The Neuroradiology Journal 21: 551-562, 2008
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Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma D. KHURJEKAR*, C. BONICELLI**, A. BACCI**, R. AGATI**, M. LEONARDI** * Omega MRI Centre; Pune, India ** Neuroradiology Unit, Department of Neurosciences, Bellaria Hospital; Bologna, Italy
Key words: lymphoma, magnetic resonance imaging, stereotactic biopsy
SUMMARY – Primary cerebral lymphoma has varied clinical and imaging presentations making the neuroradiologic diagnosis of primary cerebral lymphoma a challenge. We discuss here three cases of cerebral lymphoma, one primary and two secondary. Our aim is to highlight the importance of diffusion, perfusion and spectroscopy in addition to conventional morphological MRI, and the role of stereotactic biopsy in reaching a correct diagnosis.
Introduction Primary lymphoma of the central nervous system (CNS) is rare with an increasing incidence since the advent of AIDS-related immunodeficiency and the use of immunosuppressive drugs with organ transplantation and cancer chemotherapy. We describe here three cases studied in our neuroradiology department whose stereotactic biopsy report and the MRI report was discordant in one case and concordance in the other two. We also discuss the importance of new functional techniques in MRI in reaching a correct diagnosis. The most common initial presentation of primary CNS lymphoma is a focal intracerebral mass 1, whereas the subarachnoid space is an extremely common site for recurrent disease. Approximately 10-30% of patients with systemic lymphoma may develop secondary CNS involvement 2,3. Tumour nodules typically develop in the subcortical and subependymal white matter and the corpus striatum. The corpus callosum is frequently involved in tumour extension, and a butterfly tumour may involve both cerebral hemispheres 4. Secondary systemic and primary CNS lymphomas have similar imaging characteristics. Menin-
geal involvement occurs commonly in secondary lymphoma and less frequently in primary lymphoma. The supratentorial compartment is involved in approximately 75-85% of patients at initial presentation 5. Multiplicity is very common and has been noted in up to half of all cases. Intracranial metastases from systemic lymphoma generally fall into one of two categories: leptomeningeal (with or without parenchyma) or dural-based 6. Almost all CNS lymphomas are non-Hodgkin B-cell tumours. Typically, lymphoma is represented by histiocytic cells or large immunoblastic cells bearing B-cell surface markers. The site of origin of primary CNS lymphoma remains controversial as the CNS does not have endogenous lymphoid tissue or a lymphatic circulation. The clinical presentation of CNS lymphoma is non specific and depends on the location of the neoplasm. Patients with CNS lymphoma can present with focal neurologic impairment, cognitive changes or seizures. The neuroradiological diagnosis is often difficult with conventional MRI because neurological findings of a cerebral lymphoma may mimic other pathologies like malignant gliomas, metastasis, abscess, demyelinating lesions, toxoplasmosis in AIDS patient and other non–neoplastic lesions. 551
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
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D. Khurjekar
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Figure 1 A) Axial SE T1-w post contrast. B) Axial FSE T2-w. Large enhancing lesion with small necrotic areas involving the basal ganglia, mainly the caudate nucleus (A). Perilesional edema hyperintense on T2-w images, involving white matter in frontal lobe, corpus callosum and internal capsule (B). A
B
Figure 2 A) Axial ADC (Apparent Diffusion Coefficient) map. B) Axial T2-w. ADC is reduced in the solid portion of the lesion (82%) and increased in the cystic part of the lesion and in the edema.
Patients and Methods Case no. 1 was a 67-year-old woman who presented with complaints of parasthesia and pain on the right side of the body and face for 552
one year. In September 2007, brain MRI was normal. In January 2008, she again came to the hospital with a history of disorientation, confusion and difficulty in walking for three to four months. She also had headache for a few
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The Neuroradiology Journal 21: 551-562, 2008
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Figure 3 A) Axial perfusion rCBV map. B) Intensity/time graph. C) Axial SE T1-w post contrast. Perfusion is slightly decreased (42-67%) in the lesion (red curve) as compared to the normal white matter (green curve).
days and some episodes of urine incontinence. Her MRI done on 27th January revealed a large enhancing lesion with small necrotic areas in the right fronto-temporo-parietal white matter involving the basal ganglia, mainly the caudate
nucleus. The lesion had extensive perilesional edema appearing hyperintense on T2-w images (figure 1 A,B). T2 hyperintensities were also seen in the posterior limb of the left internal capsule, left periventricular white matter and 553
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
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D. Khurjekar
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Figure 4 A) Axial FSE T2-w with VOI (Volume of Interest-5.8 ml). B) Single voxel spectroscopy (TR 2000, TE 35). Spectroscopy reveals that NAA and creatine are absent and the peak intensities of compounds containing choline (3.2 ppm) and lipid (1.3-0.9 ppm) are increased.
