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Value of Combined Approach With Thallium-201 Single-Photon Emission Computed Tomography and Epstein-Barr Virus DNA Polymerase Chain Reaction in CSF for the Diagnosis of AIDS-Related Primary CNS Lymphoma

From the Departments of Infectious Diseases, Nuclear Medicine, Pathology, Radiology, and Neurosurgery, Catholic University, Rome, Italy.

Address reprint requests to Andrea Antinori, MD, Department of Infectious Diseases, Catholic University, L.go A. Gemelli 8, 00168 Rome, Italy; email andranto{at}tin.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the diagnostic capability of thallium-201 (²⁰¹Tl) single-photon emission computed tomography (SPECT) combined with Epstein-Barr virus DNA (EBV-DNA) in CSF for the diagnosis of AIDS-related primary CNS lymphoma (PCNSL).

PATIENTS AND METHODS: All human immunodeficiency virus (HIV)–infected patients with focal brain lesions observed between June 1996 and March 1998 underwent lumbar puncture and ²⁰¹Tl SPECT. Each CSF sample was tested with polymerase chain reaction (PCR) for EBV-DNA.

RESULTS: Thirty-one patients were included, 13 with PCNSL and 18 with nontumor disorders. In 11 PCNSL patients, EBV-DNA was positive. Thallium-201 uptake ranged from 1.90 to 4.07 in PCNSL cases (mean, 2.77; 95% confidence interval [CI], 2.35 to 3.19) and from 0.91 to 3.38 in nontumor patients (mean, 1.62; 95% CI, 1.30 to 1.94) (P < .0002). Using a lesion/background ratio of 1.95 as cutoff, a negative SPECT was found in one PCNSL case and 16 nonneoplastic cases. A cryptococcoma and a tuberculoma showed highly increased ²⁰¹Tl uptake. Epstein-Barr virus DNA was never detected in nonneoplastic patients. For PCNSL diagnosis, hyperactive lesions showed 92% sensitivity and 94% negative predictive value (NPV), whereas positive EBV-DNA had 100% specificity and 100% positive predictive value. The presence of increased uptake and/or positive EBV-DNA had 100% sensitivity and 100% NPV.

CONCLUSION: Combined SPECT and EBV-DNA showed a very high diagnostic accuracy for AIDS-related PCNSL. Because PCNSL likelihood is extremely high in patients with hyperactive lesions and positive EBV-DNA, brain biopsy could be avoided, and patients could promptly undergo radiotherapy or multimodal therapy. On the contrary, in patients showing hypoactive lesions with negative EBV-DNA, empiric anti-Toxoplasma therapy is indicated. In patients with discordant SPECT/PCR results, brain biopsy seems to be advisable.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PRIMARY CNS LYMPHOMA (PCNSL) was reported as an emerging disorder in patients with late-stage AIDS and focal brain lesions (FBL).^1,2 Among FBL-causing disorders in patients with AIDS, a change of the disease pattern has been observed in the last few years. This seems to be caused by the frequency reduction of toxoplasmic encephalitis,³ which is related to an extensive use of primary anti-Toxoplasma prophylaxis,^4,5 as well as by the prolongation of the markedly immunodepressed lifespan. At present, brain biopsy is the gold standard for the diagnosis of cerebral lymphoma and is generally deferred after the first 10 to 14 days of anti-Toxoplasma treatment if a clinical and/or neuroradiologic improvement is absent.⁶ Although several studies have shown that brain biopsy in human immunodeficiency virus (HIV)–positive patients is an effective diagnostic method,^7-10 its use may be limited by its invasiveness, acceptance by patients and surgical operators,¹¹ and cost-effectiveness evaluations.¹² Consequently, recent decision-analysis studies based on the predictive value of specific disease markers, such as the presence of positive Toxoplasma serology, anti-Toxoplasma prophylaxis, or the finding of viral DNA by polymerase chain reaction (PCR) in CSF, suggest a more accurate selection to brain biopsy for HIV-positive patients with FBL.^13,14

The unfavorable impact of delayed lymphoma diagnosis on survival time and the limited life expectancy after brain biopsy underscore the need for a rapid and, preferably, less invasive alternative diagnostic strategy for early discrimination between PCNSL and toxoplasmic encephalitis.¹⁵ Because the association between Epstein-Barr virus (EBV) infection and AIDS-related PCNSL is well-known,¹⁶ the detection of EBV-DNA in CSF by PCR has been proposed as a powerful and highly specific tumor marker.^17-20 Furthermore, recent reports show that thallium-201 (²⁰¹Tl) single-photon emission computed tomography (SPECT) may be able to differentiate between cerebral lymphoma and nonneoplastic lesions in patients with AIDS and FBL.^21,22

