PRIMARY DIFFUSE LARGE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM: AN ATYPICAL MANIFESTATION
Diffuse large B-cell lymphoma (DLBCL) is the most prevalent (around 30%) non-Hodgkin lymphoma, with about 25000 new cases annually reported only in the United States. This malignancy actually refers to a diverse spectrum of diseases, in which the central nervous system primary manifestation is not the most frequent one (it represents about 13% of the DLBCL). Here, we report a case with an atypical evolution of a primary central nervous system lymphoma (PCNSL) which probably responded to the use of corticosteroids and only received the final diagnostic after almost four years from the initials symptoms.
A 21 years old HIV-negative male with a history of epileptic episodes in 2013 was treated for neurotoxoplasmosis, based on a lesion in the left caudate nucleus enhanced by the contrast seen in MRI, and showed improvement. The MRI also demonstrated bilateral lesions in the subcortical white matter of frontal lobe. Two years later (2015), he developed weakness in the lower limbs, which was diagnosed as Guillain-Barré syndrome, although the clinical management for this disorder was not informed.
In 2016, more than three years after the beginning of seizures, he came into neurology’s nursery of the University Hospital of Federal University of Grand Dourados (HU – UFGD) presenting headaches and cognitive impairment, evolving with decreased visual acuity. His magnetic resonance imaging (MRI) showed an area with a signal alteration in the splenium of the corpus callosum extending to the cingulate gyruses and to the both forceps majors enhanced by the contrast, surrounded by vasogenic edema. His cerebrospinal fluid had an elevated level of proteins and a slightly pleocytosis. He was empirical treated to neurotuberculosis with rifampicin, isoniazid, ethambutol, pyrazinamide and corticosteroid (dexamethasone).
He returned with neurological worsening (motor and visual impairment, somnolence and new epileptic crises), coinciding with the corticosteroid weaning. A ventriculoperitoneal shunt was performed, with a symptomatic improvement. The first biopsy’s result was normal, probably because of the use of corticoisteroids. Three months later, he returned with mydriatic pupils, motor impairment, cognitive worsening, and the shunt was switched, solving the hydrocephalus problem. A new biopsy of the lesions indicated malignancy of large and medium cells. Immunohistochemistry was suggestive of diffuse large B-cell lymphoma
DISCUSSION Primary central nervous system lymphoma (PCNSL) is a rare type of tumor that may appear in brain, spinal cord, leptomeninges and eyes, without peripheric involvement. The most prevalent PCNSL are non-Hodgkin ones, especially the diffuse large B-cell lymphoma (DLBCL). Its incidence rates, in the US, are about 4 cases per million, representing 3-4% of the newly diagnosed central nervous system neoplasms and less than 1% of all non-Hodgkin lymphomas. Some of the most common symptoms of PCNSL are headaches (due to elevated intracranial pressure), seizures, and ocular and cranial nerves dysfunction, which this patient presented, along with cognitive impairment and motor disabilities. There may also appear neuropsychiatric symptoms. Differential diagnoses for the PCNSL include lesions with similar radiologic pattern like gliomas, metastatic tumors, including other types of lymphoma, infections, and demyelinating diseases. Progressive multifocal leukoencephalopathy was also considered in the present case. PCNSL and DLBCL, as a whole, have immunodeficiency (either acquired or not) as a risk factor, thus, HIV infection is strongly related with this pathology, with an occurrence 3600 times higher of PCNSL in immunodeficiency-virus infected patients. In this case, the patient was not seropositive and was immunocompetent. For these patients, the PCNSL usually appears later, around 53 to 57 years. The DLBCL are aggressive tumors (the Ki-67 cell proliferation index for this one was above 90%). Another reason for worry in DLBCL of the central nervous system is the absence of HLA type I and II in the tumors cells, which can make easier the scape of the malignant cells from the immune system control. However, this type of neoplasms usually respond well to the treatment, with methotrexate or other chemotherapy schemes. This is an unusual case, because more than three years have passed since the first symptoms until the diagnosis, and the patient probably improved with the use of dexamethasone, which is not the standard chemotherapy for DLBCL (cyclophosphamide, doxorubicin, vincristine and prednisone combination with rituximab are frequently used). There is not a pathognomonic radiological pattern for DLBCL. The most characteristic are single or multiple lesions, with a homogeneous gadolinium enhancement and accentuated restricted diffusion of water molecules. The differential diagnoses may include glioblastomas, secondary lymphomas of the central nervous system, neurotoxoplasmosis, cerebral abscess and neurosarcoidosis, in which case the
clinical evolution of the patient should be considered. The butterfly pattern also may forecast an unfavorable outcome for a PCNSL. This patient’s immunohistochemistry indicated a germinal center origin marker, BCL6, positive. Since we are dealing with a heterogeneous manifestation (some authors defend the DLBCL’s subgroups may represent distinct entities), genetic tests and not immunohistochemistry exams alone are important to predict the prognosis of DLBCL and even orientate the choice of the treatment. Rearrangements in MYC and p53 genes may predict a poorer prognosis too.
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