Giant Tuberculomas of Brain: Rare Neoplastic Mimic.

OBJECTIVE: Tuberculosis continues to be a major infectious disease in developing parts of the world. Primarily central nervous system tuberculosis manifests as meningitis, tuberculoma, or a brain abscess; however, rarely it may manifest as a large neoplastic mass such as lesion known as giant tuberculoma. Especially in central parts of India, the incidence of giant tuberculoma is quite high in pediatric population that too in posterior fossa of brain. Often, they are wrongly reported as neoplastic masses on imaging. The objective of this study was to evaluate different imaging appearances of a giant tuberculoma.
MATERIALS AND METHODS: In this prospective study, all cases of giant tuberculoma presenting to a large tertiary care center in central India for 2 years (duration 2016-2018) were imaged and followed up. A total of nine patients, six females and three males, aged 4-16 years were studied on a 3-Tesla Siemens magnetic resonance imaging (MRI) scanner.
RESULTS: In total, nine patients were included with 11 giant tuberculomas. Of 11, eight were infratentorial and three were supratentorial in location. On T2-weighted image sequence, these lesions showed central hypointensity with a peripheral hyperintense rim. Most observed finding on T1-weighted image sequence was central isointensity with peripheral hyperintense rim. Advanced imaging sequences such as magnetic resonance spectroscopy and magnetization transfer were also applied.
CONCLUSION: To the best of our knowledge, this is the largest series of giant tuberculoma in the pediatric population reported so far in any part of the world. We have described the various MRI imaging findings of this lesion in great details. Management of such rare cases and pertinent literature is reviewed briefly. Copyright:

INTRODUCTION

Tuberculosis (TB) is an infectious disease, which continues to be of major concern particularly in developing countries such as India.[1] Primarily a pulmonary disease, TB can affect multiple organs.[2] Involvement of central nervous system (CNS) takes place in approximately 5%–10% of all cases suffering with TB. It manifests as meningitis, tuberculoma, and brain abscess in CNS. In pediatric population, children with immunocompromised state, congenital heart disease, or on immunosuppressive drugs are particularly prone.[3] Tuberculomas generally result from hematogenous spread from distant sources.[3] Pathologically a tuberculoma consists of central zone of caseation with surrounding capsule of collagenous tissue. Imaging and characterization of tuberculomas is much better on magnetic resonance imaging (MRI) compared to computed tomography (CT); however, imaging features may overlap with other space occupying lesions, such as metastases, neurocysticercosis, and fungal granulomas.[4] Giant tuberculomas in posterior fossa however is a very uncommon presentation, which can easily be confused with neoplastic mass lesion. Only a few isolated case reports of such large-sized tuberculomas have been published till date. This study aimed to highlight the high incidence of such giant tuberculomas in central part of India and to discuss MRI imaging features of such lesions.

MATERIALS AND METHODS

This is a prospective study, which included all patients referred for MRI for 2 years with giant tuberculomas. Term “giant tuberculoma” has never been defined according to a specific size. A PubMed search for giant tuberculoma revealed few isolated case reports with none defining a size range for a giant tuberculoma. For the purpose of this study, giant tuberculoma was defined as a lesion with size >2.5 cm and a significant mass effect. A total of nine patients, six females and three males, aged 4–16 years (mean 9.6 years) who were admitted with varied sign and symptoms of mass lesion, fever, headache, raised intracranial tension, seizures, and other constitutional symptoms, to a major tertiary center in central part of India, between July 2016 and December 2018 were included in the study. Study was conducted under an approval by the Institutional Review Board. Probable diagnosis of tuberculoma was made on the basis of typical imaging and clinical features of the lesions. MRI was performed on 3-Tesla Siemens scanner. Following the provisional radiological and clinical diagnosis, final diagnosis of TB was based on typical cerebrospinal fluid (CSF) features (pleocytosis, high protein, and low sugar) and positive enzyme-linked immunosorbent assay (ELISA) for tuberculous immunoglobulin M and immunoglobulin G antibody and a favorable response to antitubercular drug treatment. All patients received standard dose of antitubercular treatment for variable intervals ranging from 18 months up to 24 months. They were followed up regularly in neurology outpatient department by clinical and serial CT/MRI examinations.

