Intracranial lesions mimicking neoplasms.
In this review, we have compiled a unique series of cases that presented both clinically and radiologically as intracranial mass lesions. Tumor was initially considered in each of the cases. However, pathology revealed a variety of nonneoplastic etiologies, including demyelinating disease, vascular disease, inflammation, and infection, as well as posttreatment effects. Although tumor is often the most likely diagnostic consideration in a patient presenting with a contrast-enhancing mass lesion within the brain parenchyma with surrounding edema and mass effect, that is not always the case. Not uncommonly, there can be significant overlap in the radiologic presentation between neoplastic and nonneoplastic diseases. Both neoplastic and nonneoplastic diseases can produce abnormal contrast enhancement, mass effect, and perilesional edema on both computed tomography (CT) and magnetic resonance imaging (MRI). Occasionally, some of these nonneoplastic etiologies may produce signs and symptoms mimicking tumoral disease clinically. (1) As such, these situations may offer a diagnostic challenge to both the clinician and radiologist, and often these patients undergo biopsy. In most cases, the pathologist can readily differentiate between neoplasia and nonneoplastic imitators. However, because the benign nature of some pseudoneoplastic lesions may not be immediately apparent on pathologic examination, it behooves the pathologist to be aware of their existence.
The purpose of this case series is to alert pathologists, radiologists, and other clinicians involved in the care of neurooncologic patients to consider nonneoplastic etiologies in the differential diagnosis of both intra-axial and extra-axial mass lesions.
Tumor-mimicking conditions from several etiologic categories are presented in tabular form, including infection and inflammation, demyelinating disease, vascular disease, and posttreatment conditions, with accompanying illustrations and discussion of the current and pertinent literature. Case examples of each condition discussed are described in the Table.
Case Example 1: Aspergilloma
The radiologic finding of erosion of the skull base by this mass lesion may have contributed to its interpretation as a destructive neoplasm, with the differential diagnosis including chondrosarcoma, metastatic lesion, osteosarcoma, and meningioma.
However, the histology in this case ruled out a diagnosis of neoplasm. Based on the hematoxylin-eosin morphology of a granulomatous process, a diagnosis of tuberculosis came to mind. Special stains for microorganisms solved this differential diagnostic dilemma, highlighting fungal hyphae with the characteristic acute angle branching of Aspergillus species. In retrospect, the history of otitis media and mastoidectomy in this patient pointed toward an infectious process, even in the absence of predisposing factors such as immunosuppression or diabetes. Even though most commonly occurring as an opportunistic infection, aspergilloma is well described in immunocompetent patients, especially in the context of local infection of the ear or paranasal sinuses. (1,2)
The increase in fungal central nervous system (CNS) disease seen by neurosurgeons and neuropathologists can be attributed to the increasing numbers of immunocompromised patients, which is due to wide use of immunosuppressive drugs such as steroids, large elderly and diabetic populations, and increasing numbers of long-term survivors of human immunodeficiency virus infection due to antiretroviral treatment. (3,4) The presentation can be very variable, so a high index of suspicion is required in patients with a history of immunosuppression.
Intracranial fungal infection has been described following a surgical intervention, often with fatal outcome, (5) Aspergillus species being the most commonly reported organism in these cases. Typically, cerebral aspergillosis results from hematogenous spread of the organism, or alternatively by direct extension from an adjacent focus of infection. Central nervous system Aspergillus infections can present either as an abscess or as cerebral infarcts but only rarely as meningitis. (6) Aspergilloma may also present as an extra-axial mass with extension into the brain parenchyma. Kim et al (7) described a case of extra-axial Aspergillus flavus granuloma involving the left middle and posterior cranial fossa, extending into the skull base and adjacent cerebellar parenchyma. Of note, the patient was an immunocompetent 34-year-old man with no other significant history. Radiologically, the mass was hypointense on T1-weighted MRI and exhibited irregular contrast enhancement. In the case series by Dubey et al, (4) patients with intracranial fungal granuloma most commonly presented with headache, followed by vomiting, proptosis, and visual disturbances. Other presentations could include cranial nerve palsies and symptoms/signs of elevated intracranial pressure and meningismus. (8) The granulomas were most frequently seen in the frontal lobe, although a classic location of aspergillomas is in a basal cranial location, where it is thought to arise from an infectious focus in the paranasal sinuses. (9) In the 40 cases described by Dubey et al, (4) aspergilloma was the most frequent organism found (25, 63%), followed by mucormycosis (7, 18%), cryptococcoma (3), Cladosporium (3), Bipolaris hawaiiensis (1), and Candida species (1). There was a 63% mortality rate in these patients, mostly due to meningoencephalitis.
