All 6 studies had a sensitivity of 100%. Regarding specificity, 4 out of 6 studies had a specificity of 100%, while the study by Pierce et al reported a specificity of 91% and the study by Heald et al reported a specificity of 75%. Further meta-analysis of PET studies could not be performed because no false negatives were reported for any of the 6 studies (ie, value of zero in 2 × 2 contingency table).
Bivariate meta-regression analysis was performed to detect the source of heterogeneity. We found that the analytical method used and reference standard contributed to the heterogeneity, while geography, study design, study size, tracer used, and proportion of TE in nonlymphoma cases did not contribute significantly to heterogeneity. The pooled sensitivity of studies using quantitative analysis was higher than that based on studies using visual inspection (0.94 vs 0.86). Both sensitivity (0.94 vs 0.85) and specificity (0.87 vs 0.73) in studies including follow-up as reference standard in addition to pathology and/or serology were higher than those that used only pathology and/or serology as the gold standard. The results of the subgroup meta-regression analysis for SPECT are summarized in Table 1.
Sensitivity analysis using the leave-one-out approach demonstrated that the direction and magnitude of estimates were not influenced by any 1 study removed for SPECT (Supplemental Table 5, http://links.lww.com/MD/B690). Deek funnel plot and regression test of asymmetry demonstrated a publication bias (P = 0.001) (Supplemental Fig. 1, http://links.lww.com/MD/B689).
Since the introduction of highly active antiretroviral therapy (HAART) in 1996, the epidemiology of CNS disease among HIV patients has been altered. HAART reduces plasma viral load and thus significantly decreases the incidence of opportunistic infections such as toxoplasmosis and multifocal leukoencephalopathy in immunocompromised patients. However, the incidence of HIV-related lymphoma has been on the rise. The exact pathogenic mechanism of PCNSL is not well understood, but the B-cell malignancies are consistently associated with Epstein–Barr virus. Lymphomagenesis typically occurs late in the course of HIV infection.
In the post-HAART era, a correct early diagnosis of brain lymphoma is essential for HIV patients, since lymphoma is managed differently from toxoplasmosis and other opportunistic infections. Unfortunately, brain biopsy is invasive while conventional imaging modalities have limited diagnostic accuracy.[6,12] Functional nuclear imaging modalities such as SPECT and PET have become increasingly popular diagnostic tools, as they provide images with high spatiotemporal resolution to evaluate perfusion or metabolism. SPECT relies on gamma ray emission from uptake of radiotracers such as Tc-99m, while PET utilizes positron-emitting radiotracers such as 18F-fluorodeoxyglucose. MRS aims to query the biochemical composition of tissue by using the same 1H signals recognized by conventional MRI to determine relative concentrations of target brain metabolites such as N-acetylaspartate, choline, and creatine. A generally accepted understanding of the use of SPECT, PET, and advanced MRI techniques to diagnose brain lymphoma is currently lacking due to the small number of published studies and limited cohort size. Thus, we performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of SPECT, PET, and MRS in differentiating PCNSL from other FBLs in HIV patients.
Other imaging modalities such as CT and MRI have also been studied for their ability to differentiate PCNSL from other contrast-enhancing lesions in HIV patients. However, routine CT and MRI demonstrated only modest sensitivity and specificity.[5–10] In the present study, we included only 3 papers on MRS which contain extractable data, 2 of which reported only modest sensitivity and specificity in differentiating of lymphoma from other FBLs in HIV patients.[31,32,35] Other advanced MRI techniques, such as apparent diffusion coefficient (ADC) ratios, and regional cerebral blood volume (rCBV) have even less reported evidence.[34,52] According to our literature research, only 3 studies on diffusion[26,27,34] and 1 study on MR perfusion were published on distinguishing lymphoma from other FBLs in HIV-infected patients. Two studies on diffusion demonstrated significant overlap in ADC ratios of toxoplasmosis and lymphoma.[26,27] The only study on MR perfusion reported both sensitivity and specificity of 100% in distinguishing lymphoma from other FBLs in 13 patients. Further studies are need to investigate the diagnostic accuracy of these advanced MRI techniques.
We acknowledge several limitations of our study. First, some patients were under antitoxoplasmosis treatment when SPECT or PET was performed. Steroids and other drugs used can affect lymphoma presentations and complicate the differentiation of PCNSL from toxoplasmosis. Second, the SPECT tracer 201-Tl and PET tracer 18F-fluorodeoxyglucose can accumulate in abscesses and inflammatory lesions, which can increase false-positive rates and interfere with diagnosis of dual pathology. Third, small sample size, retrospective design, heterogeneous tumor characteristics, and different imaging parameters such as scanning time can contribute to bias in estimating diagnostic accuracy of SPECT, PET, and MRS. Fourth, lesion size was reported in a small number of studies, which precluded analysis of diagnostic accuracy based on a lesion size threshold. Finally, there was evidence of publication bias in our meta-analysis of SPECT, which suggests that inclusion of small studies may have skewed our estimates for test accuracy. However, such bias is not very concerning in meta-analysis of single outcome proportions because no effect estimate is calculated (ie, no comparison between groups is made).
This work was supported by the Natural Science Foundation of China (81301988 to L.Y.), and China Ministry of Education Doctoral Program Spot Foundation (20130162120061 to L.Y.). Shenghua Yuying Project of Central South University to L.Y.
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