Breast Cancer Metastases to the Neural Axis

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CHAPTER 11 Breast Cancer Metastases to the Neural Axis

Breast cancer is the second most common primary tumor to metastasize to the central nervous system (CNS), after lung cancer.^1,^2,³ Breast cancer metastases to the neural axis typically occur late in the disease, with lung, liver, or bone metastases preceding the diagnosis of CNS metastases. The median interval between the diagnosis of breast cancer and brain metastases is 34 months. The historical 1-year survival rate after diagnosis of brain metastases is 20%.³

CNS metastases can be a challenging management issue. Brain metastases are often more debilitating and more rapidly fatal if untreated than metastases to other organ systems.

Based on data from the 1960s and 1970s, the incidence of clinically apparent brain metastases in women with stage IV breast cancer is 10% to 16%. However, autopsy data show the incidence to be greater and has been reported to be as high as 30%.¹

Younger patients are at higher risk for CNS metastases. In an autopsy series of 1044 breast cancer patients, the median age of patients with CNS metastases was 5 years younger than patients without CNS metastases.¹

Studies suggest a relationship between hormone receptor status and the incidence of CNS metastases.^1,^3,⁴ A study of 217 breast cancer patients found a difference in the rate of brain metastases between estrogen receptor–negative and –positive tumors (10% versus 4%). In a multivariate model, HER-2/neu overexpression was the strongest predictor of CNS relapse, with a 10-fold increase in the incidence of brain metastases (4.3% versus 0.4%). However, it is unclear whether HER-2/neu positive patients are actually at higher risk for CNS metastases or whether the natural history of their disease is affected by more effective systemic disease control with trastuzumab (Herceptin). HER-2 amplification occurs in 25% to 30% of breast cancers and correlates with decreased disease-free and overall survival rates. Treatment with Herceptin improves systemic disease control and overall survival of HER-2/neu positive patients with metastatic breast cancer. However, it does not cross the blood-brain barrier. The theory is that the natural history of the disease may be changed as a result of improved extra-CNS systemic disease control from Herceptin therapy, resulting in an increase in the incidence of CNS metastases. Circumstantial evidence for this includes the statistic that the incidence of CNS metastases in stage IV breast cancer patients who are treated with Herceptin is higher than historical norms, and ranges from 28% to 43%.

DISTRIBUTION OF CRANIAL METASTASES

Brain metastases result from hematogenous spread. Their predilection for the gray-white matter junction is thought to result from decreased vessel caliber at this level acting as a trap for embolized clumps of tumor cells. Similarly, there is a predilection of metastases to occur at intracranial vascular watershed levels. The distribution of metastases within brain compartments is roughly proportionate to the blood supply, with about 80% occurring in the cerebrum, 15% in the cerebellum, and 5% in the brainstem. Metastases occur most commonly at the junction of gray and white matter in the cerebral hemispheres, followed by deep gray matter (basal ganglia, thalami), intraventricular (choroid plexus), and cerebellum.^3,⁶

CNS metastases can be categorized as intra-axial, extra-axial, or cerebrospinal fluid (CSF) dissemination. Breast cancer more commonly involves multiple compartments (parenchyma, meninges, bone) than other tumors. It is the solid tumor most commonly associated with leptomeningeal involvement, although this is considerably less common than parenchymal metastases, occurring in 5% to 16% of patients at autopsy.¹ Breast cancer also metastasizes to the eye at a higher rate than other tumors. A small percentage of breast cancer metastases target the meninges or the skull diploic space. Growth of such lesions may be intracranial and can compress the brain surface, whereas metastases to the skull base dura or bone can exert mass effect on the brainstem or cranial nerves.

The most common imaging manifestation of intracranial metastatic disease is multiple intra-axial brain masses.⁶ These vary in size, shape, and enhancement patterns; the amount of associated edema can range from negligible to intense. Lesions can be solid and enhance uniformly (Figure 1), or can be cystic (Figure 2) or necrotic, with peripheral rim enhancement. Rim enhancement can be thin, thick, uniform, or irregular (Figure 3). Identifying single or multiple intracranial mass lesions in a breast cancer patient is highly suspicious for intracranial metastases, although it has mimicks with other diagnoses, including other neoplasms (metastases from other primaries, brain primary neoplasia, and CNS lymphoma), demyelinating disorders such as multiple sclerosis, multifocal infectious or granulomatous processes, and multifocal ischemic or vasculitic lesions.⁶

FIGURE 1 Enhanced T1-weighted axial MRI from a 68-year-old woman with metastatic breast cancer shows multiple, scattered, rounded, uniformly enhancing masses. Most are peripheral in location, near the brain surface.

FIGURE 2 Enhanced T1-weighted axial MRI from a 63-year-old woman with metastatic breast involvement shows a cystic midbrain lesion with an enhancing rim of variable thickness. The patient presented with new onset of ataxia. Brain metastases were identified 3 years after diagnosis of breast cancer and 1 year after development of thoracic and bone recurrent disease.

FIGURE 3 A 52-year-old woman with metastatic breast cancer to pleura and peritoneum, who developed numbness of the lips and slurred speech. Her original diagnosis of infiltrating ductal carcinoma was 14 years before, with axillary recurrence at 5 years. Brain MRIs (A, axial fluid attenuated inversion recovery (FLAIR); B, enhanced T1-weighted axial; C, coronal, fat-saturated enhanced T1-weighted) show a single brain metastasis to the left paramedian frontal lobe, adjacent to the falx. On FLAIR, the lesion itself is isointense to mildly hyperintense to brain parenchyma, but is outlined by the associated edema. Contrast-enhanced sequences show thick and irregular peripheral enhancement, which suggests central necrosis.

Extra-axial mass lesions may be formed by metastases to the skull or dura. Dural-based metastatic masses can be nodular and mass-like (Figure 4) or elongated and plaque-like (Figure 5). The underlying cerebral cortex may be compressed and edema incited in the underlying parenchyma. Morphologically, dural-based metastases may mimic meningiomas, or subdural collections.⁶

FIGURE 4 Enhanced axial T1-weighted MRI of a 51-year-old woman with metastatic breast cancer shows an enhancing, lobular, dural- and bone-based mass centered on the left sphenoid wing. The component extending into the left middle cranial fossa mimics a meningioma, being dural based and extra-axial, with well-defined margins and an enhancing dural tail. The underlying brain is compressed and edematous. Enhancing tumor also replaces the sphenoid wing bones, and on other levels, extended into the left orbit (not shown). See additional images from the same patient in Case 6 in this chapter.

