifocal hyperintensities identified on T2-weighted or FLAIR scans that do not enhance following contrast administration virtually never turn out to be metastases.

The conspicuity of metastases can be increased on T1 C+ scans with fat suppression and magnetization transfer sequences. The use of doubleand even triple-dose contrast-enhanced scans has been reported to increase sensitivity but is not in standard use. Contrast-enhanced T2 FLAIR is a new technique that improves sensitivity compared with contrast-enhanced inversion recovery (IR) and IR-prepared fast spoiled gradient echo (FSPGR) sequences.

DWI. With the exception of highly cellular neoplasms such as medulloblastoma and lymphoma, most primary brain tumors do not show restriction on DWI. Metastasis behavior on DWI is much more unpredictable. Well-differentiated adenocarcinoma metastases tend to be hypointense (nonrestricting), whereas more aggressive small and large cell neuroendocrine carcinomas are hyperintense on DWI (2721A). ADC values inversely reflect tumor cellularity, i.e., low ADC indicates high cellularity.

DTI with a combination of fractional anisotropy (FA) and ADC calculations may be helpful in distinguishing metastases from glioblastoma.

PWI. The differentiation of primary from solitary metastatic brain tumors using pMR is controversial. Some studies suggest that the diagnostic accuracy of MR—including rCBV measurement—is better at grading glial neoplasms than differentiating high-grade gliomas from solitary parenchymal metastases.

(27-23) Occasionally, metastases present with nonspecific encephalopathy. T2/FLAIR scans show a few scattered WM hyperintensities . No definite enhancement on T1 C+, multiple "blooming" foci on T2* . Metastases are from breast primary.

MRS. Prominent lipid signal is the dominating peak on MRS in the majority of brain metastases. However, lipid signal is also common in many cellular processes, including inflammation and necrosis. Choline is generally elevated, and Cr is depressed or absent in most metastases.

Molecular MR. Some MR contrast agents specifically target markers, such as endothelial vascular cell adhesion molecule-1 (VICAM-1), that are upregulated in vessels associated with brain metastases. Their use may permit early detection of micrometastases before lesions become apparent on standard gadolinium-enhanced sequences.

Nuclear Medicine Findings. Although it is effective for delineating systemic disease, standard PET/CT understages patients with brain metastases and fails to demonstrate a number of lesions easily detected on standard MR. Early results using new agents such as F18-DOPA show promise in detecting disease relapse after surgical treatment and/or radiotherapy.

Differential Diagnosis

The differential diagnosis of parenchymal metastases varies with imaging findings. The major differential diagnosis for punctate and ring-enhancing metastases is abscess. Abscesses and septic emboli typically restrict on DWI and show elevated amino acids and lactate on MRS.

Occasionally, glioblastoma (GBM) can mimic parenchymal metastases, especially a multifocal GBM with metachronous lesions or brain-to-brain tumor spread. Solitary GBM tends to be infiltrating, whereas metastases are almost always round and relatively well demarcated. GBMs are generally solitary and preferentially located in the deep cerebral white matter,

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whereas 50% of metastases are multiple, typically occurring at gray-white matter interfaces.

PARENCHYMAL METASTASES: IMAGING AND DDx

CT

•Variable density (most iso-, hypodense)

•Most enhance on CECT

•Perform bone CT for calvarial, skull base metastases

T1WI

•Most metastases: isoto slightly hypointense

•Melanoma metastases: hyperintense

•Hemorrhagic metastases: heterogeneously hyperintense

T2/FLAIR

•Varies with tumor type, cellularity, hemorrhage

•Most common: isoto mildly hyperintense

•Can resemble small vessel vascular disease

T2*

• Subacute blood, melanin "bloom"

T1 C+

•Almost all nonhemorrhagic metastases enhance strongly

•Solid, punctate, ring, "cyst + nodule"

DWI

•Variable; most common: no restriction

•Highly cellular metastases may restrict

MRS

•Most prominent feature: lipid peak

•Elevated Cho, depressed/absent Cr

Differential Diagnosis

•Most common: abscess, septic emboli

•Less common

○Glioblastoma

○Multiple embolic infarcts

○Small vessel (microvascular) disease

○Demyelinating disease

○Multiple cavernous malformations

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! Even with a "cyst + nodule" appearance, which is classic for hemangioblastoma, metastasis should still be at the top of the differential diagnosis list.

