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Logo of neuroncolAboutAuthor GuidelinesEditorial BoardNeuro-Oncology
Neuro-oncol. 2007 April; 9(2): 96–102.
PMCID: PMC1871672

High-dose methotrexate is beneficial in parenchymal brain masses of uncertain origin suspicious for primary CNS lymphoma


In patients with parenchymal brain masses of uncertain origin responsive to corticosteroids, primary CNS lymphoma (PCNSL) should be considered. PCNSL is a rare but aggressive brain tumor that is highly sensitive to high-dose methotrexate (HDMTX)–based chemotherapy. We report a series of six patients with brain masses without histologic confirmation suspicious for PCNSL based on clinical and radiomorphologic criteria after exclusion of some infectious conditions. All patients were treated with HDMTX. We observed two complete responses, two partial responses, and one stable disease. One patient had progressive disease and received rescue whole-brain irradiation. All patients were alive without disease progression 12–48 months after HDMTX start. No symptoms of late neurotoxicity have occurred so far. The response and survival data in this small series of patients are encouraging and suggest a benefit for patients with suspected PCNSL after initial treatment with HDMTX.

Keywords: brain masses, brain tumor, CNS lymphoma, high-dose methotrexate, unconfirmed diagnosis, unconfirmed histology

In patients with brain tumors, diagnosis is usually made by histologic evaluation. However, in some patients biopsy is precarious or not feasible due to size or location of the lesion, cerebral edema, concomitant disease, or lack of patient’s consent. Moreover, a conclusive histologic diagnosis cannot be achieved in up to 10% of biopsies (Bernays et al., 2002; Hall, 1998; Wild et al., 1990). A probable diagnosis must then be made on clinical, radiologic, and biochemical/serologic findings in this situation. Primary CNS lymphoma (PCNSL)2 should be considered in some of these patients, especially when response to corticosteroids is observed.

PCNSL comprises only 2%–5% of all primary brain tumors, but a threefold increase of the incidence has been reported since 1970 (Eby et al., 1988). PCNSL is a very aggressive tumor leading to irreversible deficits when treatment is delayed. Moreover, treatment of PCNSL differs from many other primary brain tumors, in that resection is not beneficial for survival. Survival in PCNSL is limited to 12–18 months with whole-brain irradiation (WBI) alone (DeAngelis, 1995; Nelson et al., 1992) and can be prolonged to more than 30 months with high-dose methotrexate (HDMTX)–based chemotherapy (Abrey et al., 1998; Glass et al., 1994). Patients treated with radiotherapy seem at higher risk for cognitive dysfunction than patients treated with HDMTX-based chemotherapy alone. Thus, a rapid and correct diagnosis is crucial in PCNSL.

The aim of this retrospective study was to analyze the outcome of six patients with histologically unconfirmed parenchymal brain masses suspect of PCNSL after treatment with HDMTX.

Materials and Methods

Six immunocompetent patients with brain lesions suspect of PCNSL without histologic or cytologic diagnosis confirmation were treated at our institution from 2002 to 2005.

Contrast-enhanced brain MRIs were obtained from all patients before steroid medication. Routine sequences were T2-weighted turbo spin echo sequence, fluid-attenuated inversion recovery sequence, and T1-weighted spin echo sequence with and without gadolinium contrast. The scans were evaluated for the number of lesions, location, contrast enhancement, T2 signal intensity, necrosis, edema, and proximity to the subarachnoid space, ventricles, calvarium, and meninges. Necrosis was defined as an area without enhancement inside a contrast-enhanced lesion. The extent of edema was determined on T2-weighted images and rated as moderate, intermediate, or extensive according to previously published criteria (Küker et al., 2005).

In one patient with hypothalamic lesion, 18F-fluoro-deoxyglucose (FDG) PET was also performed.

All patients had a thoracic and abdominal CT scan and underwent cytologic and histologic bone marrow examination to exclude systemic tumor manifestations.

