Publications by authors named "Mehar Chand Sharma"

197 Publications

Successful Multimodality Management of Atypical Teratoid/Rhabdoid Tumour of the Lower Dorsal Spine with Spinal Drop Metastasis: Illustrated Review.

Pediatr Neurosurg 2021 24;56(2):184-196. Epub 2021 Mar 24.

Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.

Introduction: Spinal atypical teratoid/rhabdoid tumour (AT/RT) is exquisitely rare and constitutes 2% of all AT/RTs.

Case Presentation: A 6-year-old boy presented with low backache for the last 5 months. MRI of the spine showed a 1.5 × 1.5 × 4.7 cm intradural extramedullary mass extending from D10 to D12, causing compression of the conus medullaris. With a preoperative diagnosis of ependymoma, a gross total resection (GTR) of tumour was performed. Post-operative histopathology showed AT/RT. The tumour cells were immunopositive for cytokeratin, epithelial membrane antigen, smooth muscle actin, and p53 and immunonegative for MIC2, desmin, glial fibrillary acidic protein, and INI1. Post-operative neuraxis MRI revealed post-operative changes (D10-D12) with a 9 mm enhancing lesion at L5-S1 junction suggesting drop metastasis. There was no lesion in brain. Cerebrospinal fluid cytology did not show any malignant cell. The metastatic work-up was normal. He received 3 cycles of chemotherapy with ICE regimen (ifosfamide, carboplatin, and etoposide). Subsequently, he received craniospinal irradiation (CSI)-36 Gy/20 fractions/4 weeks followed by focal boost to primary tumour bed and spinal drop metastasis-14.4 Gy/8 fractions/1.5 weeks. Thereafter, he received 3 more cycles of ICE regimen. End-of-treatment MRI spine showed post-op changes (D10-D12) and 38.9% reduction of the L5-S1 lesion suggesting partial response. Six monthly spinal MRI showed serial reduction of the metastatic lesion leading to complete response (CR) 1 year after completion of treatment. On last follow-up (30 months from the initial diagnosis), he was neurologically intact and in CR.

Conclusion: Multimodality management comprising GTR of tumour, CSI followed by focal boost, and multiagent chemotherapy (ICE) can lead to successful outcome in patients with this rare and aggressive spinal tumour.
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http://dx.doi.org/10.1159/000513936DOI Listing
March 2021

Prognostic impact of Notch1 receptor and clinicopathological High-Risk Predictors in lacrimal gland adenoid cystic carcinoma.

Acta Ophthalmol 2021 Mar 6. Epub 2021 Mar 6.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.

Purpose: Adenoid Cystic Carcinoma (ACC) is an aggressive malignant lacrimal gland tumour associated with poor prognosis. Aberrant Notch signalling has been investigated in various tumours. However, very few studies on Notch signalling in lacrimal gland ACC are reported. The aim of the present study was to evaluate the status of Notch1 receptor and activated Notch1 (NICD1) in lacrimal gland ACC and to correlate it with high-risk clinicopathological features.

Methods: A total of 23 cases of histopathologically proven lacrimal gland ACC, who underwent surgical treatment, were included in this study. Expression of Notch1 receptor and NICD1 was evaluated by immunohistochemistry on formalin fixed paraffin embedded tissues. The results obtained were correlated with clinicopathological high-risk features and survival of the patients. Kaplan-Meier survival and multivariate analysis was performed to determine the prognostic significance.

Results: Overexpression of Notch1 receptor and NICD1 was observed in 65% and 39% of lacrimal gland ACC cases, respectively. On Kaplan-Meier survival analysis, patients with Notch1 receptor overexpression had reduced disease free survival. On univariate analysis, male gender, bone erosion, perineural invasion, solid histologic pattern, intracranial extension and advanced tumour stage were also indicators of poor prognosis. On multivariate analysis bone erosion was the most significant poor prognostic indicator.

Conclusion: Our study demonstrates that overexpression of Notch1 receptor plays a critical role in the biology and aggressive behaviour of lacrimal gland ACC. Bone erosion, solid histologic pattern, advanced T stage, perineural invasion and intracranial extension are other high-risk clinicopathological predictors of lacrimal gland ACC.
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http://dx.doi.org/10.1111/aos.14812DOI Listing
March 2021

Comparative contribution of magnetoencephalography (MEG) and single-photon emission computed tomography (SPECT) in pre-operative localization for epilepsy surgery: A prospective blinded study.

Seizure 2021 Mar 15;86:181-188. Epub 2021 Feb 15.

Dept of Neurology, All India Institute of Medical Sciences, New Delhi, India. Electronic address:

Purpose: The aim of this study was to compare the diagnostic value and accuracy of ictal SPECT and inter-ictal magnetoencephalography (MEG) in localizing the site for surgery in persons with drug resistant epilepsy.

Method: This was a prospective observational study. Patients expected to undergo epilepsy surgery were enrolled consecutively and the localization results from different imaging modalities were discussed in an epilepsy surgery meet. Odds ratio of good outcome (Engel I) were calculated in patients who underwent surgery in concordance with MEG and SPECT findings. Post-surgical seizure freedom lasting at least 36 months or more was considered the gold standard for determining the diagnostic output of SPECT and MEG.

Results: MEG and SPECT were performed in 101 and 57 patients respectively. In 45 patients SPECT could not be done due to delay in injection or technical factors. The accuracy of MEG and SPECT in localizing the epileptogenic zone was found to be 74.26 % and 78.57 % respectively. The diagnostic odds ratio for Engel I surgical outcome was reported as 2.43 and 5.0 for MEG and SPECT respectively. The diagnostic odds ratio for MEG in whom SPECT was non-informative was found to be 6.57 [95 % CI 1.1, 39.24], although it was not significantly associated with good surgical outcome. MEG was useful in indicating sites for SEEG implantation.

