Imaging of Brain Cancer 6

6

Imaging of Brain Cancer

Soonmee Cha

I. Who should undergo imaging to exclude brain cancer?

A. Applicability to children

II. What is the appropriate imaging in subjects at risk for brain cancer?

A. Applicability to children

B. Special case: can imaging be used to differentiate posttreatment necrosis from residual tumor?

C. Special case: neuroimaging modality in patients with suspected brain metastatic disease

D. Special case: how can tumor be differentiated from tumor- mimicking lesions?

III. What is the role of proton magnetic resonance spectroscopy (MRS) in the diagnosis and follow-up of brain neoplasms?

IV. What is the cost-effectiveness of imaging in patients with suspected primary brain neoplasms or brain metastatic disease?

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Issues

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Brain imaging is necessary for optimal localization, characterization, and management of brain cancer prior to surgery in patients with sus- pected or confirmed brain tumors (strong evidence).

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Due to its superior soft tissue contrast, multiplanar capability, and biosafety, magnetic resonance imaging (MRI) with and without gadolinium-based intravenous contrast material is the preferred method for brain cancer imaging when compared to computed tomography (moderate evidence).

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No adequate data exist on the role of imaging in monitoring brain cancer response to therapy and differentiating between tumor recur- rence and therapy related changes (insufficient evidence).

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No adequate data exist on the role of nonanatomic, physiology-based imaging, such as proton magnetic resonance spectroscopy (MRS), per- fusion and diffusion MRI, and nuclear medicine imaging [single photon emission computed tomography (SPECT) and positron emis- sion tomography (PET)] in monitoring treatment response or in pre-

Key Points

dicting prognosis and outcome in patients with brain cancer (insuffi- cient evidence).

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Human studies conducted on the use of MRS for brain tumors demon- strate that this noninvasive method is technically feasible, and suggest potential benefits for some of the proposed indications. However, there is a paucity of high-quality direct evidence demonstrating the impact on diagnostic thinking and therapeutic decision making.

Definition and Pathophysiology

The term brain cancer, which is more commonly referred to as brain tumor, is used here to describe all primary and secondary neoplasms of the brain and its covering, including the leptomeninges, dura, skull, and scalp. Brain cancer comprises a variety of central nervous system tumors with a wide range of histopathology, molecular/genetic profile, clinical spectrum, treat- ment possibilities, and patient prognosis and outcome. The pathophysiol- ogy of brain cancer is complex and dependent on various factors, such as histology, molecular and chromosomal aberration, tumor-related protein expression, primary versus secondary origin, and host factors (1–4).

Unique Challenges of Brain Cancer

When compared to systemic cancers (e.g., lung, breast, colon), brain cancer is unique in several ways. First, the brain is covered by a tough, fibrous tissue, the dura matter, and a bony skull that protects the inner contents.

This rigid covering allows very little, if any, increase in volume of the inner content, and therefore brain tumor cells adapt to grow in a more infiltra- tive rather than expansive pattern. This growth pattern limits the disrup- tion to the underlying cytoarchitecture. Second, the brain capillaries have a unique barrier known as the blood—brain barrier (BBB), which limits the entrance of systemic circulation into the central nervous system. Cancer cells can hide behind the protective barrier of the BBB, migrate with minimal disruption to the structural and physiologic milieu of the brain, and escape imaging detection since an intravenous contrast agent becomes visible when there is BBB disruption, allowing the agent to leak into the interstitial space (5–9).

Epidemiology

Primary malignant or benign brain cancers were estimated to be newly

diagnosed in about 35,519 Americans in 2001 [Central Brain Tumor

Registry of the United States (10). Primary brain cancers are among the top

10 causes of cancer-related deaths (11). Nearly 13,000 people die from these

cancers each year in the United States (CBTRUS, 2000). About 11 to 12 per

100,000 persons in the U.S. are diagnosed with a primary brain cancer each

year, and 6 to 7 per 100,000 are diagnosed with a primary malignant brain

cancer. Almost one in every 1300 children will develop some form of

primary brain cancer before age 20 years (11). Between 1991 and 1995, 23%

of childhood cancers were brain cancers, and about one fourth of child- hood cancers deaths were from a malignant brain tumor.

