Novel Insights from Clinical Practice Pediatr Neurosurg 2014–15;50:145–151 DOI: 10.1159/000380769
Received: October 22, 2014 Accepted after revision: February 8, 2015 Published online: April 17, 2015
Evolution of a Pediatric Primary Cerebral ALK-1-Positive Anaplastic Large Cell Lymphoma on Serial MRI Mary J. Dunbar Ash Singhal Shahrad Rod Rassekh Christopher Dunham British Columbia Children’s Hospital, University of British Columbia, Vancouver, B.C., Canada
Established Facts • Primary central nervous system lymphoma (PCNSL) is an extremely rare tumor in the pediatric population. • PCNSL is typically uniformly enhancing and has minimal associated edema.
Novel Insights
Key Words Primary central nervous system lymphoma · Anaplastic large cell lymphoma · Magnetic resonance imaging
Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare central nervous system tumor, especially in the pediatric population. There are fewer than 20 described cases of pediatric primary central nervous system anaplastic large cell lymphoma. The child described in our case report demonstrated a dramatic evolution of this tumor in the first 4 weeks on serial imaging. Methods: Serial MRI imaging was performed followed by biopsy and chemotherapy. Results: Initial imaging revealed a T2 hyperintense lesion in the fron-
© 2015 S. Karger AG, Basel 1016–2291/15/0503–0145$39.50/0 E-Mail [email protected] www.karger.com/pne
tal lobe with abnormally enhancing sulci and minimal surrounding edema and diffusion restriction. Serial imaging revealed progressive increase in the degree of gadolinium enhancement, and the hyperintense T2 edema progressed markedly to exert mass effect. The lesion itself grew marginally. Biopsy revealed an anaplastic large cell lymphoma, only described in 14 previous pediatric patient case reports. The patient was successfully treated with chemotherapy and autologous stem cell transplant. Conclusions: Our case demonstrates the rapidity with which a PCNSL lesion can develop, and the evolution of the imaging characteristics prior to definitive diagnosis and treatment. Serial imaging by MRI may help differentiate the behavior of a PCNSL from other imitating lesions. © 2015 S. Karger AG, Basel
Mary J. Dunbar, MD, MSc Department of Pediatric Neurology, British Columbia Children’s Hospital University of British Columbia, 4480 Oak Street Vancouver, BC V6H 3V4 (Canada) E-Mail mary.dunbar @ cw.bc.ca
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• PCNSL can evolve rapidly over several weeks with increased enhancement and significant mass effect. • Serial MRI imaging may differentiate the behavior of a PCNSL from other lesions.
Primary central nervous system lymphoma (PCNSL) is a rare central nervous system tumor. In all ages, it accounts for 3–4% of central nervous system tumors [1], and in the pediatric population this tumor type occurs with an incidence of 15–20 cases per year in North America [2]. In a series of 248 patients of all ages, 70% presented with a focal deficit, 43% had neuropsychiatric symptoms, 33% had increased intracranial pressure and 14% had seizures [3]. The characteristic mass is at least 20 mm in diameter, is hyperdense on computed tomography (CT) and hypo- or isointense on T1 magnetic resonance imaging (MRI) and hyper- or isointense on T2. It is uniformly enhancing, in contact with the subarachnoid space, and has minimal edema and mass effect [4–7]. The most common site of PCNSL is the cerebral hemisphere (31%), and other common sites are the corpus callosum (16%), where it may display the classic ‘butterfly’ appearance, and basal ganglia and thalamus (16%) [7]. The lesion is solitary in approximately two thirds of cases [8]. The differential diagnosis for these lesions includes other tumors such as gliomas and metastases, infectious lesions, sarcoidosis, cerebral vasculitis or multiple sclerosis plaques [9]. Cerebrospinal fluid cannot effectively distinguish PCNSL from other neoplasms or inflammatory lesions as the changes are inconsistent and nonspecific, such as elevated cell count, protein, albumin, IgG and lactate [10]. Diagnosis by tissue biopsy is frequently delayed by weeks or months following initial presentation while other diagnoses are considered [4, 11–13]. The documentation of the evolution of PCNSL on serial imaging could provide insight into diagnostic characteristics, particularly during the radiographic evolution of the lesion. Here, we illustrate for the first time the imaging evolution of a PCNSL in a 10-year-old child who presented with abrupt onset of focal neurological symptoms. Case Report Clinical Findings The 10-year-old patient was previously well with a history of sudden onset of aphasia and right hemiparesis affecting the face and arm. His past medical history includes asthma, eczema and allergic rhinitis. Consent was obtained from the patient and his parents. Investigations and Initial Management A cranial CT scan performed in a peripheral hospital revealed an area of heterogeneous hyperdensity in the left frontal lobe
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(fig. 1Ai). The following day cranial MRI was performed and revealed ill-defined abnormal T2 hyperintensity in a number of locations in the left cerebral hemisphere and basal ganglia. These included a subtle lesion in the left thalamus and the lateral margin of the anterior limb of the left internal capsule. The largest abnormal area was in the left frontal lobe and exhibited abnormally enhancing sulci without significant diffusion restriction (fig. 1Bii, Cii, Dii). MR angiogram and CT angiogram to assess for large and medium vessel vasculitis were normal. Cerebrospinal fluid was remarkable for lymphocytosis, but no neoplastic cells were found, and protein and glucose levels were normal. Together, these findings suggested infection or inflammation, and the patient was treated empirically with intravenous cefotaxime and acyclovir. Despite intravenous antimicrobials, the patient’s clinical status remained unchanged, and therefore repeat imaging was performed 6 days after presentation (fig. 1Biii, Ciii, Diii), demonstrating increased T2 hyperintensity of the heterogeneously enhancing lesion in the left frontal cortex with leptomeningeal enhancement and surrounding edema measuring 27 mm anterior-posterior and 33 mm craniocaudal. There was also mild T1 hyperintensity of the adjacent cortex. Due to lack of clinical or radiographic response, antimicrobial coverage was broadened to vancomycin, and meropenem was added 4 days later. Repeat imaging 13 days after presentation showed no improvement, of radiographic abnormalities and increased