Conclusion: SPECT was found to be non-informative for most patients, but reported better diagnostic output than MEG. MEG may be a useful alternative for patients in whom SPECT cannot be done or was non-localizing.
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http://dx.doi.org/10.1016/j.seizure.2021.02.005DOI Listing
March 2021

Lymphoma subtypes in India: a tertiary care center review.

Clin Exp Med 2021 May 22;21(2):315-321. Epub 2021 Jan 22.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India.

Lymphomas are a group of neoplasm arising from immune cells with varied clinical presentation, molecular profile, morphology and immunophenotype. The epidemiology and response to treatment varies among patients from different geographical locations. We analyze the demographic characteristics of lymphomas in a tertiary care center of India over a period of five years. This was a retrospective study including cases from 2015 to 2019 which were classified according to WHO classification 2017. A total of 4115 lymphoma cases were diagnosed. Hodgkin lymphomas (HL) comprised 30.35% (n = 1249), and non-Hodgkin lymphoma (NHL) was 69.65% (n = 2866). Site of presentation was nodal in 64.76% cases, and 35.23% were extranodal. There was an overall male predominance. Among the NHLs, B-cell type comprised of 84.08% and 15.38% was T- and NK cell lymphomas. Mature B cell lymphomas comprised 82.41% with predominant being diffuse large B cell lymphoma type (42.53%) followed by follicular lymphoma (10.81%) and small lymphocytic lymphoma (6.10%). Among the T-cell type, PTCL NOS (2.65%) was the predominant subtype followed by ALK positive anaplastic large cell lymphoma (ALCL-ALK+) (2.44%), extranodal NK-T cell lymphoma (2.02%) and others. Classical type was predominant type (97.91%) among HL, and 2.08% were nodular lymphocyte predominant type. Among the classical HL, nodular sclerosis (28.1%) and mixed cellularity (32.18%) co-dominated. Our study indicates that the Indian population differs in the prevalence, presentation and the subtyping among various lymphomas. Higher prevalence of Hodgkin lymphoma, DLBCL, ALK + ALCL and immature cell neoplasm was noted.
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http://dx.doi.org/10.1007/s10238-021-00683-2DOI Listing
May 2021

Case Report: Isolated Central Nervous System Melioidosis from a Non-Endemic Area.

Am J Trop Med Hyg 2021 Jan 11. Epub 2021 Jan 11.

Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.

Central nervous system (CNS) melioidosis is a rare neurological infectious disease which carries a high mortality. We describe a previously healthy middle-aged female, who presented to us with left-sided hemiparesis and was on antitubercular therapy from a previous presumed diagnosis of CNS tuberculoma. Non-characteristic imaging picture, multiple negative body fluid cultures, and positive Cerebrospinal fluid galactomannan led to a further delay in diagnosis. Gram stain of the tissue obtained from brain biopsy revealed Gram-negative rods in "safety pin" appearance. By picking up the colonies that appeared on blood agar and MacConkey agar, the identification of the clinical isolates was performed using VITEK matrix (BioMerieux)-assisted laser desorption ionization time-of-flight mass spectrometry (VITEK MALDI TOF MS database version 3.2) which revealed . After the institution of appropriate treatment, she survived but with significant morbidity. A high index of suspicion should be kept for such previously healthy individuals belonging to non-endemic areas, where presentation is suspicious of an infective etiology, but not improving despite appropriate therapy. This may help in early recognition and institution of recommended treatment so that mortality can be avoided.
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http://dx.doi.org/10.4269/ajtmh.20-1166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045644PMC
January 2021

Mutational Spectrum of CAPN3 with Genotype-Phenotype Correlations in Limb Girdle Muscular Dystrophy Type 2A/R1 (LGMD2A/LGMDR1) Patients in India.

J Neuromuscul Dis 2021 ;8(1):125-136

Department of Biotechnology, Jamia Millia Islamia (A Central University), New Delhi, India.

Background: Limb girdle muscular dystrophy recessive type 1 (LGMDR1, Previously LGMD2A) is characterized by inactivating mutations in CAPN3. Despite the significant burden of muscular dystrophy in India, and particularly of LGMDR1, its genetic characterization and possible phenotypic manifestations are yet unidentified.

Material And Methods: We performed bidirectional CAPN3 sequencing in 95 LGMDR1 patient samples characterized by calpain-3 protein analysis, and these findings were correlated with clinical, biochemical and histopathological features.

Results: We identified 84 (88.4%) cases of LGMDR1 harboring 103 CAPN3 mutations (71 novel and 32 known). At least two mutant alleles were identified in 79 (94.2%) of patients. Notably, 76% exonic variations were enriched in nine CAPN3 exons and overall, 41 variations (40%) correspond to only eight exonic and intronic mutations. Patients with two nonsense/out of frame/splice-site mutations showed significant loss of calpain-3 protein as compared to those with two missense/inframe mutations (P = 0.04). We observed a slow progression of disease and less severity in our patients compared to European population. Rarely, presenting clinical features were atypical, and mimicked other muscle diseases like FSHMD, distal myopathy and metabolic myopathies.

Conclusion: This is first systematic study to characterize the genetic framework of LGMDR1 in the Indian population. Preliminary calpain-3 immunoblot screening serves well to direct genetic testing. Our findings prioritized nine CAPN3 exons for LGMDR1 diagnosis in our population; therefore, a targeted-sequencing panel of nine exons could serve well for genetic diagnosis, carrier testing, counseling and clinical trial feasibility study in LGMDR1 patients in India.
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http://dx.doi.org/10.3233/JND-200547DOI Listing
January 2021

C19MC amplification and expression of Lin28A and Olig2 in the classification of embryonal tumors of the central nervous system: A 14-year retrospective study from a tertiary care center.