pons on the right side. Diffusion study revealed that apparent diffusion coefficient (ADC) values were reduced in the solid portion of the lesion, the ratio with the normal white matter ADC values being 0.8-0.9. Whereas, ADC values in the cystic part of the lesion were increased, the ratio with the normal white matter ADC values being 2-2.3 (figure 2 A,B). Perfusion was not increased in the lesion compared to the normal white matter, the rCBV (relative Cerebral Blood Volume) values being 0.4-0.7 (figure 3 A-C). Spectroscopy revealed that N- acetyl aspartate (NAA) and creatine were absent and the peak intensities of compounds containing choline and lipid were increased (figure 4 A,B). Considering the morphology and the characteristic pattern of diffusion and spectroscopy, we concluded that the possible diagnosis was lymphoma. A stereotactic biopsy was done on the 31st January and the histology report was given as “low grade astrocytoma or periphery of a high grade tumour”. Corticosteroid treatment was started empirically and a follow-up study was done on the 7th February which showed a reduction in the mass effect and change in con554
sistency of the solid portion revealed by change in the pattern of enhancement. Follow-up studies revealed a further reduction in the size of the lesion and perilesional edema. The patient underwent an excisional biopsy and the histology report turned out to be an “anaplastic lymphoma type B with large cells”. Case no. 2 was a 50-year-old woman who was admitted to our hospital in March 2007 with complaints of dyspnea and large lateral cervical lymph nodal enlargement. Initially she was treated with corticosteroids for dyspnea. Later she was diagnosed to have mediastinal lymphoma and so radiotherapy and chemotherapy were started. She was treated completely and now has no mediastinal complaints. In January 2008 she again came to our hospital with complaints of confusion, disorientation and difficulty in speech. Computed tomography (CT) scan with contrast showed a large iso to hyperdense lesion in the left temporal lobe. On contrast administration there was a peripheral thick area of enhancement with central small necrotic non enhancing area. The lesion had surrounding edema. MRI showed a large enhancing lesion in the left temporal lobe with inhomogenous signal in every sequence. On T2-w images there were
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The Neuroradiology Journal 21: 551-562, 2008
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Figure 5 A) Axial SE T1-w post contrast. B) Axial FSE T2-w. Large enhancing lesion in left temporo-insular region (A) with inhomogenous signal on the T2 image with a few hypointense areas in the solid part of the lesion suggestive of hemosiderin deposition. There is perilesional edema causing mass effect on the ventricles and midline shift (B).
few hypointense areas in the solid part of the lesion suggestive of hemosiderin deposition. There was perilesional edema causing mass effect on the ventricles and midline shift (figure 5 A,B). Diffusion study showed a decrease in the ADC values in the solid portion of the lesion, the ratio with the normal white matter ADC values being 0.8 (figure 6 A,B). Perfusion showed that the rCBV was the same as the opposite white matter or slightly reduced in some portions, the value being 0.3 (figure 7 A-C). At spectroscopy, the peak intensities of compounds containing choline and lipid were increased, while creatine and NAA were absent (figure 8 A-C). All these aspects together suggested a lymphoma. The patient underwent surgery with left fronto-temporal craniotomy and excisional biopsy was done confirming the diagnosis of “anaplastic lymphoma type B with large cells”. Case no. 3 was a 76-year-old woman who had lymphoma of left maxillary sinus and was completely treated with chemotherapy in April 2002. In February 2008 she presented with paresthesia of the superior lip, deviation of angle of mouth and minimal motor deficit on the right side. CT scan showed a subcortical pari-
etal lesion on the left side. MRI was also done at that time which showed a similar lesion and a secondary localisation of the maxillary sinus lymphoma or an infectious lesion was suspected. Steroid therapy was started empirically. In April 2008 when she came to our hospital, there was worsening of her condition due to discontinuation of steroids. Brain MRI revealed an isointense lesion on T1-w images in the left frontoparietal lobe with perilesional edema. The lesion was slightly hyperintense on T2-w images and showed post contrast enhancement (figure 9 A,B). Diffusion study showed a decrease in the ADC values compatible with high cellularity, the ratio with the normal white matter ADC values being 0.9 (figure 10 A,B). Perfusion showed that the rCBV was the same as the opposite white matter (figure 11 A-C). At spectroscopy, the peak intensities of compounds containing choline was raised and lipids were markedly increased, while creatine and NAA were absent (figure 12 A,B). The patient underwent surgery with left frontoparietal craniotomy and excisional biopsy was done confirming the diagnosis of “non-Hodgkin lymphoma with large cells”. 555
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
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D. Khurjekar
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Figure 6 A) Axial ADC (Apparent Diffusion Coefficient) map. B) Axial T2-w. ADC is reduced in the solid portion of the lesion (78%) and increased in the edema. A
MR Protocols All MRI and localized single voxel 1H-MRS measurements were performed with a 3T whole-body scanner (General Electric Medical 556
B
Systems, Milwaukee, Wisconsin). Our standard routine clinical protocol involved the use of the standard eight-channel phased array head coil, which allowed the best signal-to-noise ratio for MRI and MRS.
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The Neuroradiology Journal 21: 551-562, 2008
C
Figure 7 A) Axial perfusion rCBV map. B) Intensity/time graph. C) Axial SE T1-w post contrast. Perfusion of the lesion (red curve) is the same as the opposite white matter (green curve).
A
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Figure 8 A) Axial FSE T2-w with VOI (Volume of Interest-1.8 ml). B) Single voxel spectroscopy (TR 2000, TE 35). Spectroscopy reveals that NAA and creatine are absent and the peak intensities of compounds containing choline (3.2 ppm) and lipid (1.3-0.9 ppm) are increased.