Both metastases and multiple embolic infarcts share a predilection for arterial "border zones" and the gray-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 small vessel microvascular disease are hyperintense on T2WI and do not enhance following contrast administration.

Multiple sclerosis (MS) occurs in younger patients and is preferentially located in the deep periventricular white matter. An incomplete ring or "horseshoe" pattern of

enhancement is more characteristic of MS and other demyelinating disorders than of metastasis.

Multiple cavernous angiomas can mimic hemorrhagic metastases. Hemorrhagic metastases generally show disordered evolution of blood products and an incomplete hemosiderin rim.

Skull and Dural Metastases

Terminology

The term "skull" refers both to the calvaria and to the skull base. As one cannot distinguish neoplastic involvement of the periosteal versus 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 calvaria.

CT Findings. Complete evaluation requires both soft tissue and bone algorithm reconstructions of the imaging data (2724). Scans with soft tissue reconstruction obscure skull lesions, which may be invisible unless bone algorithms are utilized (27-25). Soft tissue scans viewed with bone windows do not provide sufficient detail for adequate assessment.

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

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

CECT. The most common finding is a focal soft tissue mass centered on the diploic space. A biconvex shape with both subgaleal and dural extension is typical (27-26). Most dural metastases enhance strongly.

MR Findings

T1WI. Hyperintense fat in the diploic space provides excellent, naturally occurring demarcation from skull metastases. Metastases replace hyperintense yellow marrow and appear as hypointense infiltrating foci (27-27). Dural metastases thicken the dura-arachnoid and are typically isoor hypointense to underlying cortex (27-28) (27-29).

T2/FLAIR. Most skull metastases are hyperintense to marrow on T2WI, but the signal intensity of dural metastases varies. FLAIR hyperintensity in the underlying sulci suggests piasubarachnoid tumor spread (27-30). Hyperintensity in the underlying brain is present in half of all cases and suggests either tumor invasion along the perivascular spaces or compromise of venous drainage.

T1 C+. Nearly 70% of dural metastases are accompanied by metastases in the overlying skull (27-31). Involvement of the adjacent scalp is also common. Contrast-enhanced T1WI

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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 about half of all cases. Frank tumor invasion into the underlying brain is seen in one-third. Dural thickening can be smooth and diffuse or nodular and masslike.

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

Nuclear Medicine Findings. Skull metastases are intensely positive on Tc-99m scan. Integrated FDG PET/CT scans have a very high positive predictive value for bone metastases, including calvarial lesions. Dural lesions are less well visualized.

(27-24A) NECT scan in a

64y man with headache and no focal neurologic signs shows no abnormality of the brain parenchyma. A subtle irregularity of the left posterior parietal bone can be seen on soft tissue reconstruction (80 HU). (27-24B) Bone algorithm reconstruction shows a solitary permeative destructive lesion that extends through the inner, outer tables of the skull. Metastasis is from lung carcinoma.

(27-25A) NECT scan with a soft tissue algorithm reconstruction, soft tissue windows (80 HU), shows no abnormalities in this 53y man with headaches. (27-25B) Bone algorithm reconstruction shows innumerable well-defined lytic lesions in the skull. This is multiple myeloma.

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(27-33) Graphic depicts pia-subarachnoid space metastases in white, covering the brain surface and sulci and filling the subarachnoid spaces .

(27-34) This graphic depicts dura-arachnoid metastases as curvilinear thickening that follows the inner table of the skull .

(27-35) Autopsy shows diffuse leptomeningeal metastases ("sugar icing") coating the brain surfaces , filling the subarachnoid spaces .

Angiography. DSA is rarely used unless a vascular lesion is suspected. Most metastases—especially those from renal cell carcinoma—are hypervascular

(27-32).

SKULL/DURA METASTASES

General Features

•Second most common site of CNS metastases

•Skull alone or skull + dura > > isolated dural metastases

•"Dural" metastases usually dura plus arachnoid!