Childs Nerv Syst 2021 Apr 24;37(4):1067-1075. Epub 2020 Nov 24.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India, 110029.

Introduction: CNS embryonal tumors (CET) other than medulloblastomas (MB) and atypical teratoid/rhabdoid tumors (AT/RTs), previously designated as 'central nervous system primitive neuroectodermal tumors' ('CNS PNETs'), are a heterogenous subset of tumors with poorly defined diagnostic criteria. Other than the subset of embryonal tumor with multilayered rosettes (ETMR) defined by C19MC amplification, most CETs are diagnosed by exclusion of other molecularly defined entities and histological mimics including MB, AT/RTs, and high-grade gliomas, and termed as CET, not otherwise specified (NOS) in the 2016 WHO classification.

Aim: To reclassify 'CNS PNETs' as per WHO 2016, and estimate the true proportion of CET, NOS in a tertiary healthcare setting, and to evaluate the diagnostic utility of C19MC amplification, Lin28A and Olig2 expression in the subclassification of CETs.

Methods: Previously diagnosed cases of 'CNS PNETs' (2002-2016) were first evaluated by immunohistochemistry (IHC) for MIC2, RelaA, L1CAM, IDH1R132H, H3K27M, H3G34R, H3G34V, INI1, and BRG1 proteins and by fluorescence in-situ hybridization (FISH) for EWSR1 translocation to exclude histological mimics. The selected CETs (case cohort) and 79 histological mimics (comparison cohort) comprising of MB, AT/RT, pineal parenchymal tumors, Ewing sarcoma, esthesioneuroblastoma, intraocular medulloepithelioma, and H3G34R mutant high-grade glioma were subject to IHC for Olig2 and Lin28A, and FISH for C19MC amplification.

Results: Twenty-two cases of 'CNS PNETs' were retrieved, all of which were negative for the first panel of markers and showed retained INI-1/BRG1 expression. Three of them (3/22, 13.6%) showed C19MC amplification (ETMR, C19MC-altered) with ETMR histology, Lin28A positivity, and Olig2 negativity. Among the remaining 19 CETs, one showed medulloepithelioma histology (Medulloepithelioma, NOS) and remaining were non-descript small round cell tumors (CET, NOS), all negative for Lin28A. Olig2 was positive in only 3 CETs (13.6%), all being CET, NOS. All tumors in the comparison cohort were negative for C19MC amplification, Lin28A and Olig2 except for 27% of ATRTs that were Lin28A positive.

Conclusion: ETMR, C19MC-altered constitute less than 14% of CETs, with majority remaining uncharacterized as CET, NOS. Lin28A is 100% sensitive for the detection of C19MC amplification; however, its specificity is limited by its expression in ATRTs. Olig2 expression is seen only in a small subset of CET, NOS and is of limited diagnostic utility.
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http://dx.doi.org/10.1007/s00381-020-04973-0DOI Listing
April 2021

EZH2 inhibitory protein (EZHIP/Cxorf67) expression correlates strongly with H3K27me3 loss in posterior fossa ependymomas and is mutually exclusive with H3K27M mutations.

Brain Tumor Pathol 2021 Jan 1;38(1):30-40. Epub 2020 Nov 1.

Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

The PFA molecular subgroup of posterior fossa ependymomas (PF-EPNs) shows poor outcome. H3K27me3 (me3) loss by immunohistochemistry (IHC) is a surrogate marker for PFA wherein its loss is attributed to overexpression of Cxorf67/EZH2 inhibitory protein (EZHIP), C17orf96, and ATRX loss. We aimed to subgroup PF-EPNs using me3 IHC and study correlations of the molecular subgroups with other histone related proteins, 1q gain, Tenascin C and outcome. IHC for me3, acetyl-H3K27, H3K27M, ATRX, EZH2, EZHIP, C17orf96, Tenascin-C, and fluorescence in-situ hybridisation for chromosome 1q25 locus were performed on an ambispective PF-EPN cohort (2003-2019). H3K27M-mutant gliomas were included for comparison. Among 69 patients, PFA (me3 loss) constituted 64%. EZHIP overexpression and 1q gain were exclusive to PFA seen in 72% and 19%, respectively. Tenascin C was more frequently positive in PFA (p = 0.02). H3K27M expression and ATRX loss were noted in one case of PFA-EPN each. All H3K27M-mutant gliomas (n = 8) and PFA-EPN (n = 1) were EZHIP negative. C17orf96 and acetyl-H3K27 expression did not correlate with me3 loss. H3K27me3 is a robust surrogate for PF-EPN molecular subgrouping. EZHIP overexpression was exclusive to PFA EPNs and was characteristically absent in midline gliomas and the rare PFA harbouring H3K27M mutations representing mutually exclusive pathways leading to me3 loss.
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http://dx.doi.org/10.1007/s10014-020-00385-9DOI Listing
January 2021

Primary urethral small cell melanoma with neuroendocrine differentiation: a case report.

J Egypt Natl Canc Inst 2020 Oct 12;32(1):40. Epub 2020 Oct 12.

Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Background: Primary malignant melanoma of the female urethra is an exceedingly rare tumor. It represents 0.2% of all malignant melanomas. Divergent differentiation towards non-melanocytic lineages has not been reported in urethral melanoma.