MR imaging was performed with T2-w Fast Spin-Echo (FSE) sequences (4200/93,6, 24cm field of view, 512×512 matrix, 4 mm sections), Fluid Attenuated Inversion Recovery (FLAIR) sequences (9002/91,4, 24 cm field of
view, 320×320 matrix, 4 mm sections) in the axial plane and T1-w Spin-Echo (SE) sequences (560/18,6, 24 cm field of view, 384×224 matrix, 4-mm sections) in the sagittal and coronal planes before contrast agent administration 557
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
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Figure 9 A) Axial SE T-w post contrast. B) Axial T2-w. Large enhancing lesion involving the white matter in frontoparietal site, above the left lateral ventricle (A). The lesion is slightly hyperintense on T2-w images, with perilesional edema (B).
A
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Figure 10 A) Axial ADC (Apparent Diffusion Coefficient) map. B) Axial T2-w. ADC is reduced in the lesion (93%) and increased in the edema.
and coronal and axial planes after contrast agent administration. 1 H-MR spectra were acquired before administering the contrast agent by using a point-resolved spin echo sequence (PRESS) for locali558
zation, with TR 2000 ms and TE 35 ms, 128 acquisitions and a three-pulse chemical-shift selective saturation sequence (CHESS) to provide water suppression. For each spectrum 16 additional acquisi-
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The Neuroradiology Journal 21: 551-562, 2008
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Figure 11 A) Axial perfusion rCBV map. B) Intensity/time graph. C) Axial SE T1-w post contrast. Perfusion of the lesion (red curve) is the same as the opposite white matter (green curve).
tions with unsuppressed water were collected for phase correction of the metabolite spectra. Automated optimization of gradient shimming, transmitter pulse power and water suppression was used. In all cases the quality of the
shimming obtained in the voxel was controlled by the spectral line width (full width of half maximum in Hz) of the unsuppressed water, obtained by the automated pre-scanning optimisation sequence. 559
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
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Figure 12 A) Axial FSE T2-w with VOI (Volume of Interest-1.8 ml). B) Single voxel spectroscopy (TR 2000, TE 35). Spectroscopy reveals that NAA and creatine are absent and the peak intensities of compounds containing choline (3.2 ppm) and lipid (1.3-0.9 ppm) are increased.
The value of the peak intensities of the main metabolites, N-acetyl aspartate (NAA, 2.02 ppm), choline-containing compounds (Cho, 3.22 ppm), creatine and phosphocreatine (Cr, 3.03 ppm) and myo-inositol (mI, 3.56 and 4.06 ppm) were compared with the values obtained in the white matter of the left frontal region of 16 healthy volunteers aged between 25 and 67 years (mean 40,7±9). The volume of interest (VOI) was positioned over the lesions. Diffusion images were acquired by DWI (bvalue 1000 , TR - 8000 , TE - 64.1) and perfusion images with SE-EPI (TR - 1850 ,TE - 70) and were processed by Functool to measure the values of ADC and rCBV in the lesion and compare them with those in normal white matter. Spectra Analysis All MR spectra were analyzed using the Spectra Analysis programme (SAGE, General Electric Medical Systems) by the following steps. After the eight channel signals were combined, the estimated phase correction of the unsuppressed water signal was used to phase correct the corresponding metabolite (water suppressed) signal. The water suppressed signal 560
was subtracted from the unsuppressed one and the “pure water signal” obtained was scaled and subtracted from the suppressed signal to obtain the final metabolite spectrum. After a Gaussian apodization, data were Fourier transformed and interpolated to obtain a resolution of 2055/4096 Hz per point. Chemical shifts were referenced to the signal of Cho at 3.22 ppm. Discussion MRI is the examination of choice in diagnosis of cerebral lymphoma because of its high sensitivity and multiplanar capability. MRI findings in our patients resembled those reported in the literature showing one or multiple poorly demarcated masses, more or less deeply located within the brain parenchyma and involving the deep grey matter structures, periventricular regions and corpus callosum. It has also been reported that up to 75% of lymphomatous masses are seen to be in contact with ependyma, meninges or both 1. The extent of edema on MRI is generally less than that seen in conjunction with the primary gliomas or metastases of similar size. But in our cases, on the contrary there was significant edema causing mass effect. In these masses there is no calcifi-
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cation and hemorrhage is rare 7. In our second patient, we saw hemosiderin deposition in T2 axial images which is a rare finding. All three cases showed intense contrast enhancement after intravenous contrast administration, that occurs in the vast majority of cases and can be dense and homogenous, but is somewhat variable 8. If steroids are administered, the tumours may shrink and “vanish”, compromising the ability to obtain a histologic diagnosis. Considering the diverse presentations of these masses, it is a challenge to diagnose lymphoma only on the basis of morphology and hence the need for functional techniques. Diffusion plays an important role in diagnosis of lymphoma because these lesions are predominantly hyperintense to white matter on diffusion weighted images and isointense to mildly hypointense to white matter on ADC maps representing increased cellularity and low diffusivity, similar to the presentation in our cases. The reduced ADC values are considered useful for differentiation from glioma and metastases which typically show higher ADC values 9,10. The specificity and accuracy of ADC is higher than that of fractional anisotropy in differentiating primary cerebral lymphomas from glioblastoma multiforme 11. The ability of perfusion MR imaging to help detect and quantify tumour angiogenesis can potentially be useful in differentiating high grade glioma from cerebral lymphoma because angiogenesis is not a prominent feature in lymphoma. Lower rCBV values have been described for lymphoma as in our patients. A characteristic intensity – time curve has been demonstrated for lymphoma with a significant increase above baseline due to the massive leakage of contrast agent into the interstitial spaces 11. The advent of MR spectroscopy (MRS) has added to the diagnostic capabilities enabling tissue characterisation based on molecular composition. It provides information on cell proliferation, gradation, neuronal viability and energy metabolism. Based on these characteristics MRS readily differentiates normal from abnormal brain tissue 12,13. The spectra of our three cases revealed elevated peak intensities of compounds containing choline and lipids, whereas NAA and creatine were absent. These data suggested that they were lesions with high proliferative activity and necrosis, according to the literature 14,15. Before starting a specific therapy, it is important to have a precise pathological diagno-
