Ayushi Jain

Pediatric glioblastomas: A histopathological and molecular genetic study

Glioblastoma multiforme (GBM) occurs rarely in children. Relatively few studies have been performed on molecular properties of pediatric GBMs. Our objective in this study was to evaluate the genetic alterations in pediatric GBM (age < or = 18 years) with special reference to p53, p16, and p27 protein expression, alterations of the epidermal growth factor receptor (EGFR), and deletion of the phosphate and tensin homolog gene (PTEN). Thirty cases of childhood GBMs reported between January 2002 and June 2007 were selected, and slides stained with hematoxylin and eosin were reviewed. Immunohistochemical staining was performed for EGFR, p53, p16, and p27, and tumor proliferation was assessed by calculating the MIB-1 labeling index (LI). Fluorescence in situ hybridization analysis was performed to evaluate for EGFR amplification and PTEN deletion. Histopathological features and MIB-1 LI were similar to adult GBMs. p53 protein expression was observed in 63%. Although EGFR protein overexpression was noted in 23% of cases, corresponding amplification of the EGFR gene was rare (5.5%). Deletion of the PTEN gene was also equally rare (5.5%). One case showed polysomy (chromosomal gains) of chromosomes 7 and 10. Loss of p16 and p27 immunoexpression was observed in 68% and 54% of cases, respectively. In pediatric de novo/primary GBMs, deletion of PTEN and EGFR amplification are rare, while p53 alterations are more frequent compared to primary adult GBMs. Frequency of loss of p16 and p27 immunoexpression is similar to their adult counterparts. This suggests that pediatric malignant gliomas are distinctly different from adult GBMs, highlighting the need for identification of molecular targets that may be adopted for future novel therapeutic strategies.

Central neurocytoma: a multi-disciplinary review.

Benign central neurocytoma (CN) is a rare neuronal tumour of the central nervous system recognised since the early eighties. More than 300 articles have been published in the literature, mostly comprising of case reports and short series from individual specialties. These tumours, though normally benign, are more often likely to recur after surgery than previously thought. A multi-modality team involvement, therefore, has become increasingly necessary for their optimum management. In this article, the authors from various neurosciences sub-specialties, with a specific interest and experience in managing CN, review the epidemiology, clinical features, pathological findings, radiological characteristics and surgical treatment, with an emphasis on the latest developments in their histology, molecular biology and adjuvant treatment modalities for recurrent or residual disease.

O6-Methylguanine DNA Methyltransferase Gene Promoter Methylation Status in Gliomas and Its Correlation With Other Molecular Alterations: First Indian Report With Review of Challenges for Use in Customized Treatment

BACKGROUND: O6-methylguanine methyltransferase (MGMT) promoter methylation in adult glioblastomas (glioblastoma multiforme) is considered a promising molecular alteration, predictive of better response to temozolomide therapy and longer overall survival. OBJECTIVE: To look at the frequency of MGMT methylation in glial tumors of all grades and types, and correlate this alteration with loss of heterozygosity 1p/19q, TP53 gene mutations, epidermal growth factor receptor (EGFR) amplification, and isocitrate dehydrogenase 1 (IDH1) mutations. METHODS: One hundred two gliomas of various grades and subtypes were assessed by methylation-specific polymerase chain reaction for MGMT promoter methylation status. The results were correlated with 1p/19q status, EGFR amplification, TP53, and IDH1 mutations. RESULTS: There was an inverse correlation of MGMT promoter methylation frequency with tumor grade, observed in 79.4%, 70.8%, and 56.8% of grade II, grade III, and grade IV gliomas, respectively. The difference was statistically significant in grade II vs IV tumors (P = .036). The majority of cases with 1p/19q loss of heterozygosity also showed MGMT methylation, although the association was not significant. There was no significant correlation of MGMT status with IDH1 mutation. In astrocytic tumors, there was no correlation of MGMT methylation with TP53 mutation or EGFR amplification. CONCLUSION: MGMT promoter methylation was observed in a considerable proportion of all grades and subtypes of gliomas, with no significant correlation with other known genetic alterations. On extensive literature review, in both low- and high-grade gliomas, wide variability of data on the frequency of MGMT methylation and its association with other molecular alterations from various centers was noted, mostly owing to technical causes. This raises questions regarding the capacity of this test for use as an objective and reproducible marker for customized treatment in individual cases.