FIGURE 5 A 47-year-old woman with new-onset expressive aphasia and prior gamma knife therapy 7 months before for right posterior parietal metastasis. Enhanced axial T1-weighted MRI shows a localized region of plaque-like metastatic dural enhancement over the left cerebrum. Additional images on this case can be seen in Case 7 in this chapter.

Leptomeningeal tumor consists at pathologic studies of sheet-like growth of tumor on the brain, spinal cord, or nerve root surfaces. Three mechanisms are postulated for CSF dissemination of tumors.³ Tumor cells may rupture out of the subarachnoid space or pial vessels. Growing metastases in the brain cortex or pia may contact and be bathed by CSF, and thereby shed cells into it. Alternatively, hematogenous metastases to the choroid plexus may seed the CSF. Lobular carcinoma has been noted in clinical and autopsy series to be more likely to manifest as leptomeningeal tumor than ductal carcinoma. The diagnosis can be suggested by characteristic imaging findings on gadolinium-enhanced MRI or can be established by CSF cytology. The imaging hallmarks are enhancement of the leptomeninges (pia and arachnoid) on the brain or cord surface, which can be confluent and sheet-like or nodular, with extension into sulci or along cranial nerves or around the cauda equina (Figure 6).

FIGURE 6 A 51-year-old woman with metastatic breast cancer to liver, bone, and brain, imaged for progressive symptoms, with new perineal numbness, worsening weakness, and urinary incontinence. Based on prior evaluations for headache, the patient was known to have predominantly infratentorial brain parenchymal metastases, diagnosed 5 months before and treated with whole-brain radiation. Her original diagnosis of breast cancer was 9 years before, treated with mastectomy, radiation, and chemotherapy. She had been known to have liver metastases for 6 years and bone involvement for 2 years at the time of identification of brain metastases. A, Sagittal, enhanced (double-dose technique), high-resolution, T1-weighted, gradient echo image shows an enhancing inferior vermis metastasis. In the upper cervical spine included here, linear surface enhancement is seen on the cord (arrow). B, Fat-saturated, enhanced, T1-weighted sagittal view of the thoracic spine shows evidence of known spine and liver metastases. The cord surface also shows linear surface enhancement, compatible with leptomeningeal tumor (arrows). C, Fat-saturated, enhanced, T1-weighted sagittal view of the lumbar spine also shows foci of linear enhancement of cauda equina roots (arrows).

DETECTION OF CNS METASTASES BY IMAGING

Gadolinium-chelate contrast-enhanced MRI is acknowledged to be the most sensitive imaging modality for the diagnosis of neural axis metastases.^7,⁹ Enhanced MRI is superior to enhanced CT for both brain parenchymal and brain and spine leptomeningeal disease due to its higher soft tissue contrast, higher sensitivity to contrast enhancement, direct multiplanar capability, and lack of artifacts related to bone. It particularly excels in demonstration of lesions in the posterior fossa and brainstem, where beam-hardening artifacts can be problematic on CT. MRI is also superior to CT in identifying multiple lesions, which is helpful in the differential diagnosis.⁶

The role of brain PET is limited in evaluating for metastases. Although brain metastases can be seen occasionally on whole-body PET scans (see Case 4 in this chapter), the sensitivity of PET for detection of brain metastases is inferior to MRI and is size dependent. The likelihood of detecting a 1-cm lesion with PET is reported to be about 40%. On a retrospective evaluation of whole-body PET performance in identifying brain metastases, Rohren and colleagues found that PET detected only 61% of lesions found by MRI.⁵

INDICATIONS FOR IMAGING

CNS metastases may be heralded clinically by focal neurologic symptoms, seizure activity, or symptoms reflecting increased intracranial pressure, such as headache, nausea, vomiting, and mental status changes.^1,³ Focal neurologic symptoms may result from tumor-induced chemical changes causing neuron dysfunction and swelling, or from mass effect from compression of normal tissue. Tumor-induced electrical dysfunction can lead to seizure activity. Increased intracranial pressure may result from obstructive hydrocephalus, such as from mass effect from a parenchymal metastasis to the posterior fossa, or from communicating hydrocephalus due to leptomeningeal metastases.

The most common presenting symptom for brain parenchymal metastases is headache, followed by mental status changes and cognitive disturbances. Less common manifestations of CNS metastases include visual and sensory disturbances, focal weakness, seizure, ataxia, and nausea and vomiting. Leptomeningeal disease more often presents with nonlocalizing symptoms of headache or neck or back pain, although cranial neuropathies may result.

TREATMENT OPTIONS

After corticosteroid treatment for edema, therapeutic choices for brain metastases include whole-brain radiation therapy (WBRT), neurosurgery, stereotactic radiosurgery (SRS), and chemotherapy.^1,^2,³ If there are multiple metastases, WBRT has been shown to improve survival and quality of life compared with corticosteroids alone. Median survival is 4 to 5 months. Most patients (75% to 85%) will have improvement of symptoms, with best palliation achieved of seizures and headache. Imaging responses to effective radiation therapy range from complete resolution to shrinkage in size of lesions, to decreased number of identifiable lesions, to alterations of morphology, with improved mass effect and associated edema (Figure 7).

FIGURE 7 A 43-year-old woman with metastatic breast cancer to bone developed headaches. Her breast cancer had been diagnosed 3 years before, and bone metastases were identified 8 months before evaluation for headache. Whole-brain radiation was given for palliation, with improvement in the patient’s symptoms. A, Axial, enhanced, T1-weighted brain MRI at a supratentorial level shows multiple scattered, uniformly enhancing, round newly diagnosed metastases at the gray-white matter junction. B, Enhanced head CT, 4 months later, after whole-brain radiation, shows tiny scattered, smaller residual enhancing metastases, which have shrunk in response to radiation therapy. C, Seven months later, the patient presented with a new seizure. Repeat brain MRI showed progressive disease, with interval growth of several lesions and increased associated edema. A right frontal lesion has grown, and now displays ring enhancement. D, Axial FLAIR of the same lesion shows the associated edema, as well as edema associated with a left paramedian frontal lesion. E, Unenhanced head CT scan, 2 months later, after gamma knife therapy of the same lesion. Calcification is now seen of the treated lesion.

