A 69‐YEAR‐OLD MAN WITH LEFT HEMISPHERIC NECROTIZING MASS LESION

CLINICAL HISTORY

A 69‐year‐old patient with a four‐year history of CIDP was admitted for evaluation of further treatment options at a tertiary University hospital. Diagnostic criteria for CIDP established by the AAN were fulfilled (1). Six months prior to this admission, the patient had suffered from a granulocytic meningitis while he was treated with azathioprine and prednisolone. At that time, evaluation of his cerebrospinal fluid (CSF) revealed a pleocytosis of 1240 white blood cells (WBC)/µl. Immunosuppressive therapy was immediately suspended. The causative pathogen could not be identified, but the patient partially recovered after empiric antibiotic treatment with ceftriaxon and ampicillin. Residual neurological deficits included persisting mild cognitive impairment. At that time, a cranial computer tomography (CT) and a magnetic resonance imaging (MRI) scan of the brain were normal.

After 2 months of progressively worsening CIDP, treatment with mycophenolate mofetil was commenced but had to be stopped within 3 weeks because of gastrointestinal side effects. Azathioprine medication was re‐instituted, and the total leukocyte count in the peripheral blood (PB) was in the range of 3600–4700/µl. The patient was re‐admitted because of acute‐onset confusion, cognitive decline, and increasing weakness. On physical examination, the patient displayed significant attention deficits, disorientation in time, dysarthrophonia, a mild flaccid tetraparesis, areflexia of the lower limbs, gait disturbance, distal symmetric hypo‐ and dysesthesia, right‐sided hemiataxia and bradydysdiadochokinesia. A cranial CT scan showed no abnormalities (Figure 1). His total leukocyte count in the PB was 4100/µl, and his lymphocyte count 600/µl. Plasma exchange and oral corticosteroids temporarily improved his sensorimotor symptoms and signs.

Figure 1.

Following plasma exchange the patient developed diarrhoea, and his cognitive impairment continued to worsen. A brain MR scan showed bilateral periventricular edema with multiple gadolinium‐enhancing T1 lesions in the periventricular parenchyma (Figure 2). CSF analysis revealed increased albumin and IgG in the absence of WBC. Candida albicans was detected in stool specimens. Despite intravenous antibiotic, antiviral and antifungal therapy as well as administration of intravenous immunoglobulins (IVIG), the patient further deteriorated clinically with right‐sided hemiparesis and a Broca dysphasia. Polymerase chain reaction (PCR) of the CSF for Epstein‐Barr virus (EBV) was positive, while no DNA copy numbers of Candida, Aspergillus, toxoplasma, and other neurotropic viruses, including VZV, HSV, CMV, HIV were detected. Despite supportive intensive care treatment the patient died within 4 weeks.

Figure 2.

MICROSCOPIC EXAMINATION AND NEUROPATHOLOGIC FINDINGS

A stereotactic brain biopsy of affected white matter parenchyma revealed non‐specific necrosis without evidence of malignant or inflammatory cellular infiltrates. Three tiny specimens with a total size of 0,5 × 0.5 × 0.5 mm were submitted for examination (Figure 3 left side, H&E; ‐right side, expression of CD68).

Figure 3.

An autopsy was performed and gross examination of the brain demonstrated a necrotizing mass lesion in the left cerebral hemisphere approaching the ependyma and infiltrating the corpus callosum mimicking a glioblastoma (Figure 4). Microscopic examination disclosed angiocentric pleomorphic infiltrates of lymphocytes, histiocytes, large CD20‐positive cells resembling lymphoblasts, centroblasts, and scattered CD30‐positive pleomorphic polynuclear Reed‐Sternberg like cells (Figure 5A and 5B). There was a high mitotic and proliferative activity (Figure 5C). In addition, perifocal edema with marked glial fibrillary acid protein (GFAP)‐positive reactive astrocytic gliosis was noted. The EBV antigen EBNA2 was detected immunohistochemically in the majority of CD20‐positive cells (Figure 5D).

Figure 4.

Figure 5.

