The timely diagnosis of a brain tumour is crucial to optimising outcome in a group of patients with limited survival. Several common neurological conditions mimic brain tumours, causing concern to patient and physician until the correct diagnosis becomes clear. In addition, atypical presentations of brain tumours may cause diagnostic confusion, acting as chameleons and delaying correct workup and treatment. This review focuses on the important mimics and chameleons encountered in clinical practice, aiming to illustrate the wide range of clinical neurology encountered in this specialty and to provide guidance on reaching the correct diagnosis.
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Primary brain tumours account for approximately 2% of adult cancers, with an incidence of around 10 to 20 per 100 000 per annum, and overall carry a 25% mortality rate.1 ,2 They are classified according to their histological phenotype into four grades, I—IV, and may be subdivided into low grade (I and II) and high grade (III and IV) tumours. These gradings correlate with prognosis and guide management—as a general rule, surgery or surveillance is recommended for low-grade gliomas, while surgery and a combination of chemotherapy and radiotherapy for high-grade gliomas. Different considerations apply in children.
The mode of presentation of brain tumours often indicates tumour grade. Low-grade tumours typically present several years into their natural history, with seizures, evolving personality change or minor neurological deficits. They may occasionally be found incidentally on imaging. In contrast, high-grade tumours present subacutely with rapidly evolving neurological deficits, symptoms of raised intracranial pressure, rapid cognitive decline or seizures. The ‘2-week wait’ criteria outline the common red flags suggested to general practitioners that should prompt referral to the cancer network (table 1).3 However, due to the non-specific nature of early brain tumour symptoms, the conversion rate from ‘suspected’ to ‘confirmed’ brain cancer was less than 1% in one 3-year prospective audit of 1,000 new referrals on the 2-week wait criteria in the UK.4 In our service, a recent study of 139 new patients with glioma showed that the common acute presentations were focal neurological signs (32%), seizures (23%), cognitive symptoms (8%), headache (6%), falls (5%), sensory disturbance (2%) and multiple symptoms (24%) (unpublished data). None of these is specific to brain tumours but warrant imaging, which leads to a diagnosis of tumour. In practice, tumour mimics (non-neoplastic disorders presenting with features suggestive of brain tumours) and chameleons (unusual presentations of brain tumours mistaken for other diagnoses) are common diagnostic problems requiring a high level of clinical awareness to avoid inappropriate workup and treatment. Assessment depends very much on context and can be divided into clinical and radiological mimics/chameleons.
Brain tumour mimics: mistaking other diseases for brain tumours
Neurologists encounter a wide range of brain tumour mimics in clinical practice, including vascular, infective, inflammatory, toxic and metabolic lesions. Furthermore, in cases where there is cancer, they must decide its origin in order to manage the patient appropriately. Table 2 summarises some common mimics and helpful clues to their diagnosis.
Mimics: different tumour types
An important decision when faced with a scan consistent with a brain tumour is whether the patient has a primary tumour (glioma, lymphoma or meningioma being the main differential) or brain metastases. All cases of possible central nervous system (CNS) malignancy should be reviewed at a multidisciplinary team meeting before deciding on any definitive workup and intervention.
While multiple lesions clearly favour metastatic disease, it can prove difficult to distinguish from multifocal glioma on radiological grounds alone. Multifocal gliomas account for about 5% of gliomas and occasionally one of the phacomatoses underlie multifocal tumours (neurofibromatosis types 1 and 2, von Hippel–Lindau syndrome, or tuberous sclerosis). In suspicious cases, it is essential to request body imaging (eg, computerised tomography (CT) chest/abdomen/pelvis +/− mammography/testicular ultrasound). Solitary mass lesions with more vasogenic oedema than would be expected should also be screened for cancer (figure 1). Clearly, it is better to obtain a histological diagnosis from a non-CNS site in cases of suspected brain metastases.
Primary CNS lymphoma must be considered in patients with imaging compatible with malignancy. This may also present with multifocal lesions and spread intracranially at progression. In these patients, prior treatment with corticosteroids may lead to rapid tumour regression, leaving diagnostic uncertainty—as inflammatory lesions may also regress—and the absence of a biopsy target. For this reason, we would recommend withholding coritcosteroids if the scan suggests primary CNS lymphoma, unless there is evidence of raised intracranial pressure or severe neurological deficit (figure 2).