CT

•Use both soft tissue, bone reconstructions

•Skull: permeative lytic lesion(s)

•Scalp, dura: biconvex mass centered on skull

MR

•T1WI: metastases replace hyperintense fat

•T2WI: most skull metastases hyperintense

•FLAIR: look for

○Underlying sulcal hyperintensity (suggests pia-subarachnoid space tumor)

○Parenchymal hyperintensity (suggests brain invasion along perivascular spaces)

•T1 C+

○Use fat-saturation sequence

○Skull/scalp/dural lesion(s) can be focal or diffuse, enhance strongly

○"Dural tail" sign (50%)

○Less common: diffuse dura-arachnoid thickening ("lumpy-bumpy" or smooth)

•DWI: hypercellular metastases may restrict

Differential Diagnosis

•Skull metastases

○Surgical defect, venous lakes/arachnoid granulations

○Myeloma

○Osteomyelitis

•Dural metastases

○Meningioma (solitary or multiple)

Differential Diagnosis

The differential diagnosis of skull and dura-arachnoid metastases depends on which compartment is involved and whether solitary or multiple lesions are present.

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 duraarachnoid thickening. Metastatic dural thickening is generally—although not invariably—more "lumpy-bumpy" (27-28) (27-29).

Leptomeningeal Metastases

Leptomeningeal cancer dissemination is a metastatic complication with growing impact in clinical oncology. Recent advances in therapeutic management have been achieved, so early diagnosis is critical for optimal treatment. In addition to CSF examination, contrast-enhanced MR of the entire neuraxis is recommended for complete pretreatment evaluation.

Terminology

The anatomic term "leptomeninges" refers to both the arachnoid and the pia. The widely used term "leptomeningeal metastases" (LM) is technically incorrect, as it is employed to designate the imaging pattern seen when tumor involves the subarachnoid spaces and pia (27-33). Arachnoid metastases are almost always secondary to dura involvement and look quite different (27-34).

For purposes of this discussion, pia-subarachnoid space metastases are referred to as LMs. Other synonyms include meningeal carcinomatosis, neoplastic meningitis, and carcinomatous meningitis.

Epidemiology and Etiology

LMs are uncommon, seen in only 5% of patients with systemic cancers (2711). The most common extracranial primary tumor causing LM is breast cancer (27-36). The second most common source is small cell lung carcinoma. Although uncommon, leptomeningeal dissemination of melanoma carries an especially dire prognosis.

Intracranial primary tumors more commonly cause LM. In adults, the two most common are glioblastoma and lymphoma (27-35). 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. In contrast to dura-arachnoid metastases that "hug" the inner table of the calvaria, LM 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" (27-33).

CT Findings. NECT scans may be normal or show only mild hydrocephalus. Subtle sulcal-cisternal effacement with nearly isodense infiltrates can be seen replacing the hypodense CSF in some cases.

CECT scans may also be normal. Sulcal-cisternal enhancement, especially at the base of the brain, can be seen in some cases (27-37A).

MR Findings. T1 scans may be normal or show only smudged "dirty" CSF (27-38A). Most LMs are hyperintense on T2WI and may be indistinguishable from normal CSF.

FLAIR imaging shows loss of CSF suppression, resulting in nonspecific sulcalcisternal hyperintensity (27-38B). If tumor has extended from the pia into the perivascular spaces, underlying brain parenchyma may show hyperintense vasogenic edema.

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(27-36) Stain shows diffuse CSF breast carcinoma mets filling cerebellar sulci . (P. Burger, MD, DP: Neuropathology, 2e.)

(27-37A) CECT in a 63y woman with headaches, breast cancer, shows enhancing metastases covering the pia over the cerebellum, vermis .

(27-37B) T1 C+ FS shows the enhancing leptomeningeal metastases especially well. Also note metastasis to right orbit .

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(27-38A) Axial T1WI in a 55y woman being staged for small cell lung carcinoma shows subtle effacement of CSF in the superficial sulci .

(27-38B) FLAIR MR scan demonstrates definite sulcal hyperintensity in multiple areas .

Postcontrast T1 scans show meningitis-like findings. Smooth or nodular enhancement seems to coat the brain surface, filling the sulci (27-38C) and sometimes almost the entire subarachnoid space including the thecal sac (27-39). Cranial nerve thickening with linear, nodular, or focal mass-like enhancement may occur with or without disseminated disease (27-51) (2752).

