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|NI FEATURE: PATHOLOGY PANORAMA - COMMENTARY
|Year : 2015 | Volume
| Issue : 5 | Page : 736-742
A 7-year-old girl with recurrent episodes of abdominal pain, seizures, and loss of vision: Primary diffuse leptomeningeal primitive neuroectodermal tumor masquerading as chronic meningitis
Aruna Nambirajan1, Vaishali Suri1, Mehar Chand Sharma1, Ranjith Kumar2, Ajay Garg3, Sheffali Gulati2, Vivek Tandon4
1 Department of Pathology (Division of Pediatric Neurology), All India Institute of Medical Sciences, New Delhi, India
2 Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
3 Department of Neuroradiology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||6-Oct-2015|
Dr. Vaishali Suri
Department of Pathology, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Nambirajan A, Suri V, Sharma MC, Kumar R, Garg A, Gulati S, Tandon V. A 7-year-old girl with recurrent episodes of abdominal pain, seizures, and loss of vision: Primary diffuse leptomeningeal primitive neuroectodermal tumor masquerading as chronic meningitis. Neurol India 2015;63:736-42
|How to cite this URL:|
Nambirajan A, Suri V, Sharma MC, Kumar R, Garg A, Gulati S, Tandon V. A 7-year-old girl with recurrent episodes of abdominal pain, seizures, and loss of vision: Primary diffuse leptomeningeal primitive neuroectodermal tumor masquerading as chronic meningitis. Neurol India [serial online] 2015 [cited 2019 Aug 21];63:736-42. Available from: http://www.neurologyindia.com/text.asp?2015/63/5/736/166552
| » Clinical Summary|| |
A 7-year-old, previously well, female child presented with sudden onset recurrent episodes of severe abdominal pain and generalized tonic-clonic seizures for 15 days. On admission to a private institution, she was started on (Category) CAT I antitubercular therapy (ATT) based on a provisional clinical diagnosis of tubercular meningitis. She was relatively well for a month, after which she developed recurrence of abdominal pain and seizures for which she required readmission. Magnetic resonance imaging (MRI) of the brain revealed diffuse leptomeningeal enhancement and hydrocephalus [Figure 1]a. ATT administration was continued and antiepileptic drugs (sodium valproate and phenytoin) were added to her treatment regimen. Despite adequate compliance, there was no symptomatic improvement, and she was switched to CAT II ATT. She developed weight loss of 5-kg over the 10-month disease duration and had progressive visual loss over 15 days with inability to recognize faces or count fingers. Fundoscopy revealed bilateral temporal pallor. There was no altered sensorium, speech disturbances, other cranial nerve involvement, focal deficits, stiffness of limbs, ataxia, nystagmus, fever, cough, rash or abdominal distension. There was no history of contact with patients with tuberculosis (TB). At this point, she was referred to our institution. On examination, she was underweight for her age but alert and active. Her pulse rate was 100/min with normal volume, respiratory rate was 24/min, blood pressure was 100/52 mmHg, SpO2 97%, and capillary filling time <3 s. No dysmorphism, neurocutaneous marks or signs of vitamin deficiencies were noted. Her systemic examination was unremarkable. Visual assessment revealed absent perception and projection of light with intact bilateral pupillary reflexes. Plantar reflexes were flexor. Tone was normal in upper limbs but increased in lower limbs with minimal spasticity. Power was >3/5 in all four limbs. Neck rigidity was seen but no other signs of meningeal irritation were noted. No signs of cerebellar or sensory dysfunction were evident.
|Figure 1: (a) Magnetic resonance imaging (MRI) brain at the onset of symptoms revealed diffuse leptomeningeal enhancement and hydrocephalus; (b) MRI imaging 2 months later showed appearance of pseudocysts, dilated Virchow-Robin spaces in addition to leptomeningeal enhancement, and hydrocephalus; and, (c) appearance of dural based lesions in the posterior one-third of left side of falx and the right parasellar region|
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Routine blood examination revealed the following values: Hemoglobin 12.1 g%; total leukocyte count 6400/cmm; differential leukocyte count N57 L40 E3; platelet count 2,86,000/cmm; erythrocyte sedimentation rate 8 mm/1st h; peripheral smear normal; biochemistry - urea 23 mg/dL; creatinine 0.6 mg/dL; total bilirubin 0.6 mg/dL; alkaline phosphatase 224 U/L; serum glutamic-oxaloacetic transaminase 18 U/L; serum glutamic-pyruvic transaminase 19 U/L; Na 136 meq/L; K 2.7 meq/L. Tests for detection of HIV were negative. Routine urine examination was normal. The cerebrospinal fluid (CSF) was clear with glucose 10 mg/dL; protein 81 mg/dL; CSF culture: Sterile; TB polymerase chain reaction (PCR): negative; BACTEC: negative; India ink stain: negative; cryptococcal antigen: negative; cryptococcal PCR: negative; and, the CSF cytology showed a few lymphocytes with no abnormal cells. Her chest X-ray and ultrasound abdomen were normal. Electroencephalogram revealed diffuse cerebral dysfunction and visual evoked response revealed bilateral extinguished responses. Tuberculin test revealed a 6 mm induration. MRI of the brain at this juncture showed the appearance of pseudocysts, dilated Virchow-Robin (VR) spaces in addition to the leptomeningeal enhancement and hydrocephalus [Figure 1]b .