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Radiologically, fungal granulomas present as enhancing masses. (9) Adjacent to the dura, they can simulate meningiomas, even producing a dural tail sign. (3) On CT scan, they may be associated with paranasal sinusitis and small areas of bony destruction. (4) Their MRI appearances can vary somewhat depending on the organism involved. Aspergillomas tend to demonstrate intermediate signal intensity surrounded by perilesional edema on T2. (4) However, cryptococcomas have low T2-weighted signal intensity in contrast to the surrounding hyperintense cerebral edema. Other fungal infections such as histoplasmosis can also simulate brain tumors radiologically. (9)
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Case Example 2: Pituitary Cryptococcoma
In immunosuppressed individuals, cryptococcal infections typically produce a diffuse meningitis, and infiltration of the perivascular Virchow-Robin spaces by the organism can result in the formation of small intraparenchymal gelatinous pseudocysts, with a minimal or absent inflammatory response. In immunocompetent hosts, a chronic granulomatous reaction surrounds the organisms and there is neovascular growth around the granulomas, producing contrast enhancement similar to that of primary or secondary brain tumors. (10,11) Cryptococcomasmay be seen in individuals with a predisposition to fungal infections, which may not be evident on initial inquiry, and may require more detailed history and workup to identify conditions such as diabetes or sarcoidosis. (12) Cryptococcomas are most commonly found in the cerebellum, brainstem, basal ganglia, or temporoparietal lobes. Distinguishing them from tumors and abscesses due to other organisms can be challenging because there is no distinctive radiologic feature that is unique to cryptococcomas. Typically, cryptococcal disease presents on MRI as T2 hyperintense cystic lesions within the bilateral basal ganglia with variable enhancement and surrounding edema. They also often tend to insinuate in dilated Virchow-Robin perivascular spaces. Enhancing cryptococcomas often do not show restricted diffusion on diffusion-weighted imaging (DWI), (9) low signal intensity on T1-weighted imaging, and low (9) or high intensity (12) on T2 imaging, with uniform or ring enhancement. They may also have mild surrounding edema and focal calcification within them. (12) Cryptococcomas may rarely involve the parasellar or pituitary region. Yu et al (13) described a case of parasellar cryptococcoma occurring in an immunocompetent patient. The radiologic features of the lesion were similar to a pituitary adenoma, showing uniform contrast enhancement, with low signal on T1-weighted imaging and high signal on T2 imaging. The contrast enhancement of the meninges adjacent to the cryptococcoma helped in differentiating it from an adenoma.
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Case Example 3: Whipple Disease
Whipple disease is a chronic inflammatory disorder that involves multiple organ systems, typically the gastrointestinal tract and musculoskeletal system. (14) The causative agent is a soil-borne gram-positive bacillus Tropheryma whippelii. The classic presentation includes fever, steatorrhea, weight loss, skin pigmentation, lymphadenopathy, and recurrent arthritis. (14,15) The walls of the intestine and lymph nodes are found to contain accumulations of foamy macrophages containing the characteristic periodic acid-Schiff-positive organisms. The CNS is involved in 6% to 43% of patients with Whipple disease, (15) but isolated CNS disease is very rare, with only 14 cases described in the literature. (14,15) Radiologically, the lesions are predominantly hyperintense on T2-weighted magnetic resonance (MR) images and may show homogeneous or ring enhancement. (15) They can be surrounded by variable perilesional edema. Generally speaking, patients presenting with primary CNS Whipple disease can be divided into 2 groups. First, those with multiple lesions may exhibit a plethora of neurologic symptoms and signs, including seizures, ataxia, supranuclear vertical gaze palsy, headaches, papilledema, hemiplegia, syndrome of inappropriate antidiuretic hormone, and fever. Interestingly, some patients may develop oligoclonal bands in the cerebrospinal fluid similar to those found in multiple sclerosis, cerebral lupus, human immunodeficiency virus infection, and sarcoidosis. (14) Those with focal mass lesions have symptoms referable to the site involved. The patient described by Lohr et al (15) had an isolated frontal mass in the white matter, which had MRI features suggestive of a low-grade glioma. It was T2 hyperintense, was slightly hypointense on T1-weighted images, and had subtle ring enhancement without perilesional edema. As in our patient, the presentation included behavioral changes and aggressiveness. Following resection of the mass, the characteristic perivascular foamy macrophages containing periodic acid-Schiff-positive, diastase-resistant rod-shaped organisms were seen. There was marked associated gliosis.
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Other cases of solitary CNS Whipple disease have also involved the frontoparietal regions, and in one of these, there was associated destruction of the calvarium adjacent to the lesion. (16) In cases of multifocal disease, the lesions have mostly occurred in the cortical or subcortical grey matter, involving mainly the temporal lobes and thalamus. (15) Although the clinical presentation and radiologic findings in intracranial Whipple disease can closely mimic those of a low-grade glioma, the histologic picture of perivascular foamy histiocytes should prompt the pathologist to look for the periodic acid-Schiff-positive intracellular organisms and arrive at the correct diagnosis.
Case Examples 4 and 5: Bacterial Abscess
Differentiating between pyogenic brain abscesses and centrally necrotic intra-axial tumors can often be challenging radiologically, because both commonly demonstrate ring enhancement and perilesional edema. A helpful finding on MRI examination is the presence of a hypointense capsule on T2-weighted images, which is not usually seen in tumors. (9) Diffusion weighted imaging is a well-known and valuable radiologic tool in these cases: brain abscesses typically show markedly hyperintense signal changes on DWI, whereas the appearance of high-grade gliomas varies from slightly hyperintense to hypointense signal. (17) The apparent diffusion coefficient reveals reduced values in brain abscesses. These findings are, however, not entirely specific, because a centrally reduced apparent diffusion coefficient has been also reported in neoplastic lesions. (18)
Case Example 6: Nocardiosis
Brain abscess due to Nocardia species is a rare condition, and although it can occur in patients with an intact immune system, it is usually seen among immunocompromised patients. (6) It can be confused with intracranial tumors radiologically. (19) Ozturk et al (20) described a case of nocardial brain abscess occurring in a renal transplant recipient on an immunosuppressive drug regimen. Kilincer et al (19) described a further 2 cases of nocardial brain abscess, one of whom was a 39-year-old woman with systemic lupus erythematosus who developed a left frontoparietal abscess, and the other was a 43-year-old man with glomerulonephritis treated with corticosteroids who developed a ring-enhancing multiloculated abscess in the left cerebellar hemisphere, with an additional 2 small supratentorial lesions. Both underwent treatment with long-term antibiotics and evacuation of the abscess. Histologically, nocardiosis appears as a necrotic lesion with acute inflammation. The organism is weakly acid-fast with the Fite stain, having a beaded, filamentous appearance, and also is highlighted by the Gomori methenamine silver stain.