Major Histocompatibility Complex Class I and II Detection as a Diagnostic Tool in Idiopathic Inflammatory Myopathies

CONTEXT Muscle biopsy is at present the gold standard for the diagnosis of idiopathic inflammatory myopathies (IIMs), which include dermatomyositis, polymyositis, and inclusion body myositis. Currently, there is no definite diagnostic marker that helps in the discrimination of different subgroups of IIMs and the discrimination of IIMs from other clinical and morphologic mimics. Major histocompatibility complex (MHC) class I and II antigens are not expressed on normal muscle fibers. OBJECTIVE To determine the diagnostic utility of MHC class I and II antigen expression on the muscle biopsies from patients with various neuromuscular disorders and to validate its addition in the existing diagnostic armamentarium. DESIGN Expression of MHC class I and II antigen was studied on 126 muscle biopsies, of which 62 were IIMs and 64 were controls (taken from patients with other neuromuscular disorders). RESULTS When compared with controls, the sensitivity of MHC class I expression for diagnosis of IIMs was 88.7% (100%, 81.6%, and 100% for dermatomyositis, polymyositis, and inclusion body myositis, respectively), with a specificity of 89.1%. The specificity of MHC class II expression was 100% for all IIMs. CONCLUSION Detection of MHC class I and II antigen expression is extremely helpful in the diagnosis of IIMs and has high sensitivity and specificity, especially in dermatomyositis. This expression can be used as a diagnostic tool in discriminating IIMs from other muscle diseases in which it is either absent or weakly expressed.

MGMT gene promoter methylation in pediatric glioblastomas

PurposeRelatively few studies have been performed on molecular properties of pediatric glioblastoma multiforme (GBM). Methylation of DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) promoter region has been associated with favorable prognosis and prolonged survival in adult GBM patients treated with temozolomide (TMZ). We explored the frequency of MGMT gene promoter methylation in pediatric glioblastomas and compared it with the known molecular alterations in p53.MethodsTwenty pediatric GBM cases were selected. MGMT promoter methylation was assessed by methylation specific PCR. p53 expression was determined by immunohistochemistry.ResultsMGMT gene promoter methylation was observed in 50% of pediatric glioblastomas. p53 protein expression was detected in 60% of cases. Seventy percent of cases with methylated MGMT promoter were p53 immunopositive.ConclusionsThe frequency of MGMT gene promoter methylation in pediatric GBMs was similar to adult GBM patients. The pediatric GBMs should also be investigated for MGMT promoter methylation to identify a subset of patients likely to benefit from TMZ therapy. p53 protein overexpression was more common in pediatric primary GBMs. To the best of our knowledge this is only the second study on MGMT gene promoter methylation status in pediatric GBMs.

Primary malignant melanoma at unusual sites: an institutional experience with review of literature.

Apart from the skin and choroid plexus, primary malignant melanoma is rare at the other sites and lacks organized documentation. Here, we have tried to enumerate the primary malignant melanomas at various atypical sites, supported by literature review. Seventeen cases were identified from our records of the past 5 years, which had detailed clinical work-up to exclude a possibility of a metastasis. A clear female predominance with involvement of the lower genitourinary tract was identified. In addition to three cases from the vagina, two cases each from the cervix, ovary and urethra, respectively, such cases were also identified in cerebral cortex (frontal and fronto-parietal area), rectum, nasal cavity, tongue, breast and tonsillar fossa. Although many were amelanotic, no specific histology was noted. In conclusion, malignant melanomas can arise in unconventional areas. Gross tumor appearance and the unavailability of an immunohistochemical panel, may result in their misdiagnosis as primary epithelial malignancies. A possible metastasis should always be ruled out.