The child was started on empirical antifungal therapy with liposomal amphotericin B and flucytosine, which was given for 6 weeks, based on a radiological suspicion of cryptococcosis. However, she continued to have multiple episodes of abdominal pain, bifrontal headache, and vomiting associated with seizures. A repeat MRI showed infarcts in the basal ganglia and dural based lesions in the posterior one-third of left falx and right parasellar region. There was a diffuse leptomeningeal enhancement of spinal cord with loculation. Focal hemorrhage was noted in the left sized lesion [Figure 1]c. The occurrence of hemorrhage raised the suspicion of a malignant process. CSF manometry revealed a high pressure of 28 cm H2O and cytopathology revealed clusters of small round cells with nuclear molding suggestive of malignancy. A right occipital medium pressure ventriculoperitoneal shunt was placed. The neuropathological examination of a small cerebral hemisphere fragment obtained during the procedure was considered normal. Following shunt placement, her symptoms abated. A brain positron emission tomography (PET) performed showed increased uptake in the dural based lesions, while whole PET body was normal. No intraaxial masses were seen. Multiple surface brain biopsies were performed.
| » Differential Diagnoses|| |
- Cryptococcal meningitis: The clinical picture of chronic drug-resistant meningitis, radiological features of pseudocysts, and dilated VR spaces suggested a possibility of cryptococcal meningitis. However, all tests to detect the fungus were negative. In addition, dural-based cryptococcomas are extremely uncommon and not reported in literature
- Neurosarcoidosis: Although relatively rare in children, presence of leptomeningeal involvement, optic pathway involvement, and dural based lesions prompted consideration of neurosarcoidosis in this patient. A normal chest radiograph and absence of systemic symptoms made it less likely. The radiological findings of dilated VR spaces and pseudocysts were also difficult to explain
- Tubercular meningitis: In a country endemic for TB like India, TB always remains one of the differential diagnoses. The patient showed mild diffuse enhancement of the temporal lobes and cerebellar hemispheres on computed tomography suggesting a granulomatous lesion unlike malignancy, which usually shows isodense and nonenhancing lesions. However, the patient had already received two courses of ATT with no symptomatic improvement
- Neoplastic: The patient was relatively well preserved with a long duration of illness spanning nearly a year. Her initial CSF cytology was negative for malignancy. Radiological evidence of hemorrhage in the lesion was the first sign that raised suspicion for a neoplastic process and prompted a biopsy.