To determine the diagnostic capability of a combined approach with ²⁰¹Tl SPECT and EBV-DNA detection in CSF for in vivo diagnosis of PCNSL, the results of a prospective study on 31 consecutive HIV-infected patients with a definitive diagnosis of FBL-causing disorders are reported here.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
All consecutive HIV-infected patients with FBL detected by computed tomography (CT) or magnetic resonance imaging (MRI) and observed between June 1996 and March 1998 at the Department of Infectious Diseases of the Catholic University in Rome, Italy, were included in the study. After providing a written informed consent, all patients were referred to ²⁰¹Tl SPECT and underwent lumbar puncture, because it was not contraindicated by the risk of brain herniation at neurosurgical evaluation. The study protocol was previously approved by the Institutional Ethics Committee. Each CSF sample was tested for cryptococcal antigen; investigated by PCR for DNA of EBV, JC virus (JCV), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), and Mycobacterium tuberculosis; and cultured for mycobacteria and fungi. Brain biopsy was performed as previously reported after obtaining informed consent,⁷ unless it was contraindicated or refused. In patients with FBL showing mass effect, biopsy was planned in case of (1) absence of a clinical and/or radiologic response to the 2-week anti-Toxoplasma treatment trial and contemporary negative results of CSF assays for neurotropic agents (CMV, HSV, JCV, M tuberculosis, Cryptococcus neoformans), or (2) presence of positive PCR for EBV-DNA in CSF. In patients with FBL without mass effect, brain biopsy was carried out in the presence of negative assays in CSF (JCV, CMV, HSV, M tuberculosis, C neoformans). Autopsy was planned in all cases.

The diagnostic criteria for different focal brain disorders were as follows: for PCNSL, histology only; for toxoplasmic encephalitis, histology or the radiographic finding of lesions showing mass effect and/or contrast enhancement combined with response to anti-Toxoplasma treatment²³; for progressive multifocal leukoencephalopathy (PML), histology or compatible MRI findings associated with JCV-DNA detected in CSF ²⁴; for CMV, HSV, and VZV encephalitis, histology or compatible clinical and radiologic findings combined with a detectable viral DNA in CSF ²⁵; for cryptococcoma, histology and positive CSF culture; and for tuberculoma, histology only.

Epstein-Barr Virus Nucleic Acid Detection
Epstein-Barr virus DNA amplification was performed by nested PCR technique, previously described.^17,18 To improve the efficiency of PCR, CSF samples underwent a preamplification step based on a rapid purification method, including digestion with protease K according to the manufacturer's recommendations (QIAmp, Qiagen GmbH, Hilden, Germany). Ten µL of CSF was added to 50 µL of reaction volume containing 50 mmol/L KCl, 10 mmol/L Tris-HCl, 2.5 mmol/L MgCl₂, 400 µmol of each dNTP, 10% glycerol, 0.15 to 0.30 mmol/L of each primer, and 2.5 units of AmpliTaq (Perkin Elmer, Emeryville, CA). A 209 base-pair fragment from the EBNA-1 gene was amplified using EB3/EB4 as the outer primer pair and EB1/EB2 as the inner primer pair. Thirty cycles in both amplification rounds were performed, consisting of 1 minute at 95°C, 1 minute at 50°C, and 1 minute at 72°C. After the first PCR round, 2.5 µL of the amplification product were transferred in the second PCR buffer. After the second round, 10 µL of the second amplification product were electrophoresed on a 2% agarose gel containing 0.5 µg/mL of ethidium bromide and visualized by ultraviolet transillumination. The detection limit of the nested PCR was tested using serial dilutions of DNA extracted from Daudi cells. Several negative and positive controls were used during each amplification step. Rules to avoid sample contamination were strictly applied, and clinical samples were tested at least twice. To assess whether CSF specimens that had negative EBV-DNA by PCR contained DNA suitable for amplification, the samples were tested using primers GH26 and GH27 from the HLADQA1 region. Negative CSF samples at nested PCR assay were checked for the presence of PCR inhibitors. Ten EBV-DNA copies were added to the negative sample and amplified in parallel with 10 EBV-DNA copies in water. If the tested CSF sample was negative again, the presence of PCR inhibitors was assumed. If inhibitors were present, CSF samples were serially diluted up to detect a PCR-positive result.

