Primary diffuse leptomeningeal primitive neuroectodermal tumor presenting as chronic meningitis

ABSTRACT

Primary diffuse leptomeningeal primitive neuroectodermal tumor is a rare meningeal neoplasm which can masquerade as chronic meningitis. While the clinical presentation and radiological features may provide a clue to this condition, meningeal biopsy is essential to clinch the diagnosis. A high index of suspicion and a low threshold for re-evaluating cases of neuroinfection that do not respond to empirical therapy are essential in this scenario. We present the case of a nine year old boy who was initiated on antituberculous treatment for chronic meningitis with hydrocephalus. Meningeal biopsy revealed a primary diffuse leptomeningeal primitive neuroectodermal tumor.

Introduction

Chronic meningitis is a common clinical problem with a variety of possible diagnoses. The differential diagnoses to be considered depend on the geographical location and the immune status of the individual. A definitive microbiological diagnosis may not be forthcoming in many cases and empirical treatment may have to be initiated based on the clinical, radiological, and cerebrospinal fluid features. While the commonest cause in India is tuberculosis, other infectious, immune and neoplastic causes must also be considered, especially if empirical treatment does not yield the expected response.

Chronic meningitis is empirically defined by a duration exceeding four weeks. Even after extensive evaluation, a definite diagnosis may not be obtained in about a third of cases.[1] While the overall diagnostic yield of meningeal biopsy in chronic meningitis remains modest (39%), a biopsy taken from an area of enhancement identified on imaging, increases the yield to as much as 80%.[2] As results of cultures may be delayed, treatment of chronic meningitis in many cases is empirical. In such cases, it is imperative to keep an open mind about the final diagnosis. This is especially important when there is poor response to the empirical treatment given. The following case report highlights the importance of an extensive evaluation, including brain biopsy, in a case of chronic meningitis.

Case Report

A 9-year-old boy presented to a local hospital with holocranial headache, nausea and vomiting, seizures, and reduced sensorium for two days. Even after seizures were controlled with phenytoin and levetiracetam, he remained in altered sensorium necessitating mechanical ventilation. Magnetic resonance imaging (MRI) showed leptomeningeal enhancement with cerebellar swelling. Cerebrospinal fluid (CSF) study showed 1 cell/mm³ with raised protein (120 mg/dl) and normal sugar. He was started on ceftriaxone, acyclovir, and dexamathasone. Within three days, his sensorium improved and he was weaned off the ventilator. Five days after the onset of illness, he noticed binocular horizontal diplopia on looking to either side. He reported no symptoms suggestive of limb weakness, sensory system, other cranial nerve or bowel and bladder involvement. As headache and diplopia were persisting, he was referred to our center. On admission, he was conscious, oriented, with normal vitals and systemic examination. He had normal visual acuity, bilateral papilledema, with normally reacting pupils, and bilateral lateral rectus palsy with bilateral horizontal diplopia. Other cranial nerves were normal. Motor examination was normal except for bilateral extensor plantar responses. There were no signs of meningeal irritation. Differential diagnoses of tubercular meningitis, cryptococcal meningitis, neurobrucellosis, and carcinomatous meningitis were considered.

Routine blood investigations, including peripheral smear, were unremarkable. MRI brain showed obstructive hydrocephalus with diffuse leptomeningeal enhancement, most prominent over the cerebellar folia [Figure 1]. MRI of spine showed leptomeningeal enhancement along the surface of the spinal cord with a small nodular deposit in the cauda equina [Figure 2]. CSF study showed 8 cells which were lymphocytes with raised protein (206 mg/dl) and normal glucose (78 mg/dl, RBS 101 mg/dl). CSF cytology did not reveal any abnormal cells. CSF Cartridge based nucleic acid amplification test (CBNAAT), bacterial culture, acid fast bacilli (AFB stain), India ink staining, cryptococcal antigen and fungal culture, Brucella antibody were all negative. Serology for HIV was negative.

Figure 1.

(a) MRI brain (T1 post-contrast, axial) showing leptomeningeal enhancement most prominent in the cerebellar folia (blue arrow) with contrast enhancing exudates in fourth ventricle (red arrow); (b) MRI brain (T1 post-contrast, axial) showing diffuse leptomeningeal enhancement along with dilated lateral ventricles and third ventricle (yellow arrow)

Figure 2.

MRI lumbar spine (T1 post-contrast axial) showing leptomeningeal enhancement with an enhancing nodule (red arrow)

He was started on empirical antituberculous treatment (ATT) with isoniazid, rifampicin, pyrazinamide and ethambutol. However, two weeks after starting ATT, he had persistent headache, intermittent irritability, vomiting, and persistent lateral rectus palsy. Repeat CT showed hydrocephalus with tonsillar herniation [Figure 3]. Hence, he was taken up for ventriculo-peritoneal shunt surgery. During surgery, biopsy was taken from the right middle frontal region with overlying meninges. Following surgery, he became fully alert and diplopia improved.