Case Presentation: We report a rare case of neuroendocrine differentiation in a large primary small cell malignant melanoma involving the urethra, in a 62-year-old lady, who presented with obstructive urinary symptoms. Clinical and radiological workup revealed a large urethral mass with liver and lymph nodal metastases. A biopsy was performed from the urethral and liver lesions which showed poorly differentiated tumor cells with small cell morphology and presence of melanin pigment. These cells were immunopositive for melanocytic and neuroendocrine markers. Ultrastructural examination showed presence of melanosomes and neurosecretory granules in the tumor cells.

Conclusions: Although malignant melanoma with neuroendocrine differentiation is exceptionally rare, it needs to be recognized among the other well-known variants of malignant melanoma.
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http://dx.doi.org/10.1186/s43046-020-00051-3DOI Listing
October 2020

Granular Cell Astrocytoma: A Diagnostic Conundrum.

World Neurosurg 2020 11 27;143:209-213. Epub 2020 Jul 27.

Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.

Background: Granular cell astrocytoma (GCA) is an aggressive variant of astrocytoma characterized by predominantly round-to-polygonal cells with abundant eosinophilic granular cytoplasm. This tumor usually lack the morphological signatures of conventional astrocytoma and are devoid of typical features which define a malignant neoplasm, leading to potential misdiagnosis.

Case Description: We report GCA in a 50-year-old man presenting with severe headache along with vertiginous sensation and sensory seizures of left upper limb for past two months. Imaging showed multiple intra-axial, hyperintense space-occupying lesions in bilateral anterior temporal lobe, left parietal lobe, left thalamus and cerebellum, raising possibility of lymphoma/metastases. Histopathologic examination revealed sheets of large polygonal cells with distinct cellular outline, ample amount of eosinophilic PAS-positive granular cytoplasm, eccentrically placed irregular, round-to-ovoid nuclei with occasional prominent nucleoli. On immunohistochemistry, tumor cells were diffusely immunopositive for Olig2, S100, EMA, lysozyme and CD68, and they were immunonegative for GFAP, LCA, pan-CK, TTF-1, TFE-3, PAX-8, SOX10, MAP2, MBP, NF, H3K27M, H3K27me3, p53, IDH1 (R132H), CD1a, langerin and BRAFV600E. Numerous scattered macrophages were highlighted by CD163. MIB 1-labelling-index was approximately 5%-6%. Overall features were congruous with final diagnosis of GCA.

Conclusions: GCAs behave in a belligerent manner irrespective of their morphologic grade as they are seen to exhibit genetic alterations similar to glioblastoma. Thereby, they warrant early diagnosis for conducive patient management.
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http://dx.doi.org/10.1016/j.wneu.2020.07.139DOI Listing
November 2020

Clinico-pathological and molecular characterization of diffuse midline gliomas: is there a prognostic significance?

Neurol Sci 2021 Mar 14;42(3):925-934. Epub 2020 Jul 14.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.

Purpose: H3K27M mutant diffuse midline gliomas (DMGs) are considered grade IV irrespective of histological features and have dismal prognosis. We evaluated clinico-pathologic, radiological, and molecular characteristics of DMGs across all ages.

Methods: One twenty-six DMGs were identified over 10 years. Immunohistochemistry was done for H3K27M, ATRX, IDH1, and p53, and Sanger sequencing performed for IDH1 and H3K27M mutation. Patient demographics and clinico-radiologic characteristics were reviewed and survival analysis performed.

Results: DMGs comprised 5.3% of all gliomas with 49.2% H3K27M mutant and 50.8% wild types. Majority (75.68%) of pediatric and 38.20% of adults were H3K27M mutant (p = 0.0001). Amongst H3K27M mutants, brainstem (46.43%) was the commonest location in pediatric and thalamus (61.76%) in adults. H3K27M mutation was mutually exclusive with IDH mutation in 93.55%, while p53, ATRX mutation were seen in 56.4% and 30.6% cases respectively. Software-based immunohistochemistry evaluation (H-scoring) showed 99.2% concordance with sequencing for H3K27M mutation. Radiologically, no significant difference in contrast enhancement was seen between mutant and wild types (p = 0.05). The difference in overall survival (OS) was not significant in mutant versus wild types, with age or location. Tumor resection independently and on correlation with H3K27M did not influence OS (p = 0.51 and p = 0.47). Adjuvant therapy impacted survival significantly in adults (p = 0.0009), however, not in pediatric cases (p = 0.06).

Conclusions: The study highlights the differences in frequency and location of pediatric and adult DMGs. IHC (H-scoring) for H3K27M mutation is an excellent surrogate for sequencing. Prognosis remains dismal irrespective of age, location, and H3K27M status. Potential therapeutic targets need to be explored.
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http://dx.doi.org/10.1007/s10072-020-04489-0DOI Listing
March 2021

Epithelial-Myoepithelial Carcinoma of the Lacrimal Gland: Case Report of Youngest Patient.

Ophthalmic Plast Reconstr Surg 2020 Nov/Dec;36(6):e141-e144

Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences.

The authors report a case of extremely uncommon malignancy of lacrimal gland epithelial-myoepithelial carcinoma. This carcinoma is more commonly encountered in salivary glands and comprises 1% of all salivary gland tumors. Its occurrence in the orbit is very rare with only 6 cases reported in the literature, most of which arose in a pleomorphic adenoma. Epithelial-myoepithelial carcinoma is primarily a tumor of older adults, with a peak incidence in the sixth and seventh decades of life. The present case is the youngest patient reported to date and had no history of preexisting neoplasm in the lacrimal gland. Histological diagnosis of epithelial-myoepithelial carcinoma is challenging because of the similarity with other lacrimal gland epithelial tumors like malignant adenoid cystic carcinoma and benign pleomorphic adenomas.
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http://dx.doi.org/10.1097/IOP.0000000000001663DOI Listing
March 2021

Metastatic lesions of atrial myxoma. A pathologist can clinch them all.