Patients 1 and 4 had an open brain biopsy (repeated in patient 4), and patient 5 had a stereotactic procedure, and the tissue was evaluated both histologically and immunohistologically. None of these patients received steroids before biopsy. Tissue material was not sufficient for additional molecular pathology. Cerebrospinal fluid (CSF) for cytomorphologic and immunocytologic evaluation was obtained from all but one patient, who refused puncture. Protein was measured in the CSF of all patients; IgG and oligoclonal bands were measured in the CSF and serum of three patients. PCR of the third complementarity-determining region (CDR3) for detection of clonal immunoglobulin heavy-chain rearrangements was additionally performed in three patients (Gleissner et al., 2002). Herpes virus infection was excluded by consensus PCR from CSF in four patients, and enterovirus infection was excluded by PCR from CSF in two patients. Patient 1 was additionally tested for JC virus, mycobacteria, and cryptococci in CSF.

Toxoplasmosis, cytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus infection were excluded by serologic examinations in all patients. Ophthalmologic examination was performed in all but one patient.

Response evaluation was performed according to criteria recently published for PCNSL by Abrey et al. (2005) after the third and sixth course and every three months in the first year, every four months in the second year, and every six months in the third year and the following years of follow-up. Overall survival was measured from start of treatment to death or last follow-up.


The group consisted of four women and two men with a median age of 52.5 (range, 19–75) years.

Characteristics of the patients at first presentation are summarized in Table 1. Clinical symptoms deteriorated rapidly in patients 1–3, 5, and 6 and remained stable in patient 4. Corticosteroids were given before chemotherapy to all patients, which resulted in clinical improvement in all but patient 4.

Table 1
Initial characteristics, treatment, and outcome in all patients

Biopsy revealed nonspecific reactive tissue in patient 1 and perivascular T-cell and B-cell lymphocytic infiltrates in patients 4 and 5, with no evidence of demyelination or immunohistologic proof of lymphoma. Histopathology of patient 4 is shown in Fig. 1. In three patients, biopsy was considered not feasible due to lesion location (patients 3 and 6) or critical condition requiring immediate corticosteroid treatment (patient 2). Cytologic examination of CSF was initially inconclusive in all patients. In patient 3, CDR3 PCR revealed monoclonal cells after treatment had already been initiated.

Fig. 1
Histopathology: stereotactic brain biopsy (A) showing perivascular lymphoid infiltrates (hematoxylin and eosin) consisting of a mixture of CD3+ T-cells (B) and CD20+ B-cells (C) with a Ki-67 proliferative index of approximately 10%–20% (alkaline ...

Five patients had only one lesion on MRI, and one patient had two lesions. Location adjacent to the CSF space was found in all patients. Contrast enhancement was rated strong in four patients and moderate in two patients. Five patients had moderate edema on T2-weighted MRI, and one patient had intermediate edema. PET performed in patient 4 showed strong FDG uptake. Individual findings on MRI are shown in Fig. 2A and andBB.

Fig. 2A
MRI. Panel 1 shows a pontine lesion (patient 1) with moderate inhomogeneous contrast enhancement on T1-weighted axial slice (a) and moderate edema on T2-weighted axial (b) and T2-weighted fluid-attenuated inversion recovery coronal slice (c). Panel 2 ...
Fig. 2B
MRI. Panel 4 shows a moderately contrast-enhanced hypothalamic lesion (patient 4) on axial (a) and sagittal (b) slices and moderate edema on T2-weighted axial slice (c). Panel 5 shows a large temporooccipital lesion (patient 5) with strong and homogeneous ...

All patients were discussed interdisciplinarily. After thorough information about the lack of a definite diagnosis and discussion of alternative diagnoses and treatment options, all patients consented and were then treated with HDMTX, 4 g/m2, with dexamethasone in the first course. In patient 1, WBI was started before chemotherapy after a tentative diagnosis of glioma and was stopped after application of 14 Gy. Patient 3 additionally received ifosfamide starting with the fourth course after partial remission had been achieved with three courses of HDMTX.