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Case Example 7: Tuberculoma
Intracranial tuberculomas may exhibit nodular or ringlike enhancement on MRI similar to a primary or metastatic brain tumor. (10) When present, areas of caseation can correlate with isointense or mixed intensity areas seen within the mass on T1-weighted images. The surrounding collagenous fibrosis corresponds to the slightly hyperintense rim. The MRI appearance of tuberculomas varies according to the age of the lesion. On T2-weighted imaging, immature tuberculomas appear as multiple small areas of isointensity or hypointensity surrounded by hyperintense edema. Mature tuberculomas are heterogeneously hypointense or isointense throughout the lesion, with ring enhancement seen on postcontrast T1-weighted images. Clues to the granulomatous nature of the lesion are its conglomerate and ring-enhancing MRI appearance. A "targetlike" appearance with central calcification, perilesional edema, and peripheral enhancement on CT scan has been described, although is not always present. (10) Magnetic resonance spectroscopy (MRS) is typically inconclusive and does not help distinguish the condition from a neoplasm. Diffusion-weighted imaging is usually hyperintense. (9) Fortunately, if biopsy or excision is performed, the histologic appearance of tuberculoma is characteristic, with granulomatous inflammation, caseation, calcification, and surrounding gliosis. If only the edge of the lesion is biopsied, it is important for the pathologist to distinguish this reactive gliosis from a glial neoplasm.
Case Example 8: Progressive Multifocal Leukoencephalopathy
Typically, patients with progressive multifocal leukoencephalopathy (PML) present with weakness, hemianopia or quadrantanopia, and cognitive abnormalities. (21) On imaging, PML lesions typically present as large, multifocal, subcortical white matter lesions without mass effect. They are most commonly found in the parietal lobe white matter, (22) but they can also be seen in the occipital lobe, corpus callosum, and thalamus. Typically, PML does not enhance, although lesions may demonstrate mild peripheral or scalloped areas of enhancement, often associated with reconstitution of the patient's immune response. In some cases there may be low density or T2 hyperintense cystlike areas within PML lesions. (21) These may represent areas of necrosis within the lesion. The lesions may typically show no or faint contrast enhancement. In the series of Thurnher et al, (21) a third of the patients with PML lesions had significant mass effect with compression of the ipsilateral lateral ventricle, which is in contrast to the typical lack of mass effect described in the literature. Therefore, necrotic white matter lesions in acquired immunodeficiency syndrome patients, particularly with peripheral scalloping, should be considered highly suggestive of PML rather than a necrotizing tumor, and the pathologist should be on the alert for the accompanying histologic appearance. On microscopic examination of the biopsy or resection, the PML lesions exhibit demyelination and contain enlarged oligodendrocytes with hyperchromatic nuclei, some of which may contain eosinophilic intranuclear inclusions, and enlarged astrocytes with bizarre nuclei. (23) Immunohistochemistry for the JC viral capsid protein may also be performed as confirmation. (23)
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Case Example 9: Neurocysticercosis
Neurocysticercosis develops when the larval form of the tapeworm Taenia solium encysts in the brain inciting a surrounding inflammatory and granulomatous response.
It is the most common cause of acquired seizures worldwide and is increasingly seen in the United States, particularly in the immigrant community. (24) Although epilepsy is the most common presenting symptom, other manifestations include severe episodic headache, (25) meningitis, obstructive hydrocephalus if the cyst is near a ventricle or the subarachnoid space, and cognitive problems. (10,24) Radiologic diagnosis is often straightforward, although the appearance varies depending on the life cycle stage of the parasite and the age of the lesion. The lesion can appear as a single or multiple enhancing cysts with calcification, the latter representing dead larvae or nodular calcified stage. (1,10) When the larvae are invading the brain, they appear as small nonenhancing edematous lesions, later forming small enhancing nodules. (10) As the lesions become cystic and the larvae start to die, surrounding edema develops due to the inflammatory response to the cyst contents, and there is ring enhancement due to the formation of granulation tissue and a thick capsule. On DWI, the cysts have a similar signal intensity to cerebrospinal fluid, unlike pyogenic abscesses. (9) Usually the lesions are less than 20 mm in diameter. (10) A helpful finding is the identification of a scolex (larval body) within the cyst. (9) The scolex is typically hyperintense on T1-weighted sequences. (10) Solitary lesions can be difficult to distinguish from a neoplasm owing to the surrounding edema and the cyst enhancement. (9) It may even mimic a glioblastoma multiforme radiologically. (26)
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In these cases, it is helpful to correlate the findings with other clinical data such as cerebrospinal fluid immunology for T solium antibody titers. Pathologically, the presence of a fibrous cystic structure with granulomatous inflammation should prompt a search for an infectious etiology. In patients originating from endemic areas such as South America, Africa, and Asia, a careful search for the characteristic larval forms and scolices should be made.
Case Examples 10 and 11: Demyelination
Masslike features or a so-called tumefactive appearance of demyelinating plaques are well described in the literature. Multiple sclerosis, and other primarily demyelinating diseases, such as myelinoclastic diffuse sclerosis (Schilder disease) and acute disseminated encephalomyelitis can manifest as tumefactive lesions. Differentiating between demyelinating lesions and brain tumors, such as gliomas, in the presence of solitary lesions can be difficult and problematic.