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

Differential Diagnosis

The major differential diagnosis of leptomeningeal metastases 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., GBM, medulloblastoma, germinoma)

CT

•NECT: may be normal ± mild hydrocephalus

•CECT: sulcal-cisternal enhancement (looks like pyogenic meningitis)

MR

•T1WI: normal or "dirty" CSF

•T2WI: usually normal

•FLAIR: sulcal-cisternal hyperintensity (nonspecific)

•T1 C+: sulcal-cisternal enhancement (nonspecific)

Differential Diagnosis

•Meningitis

•Neurosarcoid

(27-38C) T1 C+ FS shows enhancement in the abnormal sulci . CSF documented disseminated CSF metastases.

Miscellaneous Metastases

The three areas covered above (brain parenchyma, skull/dura-arachnoid, and pia-subarachnoid spaces) are—by far—the most common sites for CNS metastatic deposits. Nevertheless, there are several "secret" sites that may also harbor metastases. The CSF, ventricles and choroid plexus, pituitary gland/infundibular stalk, pineal gland, and eye are less obvious places where intracranial metastases occur and may escape detection. In this section, we briefly consider the location and imaging appearances of these metastases.

CSF Metastases

Circulating tumor cells in the CSF can be difficult to detect using routine cytological examination and are typically identified on imaging studies in the later stages of disease dissemination.

Both extraand intracranial metastases can seed the CSF. Intracranial CSF metastases are usually seen as "dirty" CSF on T1WI and FLAIR, often occurring together with diffuse pial spread. "Drop metastases" into the spinal subarachnoid space are a manifestation of generalized CSF spread.

Ependymal spread around the ventricular walls occurs with primary CNS tumors much more often than with extracranial sources (27-39) (27-40).

Ventricles/Choroid Plexus Metastases

Location. The lateral ventricle choroid plexus is the most common site for ventricular metastases, followed by the third ventricle. Only 0.5% of ventricular metastases occur in the fourth ventricle. Solitary choroid plexus metastases are more common than multiple lesions. Choroid plexus metastases usually occur in the presence of multiple metastases elsewhere in the brain. Occasionally, a metastatic deposit can lodge in the choroid plexus before parenchymal lesions become apparent.

Clinical Issues. Intraventricular metastases from extracranial malignancies are rare, accounting for just 1-5% of cerebral metastases and 6% of all intraventricular tumors. Most involve the choroid plexus; the ventricular ependyma is affected less frequently.

The most common primary sources in adults are renal cell carcinoma and lung cancer. Melanoma, stomach, and colon cancers and lymphoma are less common causes of choroid plexus metastases. Neuroblastoma, Wilms tumor, and retinoblastoma are the most common primary tumors in children. Prognosis is generally poor with most patients succumbing to systemic disease progression or to multifocal CNS disease.

Imaging. Choroid plexus metastases enlarge the choroid plexus and are isoto hyperdense compared with normal choroid plexus on NECT scans. They enhance strongly but heterogeneously.

Choroid plexus metastases are often hypervascular, so hemorrhage is quite common. Most nonhemorrhagic choroid plexus metastases are hypointense to brain on T1WI and hyperintense on T2/FLAIR. Intense enhancement following contrast administration is typical. Choroid plexus metastases display a prolonged vascular "blush" on DSA.

Differential Diagnosis. In an older patient (especially one with known systemic cancer such as renal cell carcinoma), the differential diagnosis of a choroid plexus mass should always include metastasis. Other common choroid plexus lesions in older patients are meningioma and choroid plexus xanthogranuloma. Choroid plexus meningiomas enhance strongly and generally uniformly. Choroid plexus cysts (xanthogranulomas) are usually bilateral, multicystic-appearing lesions.

Although solitary metastasis to the third ventricle is rare, metastatic deposit to the choroid plexus in the foramen of Monro may mimic colloid cyst. Although the wall of a colloid cyst occasionally demonstrates rim enhancement, solid enhancement almost never occurs.

Pituitary Gland/Infundibular Stalk Metastases

Clinical Issues. Metastasis causes approximately 1% of all resected pituitary tumors and is found in 1-2% of autopsies. Breast and lung primaries account for two-thirds of cases, followed by GI tract adenocarcinomas. Most pituitary metastases involve the posterior lobe, probably because of its direct systemic arterial supply via the hypophyseal arteries (the anterior pituitary is mostly supplied by the hypophyseal portal venous system). Coexisting brain metastases are common, but solitary lesions do occur.