Low-grade mimics of malignant brain tumours
Occasionally, high-grade tumours present with features of benign or low-grade lesions (eg, meningioma, cavernoma). High-grade transformation of a low-grade lesion is usually an imaging diagnosis and patients starting imaging surveillance for low-grade tumours should be reimaged if they present with rapidly evolving clinical signs, to avoid missing a high-grade diagnosis (figure 3).
Mimics of high grade tumours
Numerous infective processes mimic high-grade brain tumours, and most (particularly tuberculosis) carry the inherent danger of exacerbation if the clinician assumes it is tumour and administers corticosteroids. Fever, risk factors (eg, known immunosuppression, recent travel, invasive procedures) and an acute time course may help, as may laboratory measures (serum C-reactive protein, white cell count). However, abscesses, toxoplasmosis and tuberculomas may be indistinguishable from high-grade gliomas, and may feature rim enhancement, necrosis, haemorrhage and perilesional oedema with mass effect. Lumbar puncture may be unsafe due to supratentorial mass effect (figure 4). Herpes simplex viral encephalitis may be associated with haemorrhage, raising the possibility of a high-grade tumour on imaging. Radiologically, the presence of highly restricted diffusion within the lesion suggests abscess more than tumour.
Tumefactive multiple sclerosis
This condition may be associated with evolving neurological deficits or personality change and is characterised by T2-hyperintense MRI lesions greater than 2 cm diameter, with surrounding oedema, enhancement and mass effect, that may mimic high-grade tumour. A reactive cerebrospinal fluid (CSF) with oligoclonal bands may help, although tumefactive lesions as the presenting episode of multiple sclerosis are associated with a reduced likelihood of positive bands, in the region of 50%.5 Other clues include evidence of prior optic neuritis, other white matter lesions in the appropriate distribution (ie, bilateral periventricular, or in the corpus callosum). It should be noted, however, that gliomas commonly infiltrate the corpus callosum and this should be differentiated from the punctate lesions typical of demyelination in that region. Further helpful MRI features include hypodensity on plain CT scanning in regions that enhance on MRI6 and, when present, an ‘open-ring’ pattern of enhancement within the defect at the grey-white interface7 (although most tumefactive lesions are full-ring enhancing6) (figures 5 and 6).
Mimics of low-grade tumours
Sudden onset of focal negative neurological deficits usually represents stroke in clinical practice. While the symptom time course should easily differentiate this from tumour, patients may present to stroke units because they have had a seizure and are found to have persisting lateralised signs. In the acute setting, this may raise the possibility of seizure at stroke onset if the patient has been unaware of symptoms evolving or is in a postictal state and cannot provide history. Patients may have truly hyperacute neurological signs due to tumour-associated haemorrhage. Hypodensity outside of a vascular territory aids the differentiation between tumour and stroke, as may the pattern of enhancement on postcontrast CT scan.
Viral encephalitis may present with confluent hyperintensity in the frontotemporal region on MRI, associated with cognitive symptoms, headache and confusion. The time course usually helps, along with raised inflammatory markers and positive PCR on CSF analysis. Empirical antiviral treatment should be given where viral encephalitis is suspected. Hyperintensity on MRI following resolution of herpes simplex viral encephalitis may persist but does not expand, and mass effect, perfusion abnormalities or enhancement should generally have resolved 6–10 weeks after successfully treated disease. Therefore, a MR brain scan at 3 months will usually identify other pathology, if not clinically apparent before this.