As in case 10, a peripherally enhancing lesion with a butterfly configuration occurring in a 57-year-old man with acute onset of symptoms almost automatically triggers a suspected diagnosis of glioblastoma. However, on closer examination of the images, the incomplete ring and peripheral contrast enhancement as seen in this case should give rise to suspicion and perhaps prevent a premature conclusion. This condition is a "classic" mimic of high-grade glioma, and recently, the characteristic horse-shoe-shaped contrast enhancement on MRI has been described. Additional radiologic tools, including MR perfusion imaging or MRS can further aid in arriving at the correct diagnosis, thus avoiding a surgical biopsy. (27,28) Features that favor a demyelinating lesion include a relative lack of mass effect and vasogenic edema. (10) In radiologic parlance, the "open ring sign" is contrast enhancement shaped as an open ring or a crescent in the white matter. It is often present in large contrast-enhancing demyelinative lesions and is more likely to be associated with these than with neoplasms or infections. (29) In demyelination, the incomplete ring of enhancement may have ill-defined margins. (30) Differentiation between a solitary demyelinating lesion and a glioma can be very challenging radiologically. (10,30,31) Therefore, if the presentation and imaging findings remain inconclusive and a histologic diagnosis is necessary, the pathologist has to keep this condition in the differential diagnosis, because erroneous diagnoses of high-grade glioma have been reported many times in the medical literature, even though the distinguishing features are also well documented. (32) When demyelinative lesions have a marked inflammatory component, they may be confused with a primary CNS lymphoma. The more gliotic lesions are more apt to be confused with high-grade astrocytomas, however. If one is unfamiliar with the characteristic appearance of Creutzfeldt astrocytes seen in demyelination, the possibility of substantial astrocytic pleomorphism, and the occurrence of mitotic figures in demyelinative lesions, they may be misinterpreted as high-grade glioma. (33)
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Case Example 12: Infarct
Instances in which infarcts mimic high-grade gliomas due to contrast enhancement and mass effect are documented in the literature. (34,35) To distinguish a cerebrovascular accident from a neoplasm, repeat imaging studies after a short interval or advanced techniques such as MR perfusion may also be helpful. (34,36) In most cases, diagnosis of ischemic stroke/infarction is not problematic. The characteristic clinical history of a sudden onset of neurologic symptoms and signs, in combination with the typical radiologic findings, including diffusion-restriction, T2/fluid attenuated inversion recovery hyperintense signal, mass effect, and possible gyral enhancement pattern together in a typical vascular distribution, usually leads to the correct diagnosis. (9) Confounding diagnostic features in ischemic infarction that are more suggestive of a brain tumor include an atypical presentation, such as a slow evolution of neurologic symptoms, (10) and a poorly defined cerebral lesion on imaging with associated mass effect, radiologically simulating glioma. (9,10) A subacute infarction can show irregular contrast enhancement and mimic high-grade glioma. Some infarcts can also exhibit ring enhancement, strongly resembling that of glioblastoma. (34) An understanding of the cerebral arterial vasculature is essential in arriving at a correct diagnosis. (10) Diffusion weighted imaging is a helpful modality for distinguishing between these 2 conditions, (10) particularly when the clinical history is obscure, and in the acute or early subacute phase of an ischemic stroke. (9) In late subacute to chronic infarctions, however, restricted diffusion may not be evident thus making DWI less useful in making the distinction between tumor and an infarct. (9) In this case, short-term follow-up imaging may be necessary to document the evolution of the lesion. (10)
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Case Example 13: Vasculitis
The clinical presentation and imaging findings in this case do not provide unequivocal evidence to arrive at the correct diagnosis. The sudden focal neurologic deficit and the ring enhancement of the deep white matter lesion prompted the preoperative diagnosis of high-grade glioma. There were no findings in the patient's preoperative evaluation consistent with an inflammatory process: there were no systemic symptoms and her laboratory values including an erythrocyte sedimentation rate and a white blood cell count were within reference range. Indeed, there are relatively few cases of this condition reported in the literature, especially presenting as a solitary contrast-enhancing mass. Further imaging studies (perfusion-weighted MRI, angiography) may be valuable, but it has been suggested that a stereotactic biopsy should become the gold standard in the management of these cases, even though the diagnostic yield is reportedly low. (37,38) Behcet disease has been reported to produce a solitary masslike lesion in the hemisphere, with low attenuation on T1-weighted MRI, and extensive hyperintensity on fluid attenuated inversion recovery. (39,40) However, this scenario is very rare, as Behcet disease usually presents as multiple T2 hyperintense lesions. (39) Magnetic resonance spectroscopy can be of assistance in distinguishing a vasculitic lesion from a neoplasm. Panchal et al (41) reported a case of lymphocytic vasculitis presenting as multifocal tumorlike lesions within the right cerebral hemisphere, which were enhancing on postgadolinium T1-weighted MR, with associated massive vasogenic edema involving the whole hemisphere. Radiologically, the lesions mimicked a multifocal glioma. However, the MRS pattern was more consistent with an inflammatory process (no elevated choline peak, marked elevation of glutamate/glutamine metabolites) rather than an aggressive neoplasm. The diagnosis was confirmed by craniotomy and excisional biopsy.
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Case Examples 14i and 14ii: Amyloidoma
After the initial clinical and radiologic workup, the lesion in case 14i was thought to be a schwannoma of the fifth nerve, which would fit the imaging features and presentation. A meningioma was also considered, because the lesion showed a highly suggestive "dural tail sign" on imaging. The absence of any evidence of systemic disease associated with the deposition of amyloid in this case made this a very difficult diagnosis.