RESULTS

Clinical features

Among the presenting complaints, the most common was headache (100%) followed by vomiting (80%) and increased intracranial tension leading to papilledema (80%) and hemiparesis (20%). Extracranial involvement was seen in about third of patients in form of pulmonary TB, cervical lymphadenopathy, and Pott’s spine. Fever was seen only in those patients who had other systemic manifestations. None of the patient had past medical history of TB, but two patients had history of close contact with family member who had pulmonary TB.

Magnetic resonance imaging findings

In total, nine patients were included with 11 giant tuberculomas [Table 1]. One patient had two giant tuberculomas in both cerebellar hemispheres, respectively. Another patient had two tuberculomas, one in right parietal lobe and other in left cerebellar lobe.

Table 1

Clinical and Imaging characteristics of patients

Age /sex	Chief complaints	Location (supra/infratentorial)	MRI	Size	Extrapulmonary involvement	Treatment	Follow-up/complication
9Y/M	Headache and vomiting	Infratentorial––left cerebellar lobe	T2––centrally hypointensity with hyperintense rim T1––hypointense with hyperintense rim	4.7 cm × 3.5 cm	No	Medical	No deficit
4Y/F	Headache, vomiting, and ataxia	Infratentorial––right cerebellar lobe	T2––centrally hypointensity with hyperintense rim T1––hypointense with hyperintense rim	3.2 cm × 2 cm	No	Medical, Surgical decompression	No deficit
10Y/F	Fever, headache, vomiting, and neurological deficits	Infratentorial––left cerebellar lobe	T2––concentric layers of hyper- and hypointensity T1––predominantly hyperintense Post contrast T1––targetoid enhancement	5.35 cm × 4 cm	No	Medical, Surgical decompression	No deficit
16Y/M	Headache, vomiting, and neurological deficits	Infratentorial––left cerebellar lobe	T2––centrally hypointensity with hyperintense rim T1––hypointense with hyperintense rim Post-contrast T1––thick rim with outward projections	3.2 cm × 2.9 cm	Cervical lymphadenopathy	Medical, Surgical decompression	No deficit
16Y/F	Fever, headache, vomiting, and ataxia	Infratentorial––bilateral cerebellar hemisphere	T2––two centrally hypointensity with thick hyperintense rim T1––two central hyperintensities surrounded by alternate rings of hypo and hyperintensity Post-contrast T1––thick rim of enhancement	3 cm × 2.5 cm 3 cm × 2.5 cm	Potts spine	Medical treatment	No deficit
7Y/F	Headache, vomiting, and seizures	Infratenorial––left cerebellar hemisphere	T2––concentric layers of hyper- and hypointensity T1––predominantly hypointense with a thin peripheral hyperintense rim	2.5 cm × 2.3 cm	No	Medical treatment	No deficit
9Y/M	Headache, vomiting, and seizures	Supratentorial––right parietal lobe Infratenorial––left cerebellar lobe	T2––heterointense with central hypointense areas T1––hypointense with hyperintense rim Post-contrast T1––thick rim of enhancement	2.5 cm × 2.4 cm 4 cm × 3.7 cm	No	Medical treatment	No deficit
7Y/F	Headache, vomiting, and seizures	Supratentorial––right parietal lobe	T2––hypointense T1––hypointense with hyperintense rim Post-contrast T1––thick rim of enhancement	3.5 cm × 3 cm	No	Medical treatment	No deficit
8Y/F	Hemianesthesia, hemiparesis, and seizures	Supratentorial––right thalamus	T2––multiple central hypointense foci with hyperintense rim and a focus of central necrosis T1––hypointense with hyperintense rim Post-contrast––honeycomb like enhancement pattern	3.5 cm × 3.2 cm	Pulmonary Tuberculosis	Medical treatment	No deficit

Of 11, eight were infratentorial and three were supratentorial in location. In infratentorial lesions, six were located in left cerebellar hemisphere and two in right cerebellar hemisphere, respectively. Supratentorial lesions were, one each in right parietal lobe, left parietal lobe and in right thalamus.