Occasionally, an atypical or unilateral distribution of multiple sclerosis lesions, or rarely other inflammatory disorders, may mimic a low-grade brain tumour. Steroid-responsiveness is typical but may also be associated with lymphoma and it is important to be cautious in reaching an inflammatory diagnosis. MR spectroscopy may allow differentiation of inflammatory lesions from neoplasia (a typical inflammatory spectroscopy pattern being elevated choline/creatine ratio with a normal N-acetylaspartate/creatine ratio and elevated lactate). Some cases may require a biopsy. Rarely, true demyelinating lesions (‘sentinel lesions’) may herald the onset of primary CNS lymphoma.8
Patients with a variety of antibody-mediated encephalitides may present with seizures, psychiatric symptoms and cognitive/personality change and may have asymmetric (even unilateral) medial temporal or more widespread MRI change, consistent with low-grade glioma. In these cases, CSF pleocytosis often helps while awaiting serology. The aggressive acute progression of these conditions typically leads to the correct clinical diagnosis but there is occasionally uncertainty. It is important to note that this condition may be paraneoplastic depending on the antibody found (the most commonly associated being antibodies to Hu, CRMP5, Ma2 and amphiphysin) and patients should undergo the appropriate workup for an underlying tumour.9 ,10
Longstanding or congenital lesions may be confused with low-grade glioma. Examples include cortical dysplasia, cortical migration defects, complex cysts and sequelae of congenital or early infection, for example, malaria, cycticercosis or sequelae of ‘TORCH’ infections (toxoplasmosis, rubella, cytomegalovirus and herpes simplex). Calcification is common in congenital/childhood infection but also occurs in some tumour subtypes, for example, oligodendrogliomas. Rarely, the MRI appearances of other benign lesions, for example giant Virchow–Robin spaces, may raise the possibility of CNS malignancy, especially if associated with adjacent white matter change.11 While such benign lesions are readily identified as incidental if there is no history suggesting evolving malignancy, it may be less straightforward if patients have undergone imaging for symptoms of headache or cognitive decline. Aneurysm should be included in the differential of parasellar lesions in particular, and occasionally dural arteriovenous fistulas may mimic a tumour—these lesions are easily seen on dedicated vascular imaging.
Mimics of recurrence in patients with treated brain tumour
Differentiating tumour progression from radionecrosis is critical to managing patients with treated malignant brain tumours. Radiotherapy can result in oedema, mass effect and breakdown of the blood–brain barrier that can be difficult to distinguish from tumour progression (figure 7). The underlying pathology is vascular fibrosis/thrombosis with inflammation. These effects are commonly seen years after initial treatment. ‘Pseudoprogression’, which is more frequent, is an earlier (first 3 months) phenomenon seen after chemoradiation of glioblastoma multiforme, comprising new enhancing lesions that are generally asymptomatic and regress spontaneously, but may be mistaken for early progression.12 Several imaging-based criteria using structural, functional and metabolic imaging have proven to be generally unreliable. More recently proposed methods that may provide greater sensitivity and specificity include the use of indices from dynamic contrast-enhanced MRI13 and the use of layering pattern on the apparent diffusion coefficient map.14 Given the frequency of ‘pseudoprogression’, many oncology units no longer perform early post-treatment MRI studies in order to avoid unnecessary anxiety and inappropriate interruption of important adjuvant chemotherapy.
Patients with brain tumours may develop stroke for a variety of reasons many years after treatment, including radiotherapy-induced vasculopathy. Sudden onset non-evolving neurological deficit should allow differentiation from a tumour, but outside of the acute phase, worsened neurological function along with new T2-hyperintensity on imaging may be interpreted as tumour progression. Even in the acute phase, restricted diffusion associated with enhancement may mimic tumour extension (figure 8).
Chameleons: unusual/atypical presentations of CNS malignancy
Tumour chameleons imitate other diseases, when they have a tempo of onset or symptoms that do not immediately suggest a tumour.
Occasionally, brain metastases and even high-grade tumours can present with clinical features and imaging characteristics compatible with an infective process (figures 9 and 10). The differential diagnosis of multiple ring-enhancing lesions includes pyogenic abscesses or tuberculosis. Another scenario is of an encephalitic presentation with headache, confusion and low-grade fever associated with unilateral temporal lobe hyperintensity on T2-weighted MRI. The symptom time course usually helps and patients should receive acyclovir cover in equivocal cases. Lack of resolution months after clinical recovery should prompt a tissue biopsy.15
Normal or non-specific scan
Occasionally, patients present with focal seizures and the initial MRI shows only a non-specific abnormality. In these cases, where there is a high index of clinical suspicion, patients should be rescanned within 6 weeks (figure 11).
CNS malignancy may be mistaken for stroke in cases where there are unilateral neurological deficits, particularly in cases presenting acutely and undergoing rapid assessment for possible thrombolytic therapy (figure 12). The typical CT findings in evolving stroke (eg, oedema, sulcal effacement or hypodensity) may also occur with low-grade gliomas. Gliomatosis cerebri (infiltrative low-grade glial tumour affecting three or more lobes) may also present through an acute stroke pathway with unilateral neurological deficits and CT imaging findings compatible with stroke (including the ‘dot’ sign).16
Patients presenting with symptoms compatible with optic neuritis occasionally have an infiltrative glioma of the chiasm or anterior visual pathways (figure 13). MRI will show a swollen chiasm or optic nerve. In addition, these patients either fail to improve or progress through corticosteroid therapy.
