Abstract
OBJECTIVE: To retrospectively study the clinical imaging and pathological characteristics of cases with mutual misdiagnosis of tumefactive demyelinating lesions (TDL) and primary central nervous system lymphoma (PCNSL), and to summarize the experience in order to improve the differentiation between TDL and lymphoma.
METHODS: Four cases of TDL and nine cases of PCNSL admitted to our hospital from 2005 to 2014, which had been misdiagnosed, were analyzed for clinical symptoms, imaging features such as cranial CT and cranial MRI plain and enhanced scans, and several pathological histological features.
Results.
(1) Imaging characteristics: TDL cranial CT showed hypodensity in all cases, and their MRI enhancement scans showed a variety of different disease courses (circumferential enhancement in 3 cases and focal enhancement in 1 case); PCNSL cranial CT lesions were high-density in 5 cases, low-density in 3 cases, and isointense in 1 case, and cranial MRI enhancement showed uniform and consistent enhancement in all cases.
(2) Pathological characteristics: TDL showed a large amount of myelin loss, while a few axonal breaks were damaged, with a large infiltration of inflammatory cells and astrocyte proliferation; the typical pathology of PCNSL was characterized by cuff-like arrangement of tumor cells around blood vessels, and some PCNSL was easily confused with TDL due to atypical pathology caused by the use of hormones, etc. Four patients had more than 2 biopsies to confirm the diagnosis.
Conclusions.
(1) CT of PCNSL needs to be differentiated from TDL if it shows hypodensity or isodensity.
(2) The pathological features of PCNSL after hormone therapy are similar to TDL in a few cases, which is very easy to be misdiagnosed, and hormone therapy should be used with caution before a clear diagnosis is made.
(3) The pathological manifestations of PCNSL may be related to the evolution of its disease course, so those with atypical brain biopsy pathology can be biopsied again. The combination of clinical imaging and pathology is important for diagnosis, and follow-up should be emphasized.
Keywords: tumor-like demyelinating disease; primary central nervous system lymphoma; pathological features; misdiagnosis
TDL, also known as Demyelinating Pseudotumor (DPT), is a specific white matter-dominated inflammatory demyelinating disease of the CNS, treated with glucocorticoids, first described by van der Velden et al. PCNSL is a rare intracranial tumor that often involves midline structures and the white matter region of the brain, accounting for 6% of intracranial tumors and 1-2% of systemic lymphomas. Unlike other intracranial tumors, PCNSL is extremely sensitive to glucocorticoids, and the lesions may decrease in size or disappear transiently, so it is very easy to be misdiagnosed. Some PCNSL is misdiagnosed as TDL, and some patients are even finally diagnosed after multiple biopsies. Mutual misdiagnosis of TDL and PCNSL may be caused by imaging alone or by atypical pathological features. In this paper, we review and analyze the clinico-imaging pathological features of TDL and PCNSL that have been confirmed to have previously misdiagnosed each other involving the white matter region of the brain, and summarize our experience for colleagues’ reference.
Subjects and methods
I. Subjects
Four pathologically confirmed cases of TDL and nine cases of PCNSL that had been mutually misdiagnosed and admitted to our hospital from 2005 to 2014 were collected, and all cases had clinical, imaging and pathological data.
II. Methods
1. Clinical data: All the selected cases met the diagnostic criteria of TDL and PCNSL, summarizing the age of onset, first symptoms, and cerebrospinal fluid (CSF) examination, respectively.
2. Imaging observation: The image characteristics of patients’ cranial CT, cranial magnetic resonance imaging (MRI) plain scan and enhanced scan were analyzed.
3.Pathology were performed with hematoxylin eosin staining (HE), neuromyelin solid blue staining (LFB), immunohistochemical staining (LCA, CD3 and CD20) and Ki-67 staining.
Discussion.