The epidemiologic study of brain cancer is challenging and complex due to a number of factors unique to this disease. First, primary and secondary brain cancers are vastly different diseases that clearly need to be differen- tiated and categorized, which is an inherently difficult task. Second, histopathologic classification of brain cancer is complicated due to the het- erogeneity of the tumors at virtually all levels of structural and functional organization such as differential growth rate, metastatic potential, sensi- tivity irradiation and chemotherapy, and genetic lability. Third, several brain cancer types have benign and malignant variants with a continuous spectrum of biologic aggressiveness. It is therefore difficult to assess the full spectrum of the disease at presentation (12).

The most common primary brain cancers are tumors of neuroepithelial origin, which include astrocytomas, oligodendrogliomas, mixed gliomas (oligoastrocytomas), ependymomas, choroids plexus tumors, neuroepithe- lial tumors of uncertain origin, neuronal and mixed neuronal-glial tumors, pineal tumors, and embryonal tumors. The most common type of primary brain tumor that involves the covering of the brain (as opposed to the substance) is meningioma, which accounts for more than 20% of all brain tumors (13). The most common type of primary brain cancer in adults is glioblastoma multiforme. In adults, brain metastases far outnumber primary neoplasms owing to the high incidence of systemic cancer (e.g., lung and breast carcinoma).

The incidence rate of all primary benign and malignant brain tumors based on CBTRUS is 14.0 cases per 100,000 person-years (5.7 per 100,000 person-years for benign tumors and 7.7 person-years for malignant tumors). The rate is higher in males (14.2 per 100,000 person-years) than in females (13.9 per 100,000 person-years). According to the Surveillance, Epidemiology, and End Results (SEER) program, the 5-year relative survival rate following the diagnosis of a primary malignant brain tumor (excluding lymphoma) is 32.7% for males and 31.6% for females. The prevalence rate for all primary brain tumors based on CBTRUS (11) is 130.8 per 100,000, and the estimated number of people living with a diagnosis of primary brain tumors was 359,000 persons. Two-, 5-, and 10-year observed and relative survival rates for each specific type of malignant brain tumor, according to the SEER report from 1973 to 1996, showed that glioblastoma multiforme (GBM) has the poorest prognosis. More detailed information on the brain cancer survival data is available at the CBTRUS Web site (http://www.cbtrus.org/2001/table2001_12.htm).

In terms of brain metastases, the exact annual incidence remains unknown due to a lack of a dedicated national cancer registry but is estimated to be 97,800 to 170,000 new cases each year in the U.S. The most common types of primary cancer causing brain metastasis are cancers of the lung, breast, unknown primary, melanoma, and colon.

Overall Cost to Society

Brain cancer is a rare neoplasm but affects people of all ages (11). It is more

common in the pediatric population and tends to cause high morbidity and

mortality (14). The overall cost to society in dollar amount is difficult to

estimate and may not be as high as other, more common systemic cancers.

The cost of treating brain cancer in the U.S. is difficult to determine but can be estimated to be far greater than $4 billion per year based on the estimated number of people living with brain cancer (359,000, as cited above; CBTRUS) and $11,365.23 per patient for initial cost of surgical treatment. There are very few articles in the literature that address the cost-effectiveness or overall cost to society in relation to imaging of brain cancer. One of the few articles that discusses the actual monetary cost to society is by Latif et al. (15) from Great Britain. They assessed the mean costs of medical care for 157 patients with brain cancer. Based on this study, the average cost of imaging was less than 3% of the total, whereas radio- therapy was responsible for greater than 50% of the total cost. The relative contribution of imaging in this study appears low, however, and what is not known from this report is what kind of imaging was done in these patients with brain cancer during their hospital stay and as outpatients, and how often it was done. In addition, the vastly different health care reimbursement structure in Britain and the U.S. makes interpretation difficult.