After chemotherapy, two patients achieved complete remission, two partial remission, and one patient had progressive disease before he received rescue WBI. A complete loss of FDG uptake on PET was found in patient 4, but tumor size only slightly decreased on MRI. All patients were alive 12–54 months after HDMTX start without further treatment, with no evidence of active tumor and without clinical signs of late neurotoxicity (see Table 1).


Patients with symptomatic parenchymal brain masses in whom access to tissue biopsy is not feasible or histopathology is not conclusive have very limited therapeutic options, usually reduced to steroid medication and brain radiation when a malignant tumor is suspected. However, clinical and radiomorphologic features may be indicative of PCNSL in some cases. Age greater than 50, short symptom duration (median, 2.8 months) with rapid deterioration, and rapid but transient improvement with corticosteroids are typical and were essential for considering PCNSL the most probable diagnosis in our patients. Patients 1 and 4 were exceptional in that their young age was very atypical for PCNSL. A characteristic MRI morphology with location adjacent to CSF space, strong (or at least moderate) and homogeneous contrast enhancement, moderate edema, and absence of necrosis was present in all our patients (Bühring et al., 2001; Küker et al., 2005; Roman-Goldstein et al., 1992; Schwaighofer et al., 1989). These findings are, however, not specific for PCNSL and can also be observed in other brain lesions.

On the other hand, PCNSL can sometimes present with atypical morphology, which can be attributed to low-grade histology in some cases (Jahnke et al., 2005). Analysis of the CSF did not immediately provide additional information with regard to the presence of lymphoma, but it was of utmost importance to exclude an infection.

A variety of differential diagnoses cannot be ruled out in our patients with absolute certainty. CNS sarcoidosis has especially been considered in patient 4 due to hypothalamic lesion location (Bullmann et al., 2000). However, biopsy did not show characteristic noncaseating granulomas in any patient. Moreover, isolated CNS sarcoidosis is very rare, and systemic manifestations were excluded by CT in all patients and additionally FDG PET in patient 4. Tumefactive multiple sclerosis (MS) with its variant Marburg-type MS typically shows a heterogeneous and annular contrast enhancement that differs from the radiologic appearance of lesions in our patients (Capello and Mancardi, 2004; Dagher and Smirniotopoulos, 1996; Kurihara et al., 1996; Mendez and Pogacar, 1998; Silva et al., 1999; Tan et al., 2004). Additionally, no signs of demyelination were detected in biopsies of our patients. Acute disseminated encephalomyelitis, a monophasic inflammatory demyelinating disease with long-term response to corticosteroids, usually affects children and young adults, in contrast to the older age of PCNSL patients (Marchioni et al., 2005; Menge et al., 2005; Schwarz et al., 2001). Acute disseminated encephalomyelitis should especially be considered in our two younger patients (patients 1 and 4). Autoimmune vasculitis can secondarily present with CNS manifestations (Siva, 2001); however, primary angiitis of the CNS, affecting mostly young adults (Volcy et al., 2004), is extremely rare (MacLaren et al., 2005; Rehman, 2000). Inflammatory pseudotumors, nonneoplastic lesions of unknown etiology, typically arise from meningeal structures in children and young adults and are moderately responsive to steroids (Mombaerts et al., 1996).

PCNSL seems a common diagnosis in patients with initially “unclear” brain masses responding to steroids. Of the four patients reported by Alderson et al. (1996), histology was nondiagnostic in all, with demyelination in two patients and nonspecific inflammation in one patient; however, corticosteroids were given in three patients before biopsy. All patients relapsed 7–11 months after initial response to corticosteroids with symptomatic new lesions, biopsy then revealing B-cell PCNSL. In a series of 12 patients analyzed by Bromberg et al. (2002), five were eventually diagnosed with PCNSL, with recurrence and death within 4–11 months after first presentation in four. Of the remaining patients, MS was diagnosed in two, thalamic infarct and renal carcinoma metastasis in one patient each, and no definite diagnosis could be made in three patients after follow-up ranging from three to eight years. A literature search of case reports performed by the authors revealed PCNSL in about 50% of 78 patients with similarly vanishing brain tumors. Patients with PCNSL tended to be older, and recurrence is most likely within 18 months, but clinical or radiologic features could not definitely distinguish PCNSL from non-PCNSL patients.