Signs and symptoms such as headache and visual disturbances can mimic those of pituitary macroadenoma although they often progress much more rapidly in patients with metastases. Clinical diabetes insipidus is common.

Imaging. A sellar mass with or without bone erosion, stalk thickening, loss of posterior pituitary "bright spot," and cavernous sinus invasion is typical but

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(27-39A) T1 C+ FS in a 23y man with glioblastoma shows CSF metastases in the fourth ventricle and left IAC .

(27-39B) T1 C+ FS through the lateral ventricles shows diffuse ependymal and choroid plexusmetastases.

(27-39C) Sagittal T1 C+ FS shows diffuse CSF spread ("drop metastases") with tumor coating the conus and cauda equina .

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(27-40A) Axial T1WI in a 28y woman with a remote history of medulloblastoma shows diffuse nodular ependymal thickening .

(27-40B) T2WI in the same case nicely demonstrates the subependymal nodules , which appear isointense with gray matter.

(27-40C) The nodules enhance heterogeneously on T1 C+ FS . Metastatic medulloblastoma was documented by CSF.

nonspecific. An infiltrating, enhancing pituitary and/or stalk mass is the most common finding (27-41).

Differential Diagnosis. The major differential diagnosis of pituitary metastasis is macroadenoma. Macroadenomas rarely present with diabetes insipidus. In the setting of a known systemic cancer, rapid growth of a pituitary mass with onset of clinical diabetes insipidus is highly suggestive but certainly not diagnostic of metastasis. Lymphocytic hypophysitis can also resemble pituitary metastasis on imaging studies.

Pineal Gland Metastases

Although the pineal gland is a relatively common source of primary CNS tumors that seed the CSF, it is one of the rarest sites to harbor a metastasis. Only 0.3% of intracranial metastases involve the pineal gland. Lung, breast, skin (melanoma), and kidney are the most frequent sources (27-42). When pineal metastases do occur, they are usually solitary lesions without evidence of metastatic deposits elsewhere and are indistinguishable on imaging studies from primary pineal neoplasms.

Ocular Metastases

Clinical Issues. Metastases to the eye are rare. The highly vascular uveal tract is the most common location if metastases are present. Within the uvea, the choroid is by far the most commonly affected site, accounting for nearly 90% of all ocular metastases. The iris (8-9%) and the ciliary body (2%) are other possible locations.

Breast cancer is the most common cause of ocular metastases, followed by lung cancer. The diagnosis of ocular metastases is based on clinical findings supplemented by imaging studies.

Imaging. CT and MR findings are nonspecific, demonstrating a posterior segment mass that often enhances strongly after contrast administration (27-43). Whole-brain imaging is recommended, as 20-25% of patients with choroidal metastases have concurrent CNS lesions.

Differential Diagnosis. The differential diagnosis of choroidal metastasis includes other hyperdense posterior segment masses. Primary choroidal melanoma and hemangioma may appear similar on both CT and MR. Both metastasis and melanoma can penetrate the Bruch membrane. Ocular ultrasound may be helpful in diagnosing hemangioma. Melanoma and metastases may incite hemorrhagic choroidal or retinal detachment.

Direct Geographic Spread From Head and

Neck Neoplasms

Cephalad spread from head and neck neoplasms such as sinonasal squamous cell carcinoma, adenoid cystic carcinoma, non-Hodgkin lymphoma, and esthesioneuroblastoma may extend intracranially. This direct extension is also called geographic or regional spread.

Sinonasal tumors gain access to the cranial cavity in three ways: (1) erosion superiorly through the relatively weak bone of the cribriform plate into the anterior cranial fossa, (2) direct extension into the pterygopalatine fossa (PTPF) with posterior spread into the cavernous sinus (27-44), and (3) perineural tumor spread into the PTPF, cavernous sinus, and Meckel cave. We now briefly discuss sinonasal squamous cell carcinoma as the prototypical head and neck neoplasm with geographic intracranial spread. Perineural tumor spread is considered separately below.