Goals of Neuroimaging

The goals of imaging in patients with suspected brain cancer are (1) diagnosis at acute presentation, (2) preoperative or treatment planning to further characterize brain abnormality, and (3) posttreatment evaluation for residual disease and therapy-related changes. The role of imaging is critical dependent on the clinical context that the study is being ordered (16). The initial diagnosis of brain cancer is often made based on a com- puted tomography (CT) scan in an emergency room setting when a patient presents with an acute clinical symptom such as seizure or focal neurologic deficit. Once a brain abnormality is detected on the initial scan, MRI with contrast agent is obtained to further characterize the lesion and the remain- der of the brain and to serve as a part of preoperative planning for a defin- itive histologic diagnosis. If the nature of the brain lesion is still in question after comprehensive imaging, further imaging with advanced techniques such as diffusion, perfusion, or proton spectroscopic imaging may be war- ranted to differentiate brain cancer from tumor-mimicking lesions such as infarcts, abscesses, or demyelinating lesions (17–19). In the immediate postoperative imaging, the most important imaging objectives are to (1) determine the amount of residual or recurrent disease; (2) assess early postoperative complications such as hemorrhage, contusion, or other brain injury; and (3) determine delay treatment complications such as radiation necrosis and treatment leukoencephalopathy.

Methodology

A Medline search was performed using PubMed (National Library of

Medicine, Bethesda, Maryland) for original research publications dis-

cussing the diagnostic performance and effectiveness of imaging strategies

in brain cancer. Systematic literature review was performed from 1966

through August 2003. Key words included are (1) brain cancer, (2) brain

tumor, (3) glioma, (4) diagnostic imaging, and (5) neurosurgery. In addition, the following three cancer databases were reviewed:

1. The SEER program maintained by the National Cancer Institute (www.seer.cancer.gov) for incidence, survival, and mortality rates, classi- fied by tumor histology, brain topography, age, race, and gender. The SEER is a population-based reference standard for cancer data, and it collects incidence and follow-up data on malignant brain cancer only.

2. The CBTRUS (www.cbtrus.org) collects incidence data on all primary brain tumors from 11 collaborating state registries; however, follow-up data are not available.

3. The National Cancer Data Base (NCDB) (www.facs.org/cancer/ncdb) serves as a comprehensive clinical surveillance resource for cancer care in the U.S. While not population-based, the NCDB identifies newly diag- nosed cases and conducts follow-up on all primary brain tumors from hos- pitals accredited by the American College of Surgeons. The NCDB is the largest of the three databases and also contains more complete information regarding treatment of tumors than either the SEER or CBTRUS databases.

I. Who Should Undergo Imaging to Exclude Brain Cancer?

Summary of Evidence: The scientific evidence on this topic is limited. No strong evidence studies are available. Most of the available literature is classified as limited and moderate evidence. The three most common clin- ical symptoms of brain cancer are headache, seizure, and focal weakness—

all of which are neither unique nor specific for the presence of brain cancer (see Chapters 10 and 11). The clinical manifestation of brain cancer is heavily dependent on the topography of the lesion. For example, lesions in the motor cortex may have more acute presentation, whereas more insid- ious onset of cognitive or personality changes are commonly associated with prefrontal cortex tumors (20,21).

Despite the aforementioned nonspecific clinical presentation of subjects with brain cancer, Table 6.1 lists the clinical symptoms suggestive of brain

Table 6.1. Clinical symptoms suggestive of a brain cancer

Nonmigraine, nonchronic headache of moderate to severe degree (see Chapter 10)

Partial complex seizure (see Chapter 11) Focal neurologic deficit

Speech disturbance

Cognitive or personality change Visual disturbance

Altered consciousness Sensory abnormalities Gait problem or ataxia

Nausea and vomiting without other gastrointestinal illness

Papilledema Cranial nerve palsy

cancer. A relatively acute onset of any one of these symptoms that pro- gresses over time should strongly warrant brain imaging.

