3.1 Epidemiological studies.
HIV is a neurotropic virus, and the central nervous system is vulnerable to it. It is found that more than 90% of AIDS patients pathological changes in neurological system after autopsies, which may involve the brain, spinal cord, peripheral nerves and muscles. Additionally, 11% of AIDS patients are complicated with central nervous system diseases, and 15% have central nervous system lymphoma (AR-PCNSL). After HIV infection, the incidence of AR-PCNSL rate is as high as 4-10%. In the setting of highly active antiretroviral therapy (ART), the incidence of CNS lymphoma is exceedingly low. Among these patients, the incidence of non-Hodgkin lymphoma (NHL) is significantly higher than that of Hodgkin lymphoma (HL). The prognosis of AR-PCNSL is poor, with a median clinical remission time of 4.2 months and a median survival time after clinical symptom relief of 1.6 months. The rare patient on ART with AR-PCNSL, theoretically might benefit from intensive therapy. Accurate and early diagnosis is important because the treatment and prognosis for these diseases are so different.
3.2 Diagnosis and Differential Diagnosis of AR-PCNSL and Infection.
The number of CSF cells in patients with AR-PCNSL usually increase only slightly, with an increase in protein, and sugar and chlorine levels within the normal range. These signs overlap with those of AIDS complicated with intracranial infections. Clinical manifestations of AR-PCNSL are also not specific, leading to difficulties in diagnosis. AR-PCNSL and infectious diseases present as multiple lesions in conventional MR. It is also very difficult to differentiate two diseases by radiology, which primarily manifest annular or nodular enhancement of MR[2, 19，23-24].
3.2.1 Conventional MR in Diagnosis and Differential Diagnosis of AR-PCNSL.
AR-PCNSL usually shows multiple lesions by conventional MR. The lesions are typically located slightly more supratentorial than subtentorial, around the ventricle, beside the midline, or under the cortex. The current study showed that lesions involved the paraventricle and corpus callosum was even more suggestive of an AR-PCNSL diagnosis. AR-PCNSL could easily invade the ependyma, pia mater and dura mater and spread along it, which was similar to the findings of Kasamon. The p value involving the ependyma was 0.057, but a larger sample size was required to clarify whether there was a difference between two groups. Most AR-PCNSL originated in the perivascular space and showed multicentric infiltrative growth to the periphery, forming a typical "cuff-like" pattern. Tumor mass effect is relatively light, while peritumoral edema may be light or heavy. Normally, the signals of T1WI and T2WI have no specificity. Masses without necrosis tend to be isointense relative to the grey matter. Hemorrhage is common in AR-PCNSL, which is considered to be an inhomogeneous high signal on T1WI[22,23].
Toxoplasmosis is one of the most common intracranial opportunistic infections in AIDS. The serum toxoplasma IgG test is often either a false-negative or false-positive. The clinical diagnosis is more difficult when the antitoxoplasma therapeutic effect is poor. Toxoplasma gondii circulate through the blood to the brain, mainly at the junction area of the grey matter and white matter. The supratentorial/subtentorial region can be involved, but rarely the ventricles, ependyma and meninges. MR typically presents multiple intracranial annular enhancement foci, which often involve the basal ganglia. In typical cases, T2WI and enhanced scanning show "target signs", but the incidence is less than 30%. T2WI can show hypointensity, which is associated to coagulation necrosis. Edema around the focus is severe. Luft found the median time to response with antibiotics was 5 days and 91% of patients showed improvement by 14 day. After treatment, the area is prone to bleeding easily and shows a high signal on T1WI, which increases the diagnostic difficulty of AR-PCNSL.
AIDS complicate with cerebral tuberculosis. In AIDS patients, the incidence of cerebral tuberculosis is second only to pulmonary tuberculosis and lymphoid tuberculosis. The MR shows multiple dot or ring-enhanced lesions at the junction of gray and white matter. Meninges are easily involved, often with hydrocephalus. The annular enhanced wall of tuberculoma is more tensional than that of toxoplasmosis according to our experience.
PML: PML is different from circular or nodular enhancement lesions such as AR-PCNSL, toxoplasmosis and tuberculoma. Here, we are discussing PML because there were four cases in the infection group. PML is an opportunistic demyelination of the central nervous system caused by JC virus infection. The typical signs of PML were bilateral, multiple and asymmetrical white matter lesions. These lesions can involve any part of the supratentorial (arcuate fibers/U-shapedfibers) and infratentorial white matter. Bilateral cerebral hemispheres are often involved; the parietal lobe is the most severely affected, followed by the frontal lobe. The infratentorial involvement mainly affects the bridge arm, adjacent pons and cerebellum. The lesions have a low signal on T1WI and a high signal on T2WI. Typical lesions are "finger-shaped" and "scallop-shaped". In the current study, enhancement or mild peripheral enhancement were not observed in the lesions upon enhanced scanning. Some scholars reported that after ART the edge of PML lesions showed hyperperfusion (ASL) and high signal intensity at the advancing edge, a hypointense core on diffusion-weighted imaging on DWI.. The peripheral parts could mild contrast enhancement. These regions might represent virologically active areas.
Another common opportunistic infection associated with AIDS is cryptococcal meningoencephalitis. Typical MR manifestations include thickening and enhancement of the frontal and parietal meninges and formation of a colloidal pseudocyst in the perivascular space of the basal ganglia. Clinically, a clear diagnosis can be obtained from cerebrospinal fluid positive for cryptococcus antigen or positive by ink staining. This condition is more easily distinguished from the above diseases and will not be further discussed here.
3.2. 2 Multimodal MR Differential Diagnosis.