hyperintense T1 signal in the adjacent cortex, postulated to be due to cortical laminar necrosis. Given similar lack of clinical improvement antimicrobial therapy was discontinued. With the third MRI, spectroscopy was performed, which demonstrated low N-acetylaspartate and a lactate peak within the lesion, consistent with both abscess and neoplasm. Episodic aphasia prompted an electroencephalogram (EEG) that revealed highvoltage delta waves with frequent spikes in the left anterior quadrants in drowsiness and sleep. As a consequence, levetiracetam therapy was initiated. For 10 days, he received no antibiotics, and then underwent a fourth MRI (fig. 1Biv, Civ, Div). Now, 24 days after presentation, there was significant increase in the hyperintense T2/FLAIR signal measuring maximally 29 × 39 mm with a marked increase in the internal parenchymal enhancement. There was also a dramatic increase in the amount of hyperintense T2 edema causing a mass effect with effacement of the adjacent sulci and gyri, abutting the body of the lateral ventricle and extending almost to the level of the sylvian fissure. Given persistent diagnostic uncertainty and clear progression of the lesions on imaging, neurosurgical consultation was obtained for the purpose of obtaining a tissue diagnosis. Pathological Findings Biopsy was performed by stealth-guided stereotactic craniotomy. The tissue revealed anaplastic T-cell lymphoma (fig. 2). The tumor was highly cell-dense, mitotically active, and displayed a sheet-like architecture with a superimposed angiocentric pattern. The tumor cells were also seen infiltrating the brain. Cytologically, the tumor cells displayed pleomorphic nuclei associated with varying amounts of eosinophilic cytoplasm. In particular, classic ‘kidney bean’-shaped nuclei were noted. Immunohistochemistry revealed dense CD3, LCA, ALK-1, and CD30 staining, in keeping with anaplastic large cell lymphoma (fig. 3). Occasional cells stained positively with CD20; the Ki-67 proliferation index was markedly elevated. Staining for INI1/BAF-47 revealed retention of staining within the tumor nuclei, essentially ruling out the diagno-
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Background
Ai
Bii
Biii
Biv
Cii
Ciii
Civ
Dii
Diii
Div
Bv
Dv
Fig. 2. Anaplastic large T-cell lymphoma. Routine HE staining of the tumor reveals a highly cell-dense and mitotically active tumor. Pleomorphic tumor nuclei include the classic ‘kidney bean’-shaped cells. ×1,000.
Evolution of a PCNSL on MRI
Pediatr Neurosurg 2014–15;50:145–151 DOI: 10.1159/000380769
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Color version available online
Fig. 1. Evolution of PCNSL on serial images. Ai Day of presentation, axial CT without contrast. B Axial MRI T1weighted sequence with gadolinium. C Axial MRI T2 fluid-attenuated inversion recovery (FLAIR) sequence. D Axial MRI diffusion-weighted sequence. ii Six days after presentation. iii Ten days after presentation. iv Twenty-four days after presentation. v Three years after treatment completion.
Color version available online
B
C
D
sis of atypical teratoid/rhabdoid tumor. Tumor cells were negative for glial fibrillary acidic protein and synaptophysin, and fluorescent in situ hybridization testing confirmed the presence of a translocation event involving ALK-1 using a locus-specific break-apart probe. Clinical Course Following diagnosis, bone marrow biopsy and a full-body positron emission tomography scan were performed and were negative for systemic disease. The patient was assessed to be immunocompetent by history and normal IgG, IgA and IgM levels. He was started on the Toronto PCSNL protocol with four cycles of induction chemotherapy – each consisting of vincristine, methotrexate and a 5-day course of dexamethasone. His MRI after cycle 2 was much improved with a marked reduction of the size of the mass and resolution of surrounding vasogenic edema and mass effect. His neurological exam returned to baseline. By the end of four cycles, lymphoma was undetectable with a stable high T2 signal in the left frontal lobe with linear gadolinium enhancement devoid of nodular components. There was a new adjacent hyperintense T2 signal in the white matter surrounding the site of previous lymphoma representing vasogenic edema attributed to methotrexate toxicity. He underwent two cycles of consolidation chemotherapy with cytarabine and high-dose methotrexate, followed by autologous stem cell transplant. He recovered well and had no evidence of neurological deficit on examination. Three years after autologous stem cell transplant, he is free from disease recurrence (fig. 1Bv, Cv, Dv) and does not have any sequelae of methotrexate toxicity. He continues to take levetiracetam due to EEG abnormalities consisting of occasional generalized atypical spike and waves in sleep suggestive of underlying epilepsy. He is currently followed annually and is disease-free 3 years after diagnosis and treatment.
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Discussion
PCNSL is a very rare disease, and the T-cell form even more so, accounting for only 3.6% of 220 cases [3]. There are only 14 published cases of pediatric primary central nervous system anaplastic large cell lymphomas [14–24] (table 1). These tumors were most frequently located in the frontal or parietal lobes, were often multiple, and 10 of 14 cases were known to be ALK-1-positive. Seven of 14 children were alive after 3 years. Here, we present the case of a 10-year-old immunocompetent male with evolution of ALK-1-positive anaplastic T-cell lymphoma on MRI, visualized over 24 days with four MRIs. Despite numerous descriptions of radiographic features of PCNSL in immunocompetent patients, there has been no documentation of a PCNSL evolving so rapidly on serial imaging [6, 7, 9, 11–13, 25–34]. As is typical of PCNSL, the lesion was a diagnostic challenge. The classic MRI characteristics including hypo- or isointense lesions on T1-weighted and hyperor isointense lesions on T2-weighted scans with diffusion restriction, involvement of the meninges, and homogeneous gadolinium enhancement are not specific to PCNSL, and in our case there were several atypical features. The first and most obvious is the extreme rarity of this tumor type in children, with only 14 reported cases. The sudden onset of severe symptoms prioritized vascuDunbar/Singhal/Rassekh/Dunham
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Fig. 3. Anaplastic large T-cell lymphoma immunohistochemistry. A Dense positivity for CD30. ×200. B Positivity for ALK-1. ×200. C Positivity for CD3. ×200. D High Ki67 proliferative index. ×200.