Sinonasal Squamous Cell Carcinoma

Squamous cell carcinoma (SCCa) is an aggressive malignant epithelial tumor with squamous cell or epidermoid differentiation. SCCa is the most common sinonasal malignancy, accounting for 3% of all head and neck neoplasms.

Almost all sinonasal SCCas occur in patients older than 40, with peak prevalence at 50-70 years. There is a moderate male predominance. Most patients present with symptoms of sinusitis refractory to medical therapy.

Risk factors for developing sinonasal SCCa include inhaled wood dust, metallic particles, and some chemicals. There is no direct link to smoking.

Pathology. Nearly three-quarters of sinonasal SCCas arise in the sinuses, whereas 25-30% arise primarily in the nose. The maxillary antrum is the most common site for sinonasal SCCa overall. Approximately 10% of sinus SCCas arise in the ethmoid sinuses.

Sinonasal SCCa that involves the brain is classified according to American Joint Committee on Cancer (AJCC) criteria rather than given a WHO grade. Nasal-ethmoidal SCCa that invades the cribriform plate is considered a T3 tumor. If the anterior cranial fossa is involved, the tumor is a T4a lesion. T4b tumors involve the dura, brain, middle cranial fossa, clivus, or cranial nerves other than the mandibular nerve (CN V ).

Imaging. CT scans show a solid mass with irregular margins and bone destruction. Sinonasal SCCa is isointense with mucosa on T1WI and mildly to moderately hypointense on T2WI.

SCCa shows mild to moderate enhancement following contrast administration but enhances to a lesser extent than adenocarcinoma, esthesioneuroblastoma, and melanoma. Axial and sagittal T1 C+ fatsaturated images are recommended to detect perineural tumor spread (see below). Coronal T1 C+ FS images are recommended to delineate extension through the cribriform plate into the anterior cranial fossae (27-45).

Differential Diagnosis. The differential diagnosis of sinonasal SCCa with intracranial extension includes other malignancies such as sinonasal adenocarcinoma, undifferentiated carcinoma, and non-Hodgkin lymphoma. Nonmalignant mimics of sinonasal SCCa that may extend intracranially include invasive fungal sinusitis and Wegener granulomatosis.

Perineural Metastases

Terminology

Perineural tumor (PNT) spread is defined as extension of malignant tumor along neural sheaths.

Etiology

Many head and neck cancers have a propensity to spread along nerve sheaths. Mucosal or cutaneous tumors such as SCCa and major/minor salivary gland malignancies such as adenoid cystic carcinoma all are prone to PNT spread. Other tumors such as melanoma and non-Hodgkin lymphoma also frequently spread along major nerve sheaths. Perineural invasion occurs in 2-6% of cutaneous head and neck basal carcinomas and SCCas.

PNT spread may be anterograde, retrograde, or both. "Skip" lesions and lesions that cross from one nerve to another are common.

Pathology

Location. The most common nerves to be affected by PNT are the maxillary division of the trigeminal nerve (CN V ) (27-46) (27-47) and the facial nerve

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(27-41) T1 C+ FS shows metastases to pituitary gland/stalk , 3rd ventricle , 4th ventricle choroid plexus , and vermian folia .

(27-42) Sagittal T2WI in a patient with melanoma shows metastasis to the pineal gland causing acute obstructive hydrocephalus.

(27-43) CECT scan shows a lobulated enhancing mass in the posterior segment of the left globe. This was metastatic breast carcinoma.

(27-44A) Autopsy specimen shows nasopharyngeal squamous cell carcinoma extending cephalad, eroding through the central skull base into the cavernous sinus and sellar floor .

(27-44B) Tumor extends from the cavernous sinus along CN III into the suprasellar and prepontine cistern . (Courtesy R. Hewlett, MD.)

(CN VII) (27-48). SCCa or melanoma of the cheek can infiltrate the infraorbital division of CN V . Posterior spread into the PTPF allows access to the cavernous sinus and Meckel cave via the foramen rotundum.

The mandibular nerve (CN V ) can be invaded by any masticator space malignancy. Retrograde spread up the nerve from an oral cavity mucosal SCCa is a classic example (27-49).

Parotid gland malignancies such as adenoid cystic carcinoma can "creep" up the facial nerve all the way into the internal auditory canal.

