Pathological Characteristics Of Cerebral Tumefactive Demyelinating Lesions And Its Differential Diagnosis With Primary Central Nervous System Lymphoma

Background and Purpose Analyzing the neuropathological features of acute and chronic tumefactive demyelinating lesions (TDLs) for the better diagnosis of the disorder and differential diagnosis with primary central nervous system lymphoma (PCNSL).Methods The clinical features, neuroimaging findings and pathological characteristics of 64 patients with pathologically proven TDLs and 30 patients with pathologically proven PCNSLs were retrospectively analyzed. Neuroimagings from both computer tomography and magnetic resonance imaging were assessed. Hematoxylin-and-eosin staining, myelin staining (luxol fast blue), and immunostainning of myelin basic protein, CD3, CD20, CD45RB (LCA), CD68, GFAP, S-100, Ki67 and neurofilament protein (NF) were used for pathological studies.Results 29 patients with TDL and 12 patients with PCNSL were misdiagnosed with neurological disorders.1. Clinical features:The onset age of TDL was 39.6 ± 14.7 years. The onset age of PCNSL was 54.8 ± 14.4 years. The age of onset of TDL was younger than that of PCNSL. The initial symptoms for TD included headaches (35.9%), hemiplegia (15.6%), limb numbness (15.6%) and vision loss (9.4%). The presenting symptoms for PCNSL were cognitive impairment (26.7%), headaches (23.3%) and hemiplegia (16.7%). Clinical manifestations of PCNSL were milder than that of TDL. For PCNSL, the lesions appeared severe in neuroimaging while the symptoms were milder.2. Neuroimaging Features:(1) Cranial CT:Lesions showed hypodensity in 62 cases of TDL (96.9%), isointensity in 2 cases of TDL (3.1%) and hyperintensity in 24 cases of PCNSL (80%). Lesions were isointensity in 3 cases of PCNSL (10%), and hypodense in 3 cases of PCNSL (10%). Statistical analysis showed that the constituent ratio of hyperintense lesions in PCNSL was higher than TDL lesions (P<0.001). (2) MRI scan: TDL lesions were classified into five subtypes:①ring like lesions in 25 cases (39.1%); ② Balo-like lesions in 8 cases (12.5%); ③ diffuse infiltrating lesions in 28 cases(43.8%); ④ megacystic lesions in 2cases (3.1%); ⑤ unclassified lesions in 1 case (1.5%). The neuroimagings of TDL showed diverse features at different stages of TDL. PCNSL lesions were gap, fist-like, sharp and ependymal enhanced lesions with rarely dynamic changes.3. Neuropathological features:(1) Staging of TDL:hyperacute phase in one case (1.5%), acute phase in 9 cases (13.2%), subacute phase in 24 cases(35.3%) and chronic phase in 34 cases(50%). Types of TDL Plaques:acute active plaques in 17 cases (25%), chronic active plaques in 19 cases (27.9%), smoldering demyelinated plaques in 17 cases (25%) and inactive plaques in 15 cases (22.1%). The features of acute active plaques: ① they were hypercellular demyelinated lesions. ② In the lesions, relative axonal preservation was associated with massive infiltration by macrophages that are evenly distributed throughout the lesion. The macrophages showed ingested myelin breakdown products. Despite axonal preservation, axonal injury occurred as the presence of axonal swellings. ③ Oligodendroglia were rare.④ profound perivascular and parenchymal infiltrates composed mainly of CD 3+, CD4+, CD8+ T lymphocytes. Furtermore, fewer B cells or plasma cells were present. The cuffs of lymphocytes were formed around vessels. ⑤ Reactive astrocytosis was preserved prominently. Another feature was the presence of multinucleated hypertrophic gemistocytes and Creutzfeldt-Peters cells. The features of chronic plaques: ① The lesions had sharply defined margins with relative axonal preservation. ② Myelinladen macrophages accumulated centrifugally at the lesion edges. The inactive center diminished.③ Hypertrophic gemistocytes changed into fibrous astrocytes slowly.④ CD79a+, CD38+, CD138+ plasma cells were preserved. The features of smoldering demyelinated plaques:There were activated macrophages and microglia around the inactive center. Few of activated macrophages and microglia ingested myelin breakdown products. The features of inactive plaques: ① Few of cells in the lesion center which was demyelinated lesions. ② Oligodendrocytes were increased.③ Minor infiltration by macrophages/microglia and lymphocytes were found.