Angela Mercy Ralte

Subependymal giant cell astrocytoma - a clinicopathological study of 23 cases with special emphasis on histogenesis

Subependymal giant cell astrocytomas (SEGAs) are relatively rare tumors but occur commonly in the setting of the familial syndrome of tuberous sclerosis complex (TSC). In view of its varied morphology, i.e. resemblance to astrocytic and ganglion cells, its histogenesis remains controversial. We studied 23 cases of SEGA, 19 from our own institute and 4 from NIMHANS, Bangalore. These 19 cases of SEGAs were collected over a period of 23 years (1979 to 2001), and accounted for 0.16% of intracranial tumors and 0.51% of all gliomas reported at our center. The majority of patients presented with visual disturbances (19÷23, 82.6%) in the form of decreased vision (60.8%) and blindness (21.7%), generalized tonic clonic seizures (43.4%) and focal motor seizures (4.37%). Age ranged from 4 to 37 years (mean 13.2 years) with male predominance (M:F 2.2:1), and the duration of symptoms varied from 1 month to 96 months (mean 17.2 months). Lateral ventricular involvement was the most common site (91.3%), followed by the third ventricle (8.6%). Nine patients (39.1%) had stigmata of tuberous sclerosis (6 at the time of diagnosis and 3 in the follow-up period). Two patients died due to surgical complications, while the rest were alive and well in the follow-up period ranging from 3 to 264 months (mean 37.1 months). Two patients experienced recurrences, one two years and another 22 years after surgery. Microscopic examination showed varied histology consisting of sweeping bundles of spindle cells, gemistocyte and ganglion-like cells with interspersed inflammatory cell component. The inflammatory cell component on special staining turned out to be an admixture of mast cells and T lymphocytes. Six cases showed areas of necrosis and/or mitosis, but were not indicative of aggressive nature of this tumor. Immunoreactivity for GFAP, NF, S-100, NSE and synaptophysin indicates that this is a hybrid tumor with glial and neuronal differentiation. None of the tumors was immunopositive for HMB-45. The significance of the presence of T lymphocytes and mast cells is not clear. It could be related to tumor immunology and may indicate a favorable prognosis.

Clinicopathological features, MIB-1 labeling index and apoptotic index in recurrent astrocytic tumors

This is a study of 64 cases of recurrent astrocytic tumors of all four WHO grades wherein a comparative evaluation of initial vs. recurrent tumor was done with respect to histological grading, MIB-1 labeling index (LI) and apoptotic index (AI). The aim was to identify factor/s that could influence interval to recurrence and/or malignant progression. Recurrence was noted in all grades and upon recurrence, 93.3% of grade II (low grade diffuse) astrocytomas and 63.6% of grade III anaplastic astrocytomas underwent malignant progression. However, none of the Grade I tumors showed evidence of malignant progression. Though interval to recurrence varied considerably, there was a correlation with histological grade of the initial tumor in that grade I and II tumors had a significantly longer mean interval to recurrence (43 months and 54.8 months respectively) as compared to grade III and IV (glioblastoma multiforme) tumors (17.6 and 12.8 months respectively). The interval to recurrence was also longer for grade II and III tumors which showed progression on recurrence (55.3 months for Grade II → Grade III; 54 months for Grade II → Grade IV and 20.6 months for Grade III → IV) as compared to tumors which recurred to the same grade (12.5 months for Grade III → Grade III and 12.8 months for Grade IV→ Grade IV). A statistically significant inverse correlation of MIB-1 LI with interval to recurrence was noted. Higher the MIB-1 LI, shorter was the interval to recurrence. Further a cut off MIB-1 LI value of 2.8% could be proposed in predicting recurrence free survival. Interestingly, MIB-1 LI of grade II tumors, which had progressed to grade IV was significantly higher than MIB-1 LI of grade II tumors which had progressed to grade III. Thus, this study establishes the potential role of MIB-1 LI of the initial tumor in determining interval to recurrence. However, apoptotic index has no role in predicting either interval to recurrence or malignant progression.

Subependymal giant cell astrocytoma: a clinicopathological study of 23 cases with special emphasis on proliferative markers and expression of p53 and retinoblastoma gene proteins