A single metastasis to the brain can be treated either neurosurgically or with SRS. The major advantage of neurosurgery is immediate relief of mass effect from debulking. The decision making is highly dependent on the lesion location.

Surgery can be beneficial to treat a solitary brain metastasis if the breast cancer history is remote (e.g., there is a long tumor-free interval between diagnosis and development of brain metastasis), and there is no other evidence of metastases. Survival is improved in patients undergoing surgery and WBRT for solitary brain metastasis than for those treated with radiation alone. Average survival after resection of a solitary brain metastasis and WBRT is about 1 year.

Selected patients with brain metastases from a variety of primary types (single lesions, better performance status, controlled extra-CNS disease) have better outcomes with surgery than with WBRT. Postoperative external-beam radiation is usually given after gross total tumor excision to treat microscopic residual disease. The addition of WBRT does not appear to confer a survival advantage, although there is improved local control with lower rates of relapse. The major risk of WBRT is progressive dementia.

Single or few metastases can also be treated noninvasively with SRS. Decision making is based on the size and location of the lesion. Ideal lesions for SRS are less than 3 cm in diameter. Stereotactic radiosurgery involves many radiation beams intersecting at a point, resulting in the delivery of a high additive lethal dose to a target tumor, while largely sparing the surrounding brain. Typically, SRS is given as a single, outpatient treatment. Gamma knife is one form of SRS. Contraindications are tumors of large size (>3 cm) and those with significant edema because the treatment can be expected to incite further edema. It is an option to consider for surgically inaccessible metastases (e.g., the brainstem) and can be used to treat multiple tumors.

These treatment options can also be combined. There is evidence that administration of WBRT after SRS reduces the risk for CNS relapse.

There appears to be no clear survival advantage between surgery and SRS in appropriately selected patients. Either treatment confers a survival advantage over WBRT alone.

Chemotherapy plays a lesser role in treatment of breast cancer brain metastases. Most agents used do not cross an intact blood-brain barrier; however, the blood-brain barrier may be dysfunctional with brain metastases, and responses have been reported with agents that do not cross the intact barrier.

Because CSF metastatic disease most commonly manifests as hydrocephalus, and less commonly with carcinomatous meningitis, treatment is directed toward relief of hydrocephalus with shunting, and intrathecal chemotherapy may be considered, administered either by lumbar punctures or Ommaya reservoir.

SPINAL METASTASES

Metastases that compress the spinal cord most commonly present with pain at that level. With increased compression, symptoms progress to numbness below that level and eventually to difficulty ambulating. If untreated, there can be progression to paralysis. Bowel and bladder dysfunction may occur late.

Metastases to the cauda equina produce back pain and, variably, radicular symptoms.⁹

REFERENCES

1 Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 2004;22:3608-3617.

2 Chang EL, Lo S. Diagnosis and management of central nervous system metastases from breast cancer. Oncologist. 2003;8:398-410.

3 Parker EC, Kelly PJ. Brain metastases from breast cancer. In: Roses DF, editor. Breast Cancer. Philadelphia: Elsevier Churchill Livingstone; 2005:633-643.

4 Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97(12):2972-2977.

5 Rohren EM, Provenzale JM, Barboriak DP, et al. Screening for cerebral metastases with FDG PET in patients undergoing whole-body staging of non–central nervous system malignancy. Radiology. 2003;226:181-187.

6 Yock DH. Magnetic Resonance Imaging of CNS Disease: A Teaching File. St. Louis: Mosby, 2002;2-19. 101, 439

7 Sze G, Milano E, Johnson C, et al. Detection of brain metastases: comparison of contrast-enhanced MR with unenhanced MR and enhanced CT. AJNR Am J Neuroradiol. 1990;11:785.

8 Davis PC, Hudgins PA, Peterman SB, et al. Diagnosis of cerebral metastases: double-dose delayed CT vs contrast-enhanced MR imaging. AJNR Am J Neuroradiol. 1991;12:293.

9 Douglas AF, Cooper PR. Spinal column metastases from breast cancer. In: Roses DF, editor. Breast Cancer. Philadelphia: Elsevier Churchill Livingstone; 2005:644-652.

CASE 1 Multilocular thalamic cystic metastasis

A 43-year-old woman with metastatic breast cancer to the thorax developed nausea, one episode of vomiting, progressive headache, confusion, and speech difficulty.

Her diagnosis of stage T2N1 breast cancer was 5 years before, a 4.5-cm poorly differentiated adenocarcinoma, with one positive lymph node. She underwent bilateral mastectomy and received adjuvant Cytoxan, methotrexate, 5-fluorouracil (CMF) chemotherapy and tamoxifen. Her prior medical history was notable for treatment of Hodgkin’s lymphoma at age 17 with radiation and chemotherapy.

Lung and nodal breast cancer metastases had been identified the year before with PET and CT evaluation for rising tumor markers. The diagnosis of recurrent breast cancer was confirmed by a lung nodule biopsy, which showed malignant adenocarcinoma, consistent with breast primary. The patient was begun on a regimen of docetaxel (Taxotere) and Gemzar. This was eventually discontinued because of pulmonary toxicity (see Case 12 in Chapter 10) and disease progression. The patient’s regimen was changed to capecitabine (Xeloda) for six cycles, with a good initial response, but subsequent regrowth.

When the patient developed symptoms of headache, nausea, and mental status changes, a noncontrast head CT scan was obtained (Figure 1). The head CT identified a lesion and suggested that secondary hydrocephalus was developing. Unenhanced head CT excluded a hemorrhage. Brain MRI was obtained next, which better showed the internal structure of the mass, which was solitary (Figure 2).

