Childs Nerv Syst DOI 10.1007/s00381-015-2633-6
CASE REPORT
Primary T cell central nervous system lymphoblastic lymphoma in a child: case report and literature review Marcus D. Mazur & Vijay M. Ravindra & Mouied Alashari & Elizabeth Raetz & Matthew M. Poppe & Robert J. Bollo
Received: 7 January 2015 / Accepted: 3 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Primary central nervous system lymphoma (PCNSL) of T cell origin is rare in pediatric patients. We report a case of T cell PCNSL in a 12-year-old boy and review the literature to highlight the importance of brain biopsy to definitively establish the diagnosis when PCNSL is suspected. Case report A 12-year-old boy presented with worsening leftsided weakness, nausea, vomiting, headache, blurred vision, and diplopia. Magnetic resonance imaging revealed right parietal gyral thickening with faint meningeal contrast enhancement. No clear diagnosis was identified after serum testing, cerebrospinal fluid analysis, and cerebral angiography. To establish the diagnosis definitively, a right craniotomy and open, frameless stereotactic biopsy were performed, which yielded the diagnosis of lymphoblastic T cell lymphoma. Conclusions PCNSL of T cell origin in children remains poorly studied, with only 18 detailed cases reported over the last three decades, including this case. Establishing a definitive diagnosis of PCNSL is challenging, and a brain biopsy is often required to obtain enough tissue for pathological analysis. Increasing awareness and identification of children diagnosed M. D. Mazur : V. M. Ravindra : R. J. Bollo (*) Division of Pediatric Neurosurgery, Department of Neurosurgery, Primary Children’s Hospital, University of Utah, 100 North Mario Capecchi Drive, Suite 1475, Salt Lake City, UT 84113-1100, USA e-mail: [email protected] M. Alashari Department of Pathology, University of Utah, Salt Lake City, UT, USA E. Raetz Division of Pediatric Hematology/Oncology, Primary Children’s Hospital, University of Utah, Salt Lake City, UT, USA M. M. Poppe Department of Radiation Oncology, University of Utah, Salt Lake City, UT, USA
with T cell PCNSL is needed to better understand the molecular biology of this disease and develop more standardized treatment regimens. Keywords Primary CNS lymphoma . T cell lymphoblastic lymphoma . Pediatrics
Introduction Primary central nervous system lymphomas (PCNSLs) of T cell origin are rarely seen in pediatric patients, and very few detailed cases are reported in the literature [1–15]. The natural history, optimal treatment regimen, and expected outcomes have not been determined. Further, establishing a definitive diagnosis remains a challenge. We report a rare case of T cell PCNSL in a 12-year-old boy and review the literature to highlight the importance of brain biopsy to definitively establish the diagnosis when PCNSL is suspected.
Case report Presentation and examination A previously healthy 12-year-old boy presented with worsening left-sided weakness, nausea, vomiting, headache, blurred vision, and diplopia. There was no history of fever, weight loss, or recent infection. Neurological examination revealed bilateral cranial nerve 6 palsies, weakness of the left triceps and deltoid, diminished sensation to light touch over the lateral aspect of his left forearm, and dysmetria on left-sided finger-to-nose testing. Hepatosplenomegaly and peripheral lymphadenopathy were not detected.
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Diagnostic testing Magnetic resonance imaging (MRI) of the brain revealed right parietal gyral thickening with faint meningeal contrast enhancement on T1-weighted imaging, high-intensity signal abnormalities in the right parietal and occipital subcortical and periventricular white matter and splenium of the corpus callosum on T2-weighted and fluid-attenuated inversion recovery imaging (FLAIR), and patchy cortical areas of restricted diffusion on diffusion-weighted imaging (DWI) (Fig. 1). The differential diagnosis included lymphoma, gliomatosis cerebri, vasculitis, encephalitis, and demyelinating disease. The levels of serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) were within normal limits, and cerebral angiography did not reveal evidence of vasculitis. There were no risk factors for or evidence of an underlying immunodeficiency. Cerebrospinal fluid (CSF) was obtained via lumbar puncture with an initial CSF white blood cell count of 1790/μL, and flow cytometry and immunophenotyping showed an atypical T cell population comprising 92 % of the total leukocytes (Fig. 2a). The atypical
Fig. 1 Abnormal hyperintensity in the right parietal cortical, subcortical, and periventricular regions on FLAIR MRI (a, b). Patchy regions of cortical high intensity appeared on DWI (c) with associated low intensity on apparent diffusion coefficient (ADC) mapping (d). Faint heterogeneous contrast enhancement of the leptomeninges was also observed in the right parieto-occipital region (not shown). These findings were suggestive, but not specific, for lymphoma
T cell population expressed CD3, CD5, CD7, CD8, CD38, CD56, CD57, TdT, and T cell receptor (TCR) γδ and lacked reactivity for CD1a, CD2, CD4, CD16, CD20, CD34, CD99, and TCR αβ. The CD4/CD8 ratio was 1.67. Fluorescent in situ hybridization (FISH) probes for lymphoma/leukemia markers revealed no evidence of 9p deletion, but ETV6 deletion and RUNX1 expression were present. These results were suspicious for a lymphoproliferative disorder but could not differentiate a mature T cell lymphoma (CD3 and TCR γδ positivity with lack of CD1a and CD99) from an immature T cell lymphoblastic lymphoma (TdT positivity). Such histological distinction may have survival implications because the lymphoblastic subtype has a more aggressive clinical course but may be curable [16]. Further evaluation included a positron emission tomography scan; computed tomography (CT) imaging of the neck, chest, abdomen, and pelvis; and a total spine MRI. These studies revealed no other lesions. A peripheral blood smear found no atypical lymphocytes, and bilateral bone marrow aspirates were considered normal. Direct funduscopic examination revealed no evidence of intraocular lymphoma or papilledema. In the context of symptom progression and data
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Fig. 2 Cerebrospinal fluid cytology revealed small- to intermediate-size atypical lymphoid cells with irregular nuclear contours and scant cytoplasm (a). Brain biopsy of parietal cortex showed a predominantly perivascular cuffing distribution with sheets of lymphoid cells
within the leptomeninges on hematoxylin and eosin staining (b). Immunohistochemistry demonstrated positivity for CD3 (c) and TdT (d) and >90 % proliferation rate on Ki-67 staining (e). These findings were consistent with T cell lymphoblastic lymphoma
most consistent with lymphoma, empiric corticosteroid therapy was initiated and resulted in clinical improvement. To definitively establish the diagnosis, we performed a right craniotomy and open, frameless stereotactic biopsy of MRI-defined abnormal parietal cortex and subcortical white matter, as well as overlying dura and calvaria. Intraoperatively, phase reversal was conducted to verify the location of the central sulcus and primary sensorimotor cortex. The open biopsy was obtained using an 11-blade scalpel, and the specimen was sent for pathological evaluation and divided for analyses by flow cytometry, karyotype, FISH, histology, and immunohistochemistry. Histopathological evaluation of the cortical and subcortical white matter biopsy specimen demonstrated atypical lymphoid
proliferation in a predominantly cuffed perivascular distribution with sheets of lymphoid cells within the leptomeninges. The lymphoid cells were small to intermediate in size with irregular nuclear contours, immature-appearing chromatin, occasional mitotic figures, and scant amount of cytoplasm (Fig. 2b). Immunohistochemical staining revealed that the lymphoid cells were positive for CD3 and TdT and negative for CD1a, CD2, CD4, CD8, CD20, and CD33 (Fig. 2c). The proliferation exceeded 90 % by Ki-67 staining. There was no evidence of Epstein-Barr virus by in situ hybridization. The diagnosis of lymphoblastic T cell lymphoma was made on the basis of the strong TdT expression and the high proliferation index. The gene rearrangement phenotype favored the late cortical thymocyte stage of T cell lymphoblast differentiation.