Microscopic Features. Tumor extends along a nerve via the epineurium, expressing neural cell adhesion molecules and eventually invading the nerve itself.

Clinical Issues

Early PNT spread is often asymptomatic. Trigeminal pain and paresthesia, including denervation atrophy of the muscles of mastication, are common with CN V lesions. CN VII lesions present with facial weakness or paralysis. CN VII special functions are lost as tumor gradually spreads upward along the facial nerve canal.

Imaging

General Features. Tubular enlargement of the affected nerve together with widening of its bony canal or foramen is typical. If the nerve passes through a structure such as the PTPF that is normally filled with fat, the fat becomes "dirty" or effaced.

Look for denervation atrophy—common with CN V lesions—seen as small, shrunken muscles of mastication with fatty infiltration (27-46) (27-50).

HEAD AND NECK TUMORS WITH CNS INVOLVEMENT

Direct Geographic Spread

•Etiology

○Most common = sinonasal squamous cell carcinoma (SCCa)

○Other = adenoid cystic carcinoma, undifferentiated carcinoma, non-Hodgkin lymphoma (NHL)

•Imaging

○Soft tissue mass in nasopharynx/sinuses

○Permeative destructive changes in skull base

Perineural Tumor Spread

•Etiology

○Adenoid cystic carcinoma, SCCa, NHL most common

○Can be antegrade, retrograde, or combination

•Location

○CNs V , VIII most common

•Imaging

○Look for denervation atrophy (e.g., pterygoid with V involvement)

○"Dirty fat" on T1WI (e.g., parapharyngeal space, pterygopalatine fossa)

○"Fat nerve" ± involvement of Meckel cave

○Enhancing tumor on T1 C+ FS

CT Findings. Bone CT shows smooth—not permeative destructive—enlargement of the affected foramen or canal. NECT may show abnormal soft tissue density replacing normal fat. CECT may show subtle soft tissue enhancement.

If tumor extends into the cavernous sinus, the walls may bulge outward, and Meckel cave may be filled with soft tissue instead of CSF (27-46A).

MR Findings. The natural contrast provided by fat on T1WI is extremely helpful in detecting possible PNT. Obliterated fat—especially in the PTPF—is a key finding. PNT is often isointense with nerve and difficult to see on T2WI. Tumor spread into Meckel cave replaces the normal hyperintense CSF with isointense soft tissue.

Postcontrast T1 scans should be performed with fat saturation to increase conspicuity of the enlarged, strongly and uniformly enhancing nerve.

Differential Diagnosis

The major differential diagnosis of a solitary enlarged, enhancing cranial nerve in a middle-aged or older adult is perineural metastasis versus schwannoma. Schwannomas are

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tubular or fusiform enlargements that enhance strongly but heterogeneously. The vast majority of schwannomas are vestibulocochlear, whereas the trigeminal and facial nerves are the most common sites for perineural metastases. Lymphoma can involve a single cranial nerve but is more often multifocal.

Plexiform neurofibroma can infiltrate the orbital division of CN V but almost always occurs with neurofibromatosis type 1.

Neurosarcoid and invasive fungal sinusitis can infiltrate one or more cranial nerves. Chronic inflammatory demyelinating polyneuropathy (CIDP) usually involves spinal nerves but occasionally affects cranial nerves. Multiple enhancing CNs are more common than solitary involvement in CIDP. Other causes of multifocal cranial nerve enhancement include multiple sclerosis, viral/postviral neuritis, and Lyme disease.

(27-45A) Recurrent nasopharyngeal squamous cell carcinoma shows cephalad extension into the right ethmoid sinus and both anterior cranial fossae . (27-45B) Axial T1 C+ FS scan shows the massive extension of tumor into the frontal sinuses. The frontal bones are completely eroded. The dura is thickened and disrupted with tumor extending into and obliterating the underlying subarachnoid space.

(27-46A) Enhancing lesion fills the right Meckel cave, infiltrates and thickens CN V . CN V (not shown) also demonstrated tumor involvement. (27-46B) Coronal T1 C+ shows that the ipsilateral muscles of mastication including the temporalis muscle are atrophic and fatty infiltrated compared with the normal-appearing left side. This was denervation atrophy.