In situ hybridization was performed using probes for the EBER-1 (small EBV-encoded nuclear RNA transcripts) and a nonradioactive detection kit (Dako, Glostrup, Denmark) according to the manufacturer's instructions.

Thallium-201 SPECT
Thallium-201 SPECT was performed using CER.TO 96 (SELO, Sesto S. Giovanni, Italy) cerebral tomograph 30 minutes after intravenous injection of 170 MBq of ²⁰¹Tl. A quadruple-head camera with four high-resolution collimators, 74 KeV single peak, and 20% window were used. A 40-minute examination was performed. Up to 28 transverse, coronal, and sagittal slices were reconstructed using Hanning (0.5 cycles/cm cutoff frequency) filtered back-projections and Chang's method for attenuation correction. Reconstructed sections (nominal slice thickness = 7.5 mm) were then oriented according to the three spatial planes, using a suitable software program that also permitted the realignment of sagittal sections to the canthomeatal line.

SPECT studies were visually analyzed by a consensus of two experienced nuclear medicine specialists from a computer display. All SPECT images were compared with CT and/or MRI findings to obtain anatomic correlations. A SPECT study was interpreted as being pathologic if single or multiple areas of markedly increased intracranial ²⁰¹Tl uptake were present in transverse, coronal, or sagittal slices. A semiquantitative analysis was then performed. All SPECT slices containing areas of abnormal brain activity were selected and reanalyzed on the basis of CT and/or MRI findings. Sections with the clearest demonstration of lesions were chosen. Using the CER.TO 96 software program, an elliptic regular region of interest (ROI) of varying size and position was drawn around the lesion and then mirrored on the opposite uninvolved side. Horizontal and vertical mirror images were used for lateral and medial lesions, respectively. Care was taken to exclude the normally increased ²⁰¹Tl uptake in the scalp.

An uptake ratio was then calculated by dividing the activity (counts/pixel) of the lesion by the activity (counts/pixel) in the mirrored background region. In patients with more than one lesion, every ROI was semiquantitatively evaluated. For each SPECT examination, the highest value of lesion-to-background (L/B) ratio was then selected.

Statistical Analysis
A descriptive analysis of the general characteristics of the patients included in the study has been carried out. The mean value of the ²⁰¹Tl L/B uptake ratios found at SPECT investigation was calculated and presented with the 95% confidence interval (CI) for PCNSL and non-PCNSL patients. Differences between groups were assessed using the Student's t test. Two-tailed P values of .05 or less were considered as indicating statistical significance. Sensitivity, specificity, positive and negative predictive values of SPECT investigation, and EBV-DNA detection in CSF, alone or combined, and their 95% CIs have been obtained by using the standard formulas²⁶ with the Epi Info 6.02 Statistics Program (U.S. Centers for Disease Control, Atlanta, GA).

The identification of a possible cutoff value among the ²⁰¹Tl L/B uptake ratios to discriminate between a positive and negative SPECT result was based on the relative operating characteristic (ROC) curve analysis.²⁷ The L/B ratio showing the highest sensitivity and specificity was chosen as the cutoff value.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Thirty-one consecutive patients with FBL at CT/MRI observed during the study period were enrolled. All patients underwent ²⁰¹Tl SPECT and lumbar puncture within 6 days from neuroradiologic finding of FBL. Twenty-five patients were male, and the mean age was 38 years. The CD4⁺ cell count ranged from 2 to 152/µL (mean 25/µL), and history of a previous AIDS-defining illness was present in 16 cases. Positive Toxoplasma serology was found in 19 patients. General characteristics of patients, results of SPECT investigation, and CSF analysis by PCR are listed in Table 1. None of the studied patients were diagnosed with multiple CNS disorders; the only PCNSL patient with multiple lesions and bioptic diagnosis of the neoplasm had a marked reduction of all lesions at multimodal treatment. Autopsy confirmed in vivo diagnosis in the remaining patients with multiple lesions. In all 13 patients with PCNSL, a diffuse, large B-cell lymphoma was found at brain biopsy (six cases) or autopsy (seven cases). In situ hybridization of PCNSL tissue specimens showed EBV-encoded transcripts in all patients with cerebral lymphoma. In 11 of 13 (84.6%) PCNSL cases, EBV-DNA amplification in CSF was positive. Genome amplification of serial 10-fold dilutions of DNA extracted from Daudi cells showed that the minimum detection level of the PCR assay was 10 EBV genomes.