Supporting Evidence: It remains difficult, however, to narrow down the criteria for the “suspected” clinical symptomatology of brain cancer. In a retrospective study of 653 patients with supratentorial brain cancer, Salcman (22) found that the most common clinical features of brain cancer were headache (70%), seizure (54%), cognitive or personality change (52%), focal weakness (43%), nausea or vomiting (31%), speech disturbances (27%), alteration of consciousness (25%), sensory abnormalities (14%), and visual disturbances (8%) (moderate evidence). Similarly, Snyder et al. (23) studied 101 patients who were admitted to the emergency department and discharged with a diagnosis of brain cancer (moderate evidence). They found that the most frequent clinical features were headache (55%), cog- nitive or personality changes (50%), ataxia (40%), focal weakness (36%), nausea or vomiting (36%), papilledema (27%), cranial nerve palsy (25%), seizure (24%), visual disturbance (20%), speech disturbance (20%), sensory abnormalities (18%), and positive Babinski sign (17%). No combination of these factors has been shown to reliably differentiate brain cancer from other benign causes.

A. Applicability to Children

Brain cancers in childhood differ significantly from adult lesions in their

sites of origin, histological features, clinical presentations, and likelihood

to disseminate throughout the nervous system early in the course of

disease. As succinctly summarized by Hutter et al. (24), there are vast dif-

ferences in epidemiology, topography, histology, and prognosis of brain

cancer between adults and children. Whereas the great majority of adult

tumors arise in the cerebral cortex, about half of childhood brain cancers

originate infratentorially—in the cerebellum, brainstem, or fourth ventri-

cular region. Brain metastasis from systemic cancer is rare in children,

whereas it is common in adults owing to the preponderance of systemic

cancer (lung and breast being the two most common). Metastatic cancers

in childhood mainly represent leptomeningeal dissemination from a

primary brain lesion (25) such as medulloblastoma, pineoblastoma, or ger-

minoma—hence the importance of imaging the entire neuroaxis in these

patients (i.e., brain and entire spine). The incidence of primary brain cancer

in children is most common from birth to age 4 years; the vast majority of

histologic types are medulloblastomas and juvenile pilocytic astrocytomas

(JPAs). Headache, posterior fossa symptoms (such as nausea and vomit-

ing), ataxia, and cranial nerve symptoms predominate in children due to

the fact that about half of pediatric brain cancer occurs infratentorially

(12,25,26). Nonmigraine, nonchronic headache in a child should raise a

high suspicion for an intracranial mass lesion, especially if there are any

additional posterior fossa symptoms, and imaging should be conducted

without delay (see Chapter 10).

II. What Is the Appropriate Imaging in Subjects at Risk for Brain Cancer?

Summary of Evidence: The sensitivity and specificity of MRI is higher than that of CT for brain neoplasms (moderate evidence). Therefore, in high- risk subjects suspected of having brain cancer, MRI with and without gadolinium-based contrast agent is the imaging modality of choice to further characterize the lesion. Table 6.2 lists the advantages and limita- tions of CT and MRI in the evaluation of subjects with suspected brain cancer.

There is no strong evidence to suggest that the addition of other diag- nostic tests, such as MRS, perfusion MR, PET, or SPECT, improves either the cost-effectiveness or the outcome in the high-risk group at initial presentation.

Supporting Evidence: Medina et al. (27) found in a retrospective study of 315 pediatric patients that overall, MRI was more sensitive and specific than CT in detecting intracranial space-occupying lesions (92% and 99%, respectively, for MRI versus 81% and 92%, respectively, for CT). However, no difference in sensitivity and specificity was found in the surgical space- occupying lesions (27). Table 6.3 lists the sensitivity and specificity of MRI and CT for brain cancer as outlined by Hutter et al. (24).

There has been a tremendous progress in research involving various brain radiotracers, which provide the valuable functional and metabolic pathophysiology of brain cancer. Yet the question remains as to how best to incorporate radiotracer imaging methods into diagnosis and manage- ment of patients with brain cancer. The most widely used radiotracer imaging method in brain cancer imaging is

thalium SPECT. Although very purposeful, it has a limited role in initial diagnosis or predicting the degree of brain cancer malignancy. Positron emission tomography using

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F-2-fluoro-2-deoxy-d-glucose (FDG) radiotracer can be useful in differ- entiating recurrent brain cancer from radiation necrosis, but similarly to SPECT its ability as an independent diagnostic and prognostic value above that of MRI and histology is debatable (28). There is limited evidence per-