Newer and more sophisticated methods for the detection of PCNSL might contribute to diagnosis establishment in the future. The detection of monoclonal B-cells can be facilitated by IgH PCR as shown in one of our patients, but this method is not so easily available or fast enough and is positive only in a small number of PCNSL patients (Gleissner et al., 2002). PET imaging, used in one of our patients, has been shown to be beneficial in distinguishing between highly proliferative brain tumors like PCNSL, infectious lesions, and necrosis (Hoffman et al., 1993; Roelcke and Leenders, 1999). Advances in MRI technology such as diffusion-weighted protocols and MR spectroscopy imaging have recently been studied in PCNSL and may be routinely implemented (Harting et al., 2003; Hartmann et al., 2003; Raizer et al., 2005; Reiche et al., 2007). Diffusion-weighed MRI may be helpful in separating PCNSL from diseases associated with cytotoxic (ischemic) edema (Moritani et al., 2004). Perfusion-weighed MRI has recently been reported to produce characteristic findings in PCNSL as compared to high-grade gliomas (Hartmann et al., 2003). Limited data on MR spectroscopy suggest characteristic spectra in PCNSL (Harting et al., 2003).

When histology shows mixed lymphocytic infiltrates, clonality analysis using IgH PCR should always be attempted. However, feasibility is often limited by an insufficient amount of material for PCR analysis (Hoeve et al., 2000).

Neither response to corticosteroids nor response to HDMTX is evidentiary for PCNSL. Both agents are successfully used to treat many conditions considered differential diagnoses, although typically at lower doses. PCNSL seemed the most ominous differential diagnosis when not rapidly and adequately treated. Thus, the decision to treat with HDMTX appeared reasonable also in patients 1 and 4, in whom the diagnosis of PCNSL seemed somewhat less likely. HDMTX monotherapy is relatively safe when all precautions are observed. Therefore, it is mandatory that patients are treated only at experienced institutions with sufficient expertise.

Based on our findings, patients with clinical and radiomorphologic features suggestive of PCNSL should be treated initially with a chemotherapeutic regimen including HDMTX, with WBI being postponed until progress or relapse.


2Abbreviations used are as follows: CDR3, third complementarity-determining region; CSF, cerebrospinal fluid; FDG, 18F-fluorodeoxyglucose; HDMTX, high-dose methotrexate; MS, multiple sclerosis; PCNSL, primary CNS lymphoma; WBI, whole-brain irradiation.


  • Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol. 1998;16:859–863. [PubMed]
  • Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M, Pulczynski EJ, Zucca E, Smith JR, Korfel A, Soussain C, DeAngelis LM, Neuwelt EA, O’Neill BP, Thiel E, Shenkier T, Graus F, van den Bent M, Seymour JF, Poortmans P, Armitage JO, Cavalli F.; International Primary CNS Lymphoma Collaborative Group. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol. 2005;23:5034–5043. [PubMed]
  • Alderson L, Fetell MR, Sisti M, Hochberg F, Cohen M, Louis DN. Sentinel lesions of primary CNS lymphoma. J Neurol Neurosurg Psychiatry. 1996;60:102–105. [PMC free article] [PubMed]
  • Bernays RL, Kollias SS, Khan N, Brandner S, Meier S, Yonekawa Y. Histological yield, complications, and technological considerations in 114 consecutive frameless stereotactic biopsy procedures aided by open intraoperative magnetic resonance imaging. J Neurosurg. 2002;97:354–362. [PubMed]
  • Bromberg JEC, Siemers MD, Taphoorn MJB. Is a “vanishing tumor” always a lymphoma? Neurology. 2002;59:762–764. [PubMed]
  • Bühring U, Herrlinger U, Krings T, Thiex R, Weller M, Kuker W. MRI features of primary central nervous system lymphomas at presentation. Neurology. 2001;57:393–396. [PubMed]
  • Bullmann C, Faust M, Hoffmann A, Heppner C, Jockenhovel F, Muller-Wieland D, Krone W. Five cases with central diabetes insipidus and hypogonadism as first presentation of neurosarcoidosis. Eur J Endocrinol. 2000;142:365–372. [PubMed]
  • Capello E, Mancardi GL. Marburg type and Balo’s concentric sclerosis: Rare and acute variants of multiple sclerosis. Neurol Sci. 2004;25:361–363.
  • Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology. 1996;38:560–565. [PubMed]
  • DeAngelis LM. Current management of primary central nervous system lymphoma. Oncology. 1995;9:63–71. [PubMed]
  • Eby NL, Gruffermann S, Flannelly CM, Schold SC, Vogel FS, Burger PC. Increasing incidence of primary brain lymphoma in the US. Cancer. 1988;62:2461–2465. [PubMed]
  • Glass J, Gruber ML, Cher L, Hochberg FH. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: Long-term outcome. J Neurosurg. 1994;81:188–195. [PubMed]
  • Gleissner B, Siehl J, Korfel A, Reinhardt R, Thiel E. CSF evaluation in primary CNS lymphoma patients by PCR of the CDR III IgH genes. Neurology. 2002;58:390–396. [PubMed]
  • Hall WA. The safety and efficacy of stereotactic biopsy for intracranial lesions. Cancer. 1998;82:1749–55. [PubMed]
  • Harting I, Hartmann M, Jost G, Sommer C, Ahmadi R, Heiland S, Sartor K. Differentiating primary central nervous system lymphoma from glioma in humans using localised proton magnetic resonance spectroscopy. Neurosci Lett. 2003;342:163–166. [PubMed]
  • Hartmann M, Heiland S, Harting I, Tronnier VM, Sommer C, Ludwig R, Sartor K. Distinguishing of primary cerebral lymphoma from high-grade glioma with perfusion-weighted magnetic resonance imaging. Neurosci Lett. 2003;338:119–122. [PubMed]
  • Hoeve MA, Krol ADG, Derksen PWB, Veenendaal RA, Schuuring E, Kluin PM, van Krieken JHJM. Limitations of clonality analysis of B cell proliferations using CDR3 polymerase chain reaction. J Clin Pathol Mol Pathol. 2000;53:194–200.
  • Hoffman JM, Waskin HA, Schifter T, Hanson MW, Gray L, Rosenfeld S, Coleman RE. FDG-PET in differentiating lymphoma from nonmalignant central nervous system lesions in patients with AIDS. J Nucl Med. 1993;34:567–575. [PubMed]
  • Jahnke K, Thiel E, Schilling A, Herrlinger U, Weller M, Coupland SE, Krumpelmann U, Stein H, Korfel A. Low-grade primary central nervous system lymphoma in immunocompetent patients. Br J Haematol. 2005;128:616–624. [PubMed]
  • Küker W, Nägele T. Korfel A, Heckl S. Thiel E, Bamberg M. Weller, M. and, Herrlinger U. Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients. J Neurooncol. 2005;72:169–177. [PubMed]