| » Pathological Findings|| |
Surface biopsies from the lesion in the left falx were received comprising of multiple tissue fragments measuring 0.8 cm × 0.5 cm × 0.3 cm. The tissue was formalin fixed and paraffin embedded. Routine hematoxylin and eosin stained sections were examined. Microscopy revealed sheets of small round cells with scant cytoplasm and angulated hyperchromatic nuclei infiltrating in the meninges. Rosettes, neuropil or perinuclear haloes were not seen. These small cells were seen infiltrating in the subarachnoid space and superficially into the occipital cortex along the pial vessels [Figure 2]a,[Figure 2]b,[Figure 2]c. The histopathological differential diagnosis of diffuse leptomeningeal infiltrates in the absence of an intra-axial mass include a wide range of malignancies such as leukemias, carcinomatosis, melanocytosis, and certain rarer entities such as primary leptomeningeal gliomatosis, primary diffuse leptomeningeal-primitive neuroectodermal tumor (PDL-PNET), and diffuse oligodendroglia like leptomeningeal tumor (DOGLT) [Table 1]. A wide immunopanel of markers were performed for characterization [Figure 2]d,[Figure 2]e,[Figure 2]f,[Figure 2]g. The tumor cells were negative for leukocyte common antigen (LCA), CD3, CD20, CD117, and myeloperoxidase ruling out a hemolymphoid malignancy. Pan-cytokeratin and melanocytic markers such as HMB-45 and S100 were negative ruling out carcinomatosis and melanocytosis, respectively. Stains for glial neoplasms including IDH-1, glial fibrillary acidic protein, and p53 were also negative. The tumor cells did not show loss of chromosomes 1p or 19q on fluorescence in situ hybridization (FISH) analysis. The tumor cells showed immunopositivity for chromogranin, synaptophysin, CD56, Neu-N, Beta-tubulin, and microtubule-associated protein suggesting neuronal differentiation raising the possibility of a PNET. INI-1 immunoreactivity was retained, ruling out an atypical teratoid/rhabdoid tumor (ATRT). FISH assay to detect any Ewing's sarcoma associated (EWS) translocation was performed using Vysis EWSR1 (22q12) Dual Color, Break Apart Rearrangement Probe Kit. EWSR1 translocation was not seen and tumor cells were immuno-negative for MIC-2, excluding a diagnosis of EWS/peripheral PNET [Figure 3]. A final histopathological diagnosis of PDL supratentorial PNET (sPNET) was rendered.
|Figure 2: (a) Diffuse infiltration of leptomeninges by small round cells (×40); (b) Tumor cells are infiltrating superficially into cortex and around pial vessels (×100); (c) Tumor cells have scant cytoplasm and hyperchromatic nuclei (×400); (d-g) Tumor cells are immunopositive for synaptophysin and INI-1 and are negative for leukocyte common antigen and MIC-2 (IHC, ×200)|
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|Table 1: Histopathological differential diagnoses of diffuse leptomeningeal malignant small round cell tumors|
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|Figure 3: Absence of EWSR1 rearrangement in tumor cells (Oil immersion, Dual Color, Break Apart Rearrangement Probe Kit, the 5” side flanking probe labeled in SpectrumOrange, and 3” flanking probe labeled in SpectrumGreen)|
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Primary diffuse leptomeningeal sPNET- (not otherwise specified) NOS, WHO Grade IV.
| » Further Course in Hospital|| |
The patient was referred to the oncology department where she received a palliative chemotherapy regimen (vincristine, adriamycin, cyclophosphamide alternating with ifosfamide, and etoposide) for 6 months and is currently stable and on regular clinical follow-up.
| » Discussion|| |
Malignant meningitis usually occurs as a late complication of primary central nervous system (CNS) tumors, detected in approximately 20–77% of patients on postmortem examination. Embryonal tumors such as medulloblastomas and sPNETs constitute more than half of such cases while rarely, low-grade gliomas such as pilocytic astrocytomas and oligodendrogliomas can also progress in a similar fashion., Primary malignant meningitis in the absence of an intra-axial mass is an extremely rare occurrence with an incidence of 0.01%, most of such cases being embryonal tumors (61%) followed by high-grade gliomas (27%). One of the first mentions dates back to the early 1920's with the description of a case of “sarcomatosis” of the meninges, and a case of invasion of the leptomeninges by “undifferentiated embryonic cells." These entities should be considered in patients presenting with neurological symptoms suggestive of meningitis or raised intracranial pressure and leptomeningeal enhancement on MRI, especially if they do not respond to conventional treatment. Despite leptomeningeal seeding, the detection rate of malignant cells in CSF is low, ranging from 34% to 65% in reported series. Hence, the importance of an early biopsy for definitive diagnosis cannot be overemphasized.