A
Table 1. Summary of cases of primary CNS anaplastic large cell lymphoma Age/ sex Buxton, 1998 [14] Havlioglu, 1995 [15] Merlin, 2008 [16] Abdulkader, 1999 [17]
Duration of presenting complaint/ immune status if known
10/F
2-week intermittent history of left sensory disturbance of lower limb and trunk, 8 days of ICP symptoms 4.5/F 5 days of headaches, N/V, neck stiffness, unsteady gait (ICP) 13/M 1-month headaches diplopia (ICP), immunocompetent 13/M 3 months of headaches and vomiting, cranial nerve VI palsy, papilledema (ICP), immunocompetent
George, 2003 [18] George, 2003 [18] Ozkaynak, 2009 [19]
17/M Immunocompetent
Rupani, 2005 [20]
17/M 5 months of headache, left upper limb monoparesis and left parietal seizures
Bergmann, 1991 [21] Abla, 2006 [22] Abla, 2006 [22] Abla, 2006 [22] Karikari, 2007 [23]
12/F
18/F
Immunocompetent
9/M
Nonresponsive for 1 h; developed fever and focal seizures, immunocompetent
4/F 8/M 6/F 4/M
Immunocompromised Immunocompromised Immunocompetent New GTC, discharged home, then fever, headache, emesis and neck stiffness
Shah, 2010 [24] 2/M
Progressive lethargy, motor function loss, decreased mental status, immunocompetent
Total
Presentation known in 7/14; increased ICP in 4; immune status known in 9/14; 7/9 immunocompetent
9.8 6F/ 8M
Imaging findings (number of lesions)
Initial diagnosis
ALK-1 Follow-up
Irregular heterogeneous mass in right parietal lobe against the falx with falcine uniform enhancement (1) (>5)
Glioma
+
Primary meningeal (1)
Meningitis
Initial CT normal, 2nd CT showed hypodense lesion right parietal lobe, MRI showed T1 hypointense, T2 hyperintense, two masses right frontal lobe, leptomeningeal enhancement, sulci enhancement (2) Right parietal dura, uniform gadolinium enhancement (1) Left temporal and dura, cerebellum, 4 infra- and supratentorial sites (6) Initial CT head normal, MRI after 5 days (no contrast) was normal, CT day 12 (no contrast) showed a low attenuation; CT day 13 (contrast) = right frontal lobe 1.9 cm, MRI same day = bilateral frontal lesions from frontal poles into superior frontal gyri, with meningeal enhancement between the lesions, vasogenic edema and mass effect, required shunt (2) Right frontoparietal enhancing lesion, repeat for failure to respond to treatment for tuberculosis showed a 30 × 40 mm well-circumscribed enhancing mass eroding the bone; it was adhered to the dura, right frontoparietal (1; later developed lymph node) Occipital
Mycobacterial + meningitis
NR NR NR Initial CT normal, EEG normal; repeat CT and MRI = extensive bilateral frontal edema; frontal, parietal, pineal lesions; extensive vasogenic edema; extensive thick nodular enhancement of the meninges, and heterogeneously enhancing mass in the pineal region (>3; later developed lymph node) CT: large right hemispheric and leptomeningeal invasive enhancing mass with massive edema and uncal herniation (emergent ventriculostomy and craniotomy) (1) Frontal (4), parietal (3), meningeal (1), temporal (1), occipital (1)
Died of sepsis on chemotherapy at 6 months
+ +
+ +
Multirelapse, died after transplant Died shortly after due to ICP, renal failure and systemic candidiasis
Disease-free at 4.8 years Disease-free at 5.2 years Disease-free at 26 months
Meningoencephalitis
+
Tuberculosis
+
Died after 1 month
NR
Dead at 4 months
Infection
NR NR NR +
Died after 4 months Alive after 122 months Alive after 79 months Alive
Malignancy
+
Alive 9 years from diagnosis
6/13 known; 5/6 infection, 1 glioma
10/ 10+
13/14 known, 6/13 died
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NR = Not recorded; ICP = intracranial pressure; N/V = nausea and vomiting; GTC = generalized tonic-clonic seizures.
lar, inflammatory or infectious etiology over neoplastic. In addition, the lesion was initially heterogeneously enhancing with more prominent leptomeningeal enhancement, rather than the homogeneous enhancement that is classic. This presentation may be more typical of Tcell PCNSL in children, given that the majority of reported cases were diagnosed as infection before biopsy [16, 17, 19, 20, 23]. Finally, never before has such a rapid expansion of a PCNSL been documented in a child or adult. The initial diagnosis of abscess was not supported by the lack of fever, cavity, ring enhancement or central diffusion restriction more commonly seen in abscesses [27]. The radiographic features supporting a diagnosis of PCNSL included the contact with the arachnoid space, typical size and location in the frontal lobe.
This case illustrates a small lesion with abnormally enhancing sulci, diffusion restriction, and leptomeningeal involvement that evolved rapidly to a hyperintense, highly enhancing lesion with diffusion restriction and significant edema. This adds an important observation to the literature describing MRI characteristics of PCNSL: that serial imaging by MRI may help differentiate the behavior of a PCNSL from other imitating lesions. Our case demonstrates the rapidity with which a PCNSL lesion can develop, and the evolution of the imaging characteristics prior to definitive diagnosis and treatment.
Acknowledgment The authors would like to thank the patient and his family.
1 Hoffman S, Propp JM, McCarthy BJ: Temporal trends in incidence of primary brain tumors in the United States, 1985–1999. Neuro Oncol 2006;8:27–37. 2 Kadan-Lottick NS, Skluzacek MC, Gurney JG: Decreasing incidence rates of primary central nervous system lymphoma. Cancer 2002;95:193–202. 3 Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, et al: Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg 2000;92:261–266. 4 Coulon A, Lafitte F, Hoang-Xuan K, MartinDuverneuil N, Mokhtari K, Blustajn J, et al: Radiographic findings in 37 cases of primary CNS lymphoma in immunocompetent patients. Eur Radiol 2001;12:329–340. 5 Scott BJ, Douglas VC, Tihan T, Rubenstein JL, Josephson SA: A systematic approach to the diagnosis of suspected central nervous system lymphoma. JAMA Neurol 2013;70:311–319. 6 Küker W, Möhrle S, Mader I, Schöning M, Nägele T: MRI for the management of neonatal cerebral infarctions: importance of timing. Childs Nerv Syst 2004;20:742–748. 7 Bühring U, Herrlinger U, Krings T, Thiex R, Weller M, Küker W: MRI features of primary central nervous system lymphomas at presentation. Neurology 2001;57:393–396. 8 Küker W, Nägele T, Korfel A, Heckl S, Thiel E, Bamberg M, et al: Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients. J Neurooncol 2005;72:169–177. 9 Korfel A, Schlegel U: Diagnosis and treatment of primary CNS lymphoma. Nat Rev Neurol 2013;9:317–327.