Table 6.2. Advantages and limitations of computed tomography (CT) and magnetic resonance imaging (MRI)

Advantages Limitations

CT Widely available Inferior soft tissue

Short imaging time resolution

Lower cost Prone to artifact in posterior

Excellent for detection of acute fossa

hemorrhage or bony abnormality Ionizing radiation

Risk of allergy to iodinated contrast agent

MRI Multiplanar capability Higher cost

Superior soft tissue resolution Not as widely available No ionizing radiation Suboptimal for detection of Safer contrast agent acute hemorrhage or

(gadolinium-based) profile bony/calcific abnormality

taining to perfusion MRI in tumor diagnosis and grading despite several articles proposing its useful role. Similar to proton MRS (see issue III, below), perfusion MRI remains an investigational tool at this time pending stronger evidence proving its effect on health outcomes of patients with brain cancer.

A. Applicability to Children

In children with aggressive brain cancer such as medulloblastoma or ependymoma, special attention should be paid to the entire craniospinal axis to evaluate drop metastasis. Neuroimaging of the entire craniospinal axis should be done prior to the initial surgery in order to avoid post- surgical changes complicating the evaluation. Magnetic resonance imaging with gadolinium-based contrast agent is the modality of choice to look for enhancement along the leptomeningeal surface of the spinal cord (29,30).

B. Special Case: Can Imaging Be Used to Differentiate Posttreatment Necrosis from Residual Tumor?

Imaging differentiation of treatment necrosis and residual/recurrent tumor is challenging because they can appear similar and can coexist in a single given lesion. Hence the traditional anatomy-based imaging methods have a limited role in the accurate differentiation of the two entities. Nuclear medicine imaging techniques such as SPECT and PET provide functional information on tissue metabolism and oxygen consumption and thus offer a theoretical advantage over anatomic imaging in differentiation tissue necrosis and active tumor. Multiple studies demonstrate that SPECT is more sensitive and specific than is PET in differentiating tumor recurrence from radiation necrosis (24) (Table 6.2). There is also insufficient evidence of the role of MRS for this tumor type (see issue III, below).

Table 6.3. Sensitivity and specificity of brain tumor imaging

cancer Imaging modality Sensitivity (%) Specificity (%) Primary brain MRI with contrast Gold standard —

cancer CT with contrast 87 79

Primary brain cancer MRI 92 99

in children (27) CT 81 92

Brain metastasis MRI with single dose 93–100 — contrast

MRI without contrast 36 —

201Tl SPECT 70 —

18FDG PET 82 38

Recurrent tumor vs. ²⁰¹Tl SPECT 92 88

treatment related ¹⁸FDG PET

necrosis MRI with co- 86 80

registration

MRI without co- 65 80

registration

Source: Adapted from Hutter et al. (24), with permission from Elsevier.

C. Special Case: Neuroimaging Modality in Patients with Suspected Brain Metastatic Disease

Brain metastases are far more common than primary brain cancer in adults owing to the higher prevalence of systemic cancers and their propensity to metastasize (31–33). Focal neurologic symptoms in a patient with a history of systemic cancer should raise high suspicion for intracranial metastasis and prompt imaging. The preferred neuroimaging modality in patients with suspected brain metastatic disease is MRI with a single dose (0.1 mmol/kg body weight) of gadolinium-based contrast agent. Most studies described in the literature suggest that contrast-enhanced MRI is superior to contrast- enhanced CT in the detection of brain metastatic disease, especially if the lesions are less than 2 cm (moderate evidence).