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Treatment Because of progressive left-sided weakness, the patient was given dexamethasone while the non-invasive diagnostic testing was performed, but this was discontinued 3 days prior to the brain biopsy. After the diagnosis of lymphoblastic T cell PCNSL was made, the patient received a total of four cycles of systemic chemotherapy: two cycles of high-dose cytarabine and etoposide, a regimen commonly used in children with mature B cell non-Hodgkin’s lymphoma with CNS involvement, and two cycles of high-dose methotrexate (5 g/m2), vincristine, and 6-mercaptopurine, a regimen commonly used in acute lymphoblastic leukemia with CNS involvement. He also received four cycles of intrathecal methotrexate and systemic hydrocortisone and cytarabine. Shortly after beginning chemotherapy, he had complete resolution of prior neurological symptoms, including diplopia. He experienced a steady reduction in CSF pleocytosis and ultimately had no detectable disease in his CSF by morphology or flow cytometry after the completion of four cycles of systemic and intrathecal chemotherapy. Following chemotherapy, the patient underwent craniospinal radiation therapy to a total dose of 22.5 Gy, given in 1.5-Gy daily fractions. This was followed 3 weeks later by 13.2 Gy of total body irradiation, given in 1.65-Gy, twicedaily fractions for 4 days, prior to allogeneic stem cell transplant. Serial MRIs throughout treatment have revealed steady improvement with resolution of meningeal enhancement on T1-weighted contrast-enhanced imaging and decrease in signal abnormality involving the corpus callosum and periventricular and subcortical white matter. The patient remains alive 12 months after the initial presentation with no evidence of active disease.
Discussion Epidemiology PCNSL is distinct from systemic lymphoma of the same histological subtype, with a significantly lower incidence and worse prognosis [17]. In immunocompetent patients, PCNS L accounts for only 5 % of primary intracranial neoplasms and 1–2 % of non-Hodgkin’s lymphoma [18, 19]. Only 1 % of all reported PCNSL cases occur in children, giving an estimate of 15–20 pediatric cases per year in North America [20, 21], but the overwhelming majority of PCNSLs are of B cell origin. T cell lymphomas are rare among both adults and children, comprising only 2–8 % of PCNSL cases [22–26]. In contrast, systemic T cell lymphomas account for 15–20 % of cases of non-Hodgkin’s lymphoma [25]. The reason for the difference in proportion of T cell versus B cell lymphomas in systemic versus PCNSL is largely unknown [22–24, 26]. Most
published clinical series and literature reviews of T cell PCNSL are composed of a heterogenous group of patients with a wide age range. Few studies have focused on the pediatric age group. After review of the literature, we identified only 18 cases (13 male, 5 female) of T cell PCNSL reported in patients under 18 years (range 2–17 years), including our patient (Table 1). Three patients were immunocompromised, 11 were immunocompetent, and the immune status of 4 was unknown. Eleven patients had more than 18 months of follow-up and were still alive at the time that the cases were reported; six of these survived at least 5 years after diagnosis. Five patients died within 6 months of diagnosis. The three immunocompromised patients were still alive after a follow-up of 20 months, 6 years, and 10 years, respectively. There is considerable variation in presentation, diagnostic workup, treatment modalities, and clinical outcomes among these cases, which limited the opportunity to draw conclusions about T cell PCNSL as a disease entity. Given the paucity of reported cases in children, it is likely that T cell PCNSL is under-recognized [27]. This may be explained in part because it presents a diagnostic challenge, both radiographically and pathologically. Diagnosis and imaging T cell PCNSL can present in many different forms. Tumors can involve the cortical and subcortical cerebrum, cerebellum, basal ganglia, leptomeninges, and dura. Multifocal disease at the time of presentation is common, even in immunocompetent patients. A space-occupying parenchymal mass is the most common presentation of PCNSL; solitary leptomeningeal disease is a rare variant [28, 29]. Leptomeningeal dissemination, however, is a common manifestation for PCNSL of either B cell or T cell origin, occurring in 7–42 % of patients [30, 31]. The presence of leptomeningeal involvement does not appear to influence outcome [30–34]. Because of the variability in appearance on radiographic imaging, PCNSL cannot be distinguished definitively from reactive processes, including demyelinating lesions, infection, abscess, inflammation, and other neoplasms, such as highgrade glial tumors or metastases. Homogeneous enhancement is common in PCNSL of B cell origin [35, 36], but T cell PCNSL is often characterized by heterogeneously enhancing lesions [37, 38]. The presence of ring enhancement or significant peritumoral edema is variable [27, 37]. Cystic degeneration with or without hemorrhage was thought to be more common in immunocompromised patients but has also been seen in immunocompetent patients and may be more common in PCNSL of T cell origin than cases of B cell origin [37]. Regions of high and low signal intensities on DWI resembling an abscess or necrosis have been observed [37]. MRI may underestimate the extent of disease, because microscopic
Right parietal and frontal lobes Left parietal lobe
17, M
16, M
10, F
O’Neill et al. [13]
Ng et al. [12]
Buxton et al. [6]
Abdulkader et al. [1] 13, M
Uetsuka et al. [15]
Right parieto-occipital lobe Right parietal dura
17, F
17, M
10, M
6, F 7, M 8, M 10, M
2, M
6, M
5, M 12, M
Choi et al. [7]
George et al. [8]
Bassuk et al. [4]
Abla et al. [2] Abla et al. [2] Abla et al. [2] Gualco et al. [10]
Shah et al. [14]
Leuth et al. [11]
Goodyer et al. [9] Mazur et al.