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10 Herrlinger U, Schabet M, Bitzer M, Petersen D, et al: Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neurooncol 1999;43:219–226. 11 Sobrido Sampedro C, Corroto JD, et al: Findings at presentation in primary CNS diffuse large B-cell lymphoma of the brain: a comparison of immunocompetent and immunodeficient patients. J Biomed Graphics Computing 2013;3:59–69. 12 Haldorsen IS, Espeland A, Larsson EM: Central nervous system lymphoma: characteristic findings on traditional and advanced imaging. AJNR Am J Neuroradiol 2011; 32: 984– 992. 13 Zhang D, Hu L-B, Henning TD, Ravarani EM, Zou L-G, Feng X-Y, et al: MRI findings of primary CNS lymphoma in 26 immunocompetent patients. Korean J Radiol 2010; 11: 269– 277. 14 Buxton N, Punt J, Hewitt M: Primary Ki-1positive T-cell lymphoma of the brain in a child. Pediatr Neurosurg 1998;29:250–252. 15 Havlioglu N, Manepalli A, Galindo L, SoteloAvila C, Grosso L: Primary Ki-1 (anaplastic large cell) lymphoma of the brain and spinal cord. Am J Clin Pathol 1995;103:496–499. 16 Merlin E, Chabrier S, Verkarre V, Cramer E, Delabesse E, Stéphan J-L: Primary leptomeningeal ALK+ lymphoma in a 13-year-old child. J Pediatr Hematol Oncol 2008;30:963– 967. 17 Abdulkader I, Cameselle-Teijeiro J, Fraga M, Rodriguez-Núnez A, Allut AG, Forteza J: Primary anaplastic large cell lymphoma of the central nervous system. Hum Pathol 1999;30: 978–981.
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18 George DH, Scheithauer BW, Aker FV, Kurtin PJ, Burger PC, Cameselle-Teijeiro J, et al: Primary anaplastic large cell lymphoma of the central nervous system: prognostic effect of ALK-1 expression. Am J Surg Pathol 2003;27: 487–493. 19 Ozkaynak MF: Favorable outcome of primary CNS anaplastic large cell lymphoma in an immunocompetent patient. J Pediatr Hematol Oncol 2009;31:128–130. 20 Rupani A, Modi C, Desai S, Rege J: Primary anaplastic large cell lymphoma of central nervous system – a case report. J Postgrad Med 2005;51:326–327. 21 Bergmann M, Edel G: Primary intracerebral non-Hodgkin’s lymphoma. Pathologe 1991; 12:246–253. 22 Abla O, Sandlund JT, Sung L, Brock P, Corbett R, Kirov I, et al: A case series of pediatric primary central nervous system lymphoma: favorable outcome without cranial irradiation. Pediatr Blood Cancer 2006;47:880–885. 23 Karikari IO, Thomas KK, Lagoo A, Cummings TJ, George TM: Primary cerebral ALK1-positive anaplastic large cell lymphoma in a child. Case report and literature review. Pediatr Neurosurg 2007;43:516–521. 24 Shah AC, Kelly DR, Nabors LB, Oakes WJ, Hilliard LM, Reddy AT: Treatment of primary CNS lymphoma with high-dose methotrexate in immunocompetent pediatric patients. Pediatr Blood Cancer 2010; 55: 1227– 1230. 25 Manenti G, Di Giuliano F, Bindi A, Liberto V, Funel V, Garaci FG, et al: A case of primary T-cell central nervous system lymphoma: MR imaging and MR spectroscopy assessment. Case Rep Radiol 2013;2013:916348.
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References
Evolution of a PCNSL on MRI
29 Haldorsen IS, Kråkenes J, Krossnes BK, Mella O, Espeland A: CT and MR imaging features of primary central nervous system lymphoma in Norway, 1989–2003. AJNR Am J Neuroradiol 2009;30:744–751. 30 Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW: Patterns of contrast enhancement in the brain and meninges. Radiographics 2007;27:525–551. 31 Gliemroth J, Kehler U, Gaebel C, Arnold H, Missler U: Neuroradiological findings in primary cerebral lymphomas of non-AIDS patients. Clin Neurol Neurosurg 2003; 105: 78– 86.
32 Erdag N, Bhorade RM, Alberico RA, Yousuf N, Patel MR: Primary lymphoma of the central nervous system. AJR Am J Roentgenol 2001;176:1319–1326. 33 Koeller KK, Smirniotopoulos JG, Jones RV: Primary central nervous system lymphoma: radiologic-pathologic correlation. Radiographics 1997;17:1497–1526. 34 Johnson BA, Fram EK, Johnson PC, Jacobowitz R: The variable MR appearance of primary lymphoma of the central nervous system: comparison with histopathologic features. AJNR Am J Neuroradiol 1997; 18: 563–572.
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26 Tang YZ, Booth TC, Bhogal P, Malhotra A, Wilhelm T: Imaging of primary central nervous system lymphoma. Clin Radiol 2011;66: 768–777. 27 Yap KK, Sutherland T, Liew E, Tartaglia CJ, Pang M, Trost N: Magnetic resonance features of primary central nervous system lymphoma in the immunocompetent patient: a pictorial essay. J Med Imaging Radiat Oncol 2012;56:179–186. 28 Schwingel R, Reis F, Zanardi VA, Queiroz LS, França MC: Central nervous system lymphoma: magnetic resonance imaging features at presentation. Arq Neuropsiquiatr 2012; 70: 97–101.