Neuropathology 2020 Jun 30;40(3):295-301. Epub 2020 Mar 30.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.

Atrial myxomas are the most common primary benign cardiac tumors. The embolization of tumor particles is not infrequent, and in nearly half of them, the cerebral arteries are affected, usually leading to embolic ischemic stroke. Formation of intracranial aneurysms, development of parenchymal brain metastasis, and intracerebral hemorrhage due to ruptured aneurysms are rarer. Diagnosis of such lesions in a previously undiagnosed case of myxoma may be challenging for a pathologist. Herein, we present two patients of cardiac myxoma with varied neurological manifestations and their pathological findings.
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http://dx.doi.org/10.1111/neup.12640DOI Listing
June 2020

Multiple Neurologic Deficits and Cognitive Decline in a Young Woman.

Ann Indian Acad Neurol 2019 Oct-Dec;22(4):506-512. Epub 2019 Oct 25.

Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.

We present the clinicopathologic conference of a 34-year-old lady with history of facial palsy 14 years ago who developed new deficits of mononeuritis multiplex, maculopapular rash, pancytopenia, splenomegaly, lung involvement and cognitive decline rapidly over three years. Investigations revealed pancytopenia, reversal of albumin globulin ratio, mediastinal adenopathy, ANA positivity, low C3 levels with the CSF being inflammatory and MRI showing extensive hemorrhagic lesions with mass effect. She had a rapidly progressive fatal course over three years with the disease being undiagnosed. This case was presented in the annual meeting of the Indian Academy of Neurology in September 2018.
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http://dx.doi.org/10.4103/aian.AIAN_293_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839316PMC
October 2019

Drug Refractory Epilepsy - A Series of Lesions with Triple Pathology.

Neurol India 2019 Jul-Aug;67(4):1093-1096

Department of Neurology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.

The associations between gangliogliomas, dysembryoplastic neuroepithelial tumors (DNETs), and cortical dysplasias remain debatable. We report five cases of drug refractory epilepsy with temporal lobe lesions. On resection, histopathological examination showed distinctive areas of gangliogliomas and DNETs with cortical dysplasia. The coexistence of the above three lesions as distinct entities in a single lesion is virtually unknown. This points to the presence of a possible etiological relationship among them. Finally, we also delve into a plausible hypothesis for such a pathogenesis.
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http://dx.doi.org/10.4103/0028-3886.266289DOI Listing
March 2020

Management and Outcome Analysis of Conus and Filum ependymoma: A Tertiary Center Study.

Asian J Neurosurg 2019 Jul-Sep;14(3):821-827

Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.

Background: Spinal ependymomas constitute approximately 2%-8% of primary adult central nervous system tumors. Authors analyzed demographic, clinical, radiological, surgical, and histopathological factors which correlated with the postoperative neurological outcome of patients who underwent surgery for conus and filum ependymoma (CFE).

Materials And Methods: A retrospective analysis of 31 patients regarding clinical feature, imaging study, surgical management, and McCormick grading system for assessing functional neurological status was carried out, who underwent surgical management for CFE between January 2009 and April 2014. Final neurological outcome at follow-up period was correlated with various factors in search to find out probable prognostic factors affecting final neurological outcome following surgical management.

Results: The myxopapillary ependymoma was observed in 55% of cases ( = 17), while 39% cases ( = 12) had Grade II ependymoma and rest 6% ( = 2) cases had anaplastic ependymomas. The mean age was 30 years (range 7-60 years) with male to female ratio of 1:0.82. Patients predominantly presented with pain (80.65%); mean duration of symptoms was 28.61 months. Only, the preoperative McCormick grade was found to be the statistically significant prognostic factor ( = 0.045), affecting neurological outcome however, the age, sex, duration of symptoms, location of the tumor, extent of the tumor, extradural spread, degree of surgical excision, vascularity of tumor, and histopathological World Health Organization grades were not found to be significant prognostic factors in the current study.

Conclusion: The preoperative McCormick score was found to be the only statistically significant factor predicting the functional and neurological outcome after surgery, so surgical treatment should be offered early in the course of the disease to provide chance of preservation and good neurological recovery.
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http://dx.doi.org/10.4103/ajns.AJNS_326_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703025PMC
September 2019

Management of Cushing's Disease: Changing Trend from Microscopic to Endoscopic Surgery.

World Neurosurg 2020 Feb 3;134:e46-e54. Epub 2019 Sep 3.

Department of Neurosurgery, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, India.

Background: Cushing's disease (CD) is a spectrum of clinical manifestations due to adrenocorticotropic hormone-secreting pituitary adenoma. Transsphenoidal adenomectomy remains the standard treatment. There has been a paradigm shift from microscopic to endoscopic transsphenoidal surgery in recent years. However, the efficacy of endoscopic transsphenoidal surgery has not been established. Therefore, it is of interest to determine the superiority of endoscopic transsphenoidal surgery, if any, over microscopic surgery.

Objective: To assess the efficacy of endoscopic endonasal transsphenoidal surgery for the treatment of CD and to determine the factors affecting remission.

Methods: Patients undergoing surgery for CD from 2009 to 2017 were analyzed retrospectively. Transsphenoidal resection was the preferred treatment, with recent trends in favor of the endonasal endoscopic skull base approach. Postoperative cortisol level of <2 μg/dL was taken as remission and value between 2 and 5 μg/dL as possible remission.