Davis and colleagues (34) assessed imaging studies in 23 patients, com- paring contrast-enhanced MRI with double dose-delayed CT (moderate evidence). Contrast-enhanced MRI demonstrated more than 67 definite or typical brain metastases. The double dose-delayed CT revealed only 37 metastatic lesions. The authors concluded that MRI with enhancement is superior to double dose-delayed CT scan for detecting brain metastasis, anatomic localization, and number of lesions. Golfieri and colleagues (35) reported similar findings (moderate evidence). They studied 44 patients with small-cell carcinoma to detect cerebral metastases. All patients were studied with contrast-enhanced CT scan and gadolinium-enhanced MRI;

43% had cerebral metastases. Both contrast-enhanced CT and gadolinium- enhanced MRI detected lesions greater than 2 cm. For lesions smaller than 2 cm, 9% were detected only by gadolinium-enhanced T1-weighted images. The authors concluded that gadolinium-enhanced T1-weighted images remain the most accurate technique in the assessment of cerebral metastases. Sze and colleagues (36) performed prospective and retrospec- tive studies in 75 patients (moderate evidence). In 49 patients, MRI and contrast-enhanced CT were equivalent. In 26 patients, however, the results were discordant, with neither CT nor MRI being consistently superior; MRI demonstrated more metastases in 9 of these 26 patients. Contrast-enhanced CT, however, better depicted lesions in eight of 26 patients.

There are several reports on using a triple dose of contrast agent to increase the sensitivity of lesion detection (37,38). Another study by Sze et al. (39), however, found that routine triple-dose contrast agent admin- istration in all cases of suspected brain metastasis was not helpful, and could lead to an increasing number of false-positive results. The authors concluded that the use of triple-dose contrast material is beneficial in selected cases with equivocal findings or solitary metastasis. Their study was based on 92 consecutive patients with negative or equivocal findings or a solitary metastasis on single-dose contrast-enhanced MRI who under- went triple-dose studies.

D. Special Case: How Can Tumor Be Differentiated from Tumor-Mimicking Lesions?

There are several intracranial disease processes that can mimic brain cancer

and pose a diagnostic dilemma on both clinical presentation and conven-

tional MRI (16,40–44), such as infarcts, radiation necrosis, demyelinat-

ing plaques, abscesses, hematomas, and encephalitis. On imaging, any one

of these lesions and brain cancer can both demonstrate contrast enhance- ment, perilesional edema, varying degrees of mass effect, and central necrosis.

There are numerous reports in the literature of misdiagnosis and mis- management of these subjects who were erroneously thought to have brain cancer and, in some cases, went on to surgical resection for histopathologic confirmation (15,43,45). Surgery is clearly contraindicated in these subjects and can lead to an unnecessary increase in morbidity and mortality. A large acute demyelinating plaque, in particular, is notorious for mimicking an aggressive brain cancer (43,46–49). Due to the presence of mitotic figures and atypical astrocytes, this uncertainty occurs not only on clinical pre- sentation and imaging but also on histopathologic examination (44). The consequence of unnecessary surgery in subjects with tumor-mimicking lesions can be quite grave, and hence every effort should be made to differentiate these lesions from brain cancer.

Anatomic imaging of the brain suffers from nonspecificity and its inabil- ity to differentiate tumor from tumor-mimicking lesions (15). Recent devel- opments in nonanatomic, physiology-based MRI methods, such as diffusion/perfusion MRI and proton spectroscopic imaging, promise to provide information not readily available from structural MRI and thus improve diagnostic accuracy (50,51).

Diffusion-weighted MRI has been shown to be particularly helpful in differentiating cystic/necrotic neoplasm from brain abscess by demon- strating marked reduced diffusion within an abscess. Chang et al. (52) com- pared diffusion-weighted imaging (DWI) and conventional anatomic MRI to distinguish brain abscesses from cystic or necrotic brain tumors in 11 patients with brain abscesses and 15 with cystic or necrotic brain gliomas or metastases. They found that postcontrast T1-weighted imaging yielded a sensitivity of 60%, a specificity of 27%, a positive predictive value (PPV) of 53%, and a negative predictive value (NPV) of 33% in the diagnosis of necrotic tumors. Diffusion-weighted imaging yielded a sensitivity of 93%, a specificity of 91%, a PPV of 93%, and a NPV of 91%. Based on the analy- sis of receiver operating characteristic (ROC) curves, they found a clear advantage for DWI as a diagnostic tool in detecting abscesses when com- pared to postcontrast T1-weighted imaging.

Table 6.4 lists lesions that can mimic brain cancer both on clinical grounds and on imaging. By using diffusion-weighted imaging, acute infarct and abscess could readily be distinguished from brain cancer because of the reduced diffusion seen with the first two entities (52–56).