Intracranial tumor lesions and non-tumor occupancy-like lesions are sometimes difficult to distinguish from each other in terms of imaging and clinical features, especially without pathological confirmation, and are often misdiagnosed from each other. Most patients in China are often fearful of brain biopsy, so they are treated according to the preliminary judgment of clinical images without pathological diagnosis. Some gliomas or PCNSL are treated as TDL with glucocorticoids, and due to their anti-inflammatory effect and edema-reducing effect, the patients’ symptoms temporarily improve and the clinical judgment is that the treatment is effective. Especially once PCNSL is treated with hormones, a considerable number of patients can have dramatic reduction or even disappearance of lesions at the first treatment, which can delay the diagnosis and treatment. Really TDL starts to be treated as glioma, metastases, etc. and radiotherapy is administered, which also responds to treatment, especially since glucocorticoids are often added to these treatments and lesions gradually shrink and improve, which is often considered as effective treatment, and even some clinicians take this as their successful case of treating brain tumors. Unbeknownst to us, brain astrocytoma, PCNSL, and malignant metastases are not curable. Like the typical case 1 in this paper, precisely because it is demyelinating disease, which belongs to TDL, appropriate hormone therapy interfered with the progression of demyelination and made the patient improve temporarily. Such a prognosis would not have been possible if the tumor was truly malignant, and it is precisely the progressive worsening of the disease after 8 years that gives us an idea of the radiation encephalopathy associated with radiation therapy. Therefore, if astroglioma patients can survive as long as the patient in this case after radiotherapy, it should be possible for the vast majority to develop radiation encephalopathy.
In this study, a retrospective analysis of 13 cases of mutual misdiagnosis of TDL and PCNSL revealed the following characteristics.
(1) The age of onset of PCNSL was significantly higher than that of TDL, and the former was mainly seen in the middle-aged and elderly population, whereas TDL was predominantly seen in young and middle-aged people.
(2) The cranial CT lesions in TDL are not dense [5], while PCNSL is mostly dense and should be differentiated from TDL if it shows hypodensity or isointensity. In cranial MRI enhancement, dynamic evolution is seen in TDL cranial MRI, with punctate or patchy enhancement in the acute phase, semi-ring or ring-like enhancement in the subacute phase, and slowly decreasing enhancement in the chronic phase, which is consistent with previous studies [6]; uniform mass-like enhancement in PCNSL cranial enhancement MRI (Figure 3), as well as enhancement along the ventricular canal, is rare in TDL. In one patient in this study, the cranial CT lesion initially showed isointensity, which was misdiagnosed as TDL and then recurred after hormone therapy, and the lesion was found to develop from isointensity to high density on reexamination of the cranial CT.
(3) Pathological features of patients with TDL also show a few scattered heterogeneous lymphocytes, which must be differentiated from PCNSL and need to be judged in combination with myelin staining and immunohistochemical staining. It is important to note that myelin loss is not unique to inflammatory demyelination and that unmyelinated foci are also seen in gliomas. A small number of PCNSLs may have scattered demyelinating changes, inflammatory and macrophage infiltrates, and glial cell hyperplasia, which can be misdiagnosed even with immunohistochemical staining, some of which are atypical due to inappropriate hormonal therapy, and a very small number of PCNSLs have atypical pathology in the early stages of disease development, where no tumor cells are seen. With the development of the disease, the characteristic manifestations of tumor cells were found only after biopsy was performed again [8], and the specific mechanisms are still being explored.
As a specific type of inflammatory demyelinating disease, the diagnosis and differential diagnosis of TDL are of great interest. The typical pathological features of TDL are myelin loss and infiltration of lymphocytes (CD3, CD4, CD8) in the perivascular and brain parenchyma, with a small amount of B-cell infiltration and lymphocyte cuff formation. The morphology of glial cells varies between acute and chronic TDL lesions. In the acute stage, the lesions are poorly defined from normal tissue, soft in texture, surrounded by edematous bands, and microscopically visible as obese astrocyte proliferation and Creutzfeldt-Peters cells, which can be easily treated as astrocytoma cells. As the disease progressed, the boundary of the lesion became clearer, and microscopically, the obese astrocytes gradually changed to fibrous glial cells. In this study, it was found that even with pathological escort, a very small percentage of misdiagnosis can still occur due to the site of sampling or the specificity of the pathology in some cases. This requires neurological clinicians to be able to integrate imaging pathology together.
PCNSL is known to disappear transiently after treatment with hormones, and its pathology shows features of demyelinating pseudotumors such as reactive astrocyte hyperplasia, T-cell and foamy macrophage infiltration, making it difficult to differentiate from demyelinating disease. There are also a very small number of PCNSL even without hormone therapy, and the pathology may only suggest glial cell hyperplasia on biopsy due to the small amount of material taken or located at the margins of the lesion, while reactive T cell hyperplasia may also be present at the margins of PCNSL, making it more likely to be misdiagnosed. the mechanism why PCNSL has a small amount of demyelinating-like pathological changes is still unknown.
In this study, we found that clinical TDL and PCNSL were misdiagnosed each other, partly due to their similar clinical imaging manifestations and partly due to atypical pathological manifestations, which indicates the need to combine clinical imaging manifestations and pathological manifestations to make a comprehensive judgment and pay attention to follow-up in order to improve the diagnostic accuracy.