Results: In total, 104 patients operated primarily for CD were included for analysis; 47 patients underwent microscopic surgery, 55 endoscopic surgery, and 2 were operated transcranially. Remission was achieved in 76.47% of patients. In univariate analysis, factors significantly associated with remission were 1) type of surgery (P = 0.01); remission in endoscopy surgery (88.23%) is better than microscopy (56.6%); 2) postoperative day 1 morning cortisol (P = 0.004); and 3) postoperative day 1 morning ACTH (P = 0.015). In multivariate analysis, only postoperative day 1 cortisol was found to be significant predictor of remission (P = 0.02).

Conclusions: Postoperative plasma cortisol level is a strong independent predictor of remission. Remission provided by endoscopy is significantly better than the microscopic approach.
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http://dx.doi.org/10.1016/j.wneu.2019.08.165DOI Listing
February 2020

Expression and Clinical Significance of Translation Regulatory Long Non-Coding RNA 1 (TRERNA1) in Ependymomas.

Pathol Oncol Res 2020 Jul 5;26(3):1975-1981. Epub 2019 Sep 5.

Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Long noncoding RNAs (lncRNA) have emerged as vital molecules governing epithelial-to-mesenchymal transition (EMT) in cancers. Translation regulatory RNA 1 (TRERNA1) is one such lncRNA known to enhance the transcriptional activity of the EMT-transcription factor, Snail. We have previously demonstrated differential upregulation of EMT-transcription factors and cadherin switching across various clinico-pathologic-molecular subclasses of ependymomas (EPN). With an aim to analyze the correlation between the expression of TRERNA1 in EPNs, we performed gene expression analysis for TRERNA1 on 75 Grade II/III EPNs and correlated with tumor site, C11orf95-RELA fusions, age, MIB-1 proliferative indices, and outcome wherever available. Upregulation of gene expression levels of TRERNA1 was seen in intracranial EPNs, with highest expression levels in pediatric posterior fossa EPNs. High TRERNA1 expression was found associated with higher proliferative indices (p = 0.034) and shorter progression free survival (p = 0.002). Our study, for the first time, demonstrates an association between TRERNA1 expressions and pediatric posterior fossa EPNs. Further in-vivo and in-vitro studies are required to confirm these findings and evaluate TRERNA1 as a novel biomarker and potential therapeutic target in childhood PF-EPNs.
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http://dx.doi.org/10.1007/s12253-019-00736-8DOI Listing
July 2020

Fatal familial hemophagocytic lymphohistiocytosis with perforin gene () mutation and EBV-associated T-cell lymphoproliferative disorder of the thyroid.

Autops Case Rep 2019 Jul-Sep;9(3):e2019101. Epub 2019 Jul 19.

All India Institute of Medical Sciences, Department of Medicine. New Delhi, India.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare fatal autosomal recessive disorder of immune dysregulation. The disease presents most commonly in the first year of life; however, symptomatic presentation throughout childhood and adulthood has also been identified. Biallelic mutation in the gene is present in 20%-50% of all cases of FHL. Secondary hemophagocytic lymphohistiocytosis (HLH) in association with hematological malignancies is known; however, whether mutations in HLH-associated genes can be associated with FHL and hematolymphoid neoplasms is not well documented. Also, Epstein-Barr-virus- (EBV) positive systemic T-cell lymphoproliferative disease (SE-LPD) in the setting of FHL is not clearly understood. Here, we present the case of a young boy who presented with typical features of childhood FHL harboring the perforin gene () mutation, and had SE-LPD diagnosed on autopsy, along with evidence of recent EBV infection. The patient expired due to progressive disease. Five siblings died in the second or third decade of life with undiagnosed disease. Genetic counseling was provided to the two surviving siblings and parents, but they could not afford genetic testing. One surviving sibling has intermittent fever and is on close follow-up for possible bone marrow transplantation.
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http://dx.doi.org/10.4322/acr.2019.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6655852PMC
July 2019

Clinicopathological evaluation of PD-L1 expression and cytotoxic T-lymphocyte infiltrates across intracranial molecular subgroups of ependymomas: are these tumors potential candidates for immune check-point blockade?

Brain Tumor Pathol 2019 Oct 6;36(4):152-161. Epub 2019 Aug 6.

Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Immune check-point blockade (ICB) targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) axis has created paradigm shift in cancer treatment. 'ST-RELA' and 'PF-A' molecular subgroups of ependymomas (EPN) show poor outcomes. We aimed to understand the potential candidature of EPNs for ICB. Supratentorial (ST) Grade II/III EPNs were classified into ST-RELA, ST-YAP, and ST-not otherwise specified (NOS), based on RELA/YAP1 fusion transcripts and/or L1CAM and p65 protein expression. Posterior fossa (PF) EPNs were classified into PF-A and PF-B based on H3K27me3 expression. Immunohistochemistry for PD-L1 and CD8 was performed. RelA protein enrichment at PDL1 promoter site was analysed by chromatin immunoprecipitation-qPCR (ChIP-qPCR). Eighty-three intracranial EPNs were studied. Median tumor infiltrating CD8 + cytotoxic T-lymphocyte (CTL) density was 6/mm, and was higher in ST-EPNs (median 10/mm) as compared to PF-EPNs (median 3/mm). PD-L1 expression was noted in 17/83 (20%) EPNs, including 12/31 ST-RELA and rare ST-NOS (2/12), PF-A (2/25) and PF-B (1/13) EPNs. Twelve EPNs (14%) showed high CTL density and concurrent PD-L1 positivity, of which majority (10/12) were ST-RELA EPNs. Enrichment of RelA protein was seen at PDL1 promoter. Increased CTL densities and upregulation of PD-L1 in ST-RELA ependymomas suggests potential candidature for immunotherapy.
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http://dx.doi.org/10.1007/s10014-019-00350-1DOI Listing
October 2019

Solitary Extra-axial Intracranial Primary Meningeal Pleomorphic Xanthoastrocytoma: An Extremely Rare Case.