DIAGNOSIS

EBV‐associated diffuse large B cell lymphoma and additional microglial nodule encephalitis of the brainstem with associated severe hypoxic injury of neurons.

DISCUSSION

This is the first case of a rapidly progressive EBV‐associated primary CNS diffuse large B cell lymphoma with concomitant brainstem encephalitis in a patient with CIDP who had been treated with long‐term azathioprine. This encephalitis probably caused the patient's death due to failure of central respiratory regulation. The morphological features of microglial nodule encephalitis were suggestive of a viral pathogen. However, this could not be identified in brainstem specimens.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune‐mediated disorder of the peripheral nervous system (PNS) characterized by slowly progressive or relapsing‐remitting motor weakness and sensory deficits. A large body of evidence suggests an autoimmune origin. Primary CNS lymphoma is a rare form of aggressive extranodal non‐Hodgkin lymphoma mainly consisting of highly malignant large CD20‐positive B lymphoblasts or centroblasts respectively, and multifocal or diffuse neoplastic infiltration of the brain parenchyma (8). The diagnosis typically rests on radiographic features, detection of EBV antigens in the CSF, and histopathology. It is a well‐recognized complication in individuals with congenital or acquired immunodeficiency 7, 8. The uncontrolled and overwhelming proliferation of B‐lymphocytes driven by EBV is believed to be the primary etiological mechanism 7, 8. Treatment of primary CNS lymphoma includes high‐dose methotrexate polychemotherapy, therapy with the recombinant monoclonal chimeric anti‐CD20 monoclonal antibody rituximab, antiviral agents, and whole brain radiation 7, 8. Despite aggressive management, median survival time is 2–12 months (7).

The patient described here had received immunosuppressive therapy with azathioprine for almost 4 years. The carcinogenic risk of azathioprine has been discussed controversially in the literature (2). While autoimmune diseases themselves tend to be associated with a more frequent occurrence of malignancies there appears to be a higher incidence of lymphomas in patients with inflammatory bowel disease, rheumatoid arthritis and transplant recipients treated with this mercaptopurine 5, 9. Azathioprine treatment can result in leukopenia and lymphopenia, which may impair an effective immune surveillance, and could allow the emergence of neoplastic growth (3).

Four patients suffering from neurological autoimmune disease (all myasthenia gravis) treated with azathioprine that developed primary CNS non‐Hodgkin lymphoma have been reported 4, 6, and one patient with Crohn's disease (5). It appears reasonable to assume that impaired immunosurveillance iatrogenically induced by azathioprine treatment was causative.

We consider short‐term (3 weeks) exposure to mycophenolate mofetil not contributory. Recently, non‐Hodgkin lymphoma of the brain diagnosed by stereotactic biopsy was reported in an elderly patient who had been treated with mycophenolate mofetil 2 g/day for 37 months (10).

This case of CNS lymphoma in a patient with CIDP emphasizes the need for vigilantly monitoring of patients with immune‐mediated neurological disorders undergoing immunosuppressive therapies. Cognitive deficits, psychiatric aberrations and focal signs should prompt a careful diagnostic work‐up for infectious complications and CNS malignancy.

ABSTRACT

We report the first case of primary non‐Hodgkin lymphoma of the central nervous system in a 69‐year‐old patient with chronic inflammatory demyelinating polyneuropathy (CIDP) on long‐term immunosuppression. CIDP was diagnosed 4 years earlier and treated with plasma exchange, corticosteroids, azathioprine and mycophenolate mofetil. The patient developed an organic brain syndrome and cerebral MRI revealed multiple enhancing T1 lesions in the periventricular parenchyma. A stereotactic biopsy was not diagnostic, but Epstein‐Barr virus (EBV) was detected in the cerebrospinal fluid. After a fulminant course of an illness resembling an encephalitis the patient died. Postmortem analysis confirmed the diagnosis of EBV‐associated diffuse large B cell lymphoma. This case illustrates the risks of life‐threatening infections associated with continuous immunosuppression, and emphasizes the need for an extensive diagnostic work‐up in patients who present with signs and symptoms of an unexpected encephalopathy.