Aims: To gain a better insight into the biological behaviour of subependymal giant cell astrocytoma (SEGA), tumour suppressor gene protein expression and various proliferative indices were studied in these tumours and correlated with histological features and clinical outcome. Methods: We studied 23 cases of SEGA, 19 from our own Institute and four from the National Institute of Mental Health and Neurological Sciences (NIMHANS), Bangalore, India. Immunohistochemical staining for various glial and neuronal markers, proliferative markers (MIB‐1, Topoisomerase II α PCNA) and tumour suppressor gene protein expression of p53 and retinoblastoma (Rb) were performed. Results: Nineteen cases of SEGA were collected over a period of 23 years (January 1978–December 2001), which accounted for 0.16% of all intracranial tumours and 0.51% of all gliomas reported at this centre. Ages ranged from 4 to 37 years (mean 13.2 years) with a male preponderance. Nine of the 23 cases were associated with tuberous sclerosis (TS), six at the time of diagnosis, while three developed TS during the follow‐up period. Treatment consisted of surgical resection (total in nine cases and subtotal in 14 cases) followed by radiotherapy in seven cases. Except for two patients who died in the immediate post‐operative period of surgical complications, the remaining patients were all alive in the follow‐up period (mean 37.1 months). One patient experienced recurrence 22 years after the first surgery and a second patient after 2 years. Necrosis and/or mitoses were observed in five cases. Immunohistochemically, tumours were positive for both glial and neuronal markers. Interspersed inflammatory cells were a mixture of mast cells and lymphocytes of T immunophenotype. The MIB‐1 labelling index (LI) ranged from 0 to 8% (mean 3.0%), topoisomerase II α (topo II α) LI from 0 to 9.5% (mean 2.9%) and PCNA LI from 10 to 59% (mean 32.5%). The difference in the labelling indices of tumours with and without mitoses and/or necrosis was not statistically significant. None of the tumours revealed loss of Rb gene protein expression. p53 immunopositivity was seen in 14 cases (labelling indices ranged from 1 to 7.3% with a mean of 2.4%). The correlation between the MIB‐1 LI and topo II α LI, and topo II α LI and PCNA LI was significant (P<0.05) but not so with other parameters like p53 protein expression, duration of survival and morphological features such as mitoses and necrosis. Conclusions: SEGAs are rare intraventricular tumours associated with TS and express both neuronal and glial markers. They have a low proliferative potential. Mitoses and necrosis are not associated with a worse prognosis. In view of the low proliferative indices and long survival of these patients without recurrence, the role of post‐operative radiotherapy is questionable. These patients should be followed up closely as many of them develop stigmata of tuberous sclerosis at a later stage.

Recurrent astrocytic tumours — a study of p53 immunoreactivity and malignant progression

Recurrence and progression to higher grade lesions are characteristic of the clinical course of astrocytic tumours. Though p53 gene mutation is an impor tant initiating event in astrocytic tumourigenesis, its role in malignant progression remains controversial. We have therefore analysed p53 protein expression in paired histological samples from 48 cases of astrocytic tumours and their recurrences - 29 diffuse astrocytoma, 10 anaplastic astrocytoma and 14 glioblastoma multiforme (GBM). Malignant progression at recurrence was noted in 93% of diffuse and 64% of anaplastic astrocytomas. An association was observed of p53 protein immunopositivity and malignant progression at recurrence. Thus, 27 of 48 (56%) primary tumours were initially p53 positive, while in recurrent tumours associated with malignant progression this frequency increased to 71% (34/48 cases). This was because seven of the 13 cases (4/8 diffuse and 3/5 anaplastic astrocytoma) that were initially p53 negative acquired immunopositivity on malignant progression at recurrence. In contrast, none of the 19 tumours that recurred to the same grade showed any change of p53 status at recurrence. Furthermore recurrence was associated with increase in the percentage of p53 immunopositive cells (p53 labelling index), which was also higher in tumours with progression. This new acquisition of p53 immunopositivity on progression at recurrence has not been documented in earlier studies in English language literature, though increase in p53 LI has been documented. Thus, this study conclusively indicates the role of p53 in malignant progression of astrocytic tumours. Also, it suggests a potential role of p53 LI in predicting malignant progression at recurrence because the highest initial LI was noted in those tumours which progressed to GBM as compared with those which recurred to the same grade or progressed to anaplastic astrocytoma. No correlation could, however, be demonstrated between p53 immunoreactivity and interval to recurrence.

Intramedullary subependymoma of the spinal cord: a case report and review of literature

A case of cervical spine intramedullary subependymoma in a 52-year-old female is reported. Also, the relevant literature on the 40 cases reported till date is reviewed. Magnetic resonance imaging, even with enhancement, does not show any distinctive features making pre-operative diagnosis often difficult. These tumours are eccentrically located within the spinal cord, thus enabling complete tumour removal in most cases. They are benign with low proliferative potential and hence no post-operative radiotherapy should be administered.

Loss of heterozygosity of a locus in the chromosomal region 17p13.3 is associated with increased cell proliferation in astrocytic tumors

We had previously reported that loss of heterozygosity (LOH) of the D17S379 locus on 17p13.3 was significantly more frequent in high-grade gliomas (anaplastic astrocytoma, AA; glioblastoma multiforme, GBM) than in those of a low-grade diffuse astrocytoma (DA); however, this was independent of alterations at the TP53 locus, We also showed that LOH of D17S379 was associated with positive staining for p53 protein on immunohistochemistry, but LOH of the TP53 gene had no such association. In this work we show that cell proliferation as determined by MIB-1 labeling index (LI) was significantly higher in tumors with LOH of D17S379 than those with no LOH (NLOH). In accord with our previous results, p53 protein immunopositivity was also associated with increased MIB-1 LI; however, we observed no such association of LI with TP53 LOH. The results further confirm that alteration of one or more putative tumor suppressor loci at 17p13.3 is associated with increased proliferation in astrocytic tumors.

