A 76‐YEAR‐OLD MAN WITH COGNITIVE AND NEUROLOGICAL SYMPTOMS

CLINICAL HISTORY

A 76‐year‐old man presented with progressively worsening vertigo, memory and concentration impairment, spatial disorientation and mild expressive dysphasia for 6 months. His medical history included hypertension and a surgically treated abdominal aortic aneurysm. A few weeks before admission, headache, fatigue, weakness of the lower limbs and left arm, a tendency to fall to the left, incontinence, and episodes of confusion occurred. Upon admission the patient showed marked fatigue, confusion and apathy, and a contrast‐enhancing round lesion, 1 cm in diameter, was seen in the left temporal lobe on magnetic resonance imaging (MRI). Repeated cognitive testing demonstrated fluctuating deficits in language, working and episodic memory, visuospatial ability, attention and psychomotor speed. A second MRI, performed one month after the first, showed attenuation of the previous lesion, with general signal enhancement in the leptomeninges, a heterogeneous contrast‐enhancing lesion measuring 1 × 2 cm in the left frontal lobe, and a smaller lesion near the left sylvian fissure (Figure 1).

Figure 1.

There was no sign of infection, and blood tests were normal. Repeated lumbar punctures were performed; cerebrospinal fluid (CSF) analyses showed slightly elevated counts of mononuclear cells (7–10 × 10⁶ cells/L) that were cytologically normal. There was evidence of severe blood brain barrier disruption with elevated albumin levels and oligoclonal IgG bands on electrophoresis. The levels of neurodegenerative markers were increased with a total tau of 910 ng/L (ref < 400) and neurofilament protein of 2540 ng/L (ref < 750). Extensive screening for infectious agents was negative. Octreotide scintigraphy (octreotide used as a radiolabelled somatostatin analogue for detection of neuroendocrine tumors, granulomatous disease, et cetera) showed uptake in the frontal and temporal lobe lesions (Figure 2a), a finding which led to the diagnostic suggestion of neurosarcoidosis and to subsequent medication with high dose corticosteroids. Initially, the treatment appeared to have a beneficial effect, but the condition soon deteriorated clinically and radiologically. Four months after the start of treatment the patient died from aspiration pneumonia following a seizure episode.

Figure 2.

PATHOLOGY

Macroscopically, a tumor‐like mass, 5 × 4 × 3 cm in size with poorly defined margins, was found in the centre of the left frontal lobe within the white matter (Figure 2b; Luxol fast blue stain). No other lesions were seen in the brain or the meninges.

Microscopic examination revealed a diffuse mononuclear cell infiltrate with variable cell density infiltrating the neuropil rather than growing in sheets. The cells were small with a lymphoid appearance and round, oval or irregular nuclei, inconspicuous nucleoli, and scant cytoplasm (Figure 3a, 3b). Scattered mitoses, as well as necrotic areas and oedema, were present, and cells infiltrated the meninges, perivascular spaces and vessel walls. The infiltrates extended from the left into the right frontal lobe, but were absent in the temporal and parietal lobes. The affected brain tissue exhibited some reactive gliosis, mainly in the white matter, but no granulomas or plasmacytoid cells were detected. The histology was neither typical of a central nervous system (CNS) lymphoma nor of an inflammatory disease.

Figure 3.

Immunohistochemically, the vast majority of the infiltrating cells stained positive for CD3 (Figure 3c) and over half of them were positive for CD2 and T‐cell intracellular antigen 1 (TIA1). Almost half of the cells were positive for the activated T‐cell marker granzyme B, and some for CD7. Occasional lymphocytes expressed CD4, CD5, CD8 and CD30, while staining for the B‐cell marker CD20 and for CD56, activin receptor‐like kinase 1 (Alk1) and T‐cell receptor alpha/beta (TCR alpha/beta) was consistently negative.

DIAGNOSIS

Cerebral T‐cell lymphoma.

DISCUSSION

Primary CNS lymphomas constitute about 6% of all primary brain tumors and most are of B‐cell phenotype. In Western countries only 2–5% of CNS lymphomas are derived from T‐cells (3). Primary CNS lymphomas of T‐cell type (T‐PCNSL) may appear at any age, with a median age of about 60 years at diagnosis (10). Most affected patients are immunocompetent, but T‐PCNSL has been reported in patients with human immunodeficiency virus (HIV) or human T‐lymphotropic virus 1 (HTLV‐1) infections 9, 10. Epstein‐Barr virus (EBV) has not been linked to T‐PCNSL 5, 8. In the present case, a serologic test for HIV was negative, but HTLV‐1 status was not determined. In situ hybridization for EBV on autopsy material was negative.

Patients with T‐PCNSL are usually treated with chemotherapy followed by irradiation, with or without initial corticosteroid treatment. The prognosis is poor, with a 5‐year disease‐specific survival of 17% and a median progression‐free survival of 22 months(10). Several factors have been linked to a worse prognosis, such as advanced age, tumor in deep brain structures (cerebellum, brainstem, corpus callosum, and basal ganglia), elevated serum lactate dehydrogenase, and elevated CSF protein levels 1, 6. In the present case, the approximate duration of the illness was 14–15 months.

It may prove difficult to clinically diagnose a T‐cell lymphoma of the CNS. As in this case, MRI often shows a non‐specific solitary mass located in one of the cerebral hemispheres 7, 8, 10, and brain biopsy is required for diagnosis. However, in the CNS, T‐cell lymphomas often present as infiltrating cells with small nuclei and bland morphology, although pleomorphic or large cell phenotypes are not infrequent (10), which explains why T‐PCNSL may be mistaken for non‐neoplastic lymphoid infiltrates. In addition, previously administered corticosteroid treatment may further complicate the histopatholoigcal diagnosis.

Genotypic analysis for TCR gamma (5) and other (4) TCR gene rearrangements, in order to detect monoclonality, may be necessary to establish the diagnosis, as no immunohistochemical marker to detect T‐cell monoclonality exists. In the present case, in which a tumor diagnosis was not anticipated, the whole brain was routinely fixed for several days in formaldehyde solution before sectioning and staining, and genotypic analysis was therefore not possible. However, the autopsy could provide a more solid base for diagnosis than a brain biopsy would have done in this case, especially in the light of the rather loosely scattered tumor cells and their non‐neoplastic appearance. The immunophenotype of T‐PCNSL varies. Staining may be positive for either or both CD4 and CD8 or as in the present case both may be negative 2, 5, 8. Also, lymphoma cells may lose their expression of CD5 and CD7 (5), as seen in many cells in the present case. Although alternative conditions (such as infection, granulomatous diseases and other inflammation) may be considered, the presentation of unusually fluctuating symptoms in a patient with progressive deterioration and contrast‐enhancing lesions on MRI should be considered to represent a brain tumor until proven otherwise.

ABSTRACT

A 76‐year‐old man presented with cognitive symptoms, followed by headache and weakness of the lower limbs and left arm. The clinical course was progressive but fluctuating. On magnetic resonance imaging (MRI), a contrast‐enhancing lesion 1 cm in diameter was seen in the left temporal lobe. This lesion became attenuated and a new contrast‐enhancing lesion 1 x 2 cm was seen in the left frontal lobe on a subsequent MRI. Following additional tests, treatment with corticosteroids for presumptive neurosarcoidosis was started, however, he soon expired. At autopsy, there was a tumor‐like mass in the left frontal lobe. Pathologic evaluation revealed a primary T‐cell lymphoma of the central nervous system (CNS). CNS T‐cell lymphomas may be difficult to diagnose, even histologically, due to their frequent small cell morphology and lack of significant atypia.