Primary leptomeningeal T-cell lymphoblastic lymphoma: a rare cause of chronic meningitis

Abstract

Primary leptomeningeal lymphomatosis is a rare disease with only a few hundred cases reported. We present a patient with a relatively short history of 25 days of headache followed by diplopia who was found to have primary leptomeningeal T-cell lymphoma without evidence of systemic lymphoma. The patient responded well to chemotherapy along with intrathecal medication and cranial irradiation and returned to a completely normal state of health. Not all chronic meningitis is due to infection or self-limiting inflammatory causes. It is important to consider lymphoma as a differential even in the absence of constitutional features such as loss of weight, appetite, night sweats, lymphadenopathy or hepatosplenomegaly. T-cell lymphoma with only Central Nervous system (CNS) involvement is a rare cause of chronic meningitis, which is eminently amenable to treatment and is fatal if missed.

Background

Primary leptomeningeal lymphomatosis (PLML) is rare. The diagnosis is often missed due to its rarity and difficulty in diagnosis as repeated cerebrospinal fluid (CSF) examination may be needed to diagnose, especially in cases when the MRI is normal. Due to raised intracranial pressure and normal initial CSF findings, it may be misdiagnosed as idiopathic intracranial hypertension.^{1 2} Moreover, in developing countries such as India, patients with chronic meningitis are given empiric treatment with antitubercular drugs along with steroids, and steroids can mask the presence of lymphoma and make diagnosis more difficult. It is important to diagnose it early as early treatment initiation is one of the important prognostic factors.

Case presentation

A 32-year-old man had presented with 25-day history of fever and holocranial headache. The fever was continuous and in a few days, he developed binocular horizontal diplopia. He also had neck pain and restriction of neck movements. He also had photophobia and phonophobia associated with the headache. He was evaluated at another centre and started on antitubercular treatment along with steroids based on CSF examination, which showed lymphocytic pleocytosis and MRI showing leptomeningitis. Two weeks later, he developed heaviness in both lower limbs and he also had developed abnormal perineal sensation and urinary retention.

There was no lymphadenopathy. Cardiovascular and respiratory systems were normal and he had no hepatosplenomegaly or testicular enlargement. Neurologic examination revealed bilateral papilledema, with bilateral abducent nerve palsy, which was likely due to raised intracranial pressure. There was paraparesis with perianal sensory loss and the rest of the sensory examination was normal. Bilateral ankle jerks were absent with rest of the deep tendon reflexes being normal.

Differential diagnosis

The patient had chronic meningitis with raised intracranial pressure. The differentials for this condition includes infective causes such as tubercular meningitis, fungal, nocardial or other atypical bacterial causes, non-infectious inflammatory causes such as sarcoidosis and malignancy including lymphoma and carcinomatous meningitis.

Investigations

Hematologic investigations revealed normal cell counts of all lineages and peripheral smear did not reveal any atypical cells. Renal functions, serum electrolytes and liver enzymes were normal, as was the bilirubin. Serum LDH (Lactate dehydrogenase) was slightly raised at 600 U/L. Bone marrow examination did not reveal any evidence of lymphoma.

MRIs (figure 1A–F) of the spine and brain were performed and revealed clumping of cauda equina nerve roots and thickening and contrast enhancement. There were a few areas of diffusion restriction in the right high parietal lobe and mildly increase leptomeningeal gadolinium enhancement. CSF examination revealed raised opening pressure of 32 cm of CSF. CSF cell count was 3200 cells/µL, which was 90% lymphocytic. CSF protein was elevated and was 147 mg/dL, CSF glucose was 65 mg/dL and corresponding blood sugar was 157 mg/dL. CSF cytology (figure 2), immunocytochemistry and flow cytometry revealed T-cell lymphoblastic lymphoma with Breakpoint cluster region-tyrosine kinase (BCR-ABL) gene mutation negative.

Figure 1.

(A–C) T1-weighted contrast-enhanced MRI axial images of brain showing leptomeningeal contrast enhancement (red arrows). (D) Diffusion restricting lesion in right high frontal region (blue arrow) suggesting a lymphomatous lesion. There is no hydrocephalus. Spine images (E) sagittal T1-weighted contrast-enhanced image showing enhancing roots (red arrows). (F) Axial contrast-enhanced T1-weighted image showing specks of contrast enhancement (red arrow head).

Figure 2.

×40 magnification of cerebrospinal fluid cytology specimen showing large immature T lymphoblasts.

CSF was tested for cryptococcal antigen, and GeneXpert for tuberculosis, which were negative as were the cultures. Contrast-enhanced CT scan of the chest and abdomen did not reveal lymphadenopathy or organomegaly to suggest systemic lymphoma.