On MRI brain, T2-weighted image (T2WI) sequence showed central hypointensity with peripheral hyperintense rim within the lesion [Figures 1 and 2]. Concentric/onion bulb like pattern of hypo- and hyperintensity on T2WI was also seen in few cases [Figure 5]. Surrounding moderate peri-lesional edema with tentorial herniation and brain-stem compression was a common finding in infratentorial lesions. Most observed finding on T1-weighted image (TIWI) was central isointensity with peripheral hyperintense rim [Figures 3]. In two of the cases central hyperintensity and a peripheral hyperintense rim separated by an isointense rim was observed [Figures 4 and 5]. Post-contrast study showed thick irregular solitary/conglomerate rings of enhancement [Figures 4 and 5]. Targetoid type of enhancement was also noted in one of the patients [Figure 3]. Honeycomb pattern of enhancement was seen in the lesion involving thalamus.

Figure 1

T2WI showing an irregular walled centrally hypointense mass lesion with peripheral hyperintense rim in left medial cerebellar lobe with moderate peri-lesional edema (A). On T1WI, the lesion appears predominantly hypo/isointense with a hyperintense rim (B). Irregular rim of peripheral enhancement is seen on post contrast T1WI (C and D). Note is also made of dilated ventricular system secondary to mass effect by giant tuberculoma

Figure 2

T2WI showing an irregular walled mass lesion with concentric/onion bulb like layers of hyper- and hypointensity in right cerebellar lobe with peri-lesional edema (A). On T1WI, the lesion appears predominantly isointense with a thin peripheral hyperintense rim and a focus of central hypointensity (B). DWI and ADC images show no restriction (C and D). MRS image shows a distinct lipid peak (E)

Figure 5

T2WI showing two thick walled lesions in bilateral cerebellar hemispheres showing central hypointensity surrounded by thick hyperintense rims with moderate peri-lesional edema (A). On T1WI, two central hyperintensities surrounded by alternate rings of hypo and hyperintensity are noted (B). Thick irregular rim of peripheral enhancement with small inward projections are seen on post-contrast T1WI (C and D)

Figure 3

T2WI showing an irregular walled large lesion with concentric/onion bulb like layers of hyper- and hypointensity in left cerebellar lobe with peri-lesional edema. An eccentric area of hypointensity is present (A). On T1WI, the lesion appears predominantly hyperintense (B). Irregular thick rim of peripheral enhancement is seen on post contrast T1WI with eccentric enhancing mural nodules (targetoid pattern) (C and D). Note is also made of dilated ventricular system secondary to mass effect by giant tuberculoma

Figure 4

T2WI showing an irregular walled lesion showing two central hypointensities surrounded by thick hyperintensity and a thin peripheral hypointense rim in left cerebellar lobe with moderate peri-lesional edema (A). On T1WI, two central hyperintensities surrounded by hypointensity and a peripheral thin hyperintense rim is seen (B). Thick irregular rim of peripheral enhancement with irregular outward projections is seen on post contrast T1WI (C and D)

Strong positive magnetization transfer (MT) effect was observed where MT sequence was applied.

Magnetic resonance spectroscopy (MRS) revealed lipid peak, which was uniformly seen in all cases. Other findings were reduction in NAA and creatinine, with choline to creatinine ratio >1 [Figure 2].