Leigh's syndrome.

A 15-month-old female child presented with sudden onset cough and hyperventilation along with evidence of metabolic acidosis. She had past history of recurrent vomiting, episodes of abnormal posturing, difficulty in deglutition and regression of milestones since 12 months of age. CT scan of the brain revealed hypodense lesions in bilateral basal ganglia and on MRI there were T2 hyperintensities in bilateral lentiform nuclei, caudate nuclei, thalamus, red nuclei and dentate nuclei. Biochemical examination revealed persistently elevated serum lactate levels with high lactate/pyruvate ratio. Resuscitative measures were of no avail and the child succumbed to the illness on the second day of admission. Neuropathological examination at autopsy demonstrated marked spongiosis, focal necrosis, endothelial proliferation, reactive astrogliosis and extensive demyelination involving bilateral basal ganglia, midbrain and spinal cord which were typical of Leigh’s sub acute necrotizing encephalomyelopathy.

Intraventricular glioneuronal hamartoma : histopathological correlation with magnetic resonance spectroscopy

SummaryIntraventricular hamartomas are extremely uncommon lesions outside of a setting of tuberous sclerosis. The second case of its kind in medical literature is presented and its possible aetiopa-thogenesis, imaging characteristics, pathognomonic magnetic resonance spectroscopy (MRS) and histopathology are discussed. An 11-year-old male presented with a seizure disorder for one year, with headache and vomiting for 15 days. Computerized tomography (CT) revealed a non-enhancing, heterogeneous, left-sided, trigonal lesion with areas of calcification trapping the left frontal horn. Magnetic resonance imaging (MRI) indicated that the lesion was iso to hypointense on T1 weighted images (T1WI) and iso to hyperintense on T2 weighted images (T2WI). A pathognomonic neurochemical signature was elicited on 1H MRS showing low N-acetylaspartate resonance and normal creatine:choline ratios. Radical decompression of the tumor resulted in an excellent outcome. The diagnosis was established by positive immunohistochemical reactivity for synaptophysin, glial fibrillary acidic protein (GFAP) and myelin basic protein. This is the first case report in existing medical literature in which a histopathological correlation is available for a hamartoma with an unequivocal MRS signal. The authors advocate the use of MRS in patients with tuberous sclerosis or neurofibromatosis with suspected hamartomas to distinguish these benign lesions from gliomas prior to a surgical exploration.

Giant Calvarial Ewing’s Sarcoma

Accessible online at: www.karger.com/pne Ewing’s sarcoma was first described by James Ewing in 1921 as ‘an endothelioma of bone’ arising from endothelial cells of blood vessels in the bone [1]. It is a rare tumor of childhood that arises from the neuroectodermal cells of the medullary cavity [2]. It arises mainly from the long bones and pelvis, and rarely in the skull [3]. There have been only 7 case reports of calvarial Ewing’s carcinoma in children ̂ 5 years of age. We present a case of a 2-year-old male child who had a large, painless, progressive swelling over his right temporoparietal area for the last year. There was no history of vomiting, headache, excessive crying, poor feeding, seizures or weakness in any of the limbs. On examination, his vital signs were stable and he had no neurologic deficits. Local examination revealed a 10 ! 8 cm large mass over the right temporoparietal region which was bony, firm, nontender, nonpulsatile and fixed to the underlying bone (fig. 1). Routine hemogram and serum chemistry were within normal limits. X-ray of the skull revealed a soft tissue mass with a sunburst appearance in the right temporoparietal region (fig. 2). Contrast-enhanced computed tomography (CT) scan of the head revealed a large temporoparietal mass which was partly extracranial and partly intracranial (fig. 3a, b). There was spiculated gross periosteal reaction, which suggested a malignant bony tumor (fig. 4a, b). Radiological skeletal survey, technetium-99 bone scans and contrast-enhanced CT scan of the chest and abdomen were all normal. Fine-needle aspiration cytology showed features suggestive of a malignant round cell tumor.

Primary plasma cell granuloma of petrous bone

Plasma cell granulomas are rare intracranial lesions that can mimic a variety of intracranial tumours. As they are usually benign lesions, their identification assumes importance. We report a case of plasma cell granuloma in a 52-year-old man presenting with features of left sided V, VII and bilateral VIII nerve involvement who underwent subtotal excision of the lesion. The relevant literature is reviewed.