Highly cellular brain cancer can have reduced diffusion but not to the same degree as acute infarct or abscess (57).

Table 6.4. Brain cancer mimicking lesions

Radiation necrosis Abscess

Demyelinating plaque Subacute hematoma Encephalitis

III. What Is the Role of Proton Magnetic Resonance Spectroscopy (MRS) in the Diagnosis and Follow-Up of Brain Neoplasms?

Summary of Evidence: The Blue Cross–Blue Shield Association (BCBSA) Medical Advisory Panel concluded that the MRS in the evaluation of sus- pected brain cancer did not meet the Technology Evaluation Center (TEC) criteria as a diagnostic test, hence further studies in a prospectively defined population are needed.

Supporting Evidence: Recently, BCBSA Medical Advisory Panel made the following judgments about whether

H MRS for evaluation of suspected brain tumors meets the BCBSA TEC criteria based on the available evidence (58). The advisory panel reviewed seven published studies that included up to 271 subjects (59–65). These seven studies were selected for inclusion in the review of evidence because (1) the sample size was at least 10; (2) the criteria for a positive test were specified; (3) there was a method to confirm

H MRS diagnosis; and (4) the report provided sufficient data to calculate diagnostic test performance (sensitivity and specificity).

The reviewers specifically addressed whether

H MRS for evaluation of suspected brain tumors meets the following five TEC criteria:

1. The technology must have approval from the appropriate governmen- tal regulatory bodies.

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

3. The technology must improve the net health outcomes.

4. The technology must be as beneficial as any established alternatives.

5. The improvement must be attainable outside the investigational settings.

With the exception of the first criterion, the reviewers concluded that the available evidence on

H MRS in the evaluation of brain neoplasm was insufficient. The TEC also concluded that the overall body of evidence does not provide strong and consistent evidence regarding the diagnostic test characteristics of MRS in determining the presence or absence of brain neo- plasm, both for differentiation of recurrent/residual tumor vs. delayed radiation necrosis (65) and for diagnosis of brain tumor versus other non- tumor diagnosis (59,60,62,64). Assessment of the health benefit of MRS in avoiding brain biopsy was evaluated in two studies (59,64), but the studies had limitations. However, other human studies conducted on the use of MRS for brain tumors demonstrate that this noninvasive method is techni- cally feasible and suggest potential benefits for some of the proposed indi- cations. But there is a paucity of high-quality direct evidence demonstrating the impact on diagnostic thinking and therapeutic decision making.

IV. What Is the Cost-Effectiveness of Imaging in Patients with Suspected Primary Brain Neoplasms or Brain Metastatic Disease?

Summary of Evidence: Routine brain CT in all patients with lung cancer has a cost-effectiveness ratio of $69,815 per quality-adjusted life year (QALY).

However, the cost per QALY is highly sensitive to variations in the nega-

tive predictive value of a clinical evaluation, as well as to the cost of CT.

Cost-effectiveness analysis (CEA) of patients with headache suspected of having a brain neoplasm are presented in Chapter 10.

Supporting Evidence: In a study in the surgical literature, Colice et al. (64) compared the cost-effectiveness of two strategies for detecting brain metas- tases by CT in lung cancer patients: (1) routine CT for all patients irre- spective of clinical (neurologic, hematologic) evidence of metastases (CT first); and (2) CT for only those patients in whom clinical symptoms devel- oped (CT deferred). For a hypothetical cohort of patients, it was assumed that all primary lung carcinomas were potentially resectable. If no brain metastasis were detected by CT, the primary lung tumor would be resected. Brain metastasis as detected by CT would disqualify the patient for resection of the primary lung tumor. Costs were taken from the payer’s perspective and based on prevailing Medicare payments. The rates of false- positive and false-negative findings were also considered in the calculation of the effectiveness of CT. The cost of the CT-first strategy was $11,108 and the cost for the CT-deferred strategy $10,915; however, the CT-first strat- egy increased life expectancy by merely 1.1 days. Its cost-effectiveness ratio was calculated to be $69,815 per QALY. The cost per QALY is highly sen- sitive to variations in the negative predictive value of a clinical evaluation, as well as to the cost of CT. This study is instructive because it highlights the importance of considering false-positive and false-negative findings and performing sensitivity analysis. For a detailed discussion of the specifics of the decision-analytic model and sensitivity analysis, the reader is referred to the articles by Colice et al. (66) and Hutter et al. (24).