Nonetheless, several such lesions in this location with similar presentation and imaging findings have been reported. Interestingly, the deposits were histochemically composed of [lambda] protein, as in the present case. (42-44)
The most frequent presentation of intracranial amyloid is as cerebral amyloid angiopathy, or as deposits within the senile plaques of Alzheimer disease. Amyloidoma is seen much less frequently. Amyloid presenting clinically and radiologically as an intracranial tumor is rare. Amyloid presenting as a tumorlike mass has been reported in the cerebral hemispheres in patients ranging in age from 28 to 60 years, including the temporal (45,46) and occipital lobes, (46,47) and also the cerebellopontine angle. (43) Typically, they appear as supratentorial white matter masses that are high density on nonenhanced CT scan, with little to no mass effect. (48) They can extend up to the walls of the lateral ventricle and have fine, irregular enhancing margins. Central nervous system amyloid can also present as multiple contrast-enhancing lesions in the hemispheres. (49)
Other locations have included the Gasserian ganglion (43) manifesting clinically as trigeminal neuropathy, which had a signal intensity similar to cortex on T1-weighted imaging, heterogeneous signal intensity on T2 imaging, with marked uniform enhancement on postcontrast T1 imaging. The mass was thought to be a meningioma or schwannoma preoperatively. The sella (50) and choroid plexus are other known sites. Ragel et al (47) described a 59-year-old man with a 6-month history of confusion and headaches; MRI revealed a left parietooccipital lesion extending to the splenium of the corpus callosum. The mass had MRI and MRS features of a high-grade glioma, with a stellate hyperintense rim on T2-weighted imaging, and elevated choline peak on MRS. Biopsy findings were those of amyloidoma, with amorphous congophilic deposits and apple green birefringence. Findings not consistent with high-grade glioma were the lack of peritumoral edema and minimal mass effect. Another article (45) described a right temporal lobe mass in a 51-year-old woman presenting with hearing loss and recurrent right-sided otitis media. The MRI and CT findings were suspicious for glioma, and stereotactic biopsy with intraoperative squash preparation followed by routine histology and electron microscopy revealed amyloidoma.
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Cerebral amyloid angiopathy can also mimic glioma radiologically and clinically. Safriel et al (46) reported 2 patients with MR findings suggestive of low-grade glioma. The first case was a 49-year-old man with a tumefactive mass in the occipitotemporal lobe without enhancement or restricted diffusion and unremarkable spectra. Biopsy and histopathology revealed cerebral amyloid angiopathy with angiitis. The second case was a 71-year-old woman with an ill-defined infiltrative nonenhancing mass, without restricted diffusion, within the right occipital and parietal lobes, and unremarkable MRS findings. Biopsy revealed cerebral amyloid angiopathy. Cerebral amyloid angiopathy may also present as a mass within the brain. Osumi et al (51) describe a 59-year-old woman presenting with a large right temporoparietal lobe mass lesion, which was white matter based, and was nonenhancing, nonhemorrhagic, and low attenuation on MRI examination. A diagnosis of low-grade glioma was considered. Biopsy was nondiagnostic, revealing only gliosis. Subtotal resection of the right temporal lobe was then performed, and histology showed congophilic vascular mural deposits of amyloid, with diffuse white matter gliosis and edema. There was no evidence of tumor.
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NONINFECTIOUS INFLAMMATORY CONDITIONS
Case Example 15: Castleman Disease
Castleman disease, also known as angiofollicular lymph node hyperplasia, occurs in 2 forms. Most cases are the hyaline-vascular type, as in our case, with the typical histologic finding of hyalinized follicular centers with a radial penetrating vessels and prominent interfollicular capillary proliferation. The plasma cell type represents only 5% to 10% of cases, and is characterized by large lymphoid follicles separated by sheets of mature plasma cells and less stromal vascularization. (52,53) Localized forms of the disease are generally asymptomatic, while the generalized form may present with fever, weight loss, anemia, polyneuropathy, organomegaly, and monoclonal proteinemia, thus resembling a paraneoplastic syndrome. Intracranial Castleman disease is very rare, with 13 cases described in the literature, and in this locality it may mimic a neoplasm, in particular a meningioma. Previously described locations include the hemisphere convexities and adjacent to the falx. As expected with the predominantly cortical location of the lesion, patients presented most commonly with seizures, and focal signs such as right hand clumsiness, (53) left hemiparesis, and incoherent speech. (52) By CT imaging, the lesions were homogeneously enhancing with perilesional edema. (52) Some demonstrated dural enhancement by MRI, mimicking a meningioma. (53) Angiography of these intracranial cases revealed no vascular blush, in contrast to other sites where there is typically a homogeneous capillary blush from neovascularization. (52) Although most cases occur in adults, there is a single report in an 8-year-old girl. (54) The child presented with sudden onset of partial motor seizures and a left posterior parietal, partially mineralized, contrast-enhancing meningeal mass.
The treatment of choice for localized Castleman disease is gross total resection of the lesion, after which total and complete recovery is the rule (52,54) including resolution of the systemic manifestations of the disorder. In summary, although it is a rare entity in the CNS, Castleman disease should be considered in the differential diagnosis of intracranial meningeal tumors.
Case Example 16: Rosai-Dorfman Disease
Sinus histiocytosis with massive lymphadenopathy, or Rosai-Dorfman disease, was first described in 1969. (55) It typically presents in children and young adults, and has a mean age of onset of 20.6 years, with bilateral, painless cervical lymphadenopathy. Some patients also have systemic symptoms such as elevated sedimentation rate, fever, leukocytosis, and polyclonal hypergammaglobulinemia. (55) Extranodal involvement also occurs in more than 40% of patients, particularly in the paranasal sinuses, orbit, skin, and upper respiratory tract. (56) Central nervous system involvement is less common, being found in 22% of patients, and isolated CNS disease is rarer still. Disease of the CNS typically manifests itself in the epidural or subdural compartments, (56) but a suprasellar location has been reported. (55) Patients presenting with or developing cranial involvement have a mean age of 34.9 years, with a male predominance. Some of the usual presentations of intracranial disease include seizures, headache, cranial nerve deficits, hemiparesis, and dysphasia. (55) Imaging reveals single or multiple meningeal-based masses, which are enhancing, with variable surrounding edema, and can appear identical to a meningioma on CT and MRI scan. (55,57,58) Associated lytic lesions may be seen in the skull. (56) On surgical resection, the lesion may also grossly be indistinguishable from a meningioma, and so diagnosis will rest with histology. Fortunately, differentiation of sinus histiocytosis with massive lymphadenopathy from meningioma presents no difficulty in most cases, with the possible exception of the lymphoplasmocyte-rich variant of meningioma. (57)
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Helpful histologic features include the characteristic pale-staining histiocytes with delicate nuclear membranes, exhibiting emperipolesis, that is, intact lymphocytes, neutrophils, and plasma cells within the cytoplasm. There may also be erythrophagocytosis and perivascular collections of plasma cells. (56) Immunohistochemistry is helpful in demonstrating the characteristic S100 protein, CD68, and factor XIIIa-positive histiocytes, which unlike those in Langerhans cell histiocytosis, are negative for CD1a. (57)
Because there are as yet only a few reports of intracranial Rosai-Dorfman disease, the ideal treatment for this condition is so far undefined. Surgery has been the treatment of choice. (55) Adjunctive therapy has included chemotherapy, irradiation, and steroids. So far, no deaths from intracranial sinus histiocytosis with massive lymphadenopathy have been reported, and patients who underwent complete resections had no recurrences. (55) The effectiveness of steroids in this condition has been described. McPherson et al (59) reported a 53-year-old male patient with multiple skull base lesions who underwent craniotomy for 1 lesion and experienced marked resolution of the remaining lesions following corticosteroid administration.