Received: October 22, 2014 Accepted after revision: February 8, 2015 Published online: April 17, 2015
Evolution of a Pediatric Primary Cerebral ALK-1-Positive Anaplastic Large Cell Lymphoma on Serial MRI Mary J. Dunbar Ash Singhal Shahrad Rod Rassekh Christopher Dunham British Columbia Children’s Hospital, University of British Columbia, Vancouver, B.C., Canada
Established Facts • Primary central nervous system lymphoma (PCNSL) is an extremely rare tumor in the pediatric population. • PCNSL is typically uniformly enhancing and has minimal associated edema.
Novel Insights
Key Words Primary central nervous system lymphoma · Anaplastic large cell lymphoma · Magnetic resonance imaging
Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare central nervous system tumor, especially in the pediatric population. There are fewer than 20 described cases of pediatric primary central nervous system anaplastic large cell lymphoma. The child described in our case report demonstrated a dramatic evolution of this tumor in the first 4 weeks on serial imaging. Methods: Serial MRI imaging was performed followed by biopsy and chemotherapy. Results: Initial imaging revealed a T2 hyperintense lesion in the fron-
© 2015 S. Karger AG, Basel 1016–2291/15/0503–0145$39.50/0 E-Mail [email protected] www.karger.com/pne
tal lobe with abnormally enhancing sulci and minimal surrounding edema and diffusion restriction. Serial imaging revealed progressive increase in the degree of gadolinium enhancement, and the hyperintense T2 edema progressed markedly to exert mass effect. The lesion itself grew marginally. Biopsy revealed an anaplastic large cell lymphoma, only described in 14 previous pediatric patient case reports. The patient was successfully treated with chemotherapy and autologous stem cell transplant. Conclusions: Our case demonstrates the rapidity with which a PCNSL lesion can develop, and the evolution of the imaging characteristics prior to definitive diagnosis and treatment. Serial imaging by MRI may help differentiate the behavior of a PCNSL from other imitating lesions. © 2015 S. Karger AG, Basel
Mary J. Dunbar, MD, MSc Department of Pediatric Neurology, British Columbia Children’s Hospital University of British Columbia, 4480 Oak Street Vancouver, BC V6H 3V4 (Canada) E-Mail mary.dunbar @ cw.bc.ca
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• PCNSL can evolve rapidly over several weeks with increased enhancement and significant mass effect. • Serial MRI imaging may differentiate the behavior of a PCNSL from other lesions.
Primary central nervous system lymphoma (PCNSL) is a rare central nervous system tumor. In all ages, it accounts for 3–4% of central nervous system tumors [1], and in the pediatric population this tumor type occurs with an incidence of 15–20 cases per year in North America [2]. In a series of 248 patients of all ages, 70% presented with a focal deficit, 43% had neuropsychiatric symptoms, 33% had increased intracranial pressure and 14% had seizures [3]. The characteristic mass is at least 20 mm in diameter, is hyperdense on computed tomography (CT) and hypo- or isointense on T1 magnetic resonance imaging (MRI) and hyper- or isointense on T2. It is uniformly enhancing, in contact with the subarachnoid space, and has minimal edema and mass effect [4–7]. The most common site of PCNSL is the cerebral hemisphere (31%), and other common sites are the corpus callosum (16%), where it may display the classic ‘butterfly’ appearance, and basal ganglia and thalamus (16%) [7]. The lesion is solitary in approximately two thirds of cases [8]. The differential diagnosis for these lesions includes other tumors such as gliomas and metastases, infectious lesions, sarcoidosis, cerebral vasculitis or multiple sclerosis plaques [9]. Cerebrospinal fluid cannot effectively distinguish PCNSL from other neoplasms or inflammatory lesions as the changes are inconsistent and nonspecific, such as elevated cell count, protein, albumin, IgG and lactate [10]. Diagnosis by tissue biopsy is frequently delayed by weeks or months following initial presentation while other diagnoses are considered [4, 11–13]. The documentation of the evolution of PCNSL on serial imaging could provide insight into diagnostic characteristics, particularly during the radiographic evolution of the lesion. Here, we illustrate for the first time the imaging evolution of a PCNSL in a 10-year-old child who presented with abrupt onset of focal neurological symptoms. Case Report Clinical Findings The 10-year-old patient was previously well with a history of sudden onset of aphasia and right hemiparesis affecting the face and arm. His past medical history includes asthma, eczema and allergic rhinitis. Consent was obtained from the patient and his parents. Investigations and Initial Management A cranial CT scan performed in a peripheral hospital revealed an area of heterogeneous hyperdensity in the left frontal lobe
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(fig. 1Ai). The following day cranial MRI was performed and revealed ill-defined abnormal T2 hyperintensity in a number of locations in the left cerebral hemisphere and basal ganglia. These included a subtle lesion in the left thalamus and the lateral margin of the anterior limb of the left internal capsule. The largest abnormal area was in the left frontal lobe and exhibited abnormally enhancing sulci without significant diffusion restriction (fig. 1Bii, Cii, Dii). MR angiogram and CT angiogram to assess for large and medium vessel vasculitis were normal. Cerebrospinal fluid was remarkable for lymphocytosis, but no neoplastic cells were found, and protein and glucose levels were normal. Together, these findings suggested infection or inflammation, and the patient was treated empirically with intravenous cefotaxime and acyclovir. Despite intravenous antimicrobials, the patient’s clinical status remained unchanged, and therefore repeat imaging was performed 6 days after presentation (fig. 1Biii, Ciii, Diii), demonstrating increased T2 hyperintensity of the heterogeneously enhancing lesion in the left frontal cortex with leptomeningeal enhancement and surrounding edema measuring 27 mm anterior-posterior and 33 mm craniocaudal. There was also mild T1 hyperintensity of the adjacent cortex. Due to lack of clinical or radiographic response, antimicrobial coverage was broadened to vancomycin, and meropenem was added 4 days later. Repeat imaging 13 days after presentation showed no improvement, of radiographic abnormalities and increased