The Neuroradiology Journal 21: 551-562, 2008
sis and so stereotactic biopsy may be needed. Stereotactic brain biopsy is usually considered a minimally invasive procedure for establishing the diagnosis of a brain lesion and for lesions not readily accessible through an open procedure. It allows neurosurgeons to localize and sample intrinsic lesions located anywhere within the brain accurately 16. While MRI and functional MRI techniques have the ability to analyse these lesions well, biopsy has a high risk of sampling error resulting in misdiagnosis. In our first case the stereotactic biopsy was contrary to the MRI report and it was the excisional biopsy which gave the correct diagnosis. Various pitfalls of stereotactic biopsy are reported in the literature. The amount of tissue taken from the brain is so small that sometimes the pathologist has difficulty finding enough cells that qualify for a particular diagnosis. If areas peripheral to the main lesion are sampled, the diagnosis is liable to come back either: “non specific inflammatory changes” or “gliosis”. The biopsy adds additional risks of mortality (0.9%) and major morbidity (4%) and leads to an inaccurate or imprecise diagnosis in a third to a half of cases 17. The causes of a non diagnostic specimen 18 can be: • Sampling wrong area. • Small sample size. • Inaccurate tissue targeting resulting in sampling error. • Target choice in areas of high signal on T2weighted MRI. • Small target size. • Incorrect stereotactic coordinate settings. Recently, MRI guided brain biopsies were recommended for precision in stereotactic biopsies 19. Failure to obtain a diagnosis means treatment will be delayed pending a repeat biopsy or if repeat biopsy cannot be done, perhaps indefinitely. On the basis of an incomplete workup without pathologic confirmation an incorrect diagnosis may be made and potentially injurious inappropriate treatments initiated. Conclusion Neuroradiologic diagnosis of primary cerebral lymphoma remains a challenge. We did not find differences between primary and secondary lymphoma. Conventional MRI imaging findings of cerebral lymphoma can be similar to those of other intracranial tumours or even 561
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
those of demyelinating lesions. These lesions usually enhance, can be multiple, can favour a deep gray matter or subependymal location; they frequently involve the corpus callosum and can appear similar to GBM. Reduced ADC values due to increased cellularity help us to differentiate lymphoma from high grade glioma or inflammatory disease. The ability of perfusion MR imaging to help detect and quantify
D. Khurjekar
tumour angiogenesis can potentially be useful in differentiating high grade glioma from cerebral lymphoma 20. Absence of NAA and creatine with high lipids indicates a malignant non glial neoplasm. Considering all these varied aspects of cerebral lymphoma, we emphasise that MRI can be an excellent non invasive option for making a correct diagnosis.
References 1 Hochberg FH, Miller DC: Primary central nervous system lymphoma. J Neurosurg 68: 835-853, 1988. 2 Barnard RO, Scott T: Patterns of proliferation in cerebral lymphoreticular tumours. Acta Neuropathol: Suppl VI 1977: 125. 3 Zee, Segall HD: A Study Guide. Neuroradiology, McGraw-Hill:158-60, 1996. 4 Djamil Fertikh: Brain, Lymphoma Article. Medscape Journal, on-line. 5 Jack CR, O’Neill BP et Al: Central nervous system lymphoma: histologic types and CT appearance. Radiology 167: 211-215, 1988. 6 Russell DS, Rubistein LJ: Pathology of the tumours of nervous system, 5th ed. William and Wilkins, Baltimore 1989. 7 Deckert M, Paulus W: Malignant lymphomas, WHO Classification of Tumours of the Central Nervous System, 4th Edition: 188 – 196, International Agency for Research on Cancer 2007. 8 Atlas SW: Magnetic Resonance Imaging of the brain and spine. Intra axial brain tumours: 302 – 307. Raven Press, New York 1991. 9 Guo AC, Cummings TJ,et Al: Lymphoma and high grade astrocytomas: Comparision of water diffusibility and histologic characteristics. Radiology: 177-83, 2002. 10 Toh C H, Castillo M et Al: Primary Cerebral Lymphoma and Glioblastoma Multiforme: Differences in Diffusion Characteristics Evaluated with Diffusion Tensor Imaging. Am J Neuroradiology 2: 471-75, Mar 2008. 11 Rollin N, Guyotat J et Al: Clinical relevance of diffusion and perfusion magnetic resonance imaging in assessing intra-axial brain tumours. Neuroradiology 48: 150-159 DOI 10.1007/s00234-005-0030-7, 2006. 12 Bruhn H: Non invasive differentiation of tumours with use of localised H-1 MRI spectroscopy in vivo: initial experience in patients with cerebral tumours. Radiology: 541-8, 1989. 13 Butzen J, Prost R, Chetty V et Al: Discrimination between neoplastic and non neoplastic brain lesions by use of Proton MRI spectroscopy. The limits of accuracy with Logistic Regression Model. Am Soc Neuroradiology:1213-9, 2000. 14 Al-Okaili RN, Krejza J, Wang S et Al: Advanced MR imaging techniques in the diagnosis of intra axial brain tumours in adults. Radiographics: 173-89, 2005. 15 Kuhlmann T, Schroter A et Al: Diagnosis of a multifocal B cell lymphoma with preceding demyelinating central nervous system lesions by single voxel proton MR spectroscopy. J Neurol Neurosurgery Psychiatry 70: 259-262, 2001. 16 Aker FV, Hakan T et Al: Accuracy and diagnostic yield of stereotactic biopsy in the diagnosis of brain masses: Comparision of results of biopsy and resected surgical specimens. Neuropathology 25: 207-213, 2005. 17 Jackson RJ, Fuller G N et Al: Limitations of stereotactic biopsy in the initial management of gliomas. NeuroOncology: 193-200, July 2001.