Anaplastic large cell Anaplastic large cell Anaplastic large cell Medium and large atypical cells CD2+, CD3+, CD5+, CD45+, CD4−, CD8−, CD25−, CD56−, CD30−, TdT−, CD20−, TIA-1−, EBV− Anaplastic large cell CD30+, ALK1+, CD43+, EMA−, S-100−, CD1a−, CD3−, CD20−, CD15−, Small and large cells CD3+, CD7+, CD1a−, CD20−, PAX5 −, ALK−, EBV− CD3+, CD8+, EBV+
Small cell CD3+, CD8+, CD4−, CD20− Anaplastic large cell CD3+, CD45+, CD45RO+, ALK-1+ CD3+, EBV+
CD2+, CD3+, CD4+, CD5+, CD7+
Anaplastic large cell CD45RB+, CD45RO+, CD30+, ALK1+, EMA+, CD20−, EBV− BMalignant T cell^ CD3+, CD43+, CD45+, CD45RO+, CD79a−, CD20−
Large cell CD45+, MT1+ BKi-1-positive T cell lymphoma^ Gross total resection, radiotherapy, MTX, cyclophosphamide, daunorubicin, cytosine, vincristine, prednisolone Vincristine, etoposide, MTX, cytarabine, dex, cyclophosphamide
Gross total resection
MTX
Immunocompetent
Immunocompromised Allogeneic stem cell transplant Immunocompetent Brain biopsy; MTX, vincristine, 6-MP, cytarabine, etoposide; craniospinal radiation
Gross total resection
MTX, cytarabine, dex, stem cell transplant Craniospinal radiation, MTX, AraC, dex MTX, cytarabine, dex Chemotherapy, not specified
Immunocompetent
Alive at 4.8 years
Alive after 10 months
Alive after 38 months
Alive after 20 months
Death shortly after diagnosis
Death after 6 months
Death after 8 days
Alive after 6 years Alive after 6 months
Alive after 6 years
Alive after 9 years
Alive after 79 months Alive after 98 months Alive after 122 months Death after 1 month
Radiotherapy, MTX, vincristine, doxorubicin, Death after 3 months methylprednisolone, cytarabine
Immunocompetent Immunocompetent Immunocompromised Immunocompetent
Immunocompetent
Outcome
Gross total resection, craniospinal radiation, Alive after 24 months LSA(2)-L2 protocol Surgery NR
Treatment
Immunocompromised Surgical resection, prednisolone, cyclophosphamide, vincristine, daunorubicin, L-asparaginase, 6-MP, MTX, cytarabine, hydroxycarbamide Immunocompetent Craniospanial radiation, MTX, AraC, Lasparaginase NR Subtotal resection, radiotherapy, MTX, cytarabine Immunocompetent Radiotherapy
Immunocompetent
NR
Immunocompetent
NR
NR
BLymphoblastic, convoluted T cell^ Leu-1, Leu-2a, Leu-3a
Immune status
Histology/immunophenotype
6-MP 6-mercaptopurine, AraC cytosine arabinoside, dex dexamethasone, MTX methotrexate, NR not reported
Multifocal cerebral Right parieto-occipital lobe; cortical, subcortical, periventricular regions
Left frontal lobe
Right convexity, leptomeninges
Bilateral frontal and parietal lobes, caudate, basal ganglia NR NR NR Right parietal lobe, cerebellum
Cerebellum
Right frontoparietal, left cerebellum Right parietal lobe
Al-Ghamdi et al. [3] 10, F
7, M
Right parietal lobe
2, F
Bogdahn et al. [5]
Cerebellum
Age (years), Tumor site Sex
Literature review of pediatric T cell primary CNS lymphoma cases
Study
Table 1
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infiltration of parenchyma may not be associated with signal abnormality [39]. Because of this significant variability, lowand high-grade lymphomas cannot be distinguished by radiographic characteristics alone. Establishing a pathological diagnosis requires obtaining a sufficient amount of abnormal tissue from a CSF sample or brain biopsy; however, a definitive diagnosis often cannot be established even if a relatively large volume of tissue is obtained. CSF analysis fails to establish a diagnosis in approximately one third of patients with PCNSL and leptomeningeal disease [40]. Flow cytometry may enhance detection in patients with a low concentration of malignant cells in CSF [41] but is non-specific given the wide variety of conditions that exhibit monoclonal populations of lymphocytes [27, 42–45]. In this case, we could not differentiate between an immature and a mature lymphoproliferative process based on flow cytometry results alone. The specimen expressed both mature (CD3 positive, TCR γδ positive, CD1a negative, and CD99 negative) and immature features (TdT positive). When PCNS L is suspected, brain biopsy corresponding to an area of abnormal enhancement or signal intensity on T2-weighted MRI may maximize the likelihood of establishing a definitive diagnosis. Identification of histological features may have implications regarding treatment and survival. Systemic lymphomas with immature cellular features, such as the lymphoblastic subtype seen in our patient, are more aggressive but frequently responsive to treatment and can be curable [16].