hyperintense T1 signal in the adjacent cortex, postulated to be due to cortical laminar necrosis. Given similar lack of clinical improvement antimicrobial therapy was discontinued. With the third MRI, spectroscopy was performed, which demonstrated low N-acetylaspartate and a lactate peak within the lesion, consistent with both abscess and neoplasm. Episodic aphasia prompted an electroencephalogram (EEG) that revealed highvoltage delta waves with frequent spikes in the left anterior quadrants in drowsiness and sleep. As a consequence, levetiracetam therapy was initiated. For 10 days, he received no antibiotics, and then underwent a fourth MRI (fig. 1Biv, Civ, Div). Now, 24 days after presentation, there was significant increase in the hyperintense T2/FLAIR signal measuring maximally 29 × 39 mm with a marked increase in the internal parenchymal enhancement. There was also a dramatic increase in the amount of hyperintense T2 edema causing a mass effect with effacement of the adjacent sulci and gyri, abutting the body of the lateral ventricle and extending almost to the level of the sylvian fissure. Given persistent diagnostic uncertainty and clear progression of the lesions on imaging, neurosurgical consultation was obtained for the purpose of obtaining a tissue diagnosis. Pathological Findings Biopsy was performed by stealth-guided stereotactic craniotomy. The tissue revealed anaplastic T-cell lymphoma (fig. 2). The tumor was highly cell-dense, mitotically active, and displayed a sheet-like architecture with a superimposed angiocentric pattern. The tumor cells were also seen infiltrating the brain. Cytologically, the tumor cells displayed pleomorphic nuclei associated with varying amounts of eosinophilic cytoplasm. In particular, classic ‘kidney bean’-shaped nuclei were noted. Immunohistochemistry revealed dense CD3, LCA, ALK-1, and CD30 staining, in keeping with anaplastic large cell lymphoma (fig. 3). Occasional cells stained positively with CD20; the Ki-67 proliferation index was markedly elevated. Staining for INI1/BAF-47 revealed retention of staining within the tumor nuclei, essentially ruling out the diagno-
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Background
Ai
Bii
Biii
Biv
Cii
Ciii
Civ
Dii
Diii
Div
Bv
Dv
Fig. 2. Anaplastic large T-cell lymphoma. Routine HE staining of the tumor reveals a highly cell-dense and mitotically active tumor. Pleomorphic tumor nuclei include the classic ‘kidney bean’-shaped cells. ×1,000.
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Color version available online
Fig. 1. Evolution of PCNSL on serial images. Ai Day of presentation, axial CT without contrast. B Axial MRI T1weighted sequence with gadolinium. C Axial MRI T2 fluid-attenuated inversion recovery (FLAIR) sequence. D Axial MRI diffusion-weighted sequence. ii Six days after presentation. iii Ten days after presentation. iv Twenty-four days after presentation. v Three years after treatment completion.
Color version available online
B
C
D
sis of atypical teratoid/rhabdoid tumor. Tumor cells were negative for glial fibrillary acidic protein and synaptophysin, and fluorescent in situ hybridization testing confirmed the presence of a translocation event involving ALK-1 using a locus-specific break-apart probe. Clinical Course Following diagnosis, bone marrow biopsy and a full-body positron emission tomography scan were performed and were negative for systemic disease. The patient was assessed to be immunocompetent by history and normal IgG, IgA and IgM levels. He was started on the Toronto PCSNL protocol with four cycles of induction chemotherapy – each consisting of vincristine, methotrexate and a 5-day course of dexamethasone. His MRI after cycle 2 was much improved with a marked reduction of the size of the mass and resolution of surrounding vasogenic edema and mass effect. His neurological exam returned to baseline. By the end of four cycles, lymphoma was undetectable with a stable high T2 signal in the left frontal lobe with linear gadolinium enhancement devoid of nodular components. There was a new adjacent hyperintense T2 signal in the white matter surrounding the site of previous lymphoma representing vasogenic edema attributed to methotrexate toxicity. He underwent two cycles of consolidation chemotherapy with cytarabine and high-dose methotrexate, followed by autologous stem cell transplant. He recovered well and had no evidence of neurological deficit on examination. Three years after autologous stem cell transplant, he is free from disease recurrence (fig. 1Bv, Cv, Dv) and does not have any sequelae of methotrexate toxicity. He continues to take levetiracetam due to EEG abnormalities consisting of occasional generalized atypical spike and waves in sleep suggestive of underlying epilepsy. He is currently followed annually and is disease-free 3 years after diagnosis and treatment.
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Discussion
PCNSL is a very rare disease, and the T-cell form even more so, accounting for only 3.6% of 220 cases [3]. There are only 14 published cases of pediatric primary central nervous system anaplastic large cell lymphomas [14–24] (table 1). These tumors were most frequently located in the frontal or parietal lobes, were often multiple, and 10 of 14 cases were known to be ALK-1-positive. Seven of 14 children were alive after 3 years. Here, we present the case of a 10-year-old immunocompetent male with evolution of ALK-1-positive anaplastic T-cell lymphoma on MRI, visualized over 24 days with four MRIs. Despite numerous descriptions of radiographic features of PCNSL in immunocompetent patients, there has been no documentation of a PCNSL evolving so rapidly on serial imaging [6, 7, 9, 11–13, 25–34]. As is typical of PCNSL, the lesion was a diagnostic challenge. The classic MRI characteristics including hypo- or isointense lesions on T1-weighted and hyperor isointense lesions on T2-weighted scans with diffusion restriction, involvement of the meninges, and homogeneous gadolinium enhancement are not specific to PCNSL, and in our case there were several atypical features. The first and most obvious is the extreme rarity of this tumor type in children, with only 14 reported cases. The sudden onset of severe symptoms prioritized vascuDunbar/Singhal/Rassekh/Dunham
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Fig. 3. Anaplastic large T-cell lymphoma immunohistochemistry. A Dense positivity for CD30. ×200. B Positivity for ALK-1. ×200. C Positivity for CD3. ×200. D High Ki67 proliferative index. ×200.