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18 Hall W A: The Safety and Efficacy of Stereotactic Biopsy for Intracranial Lesions. Cancer: 1749-1755, May 1998. 19 Hall W A, Liu H et Al: Comparision of Stereotactic brain biopsy to Interventional Magnetic – ResonanceImaging-Guided Brain Biopsy. Stereotactic and Functional Neurosurgery 73: 148-153, 1999. 20 Cha et Al: Intracranial Mass Lesions: Dynamic Contrast – enhanced Susceptibility – weighted Echo – planar perfusion MR imaging. Radiology 223 Number1: 11-29, April 2002.
D. Khurjekar, MD Omega MRI Centre Poona Hospital Campus Sadashiv Peth 411030 Pune Maharashtra India E-mail: [email protected]
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Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma D. KHURJEKAR*, C. BONICELLI**, A. BACCI**, R. AGATI**, M. LEONARDI** * Omega MRI Centre; Pune, India ** Neuroradiology Unit, Department of Neurosciences, Bellaria Hospital; Bologna, Italy
Key words: lymphoma, magnetic resonance imaging, stereotactic biopsy
SUMMARY – Primary cerebral lymphoma has varied clinical and imaging presentations making the neuroradiologic diagnosis of primary cerebral lymphoma a challenge. We discuss here three cases of cerebral lymphoma, one primary and two secondary. Our aim is to highlight the importance of diffusion, perfusion and spectroscopy in addition to conventional morphological MRI, and the role of stereotactic biopsy in reaching a correct diagnosis.
Introduction Primary lymphoma of the central nervous system (CNS) is rare with an increasing incidence since the advent of AIDS-related immunodeficiency and the use of immunosuppressive drugs with organ transplantation and cancer chemotherapy. We describe here three cases studied in our neuroradiology department whose stereotactic biopsy report and the MRI report was discordant in one case and concordance in the other two. We also discuss the importance of new functional techniques in MRI in reaching a correct diagnosis. The most common initial presentation of primary CNS lymphoma is a focal intracerebral mass 1, whereas the subarachnoid space is an extremely common site for recurrent disease. Approximately 10-30% of patients with systemic lymphoma may develop secondary CNS involvement 2,3. Tumour nodules typically develop in the subcortical and subependymal white matter and the corpus striatum. The corpus callosum is frequently involved in tumour extension, and a butterfly tumour may involve both cerebral hemispheres 4. Secondary systemic and primary CNS lymphomas have similar imaging characteristics. Menin-
geal involvement occurs commonly in secondary lymphoma and less frequently in primary lymphoma. The supratentorial compartment is involved in approximately 75-85% of patients at initial presentation 5. Multiplicity is very common and has been noted in up to half of all cases. Intracranial metastases from systemic lymphoma generally fall into one of two categories: leptomeningeal (with or without parenchyma) or dural-based 6. Almost all CNS lymphomas are non-Hodgkin B-cell tumours. Typically, lymphoma is represented by histiocytic cells or large immunoblastic cells bearing B-cell surface markers. The site of origin of primary CNS lymphoma remains controversial as the CNS does not have endogenous lymphoid tissue or a lymphatic circulation. The clinical presentation of CNS lymphoma is non specific and depends on the location of the neoplasm. Patients with CNS lymphoma can present with focal neurologic impairment, cognitive changes or seizures. The neuroradiological diagnosis is often difficult with conventional MRI because neurological findings of a cerebral lymphoma may mimic other pathologies like malignant gliomas, metastasis, abscess, demyelinating lesions, toxoplasmosis in AIDS patient and other non–neoplastic lesions. 551
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
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D. Khurjekar
B
Figure 1 A) Axial SE T1-w post contrast. B) Axial FSE T2-w. Large enhancing lesion with small necrotic areas involving the basal ganglia, mainly the caudate nucleus (A). Perilesional edema hyperintense on T2-w images, involving white matter in frontal lobe, corpus callosum and internal capsule (B). A
B
Figure 2 A) Axial ADC (Apparent Diffusion Coefficient) map. B) Axial T2-w. ADC is reduced in the solid portion of the lesion (82%) and increased in the cystic part of the lesion and in the edema.