Treatment

The patient had a European Cooperative Oncology Group performance status of 2 and was initiated on hyper CVAD therapy (cyclophosphamide, vincristine, doxorubicin, dexamethasone and cytarabine) with intrathecal methotrexate and CNS irradiation. He tolerated the treatment well.

Outcome and follow-up

Patient’s CSF became completely normal and all his symptoms resolved. He became as normal as he was under consolidation therapy and regular follow-up.

Discussion

PLML was first described by Lachance et al in 1991, though there have been reports of series of such cases previously.² Since then only a few hundred cases have been reported. Primary CNS lymphoma (PCNSL) constitutes 2% of all brain malignancies. PLML is the involvement of leptomeninges with no other brain lesions or systemic evidence of lymphoma and represents only 7% of all cases of PCNSL.³ In a previously reported series of nine patients, it was found that the patients presented with features of cranial or spinal leptomeningeal involvement with cranial nerve palsies, spinal root dysfunction or encephalopathy and altered sensorium and syndrome of inappropriate antidiuresis.² The mean duration of symptoms before diagnosis was 1–22 months. In this series, three out of nine patients had an initial normal CSF examination and normal brain imaging leading to the diagnosis of idiopathic intracranial hypertension and subsequently found to have CSF showing lymphomatous cells. This shows the importance of repeated CSF cytologic examinations, since initial reports may be entirely normal due to intermittent shedding of cells in the CSF. Sometimes the CSF cytology may be negative for malignant cells in spite of repeated examinations though the cell counts and protein are elevated with reduced glucose and may only be diagnosed on meningeal biopsy. Three of the nine cases in the above series were diagnosed on meningeal biopsy. This reiterates the fact that the diagnosis of PLML is difficult due to normal brain imaging and sometimes normal CSF examinations leading to diagnostic delay. The authors of this series found PLML in 9/118 PCNSL cases reported till then giving an incidence of 7.6%. Out of five cases in whom immunohistochemistry data were available, only one had T-cell lymphoma. B-cell lymphoma is found more commonly and T-cell lymphomas are exceedingly rare.⁴ Immunocytochemistry is more sensitive than cytology in the diagnosis of PLML. There were two cases in this series of nine patients,² where cytology was negative with positive immunocytochemistry. One patient had negative immunocytochemistry and could be diagnosed only on biopsy of markedly thickened sacral nerve root. In another series of 48 patients with PLML,³ more than two third patients presented with multifocal symptoms and signs. Cranial neuropathies were the most common presenting features. Half of them presented with spinal symptoms and paraparesis. Headache was the presenting feature in 44% bowel and bladder dysfunction in 21% and seizure in 8% of patients.³ In this series, it was found that only 67% of patients could be diagnosed based on CSF cytology, and CSF was diagnostic after a median of two lumbar punctures (range 0–5). Overall, 33% of patients needed biopsy to be diagnosed. There have been other such reports as well.⁵ This shows that such patients should undergo immunocytochemistry and if needed leptomeningeal biopsy or in some cases biopsy of lumbar root, before declaring negative for malignancy. Meningeal biopsy is a safe procedure with infrequent complications such as surgical site infection and haemorrhage. The yield of meningeal biopsy is most when the site biopsied shows enhancement on contrast MRI. In the largest reported series of PLML, clinical follow-up revealed complete response in 47% (21/45) patients and imaging and CSF clearance of malignant cells in 69% (18/26) patients. It was also seen that progression-free survival ranged from 6 to 24 months with a median of 8 months and 11 out of 45 were alive at 50-month follow-up. The fact to be emphasised is that if diagnosed and treated appropriately, patients can be treated and a quarter cured.³ Thus, PLML is a rare diagnosis that may need repeated investigations and perseverance to diagnose and may be fatal if missed and rewarding if diagnosed and treated early.

Learning points.

• Chronic meningitis is a common diagnostic syndrome with varying causes, and primary leptomeningeal lymphomatosis is a rare cause.

• T-cell lymphoblastic picture in primary leptomeningeal lymphoma is very rare.

• The diagnosis should be strongly considered especially when the cerebrospinal fluid (CSF) cell counts are in thousands and the duration is longer than that in acute bacterial meningitis.

• Diagnostic difficulty is compounded by the fact that multiple CSF examinations may be needed before the diagnosis is made and empirical therapy with corticosteroids may mask the diagnosis and make CSF falsely negative for malignant cells.

• It is important to diagnose and start early treatment as it is a treatable condition.