is ideal. In the case presented, our patient improved clinically after initiation of empiric corticosteroids, but these were rapidly tapered and discontinued 72 h prior to surgery to optimize diagnostic yield. Normal markers of T cells include CD3, CD4, and CD8. Alterations of T cell surface markers can occur during both neoplastic transformation and reactive processes. Such change in antigen expression can include loss of CD7 and/or CD5 [43]. Cases have been reported of T cell lymphomas that are CD4 positive, CD8 positive, both CD4 and CD8 positive, and both CD4 and CD8 negative [27, 37]. CD5 expression is present in normal T cells but can also be seen in certain B cell lymphomas [48]. Aberrant expression of CD20, a marker traditionally thought to be B cell specific, may be present in up to 12 % of normal T cells as well as in lymphomas [49, 50]. A shift in the CD4/CD8 ratio has been investigated as a means to distinguish among T cell proliferative disorders; however, this ratio may fluctuate over the course of a pathologic process and CD4 or CD8 predominance can be seen in a variety of conditions [27, 42–45]. Monoclonality is usually assessed by molecular testing for TCR gene rearrangements [42, 44]; however, given the variety of conditions in which monoclonal populations of T cells have been observed, results of TCR gene rearrangements need to be interpreted within the appropriate clinical context [27, 42–45].
Potential pitfalls in diagnosis
In the few reported cases of pediatric T cell PCNSL (Table 1), a wide variety of treatment modalities have been used, including surgical resection without adjuvant treatment, radiation or chemotherapy alone, allogeneic stem cell transplant, and multimodality regimens with various combinations. Because of the paucity of confirmed cases, little information can be extrapolated from the literature to help guide treatment for T cell PCNSL in children. Current management is based on analysis of patients with PCNSL of B cell origin. The IPCG review included 29 child and adolescent patients (mean age 14 years) with PCNSL, including only 5 with T cell PCNSL, who underwent a variety of treatment regimens with 5.7 years of mean follow-up [20]. The authors found that prognosis depended on the intensity and type of chemotherapy. Good outcomes were observed in children treated with chemotherapy alone consisting mainly of regimens utilizing high-dose methotrexate. The authors also concluded that radiation can be deferred for refractory or relapsed cases, a finding that has been corroborated by others [2, 14]. In the case presented, craniospinal radiation therapy was used because of a slow clinical response to intensive chemotherapy reflected by persistent CSF pleocytosis, but evidence to guide the use of radiation therapy in patients with T cell PCNSL is lacking. Differentiating T cell lymphoma from a B cell malignancy may be important for some treatment decisions, such as
Even after obtaining a brain biopsy, there are several potential pitfalls when making a pathological diagnosis of T cell PCNS L. In contrast to B cell lymphomas, most PCNSLs of T cell origin do not show high-grade morphology or atypical features [27]. Further complicating the diagnosis is the presence of a mixed infiltrate, containing reactive T cells, B cells, and macrophages, that is a common feature in any lymphoproliferative process. Concentric perivascular lymphoid aggregates can be present in both neoplastic and reactive processes. In some cases of T cell PCNSL, reactive B cells outnumber neoplastic T cells [27]. High proliferation rates and Ki-67 staining are not specific for differentiating reactive from neoplastic infiltrates [27, 45–47]. If corticosteroids were administered prior to the biopsy, an abundance of macrophages may also obscure the identification of neoplastic T cells. Corticosteroids can induce lymphoid cells to undergo apoptosis, depleting neoplastic cells within 24–48 h, rendering the sample non-diagnostic. After a few days, PCNSL cells may develop resistance to corticosteroids and repopulate the brain parenchyma. At least one report has described obtaining a successful PCNSL diagnosis, via molecular testing, after corticosteroids were started [7], but obtaining a biopsy before initiating corticosteroid treatment
Treatment
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whether to include rituximab into the treatment protocol; however, prognosis and treatment responses do not appear to differ between T cell and B cell PCNSL, at least in adults [26]. In addition to cellular lineage, the role of tumor cell maturity and molecular phenotyping also remains unclear. While a variety of subtypes of T cell PCNSL have been described, there appears to be a distinct anaplastic large cell variant, which is typically CD30-positive [8], as well as a small cell variant. This case was characterized by lymphoblastic T cells of small to intermediate size that favored the late thymocyte stage of T cell differentiation. The significance of the T cell PCNSL subtypes has not been determined; Shenkier and colleagues [26] reported evidence that cytologic type does not affect survival. Larger studies are needed to determine whether there is a difference in treatment or survival among the various subtypes.
Conclusion Although PCNSL is rarely seen in pediatric patients, this case demonstrates the importance of brain biopsy in cases in which it is suspected. PCNSL of T cell origin in children remains poorly studied, with only 18 detailed cases reported over the last three decades, including this report. Increasing awareness and identification of children diagnosed with T cell PCNSL is needed to better understand the molecular biology of this disease and develop more standardized treatment regimens. Acknowledgments The authors thank Kristin Kraus, M.Sc., for her assistance in the preparation of this paper. Conflict of interest The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