DISCUSSION

TB still remains the worldwide public health burden, especially in developing countries such as India.[5] CNS TB accounts for approximately 5%–10% of cases of active TB.[56] Approximately 5%–10% of intracranial space occupying lesions are tuberculomas.[6] Supratentorial tuberculomas are common; however, infratentorial posterior fossa tuberculomas in pediatric age group are a rare presentation.[6] They can affect multiple organs and are usually small tumor like masses.[7] Cerebellar involvement is more commonly seen in children between 6 months and 6 years.[8] On one hand, tuberculoma is a well-known entity with characteristic imaging findings on CT and MRI; “giant tuberculomas” on the other hand have been rarely reported in literature. Extensive PubMed search reveals only few isolated case reports. But this lesion is often misdiagnosed as brain tumor and taken for surgical evacuation.

Risk factors for CNS TB are HIV, malignancy, immunosuppressive agents, age (children > adults), and alcoholism. With the increase in HIV patients, there is increase TB cases with increased CNS manifestations.[8]

Intracranial TB has a varied spectrum ranging from meningitis, miliary TB, encephalopathy, tuberculous arteriopathy, to rarer forms including space occupying mass lesions, that is, isolated or multiple tuberculomas and tuberculous abscess.[910]

Tuberculomas result from hematogenous spread of tubercle bacilli to leptomeninges and brain parenchyma.[1] Of two stages of CNS TB, in first stage there is seeding of tubercle bacilli within brain parenchyma following hematogenous dissemination during primary/postprimary TB. These foci are known as “Rich foci.” After a dormant period of few months to years, second stage starts where bacilli and its antigens are released in subarachnoid space leading to tubercular meningitis. Intracranial tubercles might not rupture, instead they may enlarge within brain parenchyma and give rise to tuberculomas which are surrounded by a thick fibrous capsule.[191011] Grossly they are nodular lesions (2–12mm in size) and round to oval in shape.[12] Multiple tuberculomas very rarely may coalesces together forming a giant size mass and producing severe mass effect and focal neurological deficits.

On the contrary, a tuberculous abscess is an encapsulated collection of pus containing viable tubercular bacilli without evidence of the classic tubercular granuloma. It is important to distinguish tuberculous abscess from a granuloma with central caseation and liquefaction mimicking pus. Tuberculous abscess is attributed to low immune resistance when patients suffer from malnutrition.

Clinically giant tuberculomas present with sign and symptoms due to raised intracranial pressure and mass effect of which most common presentation is headache followed by epilepsy, features of raised intra-cranial tension, and limb weakness.[1213] Extracranial involvement was seen in about third of patients in form of pulmonary TB, cervical lymphadenopathy, and Pott’s spine, which suggested a clue to diagnosis of TB.

Diagnosis

In our study, probable diagnosis was based on typical imaging and clinical features. Final diagnosis was done on the basis of biopsy results in cases where surgical decompression was done, positive CSF features for TB and ELISA for tuberculous antibodies and resolution of lesions on antitubercular treatment. Radiology plays an important role in diagnosis of tuberculoma. MR has enhanced our diagnostic certainty and increased case detection.[12]

On non-contrast CT, during early stages of disease irregular hypodensity may be seen representing cerebritis. With developing inflammation and central caseation, they may appear as hypodense lesions with irregular outline, appearing as small ring enhancing lesions with perilesional edema on contrast CT. The lesions are usually larger than 20 mm, but sizes may vary from 1 to 6 cm. In the Indian scenario, a solitary ring enhancing lesion in CT scan of brain is the most common radiological finding in a young adult with a new onset seizure, with the most common etiology being neurocysticercosis (NCC) followed by tuberculoma.[1415161718192021]

Conventional MRI is better than CT for anatomic delineation; however, it is difficult to differentiate tuberculoma from NCC in conventional MRI. On MRI imaging appearance varies depending on stage of maturation of tuberculoma, whether noncaseating, caseating with a solid center or caseating with a liquid center. The noncaseating tuberculomas are hypointense on T1WI, hyperintense on T2WI, and show homogenous nodular enhancement. Tuberculomas with solid caseating center appear iso- to hypointense on both TIW and T2W images with a iso- to hyperintense rim on T2W images with a peripheral rim of enhancement, whereas tuberculomas with central liquid are hypointense on T1 image and hyperintense on T2WI with peripheral hypointense rim, and rim gets enhanced on contrast study.[678918,19,21] There may be different patterns of enhancement varying from complete ring, open rings, lobular patterns or may be irregular.[1]