FIGURE 1 Noncontrast head CT scan shows a large mass lesion centered in the left thalamus. A portion of the mass has a multilocular, cystic appearance. The lateral ventricles appear prominent, suggesting developing hydrocephalus.

FIGURE 2 Brain MRIs better show the composition of the mass and the mass effect upon adjacent structures. A, T1-weighted sagittal image shows no hyperintense components to suggest hemorrhage. B, Axial FLAIR. C, Axial T2-weighted image. D, Contrast-enhanced axial T1-weighted image. E, Contrast-enhanced, fat-saturated, coronal T1-weighted image. FLAIR and T2-weighted sequences show the cyst-like components of the mass to differ in fluid signal intensity from cerebrospinal fluid (CSF). Edema is seen anterior and lateral to the mass. The third ventricle is deviated to the right. Periventricular edema at the lateral ventricular margins, well seen on FLAIR, is compatible with transependymal migration of CSF, and suggests developing hydrocephalus. Enhanced T1-weighted sequences show rim enhancement of the cystic locules. The mass pushes up on and distorts the trigone of the lateral ventricle, as well as deviating the third ventricle to the right.

The patient was evaluated by neurosurgery and radiation oncology. She was started on dexamethasone (Decadron) and elected to undergo whole-brain radiation therapy (WBRT). Her symptoms improved.

TEACHING POINTS

This patient was treated for Hodgkin’s disease with radiation as an adolescent, a demographic at known higher risk for development of breast cancer. As is usual with breast cancer CNS metastases, which typically occur late, this patient already had known extracranial metastases in the thorax at the time she presented with this presumed solitary brain metastasis.

Brain metastases may be cystic or solid. Larger lesions in particular can have associated cystic or necrotic regions. The surrounding rim of enhancing tumor can be fairly smooth and thin, irregularly thickened, or both, as seen here. Based on imaging features alone, the differential diagnosis of a neoplasm with this appearance would include a primary malignant glioma. The clinical context and presence of additional lesions in the case of metastases generally allow differentiation.

Although hematogenous brain metastases classically favor a peripheral distribution, often at the gray-white matter junction, brain metastases not uncommonly occur in deeper locations, frequently the periventricular regions. Masses such as this, occurring adjacent to ventricles, can be difficult to distinguish from masses within ventricles. MRI is very helpful in this distinction, because of its multiplanar capability and better soft tissue contrast.The higher sensitivity of MRI is also useful in the evaluation of suspected metastases by identification or exclusion of additional lesions.

Solitary brain metastases may be considered for local therapy with surgery or stereotactic radiosurgery (SRS). The available data suggest prolonged survival of suitable candidates with local therapy than patients treated with whole brain radiation therapy (WBRT) alone. The location and size of a metastasis and the control status of extra-CNS disease are factors considered in decision making. The best candidates for local therapy are those with limited disease in an accessible location who have well-controlled systemic disease. Of note, the limited data available come from series that include brain metastases from a variety of primary sources.

In this case, the lesion size (4.7 cm) would generally preclude consideration of SRS, which is usually reserved for lesions smaller than 3 cm. Surgery enables immediate decompression of large, symptomatic metastases, while establishing a histologic diagnosis.

Treatment with WBRT confers a survival advantage over treatment with corticosteroids alone, with a median survival of 4 to 6 months. Most patients (75% to 85%) can expect improvement or stabilization of their neurologic symptoms with WBRT. Administration of WBRT also decreases the incidence of subsequent CNS relapse.

CASE 2 Brain metastases mimicking multiple sclerosis

A 60-year-old woman with metastatic breast cancer to the left orbit, lungs, and bones was evaluated with brain CT for intractable nausea. Her breast cancer had been diagnosed 3 years before as a stage I infiltrative ductal carcinoma of the right breast, estrogen receptor and progesterone receptor positive, HER-2/neu positive, with five negative lymph nodes. She was treated with lumpectomy and radiation. She received no adjuvant therapy except for 1 month of tamoxifen, which was discontinued because of intolerance.

Metastatic breast cancer, estrogen receptor positive, progesterone receptor negative, HER-2/neu negative, was identified 2 years later, as a left axillary lump. Later the same year, metastatic orbital and lung involvement was identified. The lung disease was biopsy proven, with a left lower lobe wedge excision showing metastatic carcinoma to pleura and lung with lymphovascular invasion.

The patient was treated with radiation to the orbit, and systemic chemotherapy with trastuzumab (Herceptin) and capecitabine (Xeloda), without response.

At the time of evaluation for intractable nausea and dry heaves, additional symptoms of dysphagia, coughing, anorexia, and weight loss were noted. Head CT, with and without contrast enhancement, showed small, enhancing periventricular white matter lesions, and a sclerotic clivus lesion (Figures 1, 2, and 3). MRI showed comparable findings (Figures 4, 5, 6, and 7).

FIGURE 1 Unenhanced (A) and enhanced (B) head CT images obtained at the centrum semiovale level show multiple white matter lesions. On unenhanced imaging, the visualized lesions are hyperdense. The lesions enhance, and more are seen with contrast administration.

FIGURE 2 Additional enhanced head CT images (A to C, see also next page) show multiple, small, white matter, enhancing lesions in a periventricular distribution.

FIGURE 3 Head CT bone window through the skull base shows a sclerotic bone lesion in the clivus.

FIGURE 4 Sagittal T1-weighted image through the midline of the brain shows hypointensity of the calvarial and upper cervical spine bone marrow. A hypointense lesion is seen in the clivus, with some preservation of fatty marrow signal surrounding the hypointense lesion.

FIGURE 5 Axial T2-weighted images (A, through the ventricles; B, through the centrum semiovale) show multiple foci of white matter hyperintensity, many in the periventricular regions. No associated edema is seen. Some of lesions are elliptical in shape.

FIGURE 6 Enhanced T1-weighted axial series shows that most of the white matter lesions enhance. The predominant periventricular distribution is well seen here, with some of the linear and elliptical-shaped lesions oriented perpendicular to the long axis of the lateral ventricles.

FIGURE 7 Fat-saturated coronal, T1-weighted, enhanced image shows additional small, enhancing lesions in the subcortical left cerebellum.