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37. Kim EY, Kim SS (2005) Magnetic resonance findings of primary central nervous system T-cell lymphoma in immunocompetent patients. Acta Radiol 46:187–192 38. Kitajima M, Korogi Y, Shigematsu Y, Liang L, Matsuoka M, Yamamoto T, Jhono M, Eto K, Takahashi M (2002) Central nervous system lesions in adult T-cell leukaemia: MRI and pathology. Neuroradiology 44:559–567 39. Lai R, Rosenblum MK, DeAngelis LM (2002) Primary CNS lymphoma: a whole-brain disease? Neurology 59:1557–1562 40. Freilich RJ, Krol G, DeAngelis LM (1995) Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis. Ann Neurol 38:51–57 41. Bromberg JE, Breems DA, Kraan J, Bikker G, van der Holt B, Smitt PS, van den Bent MJ, van’t Veer M, Gratama JW (2007) CSF flow cytometry greatly improves diagnostic accuracy in CNS hematologic malignancies. Neurology 68:1674–1679 42. Diss TC, Watts M, Pan LX, Burke M, Linch D, Isaacson PG (1995) The polymerase chain reaction in the demonstration of monoclonality in T cell lymphomas. J Clin Pathol 48:1045–1050 43. Rao DS, Said JW (2007) Small lymphoid proliferations in extranodal locations. Arch Pathol Lab Med 131:383–396 44. Theriault C, Galoin S, Valmary S, Selves J, Lamant L, Roda D, RigalHuguet F, Brousset P, Delsol G, Al Saati T (2000) PCR analysis of immunoglobulin heavy chain (IgH) and TcR-gamma chain gene rearrangements in the diagnosis of lymphoproliferative disorders: results of a study of 525 cases. Mod Pathol 13:1269–1279 45. Went P, Agostinelli C, Gallamini A, Piccaluga PP, Ascani S, Sabattini E, Bacci F, Falini B, Motta T, Paulli M, Artusi T, Piccioli M, Zinzani PL, Pileri SA (2006) Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 24: 2472–2479 46. Liu D, Schelper RL, Carter DA, Poiesz BJ, Shrimpton AE, Frankel BM, Hutchison RE (2003) Primary central nervous system cytotoxic/ suppressor T-cell lymphoma: report of a unique case and review of the literature. Am J Surg Pathol 27:682–688 47. Sen F, Rassidakis GZ, Jones D, Medeiros LJ (2002) Apoptosis and proliferation in subcutaneous panniculitis-like T-cell lymphoma. Mod Pathol 15:625–631 48. Sun T, Akalin A, Rodacker M, Braun T (2004) CD20 positive T cell lymphoma: is it a real entity? J Clin Pathol 57:442–444 49. Mohrmann RL, Arber DA (2000) CD20-Positive peripheral T-cell lymphoma: report of a case after nodular sclerosis Hodgkin’s disease and review of the literature. Mod Pathol 13:1244–1252 50. Yokose N, Ogata K, Sugisaki Y, Mori S, Yamada T, An E, Dan K (2001) CD20-positive T cell leukemia/lymphoma: case report and review of the literature. Ann Hematol 80:372–375
CASE REPORT
Primary T cell central nervous system lymphoblastic lymphoma in a child: case report and literature review Marcus D. Mazur & Vijay M. Ravindra & Mouied Alashari & Elizabeth Raetz & Matthew M. Poppe & Robert J. Bollo
Received: 7 January 2015 / Accepted: 3 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Primary central nervous system lymphoma (PCNSL) of T cell origin is rare in pediatric patients. We report a case of T cell PCNSL in a 12-year-old boy and review the literature to highlight the importance of brain biopsy to definitively establish the diagnosis when PCNSL is suspected. Case report A 12-year-old boy presented with worsening leftsided weakness, nausea, vomiting, headache, blurred vision, and diplopia. Magnetic resonance imaging revealed right parietal gyral thickening with faint meningeal contrast enhancement. No clear diagnosis was identified after serum testing, cerebrospinal fluid analysis, and cerebral angiography. To establish the diagnosis definitively, a right craniotomy and open, frameless stereotactic biopsy were performed, which yielded the diagnosis of lymphoblastic T cell lymphoma. Conclusions PCNSL of T cell origin in children remains poorly studied, with only 18 detailed cases reported over the last three decades, including this case. Establishing a definitive diagnosis of PCNSL is challenging, and a brain biopsy is often required to obtain enough tissue for pathological analysis. Increasing awareness and identification of children diagnosed M. D. Mazur : V. M. Ravindra : R. J. Bollo (*) Division of Pediatric Neurosurgery, Department of Neurosurgery, Primary Children’s Hospital, University of Utah, 100 North Mario Capecchi Drive, Suite 1475, Salt Lake City, UT 84113-1100, USA e-mail: [email protected] M. Alashari Department of Pathology, University of Utah, Salt Lake City, UT, USA E. Raetz Division of Pediatric Hematology/Oncology, Primary Children’s Hospital, University of Utah, Salt Lake City, UT, USA M. M. Poppe Department of Radiation Oncology, University of Utah, Salt Lake City, UT, USA
with T cell PCNSL is needed to better understand the molecular biology of this disease and develop more standardized treatment regimens. Keywords Primary CNS lymphoma . T cell lymphoblastic lymphoma . Pediatrics
Introduction Primary central nervous system lymphomas (PCNSLs) of T cell origin are rarely seen in pediatric patients, and very few detailed cases are reported in the literature [1–15]. The natural history, optimal treatment regimen, and expected outcomes have not been determined. Further, establishing a definitive diagnosis remains a challenge. We report a rare case of T cell PCNSL in a 12-year-old boy and review the literature to highlight the importance of brain biopsy to definitively establish the diagnosis when PCNSL is suspected.
Case report Presentation and examination A previously healthy 12-year-old boy presented with worsening left-sided weakness, nausea, vomiting, headache, blurred vision, and diplopia. There was no history of fever, weight loss, or recent infection. Neurological examination revealed bilateral cranial nerve 6 palsies, weakness of the left triceps and deltoid, diminished sensation to light touch over the lateral aspect of his left forearm, and dysmetria on left-sided finger-to-nose testing. Hepatosplenomegaly and peripheral lymphadenopathy were not detected.