Another systemic histiocytic disease that can involve the CNS and produce lesions mimicking a primary brain tumor is Erdheim-Chester disease.
The disease is a non-Langerhans cell histiocytosis and usually affects middle-aged adults, producing osteosclerotic and lipogranulomatous lesions of the long bones and retroperitoneal and pulmonary fibrosis. (60) When there is neurologic involvement, it typically manifests itself as hypothalamic/ pituitary dysfunction. (61) A solitary left temporoparietal cortical lesion has been described in a previously healthy 26-year-old patient who experienced recent onset of seizures. (62) The lesion was solitary, well-demarcated and homogeneously enhancing on MRI examination. It had minimal surrounding edema and no mass effect. Positron emission tomography scan suggested a low-grade neoplasm, such as astrocytoma or pleomorphic xanthoastrocytoma. Intraoperative squash preparations and frozen sections revealed many multinucleate cells with a background of fibrillary astrocytes, and a diagnosis of glial neoplasm was made. On permanent histology, clusters of xanthomatous histiocytic cells were evident, many of which were multinucleate with a wreathlike nuclear arrangement, surrounded by dense gliosis. The histiocytic cells were KP-1 (CD68) immunopositive and negative for CD1a and S100 (in contrast to those seen in Rosai-Dorfman disease or Langerhans cell histiocytosis).
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Case Example 17: Inflammatory Pseudotumor
Inflammatory pseudotumors, also known as inflammatory myofibroblastic tumors, may involve any organ system. (63) In the CNS, it most commonly produces a dural-based/ meningeal mass, although it may be intraparenchymal or may occasionally arise from the choroid plexus, producing a hyperdense intraventricular mass on CT imaging. (3) Shah and McClain (64) described a form of inflammatory pseudotumor (plasma cell granuloma) involving the cavernous sinus and middle cranial fossa in a 14-year-old girl. On MRI, it was seen to extend into the pterygopalatine and infratemporal fossae producing thickening of the right lateral tentorium and edema of the right temporal lobe. Typically, inflammatory pseudotumor is hypointense on T1-weighted images and markedly hypointense on T2. Because of its polymorphous histologic appearance, ranging from hypocellular connective tissue containing scattered mixed mononuclear inflammatory cells to a proliferation of plump fibroblastic cells with a prominent inflammatory component, it may potentially be confused with a lymphoplasmacyte-rich meningioma or even a fibroblastic meningioma. The radiologic appearance of a dural-based mass may further mislead the pathologist. The demographics of patients with the 2 lesions are different, however, with most inflammatory pseudotumors (73%) occurring in those younger than 40 years. (10) There is a distinct male predominance, (10) and most cases in the CNS are solitary (82%). Intraparenchymal heterogeneously enhancing inflammatory pseudotumors may mimic a malignant brain neoplasm. (63)
Case Example 18: Radiation Necrosis
Distinguishing between radiation necrosis and glioma recurrence can be difficult. (65) In cases of high-grade glioma, both are likely to be present at the same time, but in these cases the challenge is to determine whether one or the other is predominant because this may affect treatment planning. Increased contrast enhancement secondary to irradiation may be seen within a variable time frame after administration of radiotherapy. These changes may be seen as soon as 2 to 4 months after the treatment and may improve over time. (9) Additionally, delayed radiation necrosis should be considered when patients present with a new enhancing lesion, particularly in the irradiation field, months or years after the end of treatment. (9) Obviously, obtaining an accurate clinical history is important in these cases. Diffusion weighted imaging, which shows a spotty hypointense lesion in the irradiation field, is suggestive of radiation necrosis. (66) Radiation necrosis shares some major MRI features with recurrent glioma, including contrast enhancement, vasogenic edema, and mass effect. (67) However, some additional features that may favor radiation necrosis include conversion from no enhancement to enhancement and remote new enhancement, new periventricular enhancement, and "Swiss cheese" enhancement. (68) In 1 study, MRI findings which favored recurrent tumor included involvement of the corpus callosum with subependymal spread, corpus callosal involvement with crossing of the midline and multifocal lesions, and the combination of corpus callosal involvement with subependymal spread and multiple lesions. (65) Of note, the authors found that these combinations of MRI findings rather than individual features were statistically significant. However, in many cases, the definitive diagnosis of radiation necrosis versus recurrent tumor rests with surgery and biopsy.
Accepted for publication July 25, 2008.