Extraventricular neurocytomas: a morphological and histogenetic consideration. A study of six cases

Aims: Various molecular markers have been used for diagnosis, management and prognostication of gliomas. Neurocytomas are close morphological mimics of oligodendrogliomas. While combined 1p/19q deletion has been used as a molecular signature of oligodendroglial tumours, it has also been variably reported to occur in neurocytomas, especially those in extraventricular locations (EVN). In recent studies, presence of IDH1 mutation has shown immense prognostic significance in glial tumours including oligodendrogliomas, but its role in neurocytoma pathogenesis remains unexplored. In this study, EVN cases were analysed for histomorphological features, IDH1 mutation using an antibody for specifically detecting mutant IDH1R132H protein, and 1p/19q deletion by fluorescence in situ hybridisation (FISH) assay. Results: Over a period of 10 years (2000–2009), 60 cases of neurocytoma were diagnosed, of which six were EVN. These six cases were assessed for histomorphology, IDH1 mutation and 1p/19q deletion. Five cases showed atypical histological features. While none showed mIDH1R132H, four of the five atypical cases harboured 1p/19q deletion either in isolation or in combination. The only case which was well-differentiated (typical) did not show 1p/19q loss. Conclusions: EVNs are more commonly associated with aggressive histological features. IDH1 mutations, although frequent in oligodendrogliomas, are not seen in EVN. However, similar to oligodendrogliomas, 1p/19q deletion is found in these tumours. Thus, a potential histogenetic link between oligodendrogliomas and EVN remains debatable. This molecular alteration may also have prognostic connotations, being associated with atypical morphological features. Due to the rarity of these tumours, multicentric pooling of larger studies is needed to have an insight into the impact of these molecular aberrations on their biological behaviour.

Pigmented medulloepithelioma : report of a case and review of the literature

Abstract A 9-year-old male child had a IV ventricular medulloepithelioma of classical histology, showing tubulopapillary and undifferentiated areas. The unusual feature, however, was the presence of melanin pigmentation in the cells, which was further confirmed by electron microscopy. So far 28 cases of medulloepithelioma have been reported in the English literature. However, none of them showed melanin pigmentation. To the best of our knowledge this is the first case of pigmented medulloepithelioma in the English literature.

Spectrum of pediatric brain tumors in India: a Multi-Institutional study

BACKGROUND Till date there is no published multi-institutional data regarding the epidemiological profile of pediatric brain tumors in India. AIM The present retrospective study analyses the histological spectrum of pediatric age group brain tumors in seven tertiary care hospitals in India. MATERIAL AND METHODS Data regarding frequencies of various primary brain tumors (diagnosed according to the World Health Organization (WHO) classification), in 3936 pediatric patients (<18 yrs of age), was collected from seven tertiary care hospitals in India. RESULTS The most common primary pediatric brain tumors were astrocytic tumors (34.7%), followed by medulloblastoma and supratentorial primitive neuro-ectodermal tumors (22.4%), craniopharyngiomas (10.2%) and ependymal tumors (9.8%). The most common astrocytic tumor was pilocytic astrocytoma. In comparison to adults, oligodendrogliomas and lymphomas were rare in children. CONCLUSIONS Our study is the first such report on the histological spectrum of brain tumors in children in India. Except for a slightly higher frequency of craniopharyngiomas, the histological profile of pediatric brain tumors in India is similar to that reported in the Western literature.

Detection of the membrane attack complex as a diagnostic tool in dermatomyositis

Jain A, Sharma MC, Sarkar C, Bhatia R, Singh S, Gulati S, Handa R. Detection of the membrane attack complex as a diagnostic tool in dermatomyositis.
Acta Neurol Scand: 2011: 123: 122–129.
© 2010 John Wiley & Sons A/S.