A
Table 1. Summary of cases of primary CNS anaplastic large cell lymphoma Age/ sex Buxton, 1998 [14] Havlioglu, 1995 [15] Merlin, 2008 [16] Abdulkader, 1999 [17]
Duration of presenting complaint/ immune status if known
10/F
2-week intermittent history of left sensory disturbance of lower limb and trunk, 8 days of ICP symptoms 4.5/F 5 days of headaches, N/V, neck stiffness, unsteady gait (ICP) 13/M 1-month headaches diplopia (ICP), immunocompetent 13/M 3 months of headaches and vomiting, cranial nerve VI palsy, papilledema (ICP), immunocompetent
George, 2003 [18] George, 2003 [18] Ozkaynak, 2009 [19]
17/M Immunocompetent
Rupani, 2005 [20]
17/M 5 months of headache, left upper limb monoparesis and left parietal seizures
Bergmann, 1991 [21] Abla, 2006 [22] Abla, 2006 [22] Abla, 2006 [22] Karikari, 2007 [23]
12/F
18/F
Immunocompetent
9/M
Nonresponsive for 1 h; developed fever and focal seizures, immunocompetent
4/F 8/M 6/F 4/M
Immunocompromised Immunocompromised Immunocompetent New GTC, discharged home, then fever, headache, emesis and neck stiffness
Shah, 2010 [24] 2/M
Progressive lethargy, motor function loss, decreased mental status, immunocompetent
Total
Presentation known in 7/14; increased ICP in 4; immune status known in 9/14; 7/9 immunocompetent
9.8 6F/ 8M
Imaging findings (number of lesions)
Initial diagnosis
ALK-1 Follow-up
Irregular heterogeneous mass in right parietal lobe against the falx with falcine uniform enhancement (1) (>5)
Glioma
+
Primary meningeal (1)
Meningitis
Initial CT normal, 2nd CT showed hypodense lesion right parietal lobe, MRI showed T1 hypointense, T2 hyperintense, two masses right frontal lobe, leptomeningeal enhancement, sulci enhancement (2) Right parietal dura, uniform gadolinium enhancement (1) Left temporal and dura, cerebellum, 4 infra- and supratentorial sites (6) Initial CT head normal, MRI after 5 days (no contrast) was normal, CT day 12 (no contrast) showed a low attenuation; CT day 13 (contrast) = right frontal lobe 1.9 cm, MRI same day = bilateral frontal lesions from frontal poles into superior frontal gyri, with meningeal enhancement between the lesions, vasogenic edema and mass effect, required shunt (2) Right frontoparietal enhancing lesion, repeat for failure to respond to treatment for tuberculosis showed a 30 × 40 mm well-circumscribed enhancing mass eroding the bone; it was adhered to the dura, right frontoparietal (1; later developed lymph node) Occipital
Mycobacterial + meningitis
NR NR NR Initial CT normal, EEG normal; repeat CT and MRI = extensive bilateral frontal edema; frontal, parietal, pineal lesions; extensive vasogenic edema; extensive thick nodular enhancement of the meninges, and heterogeneously enhancing mass in the pineal region (>3; later developed lymph node) CT: large right hemispheric and leptomeningeal invasive enhancing mass with massive edema and uncal herniation (emergent ventriculostomy and craniotomy) (1) Frontal (4), parietal (3), meningeal (1), temporal (1), occipital (1)
Died of sepsis on chemotherapy at 6 months
+ +
+ +
Multirelapse, died after transplant Died shortly after due to ICP, renal failure and systemic candidiasis
Disease-free at 4.8 years Disease-free at 5.2 years Disease-free at 26 months
Meningoencephalitis
+
Tuberculosis
+
Died after 1 month
NR
Dead at 4 months
Infection
NR NR NR +
Died after 4 months Alive after 122 months Alive after 79 months Alive
Malignancy
+
Alive 9 years from diagnosis
6/13 known; 5/6 infection, 1 glioma
10/ 10+
13/14 known, 6/13 died
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NR = Not recorded; ICP = intracranial pressure; N/V = nausea and vomiting; GTC = generalized tonic-clonic seizures.
lar, inflammatory or infectious etiology over neoplastic. In addition, the lesion was initially heterogeneously enhancing with more prominent leptomeningeal enhancement, rather than the homogeneous enhancement that is classic. This presentation may be more typical of Tcell PCNSL in children, given that the majority of reported cases were diagnosed as infection before biopsy [16, 17, 19, 20, 23]. Finally, never before has such a rapid expansion of a PCNSL been documented in a child or adult. The initial diagnosis of abscess was not supported by the lack of fever, cavity, ring enhancement or central diffusion restriction more commonly seen in abscesses [27]. The radiographic features supporting a diagnosis of PCNSL included the contact with the arachnoid space, typical size and location in the frontal lobe.
This case illustrates a small lesion with abnormally enhancing sulci, diffusion restriction, and leptomeningeal involvement that evolved rapidly to a hyperintense, highly enhancing lesion with diffusion restriction and significant edema. This adds an important observation to the literature describing MRI characteristics of PCNSL: that serial imaging by MRI may help differentiate the behavior of a PCNSL from other imitating lesions. Our case demonstrates the rapidity with which a PCNSL lesion can develop, and the evolution of the imaging characteristics prior to definitive diagnosis and treatment.
Acknowledgment The authors would like to thank the patient and his family.
1 Hoffman S, Propp JM, McCarthy BJ: Temporal trends in incidence of primary brain tumors in the United States, 1985–1999. Neuro Oncol 2006;8:27–37. 2 Kadan-Lottick NS, Skluzacek MC, Gurney JG: Decreasing incidence rates of primary central nervous system lymphoma. Cancer 2002;95:193–202. 3 Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, et al: Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg 2000;92:261–266. 4 Coulon A, Lafitte F, Hoang-Xuan K, MartinDuverneuil N, Mokhtari K, Blustajn J, et al: Radiographic findings in 37 cases of primary CNS lymphoma in immunocompetent patients. Eur Radiol 2001;12:329–340. 5 Scott BJ, Douglas VC, Tihan T, Rubenstein JL, Josephson SA: A systematic approach to the diagnosis of suspected central nervous system lymphoma. JAMA Neurol 2013;70:311–319. 6 Küker W, Möhrle S, Mader I, Schöning M, Nägele T: MRI for the management of neonatal cerebral infarctions: importance of timing. Childs Nerv Syst 2004;20:742–748. 7 Bühring U, Herrlinger U, Krings T, Thiex R, Weller M, Küker W: MRI features of primary central nervous system lymphomas at presentation. Neurology 2001;57:393–396. 8 Küker W, Nägele T, Korfel A, Heckl S, Thiel E, Bamberg M, et al: Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients. J Neurooncol 2005;72:169–177. 9 Korfel A, Schlegel U: Diagnosis and treatment of primary CNS lymphoma. Nat Rev Neurol 2013;9:317–327.