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Clare H. Cunliffe, MD; Ingeborg Fischer, MD; David Monoky, MD; Meng Law, MD, MBBS, FRACR; Carolyn Revercomb, MD; Susan Elrich, MD; Michael Jered Kopp, BA; David Zagzag, MD, PhD
From the Department of Pathology, Division of Neuropathology (Drs Cunliffe, Fischer, and Zagzag) and Department of Radiology, Division of Neuroradiology (Dr Monoky), New York University Medical Center, New York; the Departments of Radiology and Neurosurgery, Mount Sinai Medical Center, New York, NY (Dr Law); the Office of the Chief Medical Examiner, Washington, DC (Dr Revercomb); the Department of Neurology, Yale University Hospital, New Haven, Conn (Dr Elrich); and the Stern School of Business, New York University, New York (Mr Kopp).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Clare H. Cunliffe, MD, Department of Pathology, Division of Neuropathology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029 (e-mail: firstname.lastname@example.org).
Illustrative Case Examples With Corresponding Clinical History, Imaging Findings, Histology, and Final Pathologic Diagnosis * Case No. Age, y/Sex Clinical History 1 35/M Chronic otitis media s/p left mastoidectomy; headaches, fever, left-sided facial numbness, diplopia, confusion 2 3 7/F 10-mo H/O severe headaches, recent onset of double vision, 14-mo H/O amenorrhea, panhypopituitarism and DI 3 56/F Bizarre behavior; paranoia, Kluver-Bucy syndrome 4 33/M Generalized seizures, s/p resection of large anaplastic mixed glioma, involving right frontal lobe and basal ganglia; 2 y later, experienced 2 epi- sodes of unconsciousness 5 65/F Remote H/O breast cancer s/p right total mastectomy; recent headaches and fever 6 60/F s/p large B-cell lymphoma and CHOP Tx; new onset seizure 7 35/F Bitemporal headache, left lower extremity weakness and diminished left plantar sensation; remote PPD positive, CXR negative 8 43/M Disorientation, word- finding difficulty, right hemisensory impairment. HIV positive, CD4 109, CSF protein 54 mg/dL, glucose 53 mg/dL 9 62/F Progressive headaches for 1 y; CSF: atypical lymphocytes, histiocytes, and few eosinophils 10 57/M s/p remote testicular cancer; 3-d H/O bitemporal headache, confusion, memory impairment 11 77/M H/O seizure disorder, hypertension 2004: New onset difficulty driving, following directions; after biopsy, steroid treatment with symptom improvement 2007: Worsening speech impairment, confusion 12 64/M Headaches for 7 wk, nausea and vomiting, 40-lb weight loss; gait ataxia 13 43/F Sudden loss of right hand coordination and difficulty driving 14i 38/F 18-mo H/O progressive left facial numbness, first and second divisions trigeminal nerve 14ii 44/M 37-y H/O partial seizures, s/p resection of right frontal and temporal seizure focus; new onset increased seizure frequency and left hemiparesis 15 33/F Recent onset of headaches 16 33/M H/O seizure disorder, schizophrenia, IDDM 17 62/M H/O thyroiditis, hypertension; developed vertigo, numbness left corner of mouth, twitching left hand 18 40/M s/p remote glioma resection; 5 y later, enlarging lesion with necrosis at site of prior resection Case No. Imaging Findings Imaging Differential Diagnoses 1 MRI: Irregularly T1 Destructive neoplasm; contrast enhancing, differential centrally hypointense diagnoses: chondro- left skull base lesion sarcoma, metastasis, involving the left maxil- osteo-sarcoma, meningioma lary sinus, cavernous sinus (Figure 1, A) with erosion of left temporal bone 2 MRI: 1.5-cm sellar mass Pituitary adenoma extending to suprasellar cistern adjacent to carotid arteries (Figure 2, A); low T1 signal intensity with thin enhancing rim and septation (Figure 2, B) 3 MRI: Bilateral temporal Infectious process, eg, lobe lesions herpes encephalitis, (Figure 3, A and B) neoplasm 4 MRI: New peripherally Recurrent tumor enhancing lesion of right frontal lobe (Figure 4, A and B) with cortical extension and perilesional edema 5 MRI: Left thalamic Favor metastatic neoplasm ring-enhancing lesion over abscess (Figure 5, A and B) 6 MRI: 1.7-cm ring- Necrotic lymphoma, abscess enhancing lesion, left parietal white matter; central hypointensity on T1 (Figure 6, A), hyperintense on DWI (Figure 6, B) 7 MRI: 3-cm right basal Neoplasm: primary or ganglia peripherally meta-static enhancing lesion with surrounding edema and midline shift (Figure 7, A and B) 8 MRI: Right middle Inflammatory, cerebellar peduncle demyelinating or /hemisphere T1 lymphoproliferative pro- hypointense, T2 cess hyperintense lesion (Figure 8, A and B) 9 MRI: Heterogeneous Inflammatory process, ring-enhancing cystic neoplasm suprasellar lesion separate from pituitary and stalk, near anterior communicating artery (Figure 9, A and B) 10 MRI: Bifrontal High-grade glioma butterfly lesion, T2 hyperintense (Figure 10, A) with focal peripheral enhancement on postcontrast T1 (Figure 10, B) 11 First MRI 2004: Large 2004: neoplasm right frontal contrast- enhancing mass and edema (Figure 11, A) Second MRI 2007: 2007: Demyelination vs Contrast-enhancing neo-plasm subcortical lesion in left inferior parietal lobe (Figure 11, C) 12 MRI: Cerebellar Lhermitte-Duclos disease enhancement with mass effect and edema (Figure 12, A); surrounding gyriform enhancement of folia on DWI (Figure 12, B) 13 MRI: Left parietal lobe High-grade glioma, 2-cm white matter-based