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Diagnostic testing Magnetic resonance imaging (MRI) of the brain revealed right parietal gyral thickening with faint meningeal contrast enhancement on T1-weighted imaging, high-intensity signal abnormalities in the right parietal and occipital subcortical and periventricular white matter and splenium of the corpus callosum on T2-weighted and fluid-attenuated inversion recovery imaging (FLAIR), and patchy cortical areas of restricted diffusion on diffusion-weighted imaging (DWI) (Fig. 1). The differential diagnosis included lymphoma, gliomatosis cerebri, vasculitis, encephalitis, and demyelinating disease. The levels of serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) were within normal limits, and cerebral angiography did not reveal evidence of vasculitis. There were no risk factors for or evidence of an underlying immunodeficiency. Cerebrospinal fluid (CSF) was obtained via lumbar puncture with an initial CSF white blood cell count of 1790/μL, and flow cytometry and immunophenotyping showed an atypical T cell population comprising 92 % of the total leukocytes (Fig. 2a). The atypical
Fig. 1 Abnormal hyperintensity in the right parietal cortical, subcortical, and periventricular regions on FLAIR MRI (a, b). Patchy regions of cortical high intensity appeared on DWI (c) with associated low intensity on apparent diffusion coefficient (ADC) mapping (d). Faint heterogeneous contrast enhancement of the leptomeninges was also observed in the right parieto-occipital region (not shown). These findings were suggestive, but not specific, for lymphoma
T cell population expressed CD3, CD5, CD7, CD8, CD38, CD56, CD57, TdT, and T cell receptor (TCR) γδ and lacked reactivity for CD1a, CD2, CD4, CD16, CD20, CD34, CD99, and TCR αβ. The CD4/CD8 ratio was 1.67. Fluorescent in situ hybridization (FISH) probes for lymphoma/leukemia markers revealed no evidence of 9p deletion, but ETV6 deletion and RUNX1 expression were present. These results were suspicious for a lymphoproliferative disorder but could not differentiate a mature T cell lymphoma (CD3 and TCR γδ positivity with lack of CD1a and CD99) from an immature T cell lymphoblastic lymphoma (TdT positivity). Such histological distinction may have survival implications because the lymphoblastic subtype has a more aggressive clinical course but may be curable [16]. Further evaluation included a positron emission tomography scan; computed tomography (CT) imaging of the neck, chest, abdomen, and pelvis; and a total spine MRI. These studies revealed no other lesions. A peripheral blood smear found no atypical lymphocytes, and bilateral bone marrow aspirates were considered normal. Direct funduscopic examination revealed no evidence of intraocular lymphoma or papilledema. In the context of symptom progression and data
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Fig. 2 Cerebrospinal fluid cytology revealed small- to intermediate-size atypical lymphoid cells with irregular nuclear contours and scant cytoplasm (a). Brain biopsy of parietal cortex showed a predominantly perivascular cuffing distribution with sheets of lymphoid cells
within the leptomeninges on hematoxylin and eosin staining (b). Immunohistochemistry demonstrated positivity for CD3 (c) and TdT (d) and >90 % proliferation rate on Ki-67 staining (e). These findings were consistent with T cell lymphoblastic lymphoma
most consistent with lymphoma, empiric corticosteroid therapy was initiated and resulted in clinical improvement. To definitively establish the diagnosis, we performed a right craniotomy and open, frameless stereotactic biopsy of MRI-defined abnormal parietal cortex and subcortical white matter, as well as overlying dura and calvaria. Intraoperatively, phase reversal was conducted to verify the location of the central sulcus and primary sensorimotor cortex. The open biopsy was obtained using an 11-blade scalpel, and the specimen was sent for pathological evaluation and divided for analyses by flow cytometry, karyotype, FISH, histology, and immunohistochemistry. Histopathological evaluation of the cortical and subcortical white matter biopsy specimen demonstrated atypical lymphoid
proliferation in a predominantly cuffed perivascular distribution with sheets of lymphoid cells within the leptomeninges. The lymphoid cells were small to intermediate in size with irregular nuclear contours, immature-appearing chromatin, occasional mitotic figures, and scant amount of cytoplasm (Fig. 2b). Immunohistochemical staining revealed that the lymphoid cells were positive for CD3 and TdT and negative for CD1a, CD2, CD4, CD8, CD20, and CD33 (Fig. 2c). The proliferation exceeded 90 % by Ki-67 staining. There was no evidence of Epstein-Barr virus by in situ hybridization. The diagnosis of lymphoblastic T cell lymphoma was made on the basis of the strong TdT expression and the high proliferation index. The gene rearrangement phenotype favored the late cortical thymocyte stage of T cell lymphoblast differentiation.
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Treatment Because of progressive left-sided weakness, the patient was given dexamethasone while the non-invasive diagnostic testing was performed, but this was discontinued 3 days prior to the brain biopsy. After the diagnosis of lymphoblastic T cell PCNSL was made, the patient received a total of four cycles of systemic chemotherapy: two cycles of high-dose cytarabine and etoposide, a regimen commonly used in children with mature B cell non-Hodgkin’s lymphoma with CNS involvement, and two cycles of high-dose methotrexate (5 g/m2), vincristine, and 6-mercaptopurine, a regimen commonly used in acute lymphoblastic leukemia with CNS involvement. He also received four cycles of intrathecal methotrexate and systemic hydrocortisone and cytarabine. Shortly after beginning chemotherapy, he had complete resolution of prior neurological symptoms, including diplopia. He experienced a steady reduction in CSF pleocytosis and ultimately had no detectable disease in his CSF by morphology or flow cytometry after the completion of four cycles of systemic and intrathecal chemotherapy. Following chemotherapy, the patient underwent craniospinal radiation therapy to a total dose of 22.5 Gy, given in 1.5-Gy daily fractions. This was followed 3 weeks later by 13.2 Gy of total body irradiation, given in 1.65-Gy, twicedaily fractions for 4 days, prior to allogeneic stem cell transplant. Serial MRIs throughout treatment have revealed steady improvement with resolution of meningeal enhancement on T1-weighted contrast-enhanced imaging and decrease in signal abnormality involving the corpus callosum and periventricular and subcortical white matter. The patient remains alive 12 months after the initial presentation with no evidence of active disease.