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10 Herrlinger U, Schabet M, Bitzer M, Petersen D, et al: Primary central nervous system lymphoma: from clinical presentation to diagnosis. J Neurooncol 1999;43:219–226. 11 Sobrido Sampedro C, Corroto JD, et al: Findings at presentation in primary CNS diffuse large B-cell lymphoma of the brain: a comparison of immunocompetent and immunodeficient patients. J Biomed Graphics Computing 2013;3:59–69. 12 Haldorsen IS, Espeland A, Larsson EM: Central nervous system lymphoma: characteristic findings on traditional and advanced imaging. AJNR Am J Neuroradiol 2011; 32: 984– 992. 13 Zhang D, Hu L-B, Henning TD, Ravarani EM, Zou L-G, Feng X-Y, et al: MRI findings of primary CNS lymphoma in 26 immunocompetent patients. Korean J Radiol 2010; 11: 269– 277. 14 Buxton N, Punt J, Hewitt M: Primary Ki-1positive T-cell lymphoma of the brain in a child. Pediatr Neurosurg 1998;29:250–252. 15 Havlioglu N, Manepalli A, Galindo L, SoteloAvila C, Grosso L: Primary Ki-1 (anaplastic large cell) lymphoma of the brain and spinal cord. Am J Clin Pathol 1995;103:496–499. 16 Merlin E, Chabrier S, Verkarre V, Cramer E, Delabesse E, Stéphan J-L: Primary leptomeningeal ALK+ lymphoma in a 13-year-old child. J Pediatr Hematol Oncol 2008;30:963– 967. 17 Abdulkader I, Cameselle-Teijeiro J, Fraga M, Rodriguez-Núnez A, Allut AG, Forteza J: Primary anaplastic large cell lymphoma of the central nervous system. Hum Pathol 1999;30: 978–981.
Pediatr Neurosurg 2014–15;50:145–151 DOI: 10.1159/000380769
18 George DH, Scheithauer BW, Aker FV, Kurtin PJ, Burger PC, Cameselle-Teijeiro J, et al: Primary anaplastic large cell lymphoma of the central nervous system: prognostic effect of ALK-1 expression. Am J Surg Pathol 2003;27: 487–493. 19 Ozkaynak MF: Favorable outcome of primary CNS anaplastic large cell lymphoma in an immunocompetent patient. J Pediatr Hematol Oncol 2009;31:128–130. 20 Rupani A, Modi C, Desai S, Rege J: Primary anaplastic large cell lymphoma of central nervous system – a case report. J Postgrad Med 2005;51:326–327. 21 Bergmann M, Edel G: Primary intracerebral non-Hodgkin’s lymphoma. Pathologe 1991; 12:246–253. 22 Abla O, Sandlund JT, Sung L, Brock P, Corbett R, Kirov I, et al: A case series of pediatric primary central nervous system lymphoma: favorable outcome without cranial irradiation. Pediatr Blood Cancer 2006;47:880–885. 23 Karikari IO, Thomas KK, Lagoo A, Cummings TJ, George TM: Primary cerebral ALK1-positive anaplastic large cell lymphoma in a child. Case report and literature review. Pediatr Neurosurg 2007;43:516–521. 24 Shah AC, Kelly DR, Nabors LB, Oakes WJ, Hilliard LM, Reddy AT: Treatment of primary CNS lymphoma with high-dose methotrexate in immunocompetent pediatric patients. Pediatr Blood Cancer 2010; 55: 1227– 1230. 25 Manenti G, Di Giuliano F, Bindi A, Liberto V, Funel V, Garaci FG, et al: A case of primary T-cell central nervous system lymphoma: MR imaging and MR spectroscopy assessment. Case Rep Radiol 2013;2013:916348.
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References
Evolution of a PCNSL on MRI
29 Haldorsen IS, Kråkenes J, Krossnes BK, Mella O, Espeland A: CT and MR imaging features of primary central nervous system lymphoma in Norway, 1989–2003. AJNR Am J Neuroradiol 2009;30:744–751. 30 Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW: Patterns of contrast enhancement in the brain and meninges. Radiographics 2007;27:525–551. 31 Gliemroth J, Kehler U, Gaebel C, Arnold H, Missler U: Neuroradiological findings in primary cerebral lymphomas of non-AIDS patients. Clin Neurol Neurosurg 2003; 105: 78– 86.
32 Erdag N, Bhorade RM, Alberico RA, Yousuf N, Patel MR: Primary lymphoma of the central nervous system. AJR Am J Roentgenol 2001;176:1319–1326. 33 Koeller KK, Smirniotopoulos JG, Jones RV: Primary central nervous system lymphoma: radiologic-pathologic correlation. Radiographics 1997;17:1497–1526. 34 Johnson BA, Fram EK, Johnson PC, Jacobowitz R: The variable MR appearance of primary lymphoma of the central nervous system: comparison with histopathologic features. AJNR Am J Neuroradiol 1997; 18: 563–572.
Pediatr Neurosurg 2014–15;50:145–151 DOI: 10.1159/000380769
151
Downloaded by: University of Florida, Gainesville and Jacksonville 198.143.41.97 - 1/27/2016 3:59:49 AM
26 Tang YZ, Booth TC, Bhogal P, Malhotra A, Wilhelm T: Imaging of primary central nervous system lymphoma. Clin Radiol 2011;66: 768–777. 27 Yap KK, Sutherland T, Liew E, Tartaglia CJ, Pang M, Trost N: Magnetic resonance features of primary central nervous system lymphoma in the immunocompetent patient: a pictorial essay. J Med Imaging Radiat Oncol 2012;56:179–186. 28 Schwingel R, Reis F, Zanardi VA, Queiroz LS, França MC: Central nervous system lymphoma: magnetic resonance imaging features at presentation. Arq Neuropsiquiatr 2012; 70: 97–101.