Patients and Methods Case no. 1 was a 67-year-old woman who presented with complaints of parasthesia and pain on the right side of the body and face for 552
one year. In September 2007, brain MRI was normal. In January 2008, she again came to the hospital with a history of disorientation, confusion and difficulty in walking for three to four months. She also had headache for a few
www. centauro. it
A
The Neuroradiology Journal 21: 551-562, 2008
B
C
Figure 3 A) Axial perfusion rCBV map. B) Intensity/time graph. C) Axial SE T1-w post contrast. Perfusion is slightly decreased (42-67%) in the lesion (red curve) as compared to the normal white matter (green curve).
days and some episodes of urine incontinence. Her MRI done on 27th January revealed a large enhancing lesion with small necrotic areas in the right fronto-temporo-parietal white matter involving the basal ganglia, mainly the caudate
nucleus. The lesion had extensive perilesional edema appearing hyperintense on T2-w images (figure 1 A,B). T2 hyperintensities were also seen in the posterior limb of the left internal capsule, left periventricular white matter and 553
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
A
D. Khurjekar
B
Figure 4 A) Axial FSE T2-w with VOI (Volume of Interest-5.8 ml). B) Single voxel spectroscopy (TR 2000, TE 35). Spectroscopy reveals that NAA and creatine are absent and the peak intensities of compounds containing choline (3.2 ppm) and lipid (1.3-0.9 ppm) are increased.
pons on the right side. Diffusion study revealed that apparent diffusion coefficient (ADC) values were reduced in the solid portion of the lesion, the ratio with the normal white matter ADC values being 0.8-0.9. Whereas, ADC values in the cystic part of the lesion were increased, the ratio with the normal white matter ADC values being 2-2.3 (figure 2 A,B). Perfusion was not increased in the lesion compared to the normal white matter, the rCBV (relative Cerebral Blood Volume) values being 0.4-0.7 (figure 3 A-C). Spectroscopy revealed that N- acetyl aspartate (NAA) and creatine were absent and the peak intensities of compounds containing choline and lipid were increased (figure 4 A,B). Considering the morphology and the characteristic pattern of diffusion and spectroscopy, we concluded that the possible diagnosis was lymphoma. A stereotactic biopsy was done on the 31st January and the histology report was given as “low grade astrocytoma or periphery of a high grade tumour”. Corticosteroid treatment was started empirically and a follow-up study was done on the 7th February which showed a reduction in the mass effect and change in con554
sistency of the solid portion revealed by change in the pattern of enhancement. Follow-up studies revealed a further reduction in the size of the lesion and perilesional edema. The patient underwent an excisional biopsy and the histology report turned out to be an “anaplastic lymphoma type B with large cells”. Case no. 2 was a 50-year-old woman who was admitted to our hospital in March 2007 with complaints of dyspnea and large lateral cervical lymph nodal enlargement. Initially she was treated with corticosteroids for dyspnea. Later she was diagnosed to have mediastinal lymphoma and so radiotherapy and chemotherapy were started. She was treated completely and now has no mediastinal complaints. In January 2008 she again came to our hospital with complaints of confusion, disorientation and difficulty in speech. Computed tomography (CT) scan with contrast showed a large iso to hyperdense lesion in the left temporal lobe. On contrast administration there was a peripheral thick area of enhancement with central small necrotic non enhancing area. The lesion had surrounding edema. MRI showed a large enhancing lesion in the left temporal lobe with inhomogenous signal in every sequence. On T2-w images there were
www. centauro. it
A
The Neuroradiology Journal 21: 551-562, 2008
B
Figure 5 A) Axial SE T1-w post contrast. B) Axial FSE T2-w. Large enhancing lesion in left temporo-insular region (A) with inhomogenous signal on the T2 image with a few hypointense areas in the solid part of the lesion suggestive of hemosiderin deposition. There is perilesional edema causing mass effect on the ventricles and midline shift (B).
few hypointense areas in the solid part of the lesion suggestive of hemosiderin deposition. There was perilesional edema causing mass effect on the ventricles and midline shift (figure 5 A,B). Diffusion study showed a decrease in the ADC values in the solid portion of the lesion, the ratio with the normal white matter ADC values being 0.8 (figure 6 A,B). Perfusion showed that the rCBV was the same as the opposite white matter or slightly reduced in some portions, the value being 0.3 (figure 7 A-C). At spectroscopy, the peak intensities of compounds containing choline and lipid were increased, while creatine and NAA were absent (figure 8 A-C). All these aspects together suggested a lymphoma. The patient underwent surgery with left fronto-temporal craniotomy and excisional biopsy was done confirming the diagnosis of “anaplastic lymphoma type B with large cells”. Case no. 3 was a 76-year-old woman who had lymphoma of left maxillary sinus and was completely treated with chemotherapy in April 2002. In February 2008 she presented with paresthesia of the superior lip, deviation of angle of mouth and minimal motor deficit on the right side. CT scan showed a subcortical pari-
etal lesion on the left side. MRI was also done at that time which showed a similar lesion and a secondary localisation of the maxillary sinus lymphoma or an infectious lesion was suspected. Steroid therapy was started empirically. In April 2008 when she came to our hospital, there was worsening of her condition due to discontinuation of steroids. Brain MRI revealed an isointense lesion on T1-w images in the left frontoparietal lobe with perilesional edema. The lesion was slightly hyperintense on T2-w images and showed post contrast enhancement (figure 9 A,B). Diffusion study showed a decrease in the ADC values compatible with high cellularity, the ratio with the normal white matter ADC values being 0.9 (figure 10 A,B). Perfusion showed that the rCBV was the same as the opposite white matter (figure 11 A-C). At spectroscopy, the peak intensities of compounds containing choline was raised and lipids were markedly increased, while creatine and NAA were absent (figure 12 A,B). The patient underwent surgery with left frontoparietal craniotomy and excisional biopsy was done confirming the diagnosis of “non-Hodgkin lymphoma with large cells”. 555
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
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Figure 6 A) Axial ADC (Apparent Diffusion Coefficient) map. B) Axial T2-w. ADC is reduced in the solid portion of the lesion (78%) and increased in the edema. A
MR Protocols All MRI and localized single voxel 1H-MRS measurements were performed with a 3T whole-body scanner (General Electric Medical 556
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Systems, Milwaukee, Wisconsin). Our standard routine clinical protocol involved the use of the standard eight-channel phased array head coil, which allowed the best signal-to-noise ratio for MRI and MRS.