TEACHING POINTS

The differential diagnosis of multiple enhancing intracranial lesions is long and includes neoplasms (metastases and primary CNS lymphoma), demyelinating processes (e.g., multiple sclerosis and acute disseminated encephalomyelitis), infection (e.g., cysticercosis, tuberculosis, histoplasmosis, toxoplasmosis), granulomatous processes (e.g., sarcoid), ischemia, and vasculitis. These multiple intracranial lesions represent a relatively unusual presentation of brain metastases, with morphology and distribution mimicking multiple sclerosis plaques. The features suggesting this include the relatively uniform size of the lesions, lack of significant associated edema, and the central periventricular distribution, rather than the more typical peripheral gray matter–white matter junction location favored by many hematogenous metastases.

In this case, a repeat study obtained 11 days later showed worsening, with edema now associated with left cerebellar lesions.

CASE 3 Brain metastases mimicking multiple sclerosis

A 38-year-old woman treated for breast cancer 2 years earlier developed episodes of visual disturbance, with scintillating scotomas. Enhanced brain MRI was abnormal, with multiple enhancing elliptical white matter lesions, without edema (Figures 1 and 2). A differential diagnosis of brain metastases versus demyelinating process (multiple sclerosis) was considered.

FIGURE 1 Axial FLAIR images through the ventricles (A) and centrum semiovale (B) show scattered, small, round to elliptical foci of white matter hyperintensity, without associated edema or mass effect.

FIGURE 2 Enhanced axial T1-weighted sequence, at the same level as Figure 1B, shows enhancement of the lesions.

The patient’s breast cancer was a stage II, T2N0, estrogen receptor– and progesterone receptor–positive, HER-2/neu positive, 2.5-cm left breast high-grade infiltrating ductal carcinoma with extensive ductal carcinoma in situ, which was treated with lumpectomy, chemotherapy (four cycles of doxorubicin [Adriamycin] and cyclophosphamide [Cytoxan]), and radiation. Zero of 6 lymph nodes were involved. At the time of evaluation for the visual disturbance, the patient had recently been diagnosed with liver, mediastinal, and bone metastases and was being treated for these with vinorelbine (Navelbine) and trastuzumab (Herceptin). A symptomatic left hip metastasis was prophylactically treated with an intramedullary femoral nail. Tissue from this procedure confirmed breast metastasis.

Repeat brain MRI 2 months later showed more numerous and larger enhancing brain lesions, with a more typical appearance for metastases than on the prior study (Figure 3).

FIGURE 3 Repeat brain MRI, 2 months later, at levels corresponding to Figures 1B and 2 (A, axial FLAIR; B, enhanced axial T1-weighted) shows the lesions to be larger, with collars of perilesional edema demonstrated on FLAIR. Multiple similar appearing new enhancing lesions are seen in addition.

A cervical and thoracic spine MRI was obtained at the time of the initial brain MRI to evaluate complaints of back pain. Spine MRI showed metastatic involvement of T4 (Figure 4), and the patient underwent T3-T5 radiation for palliation of symptoms.

FIGURE 4 Sagittal spine MRIs through the cervical and upper thoracic spine (A, T1-weighted, sagittal; B, T2-weighted sagittal; C, enhanced T1-weighted sagittal) show abnormal signal intensity at T4. This is most conspicuous on unenhanced T1-weighted imaging as loss of the normal bright fatty marrow signal. Expansion of the replaced vertebral body into the anterior epidural space is well seen on all sequences. Delineation of the mass effect and ventral impression on the cord are aided by use of T2-weighted imaging, in which CSF fluid signal is bright. Dural tails of enhancement associated with the bony and epidural metastasis are depicted on the enhanced T1-weighted sequence.

TEACHING POINTS

Intracranial lesions in patients with cancer histories most often represent brain metastases, although not invariably. The differential diagnosis includes primary brain neoplasia, infection, inflammation, infarction, and as raised in this case, demyelinating processes. In a randomized trial reported by Patchell and colleagues of 54 patients who underwent either surgery and radiation therapy compared with radiation therapy after needle biopsy for treatment of single brain metastases from a variety of primaries, 11% were found to have an alternative diagnosis on pathology.

Atypical imaging presentations may require biopsy or follow-up imaging to differentiate metastatic disease from other possibilities. This case initially was a surprisingly good imaging mimic for multiple sclerosis, with the lesions small and discrete, many being elliptical in shape, located in the deep white matter and lacking associated edema. The repeat study shows more typical metastatic findings, with the larger lesions now seen on FLAIR as isointense to parenchyma, with collars of perilesional edema. The interval growth and increase in number also are strong presumptive evidence of progressive metastatic disease.

The bone metastasis depicted here at T4 shows typical imaging features (see Figure 4). The bone lesion conspicuity, based on replacement of the normal fatty marrow signal, is greatest on T1-weighted images. Bone lesion conspicuity is comparatively poor with T2-weighting where the lesion is essentially isointense to other vertebral levels. The expansion of the replaced body into the epidural space and mass effect on the cord are well depicted against the bright cerebrospinal fluid (CSF) signal afforded by T2-weighted technique. Contrast enhancement also decreases the conspicuity of the bony lesion, although depiction of the epidural extent, associated dural enhancement, and mass effect on the cord are improved.

MRI protocols for evaluation of the spine need to be designed to detect most significant pathology. Bone metastases can generally be identified without contrast enhancement, and as demonstrated in this case, contrast enhancement can actually decrease the conspicuity of bone lesions. Protocols generally include a T1-weighted sequence and a fluid-sensitive sequence, either T2-weighted or short tau inversion recovery (STIR) sequence. Contrast enhancement, although not essential for the diagnosis of bone metastases, is necessary for complete evaluation of the spinal contents. This can be obtained with a fat-saturated, T1-weighted sequence to compensate for the decreased conspicuity of enhancing bone metastases.