lymphoma, lesion with irregular metastasis, abscess enhancing rim and surrounding edema (Figure 13, A and B) 14i MRI: 1.5-cm hypointense Schwannoma vs meningioma mass at left Meckel cave, involving left trigemi- nal ganglion (Figure 14, A) 14ii CT: Hyperdense right Atypical meningioma, frontoparietal vertex calvarial/dural extra-axial mass metastasis involving calvarium (Figure 14, E) 15 MRI: Bifrontal lesion on Neurosarcoidosis, either side of falx, meningioma, with dural extension dural metastases (Figure 15, A and B) 16 MRI: Multiple skull base Meningiomas lesions (Figure 16, A) 17 MRI: Multiple enhancing Neoplasm: favor lesions in left metastatic cerebellum, corpus callosum, cingulate gyrus, pons, thalamus, suprasellar region (Figure 17, A and B) with minimal mass effect 18 MRI: Left parietal lobe Recurrent tumor with lesion with peripheral cystic change vs enhancement on T1 radiation necrosis (Figure 18, A), hyperintense, partially cystic on T2 (Figure 18, B) Case No. Surgical Procedure Histology 1 Biopsy Granulomatous inflamma- tion with extensive necrosis (Figure 1, B), numerous multinucleated giant cells (Figure 1, B, inset); GMS-positive septate hyphae with acute angle branching (Figure 1, C) 2 Transsphenoidal hy- Nonadenomatous pituitary pophysectomy gland with fibrinopuru- lent material containing small- Cryptococcoma to medium-sized encapsulated yeast forms (Figure 2, C), strongly PAS (Figure 2, D) and GMS positive (Figure 2, E), weakly mucicarmine- positive capsules (Fig- ure 2, D, inset) 3 Resection of left Lymphohistiocytic temporal lobe perivascular infiltrate (Figure 3, C); macro- phages with abundant foamy cytoplasm (Figure 3, D); strongly PAS-positive bacilliform intracellular or- ganisms (Figure 3, E) 4 Resection Bacterial abscess (Figure 4, C and D). No evidence of tumor 5 Biopsy Intense acute inflammation with gram-positive cocci (Figure 5, C and D); Streptococcus intermedius on culture 6 Biopsy Neutrophilic abscess (Figure 6, D), with adjacent gliotic brain (Figure 6, C); fine, filamentous weakly gram-positive organisms (Figure 6, E, arrow); cultures grew Nocardia species 7 Stereotactic biopsy Granulomatous inflamma- tion with rare acid-fast bacilli (Figure 7, C through E) 8 Biopsy Bizarre, enlarged oligodendrocytes and atypical astrocytes, background histiocyte accumulation (Figure 8, C and D); MIB1-labeled infected cells (Figure 8, E) 9 Biopsy Gliosis, thick-walled vessels, chronic inflammation (Figure 9, C) and numerous eosinophils (Figure 9, C, inset); eosinophilic, necrotic cystic structure with serrated rim (Figure 9, D) 10 Resection White matter vacuolation (Figure 10, C), perivas- cular chronic inflamma- tion and gliosis (Figure 10, D); relative preservation of axons (Figure 10, E) 11 2004: First biopsy First biopsy: demyelina- ting lesion (Figure 11, B) 2007: Second biopsy Second biopsy: intense infiltrate of atypical B lymphocytes (Figure 11, D and E) 12 Resection Sharply demarcated necrosis, cerebellar cortex and white matter (Figure 12, C and D) with ischemic neurons, microglial proliferation, and macrophage accumula- tion (Figure 12, E) 13 Resection Perivascular mixed inflammatory infiltrate (Figure 13, C and F through H), with fibrinoid necrosis of vessel walls (Figure 13, D) highlighted by azocarmine (Fig- ure 13, E) 14i Resection Homogeneous eosinophilic extracellular deposits (Figure 14, B), congophilic (Figure 14, C), apple green birefringence (Figure 14, C, inset); EM: haphazard fibrils (Figure 14, D) 14ii Resection Amorphous congophilic deposits with apple green birefringence (Figure 14, F) 15 Resection of firm, Hyalinized vessels gray mass surrounded by dense lymphocytic infiltrate (Figure 15, C) of pre- dominantly B-cell type (Figure 15, D and E) 16 Resection Mixed inflammatory infiltrate with admixed pale-staining histiocytes (Figure 16, B and C) 17 Biopsy Dense mixed inflammatory infiltrate (Figure 17, C) predominantly histiocytes and B cells (Figure 17, D and E) with minor T-cell component (Figure 17, F) 18 Resection Necrotic parenchyma with hemosiderin deposits and vascular channels (Figure 18, C and D) Case No. Pathologic Diagnosis 1 Aspergilloma 2 Whipple disease 3 Bacterial abscess 4 Bacterial abscess 5 Nocardiosis 6 Tuberculoma 7 PML 8 Cysticercosis 9 Tumefactive demyelination 10 Demyelination 11 Lymphoma 12 Infarct, subacute 13 Vasculitis 14i Amyloidoma 14ii Amyloidoma 15 Castleman disease hyaline- vascular type 16 Rosai-Dorfman disease 17 Inflammatory pseudotumor 18 Radiation necrosis * s/p indicates status post; MRI, magnetic resonance imaging; GMS, Gomori methenamine silver; H/O, history of; DI, diabetes insipidus; PAS, periodic acid-Schiff; CHOP, cyclophosphamide, adriamycin, vincristine, prednisone; Tx, treatment; DWI, diffusion weighted imaging; PPD, purified protein derivative; CXR, chest x-ray; HIV, human immunodeficiency virus; CSF, cerebrospinal fluid; PML, progressive multifocal leukoencephalopathy; EM, electron microscopy; CT, computed tomography; and IDDM, insulin-dependent diabetes mellitus.
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|Title Annotation:||Review Article|
|Author:||Cunliffe, Clare H.; Fischer, Ingeborg; Monoky, David; Law, Meng; Revercomb, Carolyn; Elrich, Susan;|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Jan 1, 2009|
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