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Figure 7 A) Axial perfusion rCBV map. B) Intensity/time graph. C) Axial SE T1-w post contrast. Perfusion of the lesion (red curve) is the same as the opposite white matter (green curve).
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Figure 8 A) Axial FSE T2-w with VOI (Volume of Interest-1.8 ml). B) Single voxel spectroscopy (TR 2000, TE 35). Spectroscopy reveals that NAA and creatine are absent and the peak intensities of compounds containing choline (3.2 ppm) and lipid (1.3-0.9 ppm) are increased.
MR imaging was performed with T2-w Fast Spin-Echo (FSE) sequences (4200/93,6, 24cm field of view, 512×512 matrix, 4 mm sections), Fluid Attenuated Inversion Recovery (FLAIR) sequences (9002/91,4, 24 cm field of
view, 320×320 matrix, 4 mm sections) in the axial plane and T1-w Spin-Echo (SE) sequences (560/18,6, 24 cm field of view, 384×224 matrix, 4-mm sections) in the sagittal and coronal planes before contrast agent administration 557
Importance of Functional MRI and the Role of Stereotactic Biopsy in the Diagnosis of Cerebral Lymphoma
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Figure 9 A) Axial SE T-w post contrast. B) Axial T2-w. Large enhancing lesion involving the white matter in frontoparietal site, above the left lateral ventricle (A). The lesion is slightly hyperintense on T2-w images, with perilesional edema (B).
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Figure 10 A) Axial ADC (Apparent Diffusion Coefficient) map. B) Axial T2-w. ADC is reduced in the lesion (93%) and increased in the edema.
and coronal and axial planes after contrast agent administration. 1 H-MR spectra were acquired before administering the contrast agent by using a point-resolved spin echo sequence (PRESS) for locali558
zation, with TR 2000 ms and TE 35 ms, 128 acquisitions and a three-pulse chemical-shift selective saturation sequence (CHESS) to provide water suppression. For each spectrum 16 additional acquisi-
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The Neuroradiology Journal 21: 551-562, 2008
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Figure 11 A) Axial perfusion rCBV map. B) Intensity/time graph. C) Axial SE T1-w post contrast. Perfusion of the lesion (red curve) is the same as the opposite white matter (green curve).
tions with unsuppressed water were collected for phase correction of the metabolite spectra. Automated optimization of gradient shimming, transmitter pulse power and water suppression was used. In all cases the quality of the
shimming obtained in the voxel was controlled by the spectral line width (full width of half maximum in Hz) of the unsuppressed water, obtained by the automated pre-scanning optimisation sequence. 559
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Figure 12 A) Axial FSE T2-w with VOI (Volume of Interest-1.8 ml). B) Single voxel spectroscopy (TR 2000, TE 35). Spectroscopy reveals that NAA and creatine are absent and the peak intensities of compounds containing choline (3.2 ppm) and lipid (1.3-0.9 ppm) are increased.
The value of the peak intensities of the main metabolites, N-acetyl aspartate (NAA, 2.02 ppm), choline-containing compounds (Cho, 3.22 ppm), creatine and phosphocreatine (Cr, 3.03 ppm) and myo-inositol (mI, 3.56 and 4.06 ppm) were compared with the values obtained in the white matter of the left frontal region of 16 healthy volunteers aged between 25 and 67 years (mean 40,7±9). The volume of interest (VOI) was positioned over the lesions. Diffusion images were acquired by DWI (bvalue 1000 , TR - 8000 , TE - 64.1) and perfusion images with SE-EPI (TR - 1850 ,TE - 70) and were processed by Functool to measure the values of ADC and rCBV in the lesion and compare them with those in normal white matter. Spectra Analysis All MR spectra were analyzed using the Spectra Analysis programme (SAGE, General Electric Medical Systems) by the following steps. After the eight channel signals were combined, the estimated phase correction of the unsuppressed water signal was used to phase correct the corresponding metabolite (water suppressed) signal. The water suppressed signal 560
was subtracted from the unsuppressed one and the “pure water signal” obtained was scaled and subtracted from the suppressed signal to obtain the final metabolite spectrum. After a Gaussian apodization, data were Fourier transformed and interpolated to obtain a resolution of 2055/4096 Hz per point. Chemical shifts were referenced to the signal of Cho at 3.22 ppm. Discussion MRI is the examination of choice in diagnosis of cerebral lymphoma because of its high sensitivity and multiplanar capability. MRI findings in our patients resembled those reported in the literature showing one or multiple poorly demarcated masses, more or less deeply located within the brain parenchyma and involving the deep grey matter structures, periventricular regions and corpus callosum. It has also been reported that up to 75% of lymphomatous masses are seen to be in contact with ependyma, meninges or both 1. The extent of edema on MRI is generally less than that seen in conjunction with the primary gliomas or metastases of similar size. But in our cases, on the contrary there was significant edema causing mass effect. In these masses there is no calcifi-