Figure 3.

Axial T2 weighted MRI showing hydrocephalus

Pathological Findings

Formalin fixed paraffin embedded blocks were prepared from the tissue biopsy received, from which 4-5 μm thick sections were obtained. These were subjected to routine hematoxylin eosin staining and immunohistochemistry (IHC). The biopsy showed cerebral cortex with its overlying leptomeninges which showed infiltration by small round primitive looking cells with high nuclear cytoplasmic ratio, scant cytoplasm, and hyperchromatic nuclei. They were arranged in small clusters which become distinct on deeper sectioning. These neoplastic cells were strongly and diffusely positive for synaptophysin and faintly positive for chromogranin. Rest of the IHC markers that included cytokeratin (for epithelial neoplasms), desmin (for rhabdomyoblastic tumors), CD99 (for Ewing’s, lymphoblasts), epithelial membrane antigen (for meningeal tumors, epithelial tumors), glial fibrillary acidic protein (for glial tumors), leukocyte common antigen (for leukemia, lymphoma), HMB 45 (for melanoma) CD3 (T cell), CD 20 (B cell), and myeloperoxidase (myeloid sarcoma) were negative. The INI-1 stain (for AT/RT) was retained. M1B labelling was increased. The morphological features [Figure 4a, 4b] and the immunohistochemical profile [Figure 4c-s] were compatible with the diagnosis of primary diffuse leptomeningeal primitive neuroectodermal tumor.

Figure 4.

Microphotograph showing: (a) a small round cell cluster in the leptomeninges (H and E x100), with inset showing the nuclear characters of the neoplastic cell cluster (X400). Same image (x200), with: (c) the neoplastic cells showing strong and diffuse staining for synaptophysin; (d) faint staining for chromogranin; (e) MIB -1 labeling being moderately increased; and, (f) CD99; (g) CD3; (h) CD20; (i) cytokeratin; (j) desmin; (k) epithelial membrane antigen; (l) GFAP; (m) HMB 45; (n) immunostains being negative; and INI-1 (n) being retained. Also, (o) myeloperoxidase; (p) Neu-N; (q) Olig 2; (r) S-100; and, (s) vimentin immunostains being negative

Following meningeal biopsy, the patient was shifted to an oncology center, where he was treated with radiotherapy followed by chemotherapy with vincrisrtine and carboplatin. Though he improved transiently following ventriculoperitoneal shunt and radiation, he developed pancytopenia and succumbed to sepsis.

Discussion

Neoplastic meningitis is most commonly seen in patients with known malignancy. However, in up to 20% of cases, it may precede the diagnosis of systemic malignancy.[3] The diagnosis of neoplastic meningitis can be made by CSF cytology, which is highly specific for malignancy but has low sensitivity (around 50%).[4] In children, apart from spread from systemic malignancy, CNS tumors, leukemia, and lymphoma can also present as neoplastic meningitis. In adults, metastatic disease is the commonest cause. In addition, primitive neuroectodermal tumors (PNETs) can present in children as meningitis. PNETs are small round cell tumors which occur in the CNS, in bones, or in extra-osseous soft tissues. The genetic hallmark of this condition (in around 85% of cases) is translocation t (11;22) (q24;q12).[5] In the vast majority of cases, CNS PNETs will be parenchymal with meningeal seeding. Rarely, PNET can be confined to the meninges without any parenchymal involvement. This is called primary diffuse leptomeningeal PNET (PDL PNET).[6] In a review of 19 cases of PDL PNET, headache and vomiting were the commonest features. Hydrocephalus was present in 14 cases.[6] PNETs can be central or peripheral. Peripheral PNETs also called Ewing sarcoma are usually positive for CD99 (MIC2 gene product) while central PNETs are CD99 negative.[7] The mainstay of treatment is chemotherapy with cisplatin and etoposide along with craniospinal irradiation. Proton beam therapy has been reported to be effective.[8] In cases with hydrocephalus, ventriculoperitoneal shunt may be useful. Meningeal PNETs, in general, have poor prognosis.

Primary diffuse leptomeningeal PNET is a very rare pediatric CNS neoplasm. A review of literature revealed one previous report in India of diffuse meningeal PNET without any parenchymal lesion. Nambirajan et al.[9] report a 7-year-old with abdominal pain and seizures who was put on antifungal therapy before a meningeal biopsy clinched the diagnosis. A high degree of suspicion is required in order to make this diagnosis and meningeal biopsy is essential for the same. We present this case to emphasize on the need for thorough investigation of chronic meningitis of unknown etiology, especially when empirical therapy fails and to report this rare cause of neoplastic meningitis.

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The authors certify that appropriate patient consent was obtained.

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Conflicts of interest

There are no conflicts of interest.