Discussion Epidemiology PCNSL is distinct from systemic lymphoma of the same histological subtype, with a significantly lower incidence and worse prognosis [17]. In immunocompetent patients, PCNS L accounts for only 5 % of primary intracranial neoplasms and 1–2 % of non-Hodgkin’s lymphoma [18, 19]. Only 1 % of all reported PCNSL cases occur in children, giving an estimate of 15–20 pediatric cases per year in North America [20, 21], but the overwhelming majority of PCNSLs are of B cell origin. T cell lymphomas are rare among both adults and children, comprising only 2–8 % of PCNSL cases [22–26]. In contrast, systemic T cell lymphomas account for 15–20 % of cases of non-Hodgkin’s lymphoma [25]. The reason for the difference in proportion of T cell versus B cell lymphomas in systemic versus PCNSL is largely unknown [22–24, 26]. Most
published clinical series and literature reviews of T cell PCNSL are composed of a heterogenous group of patients with a wide age range. Few studies have focused on the pediatric age group. After review of the literature, we identified only 18 cases (13 male, 5 female) of T cell PCNSL reported in patients under 18 years (range 2–17 years), including our patient (Table 1). Three patients were immunocompromised, 11 were immunocompetent, and the immune status of 4 was unknown. Eleven patients had more than 18 months of follow-up and were still alive at the time that the cases were reported; six of these survived at least 5 years after diagnosis. Five patients died within 6 months of diagnosis. The three immunocompromised patients were still alive after a follow-up of 20 months, 6 years, and 10 years, respectively. There is considerable variation in presentation, diagnostic workup, treatment modalities, and clinical outcomes among these cases, which limited the opportunity to draw conclusions about T cell PCNSL as a disease entity. Given the paucity of reported cases in children, it is likely that T cell PCNSL is under-recognized [27]. This may be explained in part because it presents a diagnostic challenge, both radiographically and pathologically. Diagnosis and imaging T cell PCNSL can present in many different forms. Tumors can involve the cortical and subcortical cerebrum, cerebellum, basal ganglia, leptomeninges, and dura. Multifocal disease at the time of presentation is common, even in immunocompetent patients. A space-occupying parenchymal mass is the most common presentation of PCNSL; solitary leptomeningeal disease is a rare variant [28, 29]. Leptomeningeal dissemination, however, is a common manifestation for PCNSL of either B cell or T cell origin, occurring in 7–42 % of patients [30, 31]. The presence of leptomeningeal involvement does not appear to influence outcome [30–34]. Because of the variability in appearance on radiographic imaging, PCNSL cannot be distinguished definitively from reactive processes, including demyelinating lesions, infection, abscess, inflammation, and other neoplasms, such as highgrade glial tumors or metastases. Homogeneous enhancement is common in PCNSL of B cell origin [35, 36], but T cell PCNSL is often characterized by heterogeneously enhancing lesions [37, 38]. The presence of ring enhancement or significant peritumoral edema is variable [27, 37]. Cystic degeneration with or without hemorrhage was thought to be more common in immunocompromised patients but has also been seen in immunocompetent patients and may be more common in PCNSL of T cell origin than cases of B cell origin [37]. Regions of high and low signal intensities on DWI resembling an abscess or necrosis have been observed [37]. MRI may underestimate the extent of disease, because microscopic
Right parietal and frontal lobes Left parietal lobe
17, M
16, M
10, F
O’Neill et al. [13]
Ng et al. [12]
Buxton et al. [6]
Abdulkader et al. [1] 13, M
Uetsuka et al. [15]
Right parieto-occipital lobe Right parietal dura
17, F
17, M
10, M
6, F 7, M 8, M 10, M
2, M
6, M
5, M 12, M
Choi et al. [7]
George et al. [8]
Bassuk et al. [4]
Abla et al. [2] Abla et al. [2] Abla et al. [2] Gualco et al. [10]
Shah et al. [14]
Leuth et al. [11]
Goodyer et al. [9] Mazur et al.
Anaplastic large cell Anaplastic large cell Anaplastic large cell Medium and large atypical cells CD2+, CD3+, CD5+, CD45+, CD4−, CD8−, CD25−, CD56−, CD30−, TdT−, CD20−, TIA-1−, EBV− Anaplastic large cell CD30+, ALK1+, CD43+, EMA−, S-100−, CD1a−, CD3−, CD20−, CD15−, Small and large cells CD3+, CD7+, CD1a−, CD20−, PAX5 −, ALK−, EBV− CD3+, CD8+, EBV+
Small cell CD3+, CD8+, CD4−, CD20− Anaplastic large cell CD3+, CD45+, CD45RO+, ALK-1+ CD3+, EBV+
CD2+, CD3+, CD4+, CD5+, CD7+
Anaplastic large cell CD45RB+, CD45RO+, CD30+, ALK1+, EMA+, CD20−, EBV− BMalignant T cell^ CD3+, CD43+, CD45+, CD45RO+, CD79a−, CD20−
Large cell CD45+, MT1+ BKi-1-positive T cell lymphoma^ Gross total resection, radiotherapy, MTX, cyclophosphamide, daunorubicin, cytosine, vincristine, prednisolone Vincristine, etoposide, MTX, cytarabine, dex, cyclophosphamide
Gross total resection
MTX
Immunocompetent
Immunocompromised Allogeneic stem cell transplant Immunocompetent Brain biopsy; MTX, vincristine, 6-MP, cytarabine, etoposide; craniospinal radiation
Gross total resection
MTX, cytarabine, dex, stem cell transplant Craniospinal radiation, MTX, AraC, dex MTX, cytarabine, dex Chemotherapy, not specified
Immunocompetent
Alive at 4.8 years
Alive after 10 months
Alive after 38 months
Alive after 20 months
Death shortly after diagnosis
Death after 6 months
Death after 8 days
Alive after 6 years Alive after 6 months
Alive after 6 years
Alive after 9 years
Alive after 79 months Alive after 98 months Alive after 122 months Death after 1 month
Radiotherapy, MTX, vincristine, doxorubicin, Death after 3 months methylprednisolone, cytarabine
Immunocompetent Immunocompetent Immunocompromised Immunocompetent
Immunocompetent
Outcome
Gross total resection, craniospinal radiation, Alive after 24 months LSA(2)-L2 protocol Surgery NR
Treatment
Immunocompromised Surgical resection, prednisolone, cyclophosphamide, vincristine, daunorubicin, L-asparaginase, 6-MP, MTX, cytarabine, hydroxycarbamide Immunocompetent Craniospanial radiation, MTX, AraC, Lasparaginase NR Subtotal resection, radiotherapy, MTX, cytarabine Immunocompetent Radiotherapy
Immunocompetent
NR
Immunocompetent
NR
NR
BLymphoblastic, convoluted T cell^ Leu-1, Leu-2a, Leu-3a
Immune status
Histology/immunophenotype
6-MP 6-mercaptopurine, AraC cytosine arabinoside, dex dexamethasone, MTX methotrexate, NR not reported
Multifocal cerebral Right parieto-occipital lobe; cortical, subcortical, periventricular regions
Left frontal lobe
Right convexity, leptomeninges
Bilateral frontal and parietal lobes, caudate, basal ganglia NR NR NR Right parietal lobe, cerebellum
Cerebellum
Right frontoparietal, left cerebellum Right parietal lobe
Al-Ghamdi et al. [3] 10, F
7, M
Right parietal lobe
2, F
Bogdahn et al. [5]
Cerebellum
Age (years), Tumor site Sex
Literature review of pediatric T cell primary CNS lymphoma cases
Study
Table 1
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infiltration of parenchyma may not be associated with signal abnormality [39]. Because of this significant variability, lowand high-grade lymphomas cannot be distinguished by radiographic characteristics alone. Establishing a pathological diagnosis requires obtaining a sufficient amount of abnormal tissue from a CSF sample or brain biopsy; however, a definitive diagnosis often cannot be established even if a relatively large volume of tissue is obtained. CSF analysis fails to establish a diagnosis in approximately one third of patients with PCNSL and leptomeningeal disease [40]. Flow cytometry may enhance detection in patients with a low concentration of malignant cells in CSF [41] but is non-specific given the wide variety of conditions that exhibit monoclonal populations of lymphocytes [27, 42–45]. In this case, we could not differentiate between an immature and a mature lymphoproliferative process based on flow cytometry results alone. The specimen expressed both mature (CD3 positive, TCR γδ positive, CD1a negative, and CD99 negative) and immature features (TdT positive). When PCNS L is suspected, brain biopsy corresponding to an area of abnormal enhancement or signal intensity on T2-weighted MRI may maximize the likelihood of establishing a definitive diagnosis. Identification of histological features may have implications regarding treatment and survival. Systemic lymphomas with immature cellular features, such as the lymphoblastic subtype seen in our patient, are more aggressive but frequently responsive to treatment and can be curable [16].