TEACHING POINTS

Brain metastases generally are heralded by the development of symptoms, leading to further imaging, usually with enhanced brain MRI. This case is unusual in that brain metastases were first identified on whole-body PET in a neurologically asymptomatic breast cancer patient being treated for bone metastases. Visualization of brain metastases on a whole-body PET scan depends on the lesions being of sufficient size and hypermetabolism to be seen against the background of normal brain activity. As demonstrated in this case, this depends on the interpreter adjusting the intensity of brain to a much lower level than would be used for evaluating the rest of the scan. Although the yield is low, this case illustrates the utility of routinely including in one’s search pattern a review of the brain with the intensity threshold adjusted to a level at which one can “see through” the brain background activity. In this case, the patient presumably would have become symptomatic with growth of the lesions. This allowed early intervention.

How frequently are brain metastases identified on whole-body PET? The answer is: not often enough to justify inclusion of the brain in whole-body fluorodeoxyglucose (FDG) PET studies performed for staging purposes. Most of the information in the literature is derived from studies of lung cancer staging, but the same principles and limitations should apply to detection of breast cancer brain metastases. In general, even dedicated brain PET is not sensitive enough to be relied on over CT or MRI. A retrospective study of PET compared with enhanced brain MRI by Rohren and associates showed PET to identify only 61% of the metastases seen on MRI. The sensitivity of FDG PET for detecting brain metastases in this study was 75%, with specificity of 83%. Lesion size is a major factor in the ability of brain PET to depict metastases. The likelihood of detecting a 1-cm metastasis has been estimated to be 40%.

Although not biopsy-proven, the diagnosis is quite certain in this case. Multiplicity is a hallmark of metastases, and as demonstrated here, metastases can vary significantly in size, appearance, and presence or absence of associated edema. It is no surprise that many more lesions were seen on MRI than were suggested on PET. It is interesting to correlate the number, size, and appearance of brain metastases seen on PET versus MRI. The metastases seen on PET scan were the largest of the lesions confirmed on MRI. “Solidity” of a lesion also contributes to conspicuity on PET. The rim-enhancing, cystic metastasis seen only on brain MRI at the right temporal lobe level is similar in overall size to the more uniformly enhancing and solid metastasis at the left temporal level, which could be seen on both PET and MRI. This result is not surprising because the right temporal cystic lesion is less cellular, and would be expected to be less metabolically active than the more solid left temporal metastasis.

CASE 5 Unusual miliary pattern of brain metastases

A 57-year-old woman with locally recurrent and metastatic breast cancer to the pleura developed new symptoms of flashing visual disturbance, progressive lower extremity weakness, low back pain, nausea, occasional vomiting, and difficulty with balance.

Her original breast cancer was treated 9 years before with lumpectomy, axillary lymph node dissection, radiation, and chemotherapy. Her tumor was a poorly differentiated, 6.5-cm primary, estrogen receptor and progesterone receptor negative, HER-2/neu negative, with negative lymph nodes. She had a biopsy-proven local recurrence identified 1 year before, as well as biopsy-proven right pleural metastases. She had been treated with chemotherapy, with paclitaxel (Taxol) and bevacizumab (Avastin), with response clinically and by imaging.

Brain MRI obtained to evaluate the new neurologic symptoms showed an unusual pattern of metastases, with innumerable, tiny, miliary, enhancing nodules, concentrated in the cerebellum and scattered supratentorially (Figures 1, 2, 3, and 4). The patient was treated with whole-brain radiation therapy for palliation of symptoms.

FIGURE 1 Axial T2-weighted brain MRI shows subtle diffuse cerebellar parenchymal heterogeneity.

FIGURE 2 Enhanced, axial T1-weighted brain MRI shows innumerable, tiny, cerebellar foci of enhancement.

FIGURE 3 Enhanced, axial T1-weighted brain MRI through the lateral ventricles shows scattered, tiny enhancing parenchymal foci.

FIGURE 4 Fat-saturated, enhanced, coronal T1-weighted brain MRI shows the nearly confluent cerebellar enhancing metastases and comparatively rare, scattered, supratentorial metastases at the gray matter–white matter junction.

TEACHING POINTS

This is an unusual pattern of brain metastases, with innumerable tiny, enhancing foci without much associated edema. The scattered supratentorial distribution of lesions, favoring the gray matter–white matter junction, is fairly typical, but the disproportionate concentration of lesions in the cerebellum is distinctly unusual. The near confluency of the cerebellar lesions suggests leptomeningeal metastases as a possibility, although these lesions are more nodular than the typical appearance of leptomeningeal metastases.

CASE 6 Dural-based sphenoid wing metastasis with orbital extension

A 50-year-old woman with metastatic breast cancer to liver and bone developed lethargy and hallucinations while on medications for intractable pain. Her right breast infiltrating ductal carcinoma with 27 involved lymph nodes had been diagnosed 5 years earlier. She was treated with partial mastectomy, radiation, and chemotherapy.

Bone and liver metastases were detected 4 years after initial diagnosis and treatment for breast cancer. Severe intractable bone pain led to prophylactic pinning of the left hip along with radiation therapy, thoracic spine radiation, right hemipelvis and femoral radiation, prophylactic bilateral total shoulder replacements, and strontium therapy.

When the patient developed confusion, she was evaluated with a head CT scan. This suggested calvarial, but no definite brain, metastases (although the study was compromised by motion artifact). About 3 weeks later, the patient developed aphasia. A brain MRI showed extensive calvarial and dural metastases, with intraorbital extension, as well as parenchymal metastases (Figures 1, 2, and 3). Whole-brain radiation therapy was given, with marked improvement in the aphasia. The patient died a month later.

FIGURE 1 Axial T2-weighted MRI shows left temporal lobe edema. Abnormal hyperintense signal is seen within the left sphenoid bone. A heterogeneous mass extends into the left orbit.

FIGURE 2 Axial T1-weighted enhanced MRI, at the same level, shows thickening and enhancement of the middle cranial fossa dura bilaterally. Abnormal enhancement is seen of both sphenoid bones, as well as of smoothly marginated masses on the left, which protrude into the orbit and the middle cranial fossa. Diffuse edema is seen of the left temporal lobe, and a separate small, enhancing metastasis is seen in the left temporal lobe.

FIGURE 3 Axial T1-weighted enhanced MRI, inferior to Figure 2, shows enhancement and expansion of the replaced left sphenoid bone. Lesser changes are seen in the right sphenoid. A lobular left temporal lobe dural-based mass is associated with a “dural tail” of enhancement that extends posteriorly.