DWI/ADC Lymphoma without necrosis showed high DWI signal and a decreased ADC value, which indicated that diffusion was limited. The differences in ADC values of the AR-PCNSL and infection groups were statistically significant. This finding is consistent with the study by Camacho, which showed that a high DWI signal and a decreased ADC value suggested AR-PCNSL from toxoplasmosis. The limited diffusion of the solid portion might be due to the tumor cell structure with less cytoplasm, larger nuclei, more euchromatin, a lack of organelles, an abundance of ribosomes, a high nuclear-cytoplasmic ratio, low of water content, rich reticular fibers and other pathological characteristics. The main component of reticular fibers is collagen, which contains little water content. These pathological characteristics lead to the limited diffusion of water molecules in the tumor body and high DWI signal. In our study, 8 cases of AR-PCNSL group showed high signal on DWI and low signal on ADC, indicating that the diffusion was limited. 7 cases of infectious lesions were hyperintense on DWI, but their ADC values were also hyperintense, indicating that the diffusion was not limited. The cause of DWI hyperintensity was the T2 penetration effect. It suggested that ADC value should be attached importance in clinical work. The ADC value excluded the influence of the T2 penetration effect on DWI signals, making the interpretation of diffusion weighted imaging more reasonable.
SWI is an imaging sequence based on differences in magnetic sensitivity and the blood oxygen level-dependent (BOLD) effect between tissues. SWI can sensitively display paramagnetic substances in tissues and has significant advantages in displaying microvascular structures and microhemorrhage foci. Hemorrhage and necrosis often occur in AR-PCNSL and present as uneven, slightly high signal on T1WI and as multiple punctate/linear and patchy low signal on SWI. Refer to Park for the classification of low SWI signal. The ITSS in AR-PCNSL was significantly higher (2-3 times) than in the infection group. There were 3 cases of toxoplasmosis in the infection group, one of which had internal hemorrhage after treatment. ITSS was divided into 3 grades, and the other 2 cases had ITSS grades of 0-1. The other infectious lesions, such as abscesses, tuberculoma, PML, and others, all had ITSS grades of 0-1. These findings were in accordance with those of Lai. The combination of SWI and DWI played an important role in differentiating brain tumors from infectious diseases.
The MR arterial spin labelling technique (ASL) technique uses water in arterial blood as an endogenous contrast agent by detecting magnetically labelled blood quality. When there is subcurrent passing through the region of interest, the change of tissue signal intensity reflects information of local tissues blood perfusion. With the continuous updates of technology, software and hardware, this technique is now in clinical practice. 3D-pCASL is widely used as a safe and reliable method to quantitatively evaluate tumor blood perfusion. Although brain lymphoma may invade vascular endothelial cells and even vascular walls, we found no obvious neovascularization, ASL hypoperfusion is apparent. Da Rocha stated that hypoperfusion was a particular sign of lymphoma that was related to the lack of angiogenesis in tumor tissues and the extrusion and infiltration of microcirculatory vessels by tumor cells. Of the nine AR-PCNSL cases, six showed hypoperfusion, a finding similar to that in previous studies of normal immune lymphoma. Among the ten cases of infectious disease, there were two cases of PML with high perfusion in the periphery, and the other eight cases showed low perfusion. There was no significant difference between two groups.
3.2.3 Improvement of diagnosis efficiency in multimodal MR combined with conventional MR
AR-PCNSL and infections are difficult to diagnose in conventional MR. When the corpus callosum is involved, it is considered to be AR-PCNSL. Infectious lesions such as PML could be considered when the lesions are not enhanced. The sensitivity specificity and a total consistent rate in diagnosis of AR-PCNSL by conventional MR were low. Conventional MR combined with DWI/ADC had improved sensitivity, but its specificity was decreased and its total consistent rate was unchanged. DWI, as a more commonly used clinical sequence, had the advantages of a short time and insensitivity to motion artifacts. Additional DWI sequence scans could reduce the missed diagnosis rate of AR-PCNSL. We should pay more attention to ADC in diagnosis of AR-PCNSL and infections. The sensitivity, specificity and total consistent rate of the conventional sequence combined with SWI-ITSS were found to be 100%, 70.0%, and 84.2%, respectively. The sensitivity and total consistent rate of the conventional sequence combined with SWI were improved compared with the conventional sequence. However, the time required to scan the whole brain takes much longer, taking approximately 4 minutes. If every AIDS patient underwent this sequence, it would undoubtedly cause great pressure to clinics and reduce work efficiency. Therefore, we recommend that when distinguishing AR-PCNSL from toxoplasmosis or tuberculoma, this sequence should be scanned as soon as possible to obtain a correct diagnosis.
3.3 The other MR methods in differential diagnosis.
1H-MRS was used in AIDS. Some research showed that the N-acetyl aspartate (NAA)/creatine (Cr) ratio was significantly lower in PML and lymphomas than in infections. The presence of a lipid signal was more frequent in lymphomas than in infections. We will use MRS in the differential diagnosis of AR-PCNSL afterwards.
MR fingerprinting accelerated with machine learning and radiomic algorithms. It could be used to predict tumor grading and mutational status of patients with cerebral gliomas. Maybe we can use it to distinguish AR-PCNSL and infections in the future.
A multivalent nanoprobe comprising one Fe3O4 nanoparticle and several rituximab antibodies was onstructed for the targeted imaging and enhanced treatment of lymphoma with CD20-positive Raji cells positive. Cell targeting experiments and MR signal (T2 measurements) can not only distinguish lymphoma from infections, but also observe the curative effect of the drug. We hope we can use it in the future.
3.4 Shortcomings of this study
The sample size of the study was insufficient. The pathology results in the infection group were more and relatively complicated, which might have affected the determination of MR signs and the total consistent rate of the statistical results. The next step in this field of study is to increase sample collection. In this way, more objective results can be obtained, leading to further clarity on the early clinical diagnosis of AR-PCNSL.