Ring-chancing lesions such as neurocysticercosis, abscess, and metastases can mimic the radiological features of tuberculous on MRI; however, diagnostic efficacy can be improved by MRS and MT sequence.[1820,21] Other granulomatous lesions such as sarcoid and fungal infections can also mimic tuberculoma.[22]

MRS adds a great value in diagnosing tuberculoma confidently, especially in cases with overlapping imaging features such as tuberculoma vs. NCC. Giant tuberculomas can mimic intracerebral tumors on MRI imaging. With characteristic MRI appearances and no accompanied clinical and laboratory findings for TB, it is difficult to differentiate it from CNS tumors such as lymphoma and glioblastoma multiformae.[1237,202122] On MRS elevated lipid peak, cholesterol ester, plasmalogen, and phenolic glycolipids are seen, which can help differentiate tuberculomas from malignant tumors and other conditions.[12] Lipid peak in MRS in the context of a ring enhancing lesion is very much specific for tuberculoma and has not been seen in any cases of NCC, the other common differential diagnosis of a ring enhancing lesion. Other findings are reduction in N-acetylaspartate (NAA) and creatinine and a choline/creatinine ratio of >1.[232425262728]

NCC will show a high lactate peak and proteins such as alanine, succinate, glutamate, glycine levels with some reduction of NAA, and creatinine.[29] In pyogenic brain abscess elevated levels of amino-acid peaks help differentiate it from tuberculoma or tubercular brain abscesses. A high choline peak is seen in MRS in case of tumors, primary or secondary, because of very high cellular turnover.[129]

Till date, only a few “giant tuberculomas” mimicking mass lesions are reported. Most of them had secondary pulmonary involvement and occurred in immunocompromised patients.[30] Primary cerebellar tuberculoma is rare in immunologically competent patient like in our cases.

Binesh et al.[8] reported a case of isolated cerebellar tuberculoma in a 42-year-old female. Based on imaging, the lesion was reported as a neoplastic mass and underwent surgery for the same. Biopsy showed granulomatous reaction with central caseation confirming tuberculoma.

Parihar et al.[12] reported a case of large infratentorial extra-axial mass lesion attached to the tentorium in a 3-year-old girl child with differential diagnosis of meningioma, lymphoma, sarcoidosis, and metastatic tumor. Histopathology turned out to be tuberculoma. Patient did well on antitubercular treatment and was asymptomatic at 1-year follow-up.

Sumer et al.[30] in their report of a 66-year-old patient comment on how giant tuberculoma can mimic brain tumors. This patient had a large cerebellar mass (4 cm × 2.5 cm) and a small nodular enhancing lesion in another cerebellar hemisphere. With a pre-diagnosis of brain tumor, surgery was performed and on histopathology it turned out to be granulomatous lesion (tuberculoma).

Satyarthee[31] reported an extra-giant tuberculoma with considerable mass effect in an 11-year-old child, located in frontal lobe with a strong suspicion of a neoplastic mass and was advised surgery. However, patient refused surgery and was kept on antitubercular and anti-edema medication. They report a drastic improvement in 6 months.

Treatment

Medical approach is primary treatment modality. There has been no consensus regarding the duration of treatment of tuberculoma.[632,33] Few of the cases in present study were treated for extended course of up to 24 months. However, most of the cases (80%) showed complete clearance within 18 months.

Looking at these favorable outcomes, mostly among those who presented early, we suggest the use of empirical anti-tubercular therapy in endemic areas after presumptive diagnosis.

However, urgent surgical intervention may be needed in cases of giant tuberculoma to relieve symptoms due to mass effect and in cases of paradoxical response to antitubercular treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.