Primary cerebral lymphoma with spontaneous remission

Dear Editor:

Primary central nervous system lymphoma (PCNSL) is a frequent type of non-Hodgkin lymphoma which affects the brain, eyes, spinal cord, and leptomeninges, with no evidence of other regions being affected at the time of diagnosis.¹ PCNSL accounts for 3% of all primary brain tumours. The main signs and symptoms are papilloedema, headache, paresis, and convulsions.² Spontaneous remission of PCNSL without administration of corticosteroids is rare^3–5 and gives rise to diagnostic problems. We present the case of an immunocompetent man aged 65 years with focal neurological signs and multiple cerebral lesions who experienced initial spontaneous remission of both clinical symptoms and pathological signs in MRI images, and whose final diagnosis of PCNSL was determined by autopsy.

A male patient aged 65 years visited the emergency department due to dizziness and vertigo with acute onset a week before the visit and progressively worsening symptoms which responded poorly to vestibular sedatives.

His personal history included a pulmonary thromboembolism 2 years before which required treatment with acenocoumarol for 6 months. Upon admission he was not taking any regular medications.

In the emergency department, neurological examination only showed mild gait instability. Cranial CT scan revealed a right frontal hypodense focus affecting the corpus callosum and reaching the contralateral hemisphere, with no enhancement after administration of intravenous contrast. T2-weighted/FLAIR images from the brain MRI showed a hyperintense right frontal lesion affecting the corpus callosum and extending to the left hemisphere, with patchy gadolinium-contrast enhancement; we also found hyperintense lesions in T2-weighted/FLAIR images with gadolinium contrast enhancement in both cerebellar hemispheres and the pons. During the first days of hospitalisation the patient's neurological state worsened with more acute dysarthria and ataxia. Brain MRI was performed again. Apart from the previous lesions, it revealed a new right frontal lesion with gadolinium contrast enhancement and increased uptake of contrast in the lesion located in the splenium of the corpus callosum (Fig. 1A and B).

Figure 1.

(A) Brain MRI, axial FLAIR sequence. Hyperintense cerebral lesions in the frontal lobes reaching the corpus callosum (slight mass effect). (B) Brain MRI, T1-weighted sequence with gadolinium. Patchy areas of gadolinium contrast enhancement. (C) and (D) Brain MRI 4 months later showing a slight signal alteration in the corpus callosum and no areas with gadolinium enhancement.

Based on a suspected diagnosis of primary cerebral lymphoma, we performed complementary blood testing, CT scan, CSF analysis, and PET scan. Blood tests: complete blood count, liver biochemistry, protein screen, electrolytes, beta-2 microglobulin, LDH, tumour markers, peripheral blood smear, autoimmunity, and serological tests for syphilis and HIV were all normal. Thoracic-abdominal-pelvic CT scan was normal. CSF was clear and acellular with normal opening pressure and normal protein and glucose levels; both flow cytology and cytometry were normal. Whole-body positron emission tomography (PET) with fluorodeoxyglucose revealed malignant hypermetabolic lesions limited to the brain. Ophthalmological examination was normal.

Given a suspected case of cerebral lymphoma, we avoided use of corticosteroids since they might affect the biopsy reading. A brain biopsy of the right frontal lesion was performed and revealed non-specific gliosis and no evidence of malignancy. The patient was discharged with no treatment and monitored in neurology outpatient consults; doctors observed a gradual improvement of his neurological situation. Four months later, the patient was asymptomatic and leading a normal life. Doctors confirmed that the patient received no corticosteroids at any time. An MRI performed four months later showed nearly complete disappearance of the lesions and no contrast uptake in any of them.

Nine months after being admitted, the patient returned for a check-up due to symptoms of headache and vomiting which began a few days prior. Upon neurological examination, the patient was drowsy and presented time disorientation, moderate dysarthria, limited vertical gaze with conjugate gaze palsy, and left faciobrachiocrural hemiparesis. A new MRI revealed several lesions with contrast uptake in the cerebellum, mesencephalon, and right internal capsule. These lesions were treated with high doses of corticosteroids. However, a few days later, the patient presented dysphagia to liquids and the paresis evolved into left hemiplegia. The cerebellar lesion was biopsied, but showed no evidence of malignancy. The patient died a few days later.

Autopsy revealed a lymphoid neoplasm diffusely infiltrating the brain parenchyma and forming concentric perivascular cuffs (Fig. 2). We also observed significant astrocytic, histiocytic, and microglial responses. The immunological and histochemical study confirmed the tumour as a B-cell lymphoid neoplasm since it was strongly positive for B-cell markers (CD20 and CD79a). The Ki-67 proliferation index was high (70%). The anatomical pathology diagnosis was large B-cell lymphoma.

Figure 2.

Anatomical pathology study (autopsy) of the cerebellar lesion. (A) Haematoxylin and eosin ×400. Large polymorphic tumour cells infiltrating the brain parenchyma. (B) Haematoxylin and eosin ×200. Tumour cells form concentric perivascular cuffs. (C) The immunological and histochemical study confirmed the lymphoid neoplasm as B-cell type was strongly positive for B-cell markers (CD20). (D) We observed a high cellular proliferation index (Ki-67).

The suspected diagnosis of PCNSL is based on the brain MRI. This kind of lymphoma is most frequently located in the cerebral hemispheres, followed by the basal ganglia, corpus callosum, and cerebellum.⁶ Immunocompetent patients have multiple lesions in 20% to 40% of all cases and they usually present homogeneous uptake of contrast. Magnetic resonance spectroscopic imaging detects decreased N-acetyl aspartate concentration and elevated choline levels. When PCNSL is suspected, corticosteroids should be avoided, since they can hinder or prevent histological diagnosis.¹ Resection of the lesion should also be avoided; any surgery should be limited to stereotactic biopsy. From a histological point of view, more than 95% of all cases present large B-cell lymphomas. Treatment for PCNSL in patients with an acceptable clinical state (Karnofsky Scale > 40) is mainly based on systemic chemotherapy with high doses of methotrexate (at least 3.5 g/m).² Between 50% and 60% of the patients respond completely to treatment.⁷

Remission of PCNSL after treatment with corticosteroids is a well-known phenomenon, but cases of spontaneous remission are rare.^3–5 Remission of the lesions and symptoms may give rise to diagnostic errors and lead doctors to wrongly suspect other processes such as inflammatory and demyelinating diseases. Relapses are typical and they usually occur some weeks or months later. However, doctors have described spontaneous remission periods lasting as long as 4 years.³ Immune theory is the most plausible explanation for this phenomenon. Some authors have found a higher percentage of natural killer cells in patients with spontaneous remission.³ In some such cases, this response was triggered by a situation in which there was a concomitant viral infection. Theoretically, this fact could lead to an increase in the percentage of natural killer cells, which are responsible for eliminating lymphomatous cells.

Spontaneous remission of PCNSL is an exceptional event, but this possibility should be considered so as to prevent diagnostic errors that may delay starting proper treatment.