  • Kurihara N, Takahashi S, Furuta A, Higano S, Matsumoto K, Tobita M, Konno H, Sakamoto K. MR imaging of multiple sclerosis simulating brain tumor. Clin Imaging. 1996;20:171–177. [PubMed]
  • MacLaren K, Gillespie J, Shrestha S, Neary D, Ballardie FW. Primary angiitis of the central nervous system: Emerging variants. QJM. 2005;98:643–654. [PubMed]
  • Marchioni E, Ravaglia S, Piccolo G, Furione M, Zardini E, Franciotta D, Alfonsi E, Minoli L, Romani A, Todeschini A, Uggetti C, Tavazzi E, Ceroni M. Postinfectious inflammatory disorders: Subgroups based on prospective follow-up. Neurology. 2005;65:1057–1065. [PubMed]
  • Mendez MF, Pogacar S. Malignant monophasic multiple sclerosis or “Marburg’s disease. Neurology. 1998;38:1153–1155. [PubMed]
  • Menge T, Hemmer B, Nessler S, Wiendl H, Neuhaus O, Hartung HP, Kieseier BC, Stuve O. Acute disseminated encephalomyelitis: An update. Arch Neurol. 2005;62:1673–1680. [PubMed]
  • Mombaerts I, Schlingemann RO, Goldschmeding R, Koornneef L. Are systemic corticosteroids useful in the management of orbital pseudotumors? Ophthalmology. 1996;103:521–528. [PubMed]
  • Moritani T, Hiwatashi A, Shrier DA, Wang HZ, Numaguchi Y, Westesson PL. CNS vasculitis and vasculopathy: Efficacy and usefulness of diffusion-weighted echoplanar MR imaging. Clin Imaging. 2004;28:261–270. [PubMed]
  • Nelson DF, Martz KL, Bonner H, Nelson JS, Newall J, Kerman HD, Thomson JW, Murray KJ. Non-Hodgkin’s lymphoma of the brain: Can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys. 1992;23:9–17. [PubMed]
  • Raizer JJ, Koutcher JA, Abrey LE, Panageas KS, DeAngelis LM, Lis E, Xu S, Zakian KL. Proton magnetic resonance spectroscopy in immunocompetent patients with primary central nervous system lymphoma. J Neurooncol. 2005;7:173–180. [PubMed]
  • Rehman HU. Primary angiitis of the central nervous system. J R Soc Med. 2000;93:586–588. [PMC free article] [PubMed]
  • Reiche W, Hagen T, Schuchardt V, Billmann P. Diffusion-weighted MR imaging improves diagnosis of CNS lymphomas: A report of four cases with common and uncommon imaging features. Clin Neurol Neurosurg. 2007;109:92–101. [PubMed]
  • Roelcke U, Leenders KL. Positron emission tomography in patients with primary CNS lymphomas. J Neurooncol. 1999;43:231–236. [PubMed]
  • Roman-Goldstein SM, Goldman DL, Howieson J, Belkin R, Neuwelt EA. MR of primary CNS lymphoma in immunologically normal patients. AJNR Am J Neuroradiol. 1992;13:1207–1213. [PubMed]
  • Schwaighofer BW, Hesselink JR, Press GA, Wolf RL, Healy ME, Berthoty DP. Primary intracranial CNS lymphoma: MR manifestations. AJNR Am J Neuroradiol. 1989;10:725–729. [PubMed]
  • Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Hagen-locher B. Acute disseminated encephalomyelitis: A follow-up study of 40 adult patients. Neurology. 2001;56:1313–1318. [PubMed]
  • Silva HC, Callegaro D, Marchiori PE, Scaff M, Tsanaclis AM. Magnetic resonance imaging in five patients with a tumefactive demyelinating lesion in the central nervous system. Arq Neuropsiquiatr. 1999;57:921–926. [PubMed]
  • Siva A. Vasculitis of the nervous system. J Neurol. 2001;248:451–468. [PubMed]
  • Tan HM, Chan LL, Chuah KL, Goh NSS, Tang KK. Monophasic, solitary tumefactive demyelinating lesion: Neuroimaging features and neuropathological diagnosis. Br J Radiol. 2004;77:153–156. [PubMed]
  • Volcy M, Toro ME, Uribe CS, Toro G. Primary angiitis of the central nervous system: Report of five biopsy-confirmed cases from Colombia. J Neurol Sci. 2004;227:85–89. [PubMed]
  • Wild AM, Xuereb JH, Marks PV, Gleave JR. Computerized tomographic stereotaxy in the management of 200 consecutive intracranial mass lesions. Analysis of indications, benefits and outcome. Br J Neurosurg. 1990;4:407–415. [PubMed]

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