The current case was a challenge to the clinicians and pathologists alike. The histological differential diagnoses included a host of tumors that can present with a small round cell morphology and purely leptomeningeal involvement [Table 1]. While most of them were easily excluded on morphology and immunohistochemical stains, distinction from Ewing's sarcoma/ peripheral PNET (EWS/PNET), medulloblastoma (MB), ATRT, and the recently described disseminated oligodendroglia-like leptomeningeal tumor of childhood (DOGLT) was more problematic. EWS/PNETs arise predominantly outside the CNS in the deep soft tissues of the trunk and lower limbs. These tumors typically express high amounts of the MIC2 antigen (CD99) and exhibit highly characteristic chromosomal translocations that result in the fusion of the EWS gene with any of several members of the E26 transformation-specific (ETS) family of transcription factors, leading to oncogenic activation of the EWS gene., Primary extraosseous intracranial EWS/PNETs are rarer than sPNETs, usually presenting as dural based masses mimicking meningiomas. However, diffuse leptomeningeal spread has also been described in these tumors. They have a better prognosis and a different treatment regimen necessitating differentiation from sPNETs. The immunonegativity for MIC2 antigen and absence of EWS translocation ruled out a EWS/PNET in this particular case. MBs are the most common embryonal tumors, predominating in children, exclusively located in the posterior fossa and having a better prognosis as compared to sPNET-NOS. They show specific molecular translocations such as isochromosome 17q and cMYC amplification that are virtually never detected in sPNET-NOS. Rare examples of MB presenting with leptomeningeal dissemination without a true mass lesion have been reported with the deposits being limited to the posterior fossa. Although i17q and cMYC amplification could not be performed in this case due to exhaustion of tumor tissue, the presence of extensive supratentorial disease and absence of cerebellar involvement nearly excluded the possibility of an early leptomeningeal spread of a MB. ATRTs can arise anywhere in the CNS and typically show rhabdoid cells admixed with primitive neuroectodermal cells. Inactivation of the INI1/hSNF5 gene is seen in virtually all cases, detected by loss of INI-1 immunoexpression on immunohistochemistry. They are associated with an extremely aggressive clinical course and a poor outcome. INI-1 immuno-staining was, however, retained in our case. The novel entity DOGLT is a diffuse leptomeningeal tumor described recently in young children and typically occurs in the absence of an intra-axial mass. It is composed of oligoid cells in a desmoplastic or myxoid stroma and was ruled out on morphological grounds.
Central nervous system PNETs, also known as sPNET – not otherwise specified (sPNET-NOS), are a heterogeneous group of tumors occurring predominantly in children and adolescents. The current WHO 2007 classification groups them under the category of embryonal tumors, which includes MB, ATRT, and rarer entities such as CNS neuroblastoma, CNS ganglioneuroblastoma, medulloepithelioma, embryonal tumor with abundant neuropil and true rosettes, and ependymoblastoma which show distinct morphological patterns. sPNET-NOS is a diagnosis of exclusion, reserved for undifferentiated or poorly differentiated embryonal tumors that occur at any extra-cerebellar site in the CNS and lack any of the characteristic morphological and molecular changes seen in other embryonal tumors. They arise in the cerebral hemispheres, brain stem or spinal cord, and may display divergent differentiation along neuronal, astrocytic, and ependymal lines. They show nonrandom cytogenetic gains and losses with no specific diagnostic or prognostic molecular marker detected till date. They are known for their early-onset, aggressive clinical behavior, and frequent cerebrospinal dissemination. Three molecular subgroups of sPNET have been recently decoded with variable prognostic and therapeutic significance.,
The literature regarding primary diffuse leptomeningeal (PDL)-PNET is sparse, and the distinction from MB and EWS/PNET is not always clear in the reported cases. There are ten case reports in English literature, describing a total of 17 patients, with cytology or histology proven PDL -PNET in the absence of an intra-axial mass.,,,,,,,,, These patients were predominantly children with a median age of 13 years (7 months – 55 years) and a striking male predilection. The patients presented with signs and symptoms of chronic meningitis, increased intracranial tension, and focal neurological deficits. Most of these patients were evaluated and treated as chronic meningitis with the initial CSF examination failing in most instances to reveal the malignant etiology. Six patients went on to develop intra-axial masses later in the course of their disease while no masses were detected in the follow-up duration or during autopsy in the remaining, suggesting that they might represent true examples of primary PDL disease. The patients were treated with radiotherapy, chemotherapy (CT) or both. The median survival was 11 months (2–67 months) with the tumor in five patients completely regressing following CT [Table 2]. Interestingly, three patients described by Jennings et al., developed systemic skeletal metastases even in the presence of a purely leptomeningeal disease. Whether these rare PDL-PNETs are a distinct biological group of embryonal tumors with a different prognosis is yet to be elucidated.
|Table 2: Reported cases of histology/cytology proven PDL-PNETs in English literature including the current case|
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The histogenesis of primary leptomeningeal PNETs is unclear. Such cases are postulated to originate from a heterotopic glial nest in the subarachnoid space.
The presentation of these tumors as meningitis serves as a reminder that neoplastic meningitis must be considered in the differential diagnosis of meningitis without identifiable organisms. The CSF cytology may not reveal malignant cells at the time of presentation although serial sampling can improve the yield. A biopsy of the MRI enhancing areas of the leptomeninges may be necessary to provide a timely histologic diagnosis.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]