The ²⁰¹Tl uptake ratio ranged from 1.90 to 4.07 in the 13 cases of PCNSL (mean, 2.77; 95% CI, 2.35 to 3.19) (Fig 1, A and B) and from 0.91 to 3.38 in the 18 nontumor patients (mean, 1.62; 95% CI, 1.30 to 1.94) (Fig 2A and 2B). This difference was statistically significant (P < .0002). The L/B ratio ranged from 0.91 to 1.87 in cases with toxoplasmic encephalitis (mean, 1.46; 95% CI, 1.26 to 1.66).

View larger version (42K): [in this window] [in a new window]   Fig 1. Patient with PCNSL (patient no. 11). (A) Computed tomography scan shows a large lesion with mass effect and nonhomogeneous contrast enhancement localized in the right basal ganglia and insula. (B) At SPECT, a markedly increased 201Tl uptake in the tumor region was found.

View larger version (41K): [in this window] [in a new window]   Fig 2. Patient with toxoplasmic encephalitis (patient no. 13). (A) MRI slice shows a large hyperintense lesion localized in the right thalamus. Two other small lesions are evident in the left thalamus and the nucleus pallidus. (B) At SPECT, absent 201Tl uptake corresponding to the region of MRI-detected abnormality was found. Selected ROIs for lesion/background assessment are shown.

At ROC curve analysis, SPECT L/B ratios ranging between 1.90 and 2.00 achieved the highest values of sensitivity (92%) and specificity (89%). Using 1.95 as cutoff value, only one PCNSL patient with a ²⁰¹Tl uptake ratio below this value was found; because no steroids were administered before SPECT investigation and the patient had multiple focal lesions, the most probable reason for this finding was the large amount of necrosis found at biopsy. Sixteen nontumor patients showed an L/B ratio of less than 1.95, and the following FBL-causing disorders were diagnosed: toxoplasmic encephalitis (10 cases), CMV encephalitis (three cases), VZV encephalitis (one case), PML (one case), and cerebral vasculitis (one case). A highly increased ²⁰¹Tl uptake at SPECT investigation was found in two patients without PCNSL; final diagnoses were a brain abscess caused by C neoformans (L/B = 3.13) and tuberculoma (L/B = 3.38). Epstein-Barr virus DNA was never detected in the CSF of these nonneoplastic patients.

The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of SPECT examination and PCR investigation for EBV-DNA in CSF for the diagnosis of AIDS-related PCNSL are listed in Table 2.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In the clinical management of FBL occurring in AIDS, differential diagnosis for a rapid selection of patients to proper treatment is the essential requirement to improve response to therapy, survival time, and quality of life. Because neuroradiologic examination by CT or MRI does not reliably distinguish PCNSL from other FBL-causing disorders, minimally invasive investigations that are easy to carry out and have an elevated diagnostic accuracy are needed to avoid loss of precious time by useless anti-Toxoplasma therapy. Furthermore, the identification of new indirect criteria without confirmatory pathology for the diagnosis of AIDS-related PCNSL could represent the new standard for clinical trials on multimodal therapy.^11,28-30

Thallium-201 SPECT has been used in HIV-positive patients because of the high uptake in growing and dividing cells; this property allows a good discrimination between neoplasms and infectious lesions. In recent studies, SPECT was suggested to be able to identify PCNSL in patients with AIDS, as it showed an 80% to 100% sensitivity and an 86% to 100% specificity.^21,22 Considering the finding of an L/B ratio of more than 1.95 as a positive test result, a 92.3% sensitivity and 88.9% specificity were consistently found in our study.

The finding of hyperactive SPECT lesions seems to be less specific for AIDS-related PCNSL than initially reported.^21,31,32 Some authors describe that patients with CMV encephalitis might show a positive SPECT finding.^21,33 Furthermore, an increased ²⁰¹Tl uptake has been found in HIV-negative patients with different mycotic infections.^34-35 In our case series, the two false-positive SPECT results both occurred in patients with definitive diagnoses other than toxoplasmosis: one cerebral cryptococcoma and one tuberculoma. We think that the heterogeneity of HIV-positive patients tested in our study well represents the AIDS-related clinical setting, in which the differential diagnosis of FBL includes not only PCNSL and toxoplasmic encephalitis, but also rarer disorders such as PML, CMV encephalitis, tuberculoma, mycotic abscesses, and cerebral vasculitis. Further studies regarding the ²⁰¹Tl SPECT pattern of opportunistic infections other than cerebral toxoplasmosis occurring in patients with AIDS are needed.