Take-Home Figure

Laboratory test:

·Blood

·Cerebrospinal fluid

·EEG/EMG

Nonanatomic imaging:

·Proton spectroscopy

·Perfusion/diffustion MRI

·SPECT or PET Patients with suspected brain cancer

based on clinical examination

·Acute focal neurologic deficit

·Nonchronic seizure or headache

·Progressive personality or cognitive changes

Figure 6.1. Decision flow chart to study patients with suspected brain cancer. In patients with presenting with an acute neurologic event such as seizure or focal deficit, noncontrast head CT examination should be done expeditiously to exclude any life-threatening conditions such as hemorrhage or herniation.

Imaging Case Studies

Several cases are shown to illustrate the pros and cons of different neu- roimaging modalities differentiating true neoplasms from lesion mimick- ing neoplasms.

Case 1

A 54-year-old man with headache and seizures and a pathologic diagno- sis of glioblastoma multiforme (GBM) (Figure 6.2 A and B).

Figure 6.2. A: Unenhanced CT image through the level of temporal lobe demonstrates no obvious mass lesion.

B: Contrast-enhanced T1-weighted MRI performed on the same day as the CT study clearly shows a rim enhancing centrally necrotic mass (black arrow) in the left temporal lobe. C: Fluid-attenuated inversion recov- ery (FLAIR) MRI better demonstrates the large extent of abnormality (white arrows) involving most of the left temporal lobe.

B C

A

Figure 6.3. A: Contrast-enhanced CT image demonstrates an enhancing solid and necrotic mass (large black arrow) within the right superior frontal gyrus associated with surrounding low density (small arrows). B: Contrast-enhanced T1-weighted MRI performed on the same day as the CT study shows similar finding. C: FLAIR MRI clearly demonstrates two additional foci of cortically based signal abnormality (white arrows) that were found to be infiltrating glioma on histopathology.

A

B

Case 2

A 42-year old woman with difficulty in balancing, left-sided weakness, and a pathologic diagnosis of GBM (Fig 6.3).

C

A,B C Figure 6.4. A: FLAIR MRI demonstrates a large mass lesion (black arrow) with extensive surrounding edema that crosses the corpus callosum (white arrow). B: Contrast-enhanced T1-weighted MRI shows thick rim enhancement (black arrowhead) and central necrosis associated with the mass. Similar pattern of abnormal- ity is noted within the frontal sinuses (white arrowheads). C: Diffusion-weighted MRI depicts marked reduced diffusion within the frontal lesion (black arrow) and the frontal sinus lesion (white arrows), both of which were proven to be a bacterial abscess at histopathology.

Case 3

A 53-year-old man with frontal abscess with irregular enhancement with central necrosis simulating a brain cancer.

Suggested Imaging Protocol

In patient with suspected primary brain neoplasm or metastasis, this is the MRI protocol recommended (Table 6.5).

Future Research

• Rigorous technology assessment of noninvasive imaging modalities such as MRS, diffusion and perfusion MRI, functional MRI, PET, and SPECT

Table 6.5. MR imaging protocol for a subject with suspected brain cancer or metastasis

3D-localizer

Axial and sagittal precontrast T1-weighted imaging Diffusion-weighted imaging

Axial fluid-attenuated inversion recovery (FLAIR) Axial T2-weighted imaging

Axial, coronal, and sagittal postcontrast T1-weighted imaging Optional: dynamic contrast-enhanced perfusion MRI

Proton MR spectroscopic imaging

Consider doing gadolinium enhanced MRI of entire spine to rule out metastatic disease

• Assessment of the effects of imaging on the patient outcome and costs of diagnosis and management

• Rigorous cost-effectiveness analysis of competing imaging modalities

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