TEACHING POINTS

This case illustrates the predilection of breast cancer to involve multiple intracranial compartments (parenchyma, meninges, bone). This patient had known bone metastases for 4 years by the time she developed neurologic symptoms. Although there are brain parenchymal metastases, the sphenoid-centered process, with encroachment on the middle cranial fossa and the secondary vasogenic edema, presumably is the culprit lesion.

CASE 7 Plaque-like dural metastases

A 47-year-old woman with metastatic breast cancer to bone, thorax, liver, and ovary developed vertigo and headache. The patient presented with stage IV disease 3.5 years earlier, with bone marrow involvement, as well as imaging evidence of bone, hilar, and pleural metastases. Her primary was a 6-cm infiltrating ductal carcinoma, estrogen receptor positive, with 12 of 13 lymph nodes involved. Prior treatments included right mastectomy, chemotherapy, high-dose chemotherapy with autologous stem cell support, breast cancer vaccine, radiation therapy to the spine, and most recently, paclitaxel (Taxol).

Brain MRI obtained to evaluate new symptoms of vertigo and headache showed two small adjacent enhancing cortical foci in the right posterior parietal lobe, with overlying dural thickening (Figures 1 and 2). This unifocal disease site was treated with gamma knife therapy.

FIGURE 1 Axial enhanced, T1-weighted brain MRI shows adjacent foci of right posterior parietal cortical enhancement, with associated thickening and enhancement of the overlying dura (arrow). The patient was treated with gamma knife therapy for presumed brain metastases (no biopsy was performed). Note also the patchy enhancement in the diploic space, consistent with bone metastases.

FIGURE 2 Axial T2-weighted MRI, from the same study, at the same level as Figure 1, shows increased cortical signal at the same level as the enhancement seen in Figure 1. Note also the generalized white matter hyperintensity, attributable in this case to prior treatment with high-dose chemotherapy (see Case 9 in this chapter for another example).

Seven months later, the patient developed new expressive aphasia and recurrent headache, as well as mild right upper extremity tingling. An enhanced head CT showed new extra-axial enhancement on the left, with subjacent parenchymal edema and swelling and mild midline shift (Figure 3). A small, separate, round, enhancing metastasis was seen in the right cerebellum, near the transverse sinus. Contrast-enhanced brain MRI confirmed the findings, which were interpreted as extensive dural metastases, with a separate right cerebellar paren chymal metastasis and diffuse skull metastases (Figures 4 and 5). The patient was treated with high-dose dexamethasone (Decadron) and whole-brain radiation therapy, with nearly complete resolution of her expressive aphasia.

FIGURE 3 Seven months later, contrast-enhanced head CT shows new left posterior temporal extra-axial heterogeneous enhancement. Edema is noted in the subjacent brain parenchyma.

FIGURE 4 Axial brain MRIs at the same level as the CT scan in Figure 3 (A, enhanced T1-weighted; B, T2-weighted) show inhomogeneous extra-axial enhancement at the left temporoparietal level, with mass effect. The underlying edema is well seen on the T2-weighted image, and mass effect is seen as localized sulcal effacement and mild asymmetry of the sylvian fissure and lateral ventricular trigone. Skull metastases are seen as patchy areas of altered signal intensity in the diploic space, bright on T2 weighting and bright because of enhancement on T1-weighted, enhanced sequences.

FIGURE 5 Additional axial (A) and coronal (B) enhanced, T1-weighted brain MR images show heterogeneous left extra-axial enhancement, compressing the subjacent brain. The sulci are effaced at the involved levels, and there is mild midline shift to the right. In addition to the localized dural thickening, there is generalized mild thickening and diffuse enhancement of the dura. Diffuse skull metastases are again noted.

Repeat MRI was obtained 3 months later (2 months after whole-brain radiation) and showed improvement in the dural thickening, with resolution of the subjacent parenchymal edema (Figure 6).

FIGURE 6 Repeat brain MRI (A, axial enhanced, T1-weighted; B, coronal fat-saturated, enhanced, T1-weighted), 3 months later (2 months after administration of whole-brain radiation), shows decreased generalized dural enhancement. The more localized left extra-axial thickening and enhancement show improvement as well. The mass effect has resolved. Note the diffuse bright signal in the diploic space on the fat-saturated coronal image, owing to enhancement of extensive skull metastases.

Six months later, the patient developed jaundice, and progressive liver metastases were confirmed. She was referred to hospice, and died soon thereafter.

TEACHING POINTS

As is typical, this patient developed brain metastases late in the course of her disease. In this case, clinical symptoms of brain metastases developed 3.5 years after her initial diagnosis of breast cancer, which initially presented with stage IV disease, metastatic to thorax and bone. The median interval between the diagnosis of breast cancer and brain metastases is 34 months.

This case is another illustration of the propensity of breast cancer, more than other tumors, to involve multiple intracranial compartments (parenchyma, meninges, bone) simultaneously. Although this patient had in the course of her disease at least one typical cerebellar parenchymal metastasis (not shown), most of her intracranial metastases manifested in less typical ways. Her presenting cerebral disease was unusual in appearance, not typical for parenchymal metastases, and unusually localized for leptomeningeal disease. This could be superficial parenchymal metastases, which secondarily involved the overlying dura, but more likely, this is leptomeningeal metastatic disease, or carcinomatous meningitis. Whatever its epicenter, this focus was suitable for local therapy with stereotactic radiosurgery (SRS). The lesion is small and localized, with no contraindications for SRS (<3 cm, minimal associated edema). SRS is noninvasive and delivers a high additive lethal radiation dose to a tumor by application of intersecting radiation beams to a target lesion. This largely spares the surrounding brain, which receives a considerably smaller dose. It typically is administered as a single treatment, as an outpatient. Gamma knife therapy, which this patient received, is a form of SRS.

When this patient relapsed in the central nervous system (CNS) 7 months later, her intracranial disease again manifested in a relatively unusual but recognized manner, forming a plaque-like dural-based mass that locally compressed and invaded the underlying cerebrum, inducing vasogenic edema. Dural-based metastases may be mass-like and nodular, or flattened and plaque-like as this case illustrates, and can mimic meningiomas and subdural collections.