④ Shadow plaques were present. (2) Staging of PCNSL referring to TDL, hyperacute phase of PCNSL in one case (3.3%), acute phase in 2 cases (6.7%), subacute phase in 10 cases (33.3%) and chronic phase in 17 cases (56.7%). The features of PCNSL were not changing dynamically and tumor cells showed diffuse lesions. No lymph follicles were detected. The cuff of tumor cells formed around the perivascular infiltrates. Hematoxylin and eosin staining showed proliferation of small blood vessels. Neuronal degeneration was observed sometimes. There was no demyelination at conventional stage. Tumor cells associated with reactive inflammatory cells and phagocytes (including CD4+ and CD8+ T cells, normal B cells, macrophages, reaction microglia and astrocytes) mixed together. The PCNSL is typically positive for CD10, CD19, CD2o and CD79a and negative for CD3, CD38 and CD138. Most tumor cells also expressed Bcl-2 and Muml. Some of lesions had cystic necrosis. (3) In this study,7 cases of TDL have been misdiagnosed as PCNSL.9 cases of PCNSL had been misdiagnosed as TDL. ① One case of TDL who was misdiagnosed as PCNSL received management with gamma knife radiosurgery and methylprednisolone and the symptoms were relieved temporarily. Nutritional supportive treatment was administered after discharge. The patient’s disease deteriorated eight years later with severe cognitive impairment. At this point she could not take care of herself and tumor recurrence was concerned. Brain biopsy was conducted and the pathological study showed demyelinating disease with radiation encephalopathy. The neuroimaging features of the remaining seven cases of TDL were similar to that of PCNSL which result to misdiagnosis. After brain biopsy, the diagnosis identified with demyelinating disease. ② Four cases of PCNSL which misdiagnosed as TDL were due to the first biopsy show no characteristic features. There were not seen tumor cells which resulted in misdiagnosis. After corticosteroid therapy, the condition was no significant remission. Brain biopsy was done again to find tumor cells (1 case had three biopsies to identify PCNSL).3 patients accepted the application of glucocorticoid empirical treatment before brain biopsy. That result in atypical histological features. The neuroimaging features of the rest 5 cases of PCNSL were similar to TDL result to misdiagnosis.Conclusions1.The general characteristics:The age of the patients with PCNSL were older than those with TDL. Headaches were common symptoms at onset of TDL. Cognitive impairment was common symptoms at onset of PCNSL.2. The neuroimaging features:(1) Hyperintense lesions in the brains of TDL were extremely rare on head CT. However, hyperintense lesions were common in the brains of the patients with PCNSL. (2) TDL lesions varied in shapes on brain MRI including ring like, Balo-like, diffuse infiltrating and megacystic lesions (which was rare). The neuroimaging features were changing at the different stages of TDL. PCNSL lesions were gap, fist-like and sharp with ependymal enhancement. The PCNSL lesions did not show changes dynamically.3. Pathological characteristics:(1) The staging of TDL was different from that of TDL lesions. Acute and chronic active plaques were more commonly found in patients with acute and subacute TDL, whereas smoldering and inactive plaques predominated in patients with chronic TDL. (2) The pathological features of a small number of PCNSL after steroids therapy were similar to TDL so that before a definite diagnosis, hormone, therapy was not bebeficial. The effect of steroids treatment is not sustained. The pathological course of the disease may be related to the evolution of the appearance-related. Repeat biopsy should be considered if no typical pathological findings were detected. (3) The key points to diagnose TDL and PCNSL: ①The edges of TDL lesion were clearer than those of PCNSL.② Hyperintense lesions on head CT basically made the diagnosis of TDL less likely.③Open-ring-like enhancement lesions and opening toward cortex or deep gray matter indicated lesions of TDL. Types of lesions were "gap", "fist-like", "sharp" sign or ependymal enhancement indicated the large possibility of PCNSL. Butterfly lesions which across the corpus callosum and strengthen the uniform were the characteristic performance of PCNSL lesions. ④ The types of strengthen lesions were changing dynamically while the disease course evoluted in TDL such as nodular or sheet strengthening in the acute phase, closed or open ring like enhancement in subacute phase, point-like or pale ring-like enhancement in chronic lesions. It correlated with the degree of inflammatory lesions. PCNSL was different. ⑤ Foamy macrophages gathered around vessels and in the center of the lesion, without any coagulation necrosis, suggesting the diagnosis of TDL.⑥ If gemistocytic astrocytes developed well and spaced apart from each other, it was more suggestive of a reactive gliosis than of a tumor. Reactive astrocytes in GFAP immunostaining were "spider" shape. Gliosis was a feature of TDL;⑦ demyelinating lesions often had clear boundaries, and tumors did not.⑧ TDL lesions were located in the periventricular white matter and in part TDL also involving the gray matter. But PCNSL had invasion for the gray and white matter. ⑨ Creutzfeldt-Peters cells in TDL were one of the features for demyelinating disease. Data of neuroimaging and pathological studies are important for the diagnosis. Follow-ups can provide useful information to help the differential diagnosis.