World Neurosurg 2019 Oct 8;130:386-390. Epub 2019 Jul 8.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.

Background: Pleomorphic xanthoastrocytomas (PXAs) are a rare type of astrocytoma, which, similar to other gliomas, can rarely arise from glial nests in the meninges, manifesting as an extra-axial mass. We describe a solitary extra-axial intracranial primary meningeal PXA in the pediatric age group, which was masquerading as a tentorial meningioma.

Case Description: A 9-year-old girl presented with features of raised intracranial pressure. Imaging revealed a dural-based mass in the tentorial region suggestive of a meningioma. This suspicion was further strengthened by intraoperative visualization of an extra-axial tumor with wide tentorial attachment. Near-total excision was achieved. Histopathologic examination established the diagnosis of PXA. Given the tumor's apparent meningeal origin and lack of connection with brain parenchyma in imaging and intraoperative findings, primary meningeal PXA was diagnosed. The absence of coexisting tumor foci on spinal magnetic resonance imaging further refined the diagnosis as solitary extra-axial intracranial primary meningeal PXA. The patient received radiotherapy for the residual tumor and was doing well at 6 months after presentation; however, she was lost to follow-up after that.

Conclusions: Solitary extra-axial intracranial primary meningeal PXA is an extremely rare entity with only 3 reported cases in the literature including the present case. This is the first report of such a tumor in a pediatric patient. This report also highlights that primary meningeal PXA can manifest as an extra-axial mass lesion and may warrant inclusion in the differential diagnosis of extra-axial mass lesions.
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http://dx.doi.org/10.1016/j.wneu.2019.06.218DOI Listing
October 2019

Primary thyroid lymphoma: A series from a tertiary care center in Northern India.

J Cancer Res Ther 2019 Jul-Sep;15(3):669-675

Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.

Objective: Primary thyroid lymphoma (PTL) is a rare entity, necessitating accurate and early diagnosis, as its management is very different from that of other neoplasms intrinsic to the thyroid.

Materials And Methods: Cases diagnosed between January 2009 and March 2015 were retrieved, and clinical details were noted. Hematoxylin- and eosin-stained slides were reviewed. Immunohistochemistry (IHC) was performed for immunophenotyping, and cases were classified according to the World Health Organization 2017 classification of hematolymphoid neoplasms.

Results: Eleven patients with PTL were identified, with a mean age of 64.6 years (range: 40-76 years), including three males and eight females. Duration of symptoms ranged from 2 to 36 months (mean: 9.3 months). Diffuse large B-cell lymphoma (DLBCL) was most frequent, followed by extranodal marginal zone lymphoma. Most DLBCLs were nongerminal center type. BCL2 was positive in all DLBCLs. Strong p53 immunopositivity was not seen in any of the cases analyzed.

Conclusion: Histopathological evaluation supplemented by IHC is the gold standard for the diagnosis of PTL. Combined chemoradiotherapy appears to be the best treatment modality, irrespective of histological type. MIB-1 and MUM1 IHC may have a role in identifying DLBCL, particularly in small biopsies. Role of p53 and BCL2 needs further evaluation.
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http://dx.doi.org/10.4103/jcrt.JCRT_135_17DOI Listing
November 2019

Approach to molecular subgrouping of medulloblastomas: Comparison of NanoString nCounter assay versus combination of immunohistochemistry and fluorescence in-situ hybridization in resource constrained centres.

J Neurooncol 2019 Jul 18;143(3):393-403. Epub 2019 May 18.

Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.

Introduction: Molecular classification of medulloblastomas (MB) is prognostically and therapeutically relevant and helps in better risk-stratification. Translation of this subgrouping to routine practice still remains a challenge. The most pathologist accessible techniques for molecular subgrouping include immunohistochemistry (IHC), fluorescent in-situ hybridization (FISH) and NanoString.

Objectives: (1) Molecular subgrouping of MBs by IHC and FISH, and NanoString assay (2) To compare their efficacy and cost for applicability in resource constrained centers.

Methods: Ninety-five cases of MB with adequate tissue were included. Molecular subgrouping was performed by IHC for β-catenin, GAB1 and YAP1; FISH for MYC amplification, and sequencing for CTNNB1, and by NanoString Assay on the same set of MBs. A subset of cases was subjected to 850k DNA methylation array.

Results: IHC + FISH classified MBs into 15.8% WNT, 16.8% SHH, and 67.4% non-WNT/non-SHH subgroups; with MYC amplification identified in 20.3% cases of non-WNT/non-SHH. NanoString successfully classified 91.6% MBs into 25.3% WNT, 17.2% SHH, 23% Group 3 and 34.5% Group 4. However, NanoString assay failure was seen in eight cases, all of which were > 8-years-old formalin-fixed paraffin-embedded tissue blocks. Concordant subgroup assignment was noted in 88.5% cases, while subgroup switching was seen in 11.5% cases. Both methods showed prognostic correlation. Methylation profiling performed on discordant cases revealed 1 out of 4 extra WNT identified by NanoString to be WNT, others aligned with IHC subgroups; extra SHH by NanoString turned out to be SHH by methylation.

Conclusions: Both IHC supplemented by FISH and NanoString are robust methods for molecular subgrouping, albeit with few disadvantages. IHC cannot differentiate between Groups 3 and 4, while NanoString cannot classify older-archived tumors, and is not available at most centres. Thus, both the methods complement each other and can be used in concert for high confidence allotment of molecular subgroups in clinical practice.
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http://dx.doi.org/10.1007/s11060-019-03187-yDOI Listing
July 2019

Combined Modality Management of Sinonasal Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma in a Young Adult-Report of a Rare Case.