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cation and hemorrhage is rare 7. In our second patient, we saw hemosiderin deposition in T2 axial images which is a rare finding. All three cases showed intense contrast enhancement after intravenous contrast administration, that occurs in the vast majority of cases and can be dense and homogenous, but is somewhat variable 8. If steroids are administered, the tumours may shrink and “vanish”, compromising the ability to obtain a histologic diagnosis. Considering the diverse presentations of these masses, it is a challenge to diagnose lymphoma only on the basis of morphology and hence the need for functional techniques. Diffusion plays an important role in diagnosis of lymphoma because these lesions are predominantly hyperintense to white matter on diffusion weighted images and isointense to mildly hypointense to white matter on ADC maps representing increased cellularity and low diffusivity, similar to the presentation in our cases. The reduced ADC values are considered useful for differentiation from glioma and metastases which typically show higher ADC values 9,10. The specificity and accuracy of ADC is higher than that of fractional anisotropy in differentiating primary cerebral lymphomas from glioblastoma multiforme 11. The ability of perfusion MR imaging to help detect and quantify tumour angiogenesis can potentially be useful in differentiating high grade glioma from cerebral lymphoma because angiogenesis is not a prominent feature in lymphoma. Lower rCBV values have been described for lymphoma as in our patients. A characteristic intensity – time curve has been demonstrated for lymphoma with a significant increase above baseline due to the massive leakage of contrast agent into the interstitial spaces 11. The advent of MR spectroscopy (MRS) has added to the diagnostic capabilities enabling tissue characterisation based on molecular composition. It provides information on cell proliferation, gradation, neuronal viability and energy metabolism. Based on these characteristics MRS readily differentiates normal from abnormal brain tissue 12,13. The spectra of our three cases revealed elevated peak intensities of compounds containing choline and lipids, whereas NAA and creatine were absent. These data suggested that they were lesions with high proliferative activity and necrosis, according to the literature 14,15. Before starting a specific therapy, it is important to have a precise pathological diagno-
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sis and so stereotactic biopsy may be needed. Stereotactic brain biopsy is usually considered a minimally invasive procedure for establishing the diagnosis of a brain lesion and for lesions not readily accessible through an open procedure. It allows neurosurgeons to localize and sample intrinsic lesions located anywhere within the brain accurately 16. While MRI and functional MRI techniques have the ability to analyse these lesions well, biopsy has a high risk of sampling error resulting in misdiagnosis. In our first case the stereotactic biopsy was contrary to the MRI report and it was the excisional biopsy which gave the correct diagnosis. Various pitfalls of stereotactic biopsy are reported in the literature. The amount of tissue taken from the brain is so small that sometimes the pathologist has difficulty finding enough cells that qualify for a particular diagnosis. If areas peripheral to the main lesion are sampled, the diagnosis is liable to come back either: “non specific inflammatory changes” or “gliosis”. The biopsy adds additional risks of mortality (0.9%) and major morbidity (4%) and leads to an inaccurate or imprecise diagnosis in a third to a half of cases 17. The causes of a non diagnostic specimen 18 can be: • Sampling wrong area. • Small sample size. • Inaccurate tissue targeting resulting in sampling error. • Target choice in areas of high signal on T2weighted MRI. • Small target size. • Incorrect stereotactic coordinate settings. Recently, MRI guided brain biopsies were recommended for precision in stereotactic biopsies 19. Failure to obtain a diagnosis means treatment will be delayed pending a repeat biopsy or if repeat biopsy cannot be done, perhaps indefinitely. On the basis of an incomplete workup without pathologic confirmation an incorrect diagnosis may be made and potentially injurious inappropriate treatments initiated. Conclusion Neuroradiologic diagnosis of primary cerebral lymphoma remains a challenge. We did not find differences between primary and secondary lymphoma. Conventional MRI imaging findings of cerebral lymphoma can be similar to those of other intracranial tumours or even 561
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those of demyelinating lesions. These lesions usually enhance, can be multiple, can favour a deep gray matter or subependymal location; they frequently involve the corpus callosum and can appear similar to GBM. Reduced ADC values due to increased cellularity help us to differentiate lymphoma from high grade glioma or inflammatory disease. The ability of perfusion MR imaging to help detect and quantify
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tumour angiogenesis can potentially be useful in differentiating high grade glioma from cerebral lymphoma 20. Absence of NAA and creatine with high lipids indicates a malignant non glial neoplasm. Considering all these varied aspects of cerebral lymphoma, we emphasise that MRI can be an excellent non invasive option for making a correct diagnosis.
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18 Hall W A: The Safety and Efficacy of Stereotactic Biopsy for Intracranial Lesions. Cancer: 1749-1755, May 1998. 19 Hall W A, Liu H et Al: Comparision of Stereotactic brain biopsy to Interventional Magnetic – ResonanceImaging-Guided Brain Biopsy. Stereotactic and Functional Neurosurgery 73: 148-153, 1999. 20 Cha et Al: Intracranial Mass Lesions: Dynamic Contrast – enhanced Susceptibility – weighted Echo – planar perfusion MR imaging. Radiology 223 Number1: 11-29, April 2002.
D. Khurjekar, MD Omega MRI Centre Poona Hospital Campus Sadashiv Peth 411030 Pune Maharashtra India E-mail: [email protected]