The more diffuse dural enhancement noted in this case could reflect diffuse dural metastatic disease or be reactive. The extent of the dural process and presence of edema were considered in the decision to treat with whole-brain radiation. After whole-brain radiation, the plaque-like dural-based mass decreased in thickness and much of the diffuse dural enhancement resolved. The vasogenic edema associated with the dural-based mass also resolved. The patient had an excellent clinical response, with nearly complete resolution of her presenting expressive aphasia. It is worth noting that administration of whole-brain radiation therapy decreases the incidence of subsequent CNS relapse and neurologic death.

CASE 8 Skull metastases with extracranial and intracranial extension

A 69-year-old woman with stage IV metastatic breast cancer developed new weakness of right upper and lower extremities, and a mild headache. The patient had known skull metastases with scalp and dural-based components. These had been identified on brain MRI 9 months earlier when she developed forgetfulness and slurring of words. At that time, she was evaluated for radiation therapy, but deferred because her measurable disease (scalp masses) appeared to be responding to systemic therapy, her symptoms were mild, and there was concern that scalp radiation could compromise future whole-brain radiation. The patient had known extensive bony metastatic disease diagnosed 6 years earlier, and for which she had undergone palliative radiation to the pelvis and hips, as well as systemic treatment with samarium. Her original diagnosis of left breast cancer was 18 years before the onset of central nervous system (CNS) metastases. This was a T1cN1M0, left 1.9-cm infiltrating ductal carcinoma with 1 of 20 lymph nodes involved. She was treated with mastectomy as well as breast and regional lymphatic radiation.

When the patient developed symptoms of right-sided weakness, repeat brain MRI was obtained, which showed progression of metastases and increased mass effect and edema (Figures 1, 2, and 3). She was treated with dexamethasone and palliative whole-brain radiation therapy (WBRT) but had continued deterioration, with limited use of her right arm and inability to walk. Systemic therapy was discontinued in favor of hospice care.

FIGURE 1 Sagittal, T1-weighted MRI shows diffuse hypointensity of the calvarium. At the right frontal level, there is edema as well as a subgaleal mass.

FIGURE 2 Axial brain MRIs from the same level (A, FLAIR; B, T2-weighted; C, enhanced, T1-weighted) shows a lobular, right frontal dural-based enhancing mass, with a similar-appearing subgaleal mass overlying the calvarium at the same level. The skull is extremely hypointense at this level, but patchy areas of enhancement are seen within the diploic space elsewhere. Edema accompanying the right frontal metastasis is seen on FLAIR and T2 weighting, as is edema at the left parietal level from another lesion (illustrated in Figure 3).

FIGURE 3 Brain MRIs showing the vertex (A, T2-weighted axial; B, enhanced, T1-weighted axial; C, fat-saturated, coronal, enhanced, T1-weighted) where a similar-appearing mass centered on the skull shows protruding extracranial (scalp) and intracranial (dural-based) components. The underlying brain is compressed and infiltrated. Left temporal cystic encephalomalacia seen in C was due to a remote and unrelated history of surgery for intracranial hemorrhage.

TEACHING POINTS

Although the dural-based component of these metastases resembles Case 7, the epicenter of disease in this case is in the skull, from which expansile soft tissue components extend into the scalp and intracranially, infiltrating the dura and underlying brain. This patient had known extensive, refractory bone metastases for 6 years before developing CNS symptoms.

The timing of radiation therapy or other interventions for CNS metastases must take into account the patient’s overall functional status as well as the level of control of her systemic disease. In this case, the patient had disease (palpable scalp masses) that could be monitored clinically to assess response to systemic therapy, and at initial presentation, she was minimally symptomatic. Because she appeared to be responding to systemic therapy with declining size of the scalp masses, radiation therapy to the scalp was deferred out of concern that it could compromise future whole-brain irradiation. When her symptoms progressed to the point at which radiation was necessary, she had little clinical response. These neurologic developments proved to be terminal for this patient.

CASE 9 Skull metastasis and chemotherapy-induced leukoencephalopathy

A 59-year-old woman with a history of premenopausal breast cancer presented for medical oncologic evaluation for possible metastatic disease. Her breast cancer history had been 10 years before, presenting as a large palpable left breast mass. She was treated with neoadjuvant chemotherapy (two cycles of Cytoxan, methotrexate, 5-fluorouracil (CMF), followed by one cycle of Cytoxan, Adriamycin, 5-fluorouracil (CAF) with clinical response, followed by high-dose chemotherapy with cyclophosphamide (Cytoxan), cisplatin, and bischlorethylnitrosourea (BCNU), with stem cell rescue. Mastectomy and flap reconstruction were performed. The pathology specimen showed a 6-cm infiltrating lobular carcinoma (ILC), estrogen receptor positive, progesterone receptor negative. Six of 10 lymph nodes were involved. Chest wall radiation was performed. She declined tamoxifen therapy.

A month before presentation, the patient developed left back pain, radiating laterally and to the front of the chest. A bone scan was abnormal at multiple levels, including T5, T11, the skull, and right humerus.

Oncologic evaluation included tumor markers, which were elevated (CEA and CA 27.29). Positron emission tomography (PET) and CT imaging showed hypermetabolic mediastinal and hilar adenopathy and bone metastases (see Case 7 in Chapter 8). The patient had been noted to be hoarse on physical examination, and PET showed asymmetrical muscular activity of the vocal cords.

Fine-needle aspiration was performed of a mediastinal lymph node, confirming metastatic disease, which was estrogen receptor and progesterone receptor positive, HER-2/neu negative. Radiation therapy was begun to the spine for palliation of pain. The patient developed nausea during radiation therapy.

Brain MRI obtained to evaluate the nausea showed no focal intracranial lesions or enhancement to suggest brain parenchymal metastases. There was instead extensive, confluent, symmetrical white matter hyperintensity, or leukoencephalopathy, seen on fluid-sensitive sequences (Figure 1). Skull metastases were also seen, including the right frontal level (Figures 2, 3, and 4).