is ideal. In the case presented, our patient improved clinically after initiation of empiric corticosteroids, but these were rapidly tapered and discontinued 72 h prior to surgery to optimize diagnostic yield. Normal markers of T cells include CD3, CD4, and CD8. Alterations of T cell surface markers can occur during both neoplastic transformation and reactive processes. Such change in antigen expression can include loss of CD7 and/or CD5 [43]. Cases have been reported of T cell lymphomas that are CD4 positive, CD8 positive, both CD4 and CD8 positive, and both CD4 and CD8 negative [27, 37]. CD5 expression is present in normal T cells but can also be seen in certain B cell lymphomas [48]. Aberrant expression of CD20, a marker traditionally thought to be B cell specific, may be present in up to 12 % of normal T cells as well as in lymphomas [49, 50]. A shift in the CD4/CD8 ratio has been investigated as a means to distinguish among T cell proliferative disorders; however, this ratio may fluctuate over the course of a pathologic process and CD4 or CD8 predominance can be seen in a variety of conditions [27, 42–45]. Monoclonality is usually assessed by molecular testing for TCR gene rearrangements [42, 44]; however, given the variety of conditions in which monoclonal populations of T cells have been observed, results of TCR gene rearrangements need to be interpreted within the appropriate clinical context [27, 42–45].
Potential pitfalls in diagnosis
In the few reported cases of pediatric T cell PCNSL (Table 1), a wide variety of treatment modalities have been used, including surgical resection without adjuvant treatment, radiation or chemotherapy alone, allogeneic stem cell transplant, and multimodality regimens with various combinations. Because of the paucity of confirmed cases, little information can be extrapolated from the literature to help guide treatment for T cell PCNSL in children. Current management is based on analysis of patients with PCNSL of B cell origin. The IPCG review included 29 child and adolescent patients (mean age 14 years) with PCNSL, including only 5 with T cell PCNSL, who underwent a variety of treatment regimens with 5.7 years of mean follow-up [20]. The authors found that prognosis depended on the intensity and type of chemotherapy. Good outcomes were observed in children treated with chemotherapy alone consisting mainly of regimens utilizing high-dose methotrexate. The authors also concluded that radiation can be deferred for refractory or relapsed cases, a finding that has been corroborated by others [2, 14]. In the case presented, craniospinal radiation therapy was used because of a slow clinical response to intensive chemotherapy reflected by persistent CSF pleocytosis, but evidence to guide the use of radiation therapy in patients with T cell PCNSL is lacking. Differentiating T cell lymphoma from a B cell malignancy may be important for some treatment decisions, such as
Even after obtaining a brain biopsy, there are several potential pitfalls when making a pathological diagnosis of T cell PCNS L. In contrast to B cell lymphomas, most PCNSLs of T cell origin do not show high-grade morphology or atypical features [27]. Further complicating the diagnosis is the presence of a mixed infiltrate, containing reactive T cells, B cells, and macrophages, that is a common feature in any lymphoproliferative process. Concentric perivascular lymphoid aggregates can be present in both neoplastic and reactive processes. In some cases of T cell PCNSL, reactive B cells outnumber neoplastic T cells [27]. High proliferation rates and Ki-67 staining are not specific for differentiating reactive from neoplastic infiltrates [27, 45–47]. If corticosteroids were administered prior to the biopsy, an abundance of macrophages may also obscure the identification of neoplastic T cells. Corticosteroids can induce lymphoid cells to undergo apoptosis, depleting neoplastic cells within 24–48 h, rendering the sample non-diagnostic. After a few days, PCNSL cells may develop resistance to corticosteroids and repopulate the brain parenchyma. At least one report has described obtaining a successful PCNSL diagnosis, via molecular testing, after corticosteroids were started [7], but obtaining a biopsy before initiating corticosteroid treatment
Treatment
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whether to include rituximab into the treatment protocol; however, prognosis and treatment responses do not appear to differ between T cell and B cell PCNSL, at least in adults [26]. In addition to cellular lineage, the role of tumor cell maturity and molecular phenotyping also remains unclear. While a variety of subtypes of T cell PCNSL have been described, there appears to be a distinct anaplastic large cell variant, which is typically CD30-positive [8], as well as a small cell variant. This case was characterized by lymphoblastic T cells of small to intermediate size that favored the late thymocyte stage of T cell differentiation. The significance of the T cell PCNSL subtypes has not been determined; Shenkier and colleagues [26] reported evidence that cytologic type does not affect survival. Larger studies are needed to determine whether there is a difference in treatment or survival among the various subtypes.
Conclusion Although PCNSL is rarely seen in pediatric patients, this case demonstrates the importance of brain biopsy in cases in which it is suspected. PCNSL of T cell origin in children remains poorly studied, with only 18 detailed cases reported over the last three decades, including this report. Increasing awareness and identification of children diagnosed with T cell PCNSL is needed to better understand the molecular biology of this disease and develop more standardized treatment regimens. Acknowledgments The authors thank Kristin Kraus, M.Sc., for her assistance in the preparation of this paper. Conflict of interest The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
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