J Adolesc Young Adult Oncol 2019 08 17;8(4):469-476. Epub 2019 Apr 17.

3Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.

Sinonasal anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) without nodal involvement is extremely rare and the rarity of this tumor often leads to diagnostic dilemma. It has been predominantly reported in pediatric, adolescent and young adult patients, mostly of Asian origin. A 21-year-old female patient presented with history of epistaxis for 1 year. On clinical and radiological examination, there was a 5 cm mass in the right nasal cavity, ethmoid, and frontal sinus. Biopsy at a local center had shown moderately differentiated squamous cell carcinoma. Rebiopsy at our center showed possibility of a hematolymphoid malignancy(pancytokeratin-, CD45+, CD3-, CD20-) and further immunohistochemistry studies(CD4+, CD43+, CD30+, ALK+) revealed ALK-positive ALCL. Rest of the lymphoma work-up was essentially normal and she had stage IE disease. She was treated with a combination of four cycles of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone (CHOP) regimen followed by local radiotherapy (36 Gray/20 fractions/4 weeks) by three-dimensional conformal technique. She tolerated the treatment well without any severe toxicity and had complete clinical and radiological response. At last follow-up visit, 40 months from the initial diagnosis, she was alive and disease free. Sinonasal ALK-positive ALCL is a rare tumor, which can be effectively treated with a combination of multiagent CHOP/CHOP-like regimen and local conformal radiotherapy.
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http://dx.doi.org/10.1089/jayao.2018.0158DOI Listing
August 2019

A Rare Case of Primary Central Nervous System Lymphoma in an Adolescent Female Treated with High-Dose Methotrexate and Rituximab-Based Chemoimmunotherapy and Consolidation Whole Brain Radiotherapy.

Pediatr Neurosurg 2019 22;54(1):57-65. Epub 2019 Jan 22.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.

Primary central nervous system lymphoma (PCNSL) is a rare pediatric brain tumor. A 16-year-old female patient presented to the clinic with complaints of multiple episodes of generalized tonic clonic seizures, nystagmus, and weakness on the left side of the body for 3 weeks. She had similar symptoms, waxing and waning for the last 2 years, responding to corticosteroids. Repeat magnetic resonance imaging (MRI) of the brain showed multiple areas of signal abnormalities involving the left temporal lobe, the basal ganglion, the thalamus, and the right frontal and occipital lobes with contrast enhancement in bitemporal lesions. With a clinico- radiological diagnosis of demyelinating disorder, she underwent an image-guided right frontal lobe biopsy, which revealed sheets of atypical lymphoid cells diffusely immunopositive for CD20 but negative for CD3, CD10, BCL-6, and MUM-1, suggesting diffuse large B-cell lymphoma, germinal center B-cell subtype. The systemic lymphoma workup was essentially normal. She received 5 cycles of chemoimmunotherapy with rituximab, high-dose methotrexate (HDMTX), vincristine, and procarbazine and had a complete radiological response (CR). This was followed by whole brain radiotherapy (WBRT) to a dose of 36 Gy in 20 fractions over 4 weeks. Subsequently she received 2 cycles of consolidation chemoimmunotherapy with rituximab and high-dose cytarabine. Serial brain MRI done 1, 4, and 8 months after completion of treatment showed persistence of the CR. At the last follow-up visit, 15 months from the date of diagnosis, she was disease free and asymptomatic. This report underlines the fact that PCNSL in adolescents may be effectively treated with a combination of HDMTX- and rituximab-based chemoimmunotherapy followed by consolidation with WBRT.
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http://dx.doi.org/10.1159/000495789DOI Listing
April 2019

Transcriptional co-expression regulatory network analysis for Snail and Slug identifies , an inflammatory cytokine receptor, to be preferentially expressed in ST-EPN- and PF-EPN-A molecular subgroups of intracranial ependymomas.

Oncotarget 2018 Oct 26;9(84):35480-35492. Epub 2018 Oct 26.

Department of Pathology, All India Institute of Medical Sciences, New Delhi-110029, India.

Recent molecular subgrouping of ependymomas (EPN) by DNA methylation profiling has identified ST-EPN- and PF-EPN-A subgroups to be associated with poor outcome. Snail/Slug are cardinal epithelial-to-mesenchymal transcription factors (EMT-TFs) and are overexpressed in several CNS tumors, including EPNs. A systematic analysis of gene-sets/modules co-expressed with and genes using published expression microarray dataset (GSE27279)identified 634 genes for with enriched TGF-β, PPAR and PI3K signaling pathways, and 757 genes for with enriched focal adhesion, ECM-receptor interaction and regulation of actin cytoskeleton related pathways. Of 37 genes commonly expressed with both and , , a cytokine receptor of interleukin-1 receptor family, was positively correlated with Snail (r=0.43) and Slug (r=0.51), preferentially expressed in ST-EPN- and PF-EPN-A molecular groups, and enriched for pathways related to inflammation, angiogenesis and glycolysis. expression was fairly specific to EPNs among various CNS tumors analyzed. It also showed significant positive correlation with EMT, stemness and MDSC (myeloid derived suppressor cell) markers. Our study reports as a poor prognostic marker associated with EMT-like phenotype and stemness in EPNs. Our findings emphasize the need to further examine and validate IL1R1 as a novel therapeutic target in aggressive subsets of intracranial EPNs.
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http://dx.doi.org/10.18632/oncotarget.26211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231457PMC
October 2018