Patients with spread from primary cancer elsewhere may present with cranial neuropathies and symptoms of meningeal irritation where the meninges are involved. In patients known to have cancer the possibility of meningeal carcinomatosis should be aggressively pursued with gadolinium-enhanced MRI and high-volume CSF studies (three samples of at least 10 mL each)—compatible findings include raised protein, low glucose, pleocytosis and tumour cells on cytology (figure 14). Lymphocytes should be subtyped. A differential here includes paraneoplastic meningoencephalitis (eg, anti-Hu).
Intracerebral haemorrhage accounts for approximately 10% of stroke, increasing significantly after the age of 55 years; the question of primary versus secondary bleed must always be addressed. In some cases, location (eg, basal ganglia or thalamus) coupled with a history of hypertension, may strongly support the diagnosis of a primary hypertensive bleed. In an older patient with a lobar haemorrhage and multiple old microbleeds on susceptibility-weighted imaging or gradient-echo sequences, it is reasonable to suspect amyloid angiopathy. Underlying tumour may account for up to 11% of intracerebral haemorrhage;17–21 common lesions are glioblastoma multiforme or metastases from melanoma, colon, renal, lung or breast carcinoma. Intratumoural bleeds may lead to disproportionate mass effect and oedema, as well as enhancing satellite lesions. Many patients require interval imaging to identify secondary causes, including vascular lesions (eg, cavernoma, arteriovenous malformation) and CNS malignancy. It is important to note that patients with cancer show a generally increased prevalence of intracranial haemorrhage.22
CNS malignancy, particularly primary CNS lymphoma, can present with the clinical and imaging characteristics of inflammatory/autoimmune conditions. Subacute evolution of fluctuating cognitive/psychiatric symptoms, focal neurological deficits and seizures in a young patient may all suggest autoimmune encephalitis or, depending on imaging characteristics, fulminant demyelination or a multitude of inflammatory conditions, including sarcoidosis and systemic lupus erythematosus. Some of these conditions are associated with lymphadenopathy, raising the possibility of systemic malignancy. Useful red flags include a lack of systemic inflammatory features (eg, arthralgia, fever, rash), lack of specific imaging findings (eg, basal meningitis in sarcoidosis) and lack of inflammatory CSF findings. Where autoimmune encephalitis is confirmed on serology, it is important to pursue underlying malignancy in most cases. While it is more common for tumefactive multiple sclerosis to mimic a high-grade tumour, occasionally the reverse may be true where a patient felt to represent acute multiple sclerosis with enhancing lesions turns out to have lymphoma or metastases. Low-grade lesions may certainly be mistaken for inflammatory diagnoses, including multiple sclerosis, but serial imaging in tandem with clinical progression usually leads to the diagnosis (figures 10 and 15). In the case of lymphoma, there may be asymptomatic demyelinating lesions with enhancement on MRI at the onset of disease (‘sentinel lesions’). In one series of four patients, CSF was normal, biopsy showed demyelination with axonal sparing or non-specific inflammation, and the diagnosis of symptomatic B cell primary CNS lymphoma was detected only after 7–11 months.8 One hypothesis is control of evolving lymphoma by host immunity. We recommend that a patient aged over 50 years presenting with new enhancing lesions that show demyelination on biopsy should be closely monitored for evidence of primary CNS lymphoma.
The diagnosis of CNS malignancy can prove challenging, with several common mimics and important chameleons. All cases of suspected brain tumour should be discussed at a multidisciplinary meeting before planning formal investigation and management. Corticosteroids should be avoided in cases where there is no evidence of raised intracranial pressure or of severe/evolving neurological deficit. Empirical antimicrobial cover for infectious disorders should be started if there is uncertainty. Clinical and radiological findings should usually differentiate between CNS malignancy and its mimics, but biopsy is sometimes required to ensure the correct diagnosis and management.
Contributors DB wrote the manuscript and reviewed cases. JR reviewed cases and edited the manuscript.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Brenan McLean, Truro, UK.