The rather limited specificity (88.9%) and PPV (85.7%) of SPECT alone support its useful combination with the detection of EBV-DNA in CSF by PCR, which is considered a sensitive and highly specific diagnostic tumor marker in AIDS-related PCNSL.^17-20 Actually, a prospective in vivo evaluation of lumbar puncture feasibility in HIV-positive patients with FBL has revealed safety and good feasibility of this procedure.¹⁴ In our case series, EBV-DNA showed a sensitivity, specificity, PPV, and NPV comparable to that previously reported in a large cohort study²⁹ and was detectable by PCR amplification in the CSF of all but two PCNSL patients. The reason for this failed detection is still unknown; the most likely explanation could be the presence in CSF of some PCNSL patients of a very low viral DNA amount, which might be under the sensitivity threshold and therefore not enough to give a positive display at nested PCR.²⁹

In the presence of hyperactive lesions at SPECT combined with positive EBV-DNA in CSF, specificity and PPV for the diagnosis of PCNSL increased to 100%. Because the likelihood of PCNSL is extremely high in this case, we think that brain biopsy could be avoided and patients should promptly undergo radiotherapy or multimodal treatment. On the other hand, a 100% NPV for PCNSL was the result in patients showing hypoactive SPECT lesions together with negative PCR findings for EBV-DNA in CSF. In our opinion, based on the very low probability of PCNSL, these patients should first undergo an empiric anti-Toxoplasma treatment trial, whereas biopsy should only be considered in the case of absent therapy response. In our experience, the positivity of at least one of the two tests was found in all patients with PCNSL. Nevertheless, the execution of brain biopsy as first-line approach seems to be advisable in patients with discordant results at PCR and SPECT. Obviously, in a case of hyperactive lesions at SPECT with undetectable EBV-DNA, other FBL-causing disorders, such as abscesses caused by mycobacteria and fungi or viral encephalitis, have to be excluded.

Thallium-201 SPECT in patients with AIDS and FBL may be particularly useful to better describe the target lesion for brain biopsy, to identify lymphomatous lesions in case of coexisting cerebral disorders, and, possibly in the near future, to monitor response to therapy when combined with quantitative EBV-DNA determination in CSF.^30,36 Nevertheless, because some open issues remain concerning the use of these new diagnostic methods in the management of PCNSL patients with AIDS, their adoption in clinical practice should proceed with the greatest prudence. Due to the variability among different clinical centers of sensitivity, specificity, and PPV of PCR assay for the detection of EBV-DNA in CSF, a standardization of PCR tests is desirable. Furthermore, in order to discriminate between PCNSL and other FBL-causing disorders, the best values for ²⁰¹Tl SPECT uptake have yet to be soundly established in a larger number of patients, even though technical differences may affect the results. Finally, it is possible that the PPV of SPECT for PCNSL may depend on the prevalence of other FBL-causing disorders alternative to PCNSL among the study population of each specific clinical center. Because positron emission tomography scanning of the brain has been described as an alternative technique that is able to distinguish between PCNSL and nonneoplastic cerebral disorders in AIDS,³⁷ studies with the aim of comparing the diagnostic efficiency of the two approaches should be designed.

In conclusion, this study shows a very high diagnostic accuracy of a combined approach with ²⁰¹Tl SPECT and EBV-DNA in CSF for the discrimination of PCNSL and nonneoplastic FBL in patients with AIDS. These minimally invasive, easy, and safe diagnostic tools might in some cases represent a valid alternative to invasive procedures, also allowing for a better and faster identification of patients requiring brain biopsy. This is in order to shorten time to diagnosis, avoid unnecessary empiric anti-Toxoplasma therapy, and accelerate the start of appropriate treatment in patients with PCNSL. Moreover, in a cost-benefit evaluation, radionuclides and biomolecular technology seem to be less expensive than a standard diagnostic approach, especially when considering surgical procedures and hospitalization time.

	ACKNOWLEDGMENTS

 
Supported by the Istituto Superiore di Sanità, IX Progetto AIDS 1996 (grant 9404-26) and the Istituto Superiore di Sanità, Programma Nazionale di Ricerca sull'AIDS-1997.

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Submitted June 1, 1998; accepted October 6, 1998.

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