Downregulation of ARID1B, a tumor suppressor in the WNT subgroup medulloblastoma, activates multiple oncogenic signaling pathways.

Medulloblastoma, a common pediatric malignant brain tumor, consists of four distinct molecular subgroups WNT, SHH, Group 3 and Group 4. Exome sequencing of 11 WNT subgroup medulloblastomas from an Indian cohort identified mutations in several chromatin modifier genes, including genes of the mammalian SWI/SNF complex. The genome of WNT subgroup tumors is known to be stable except for monosomy 6. Two tumors, having monosomy 6, carried a loss of function mutation in the ARID1B gene located on chromosome 6. ARID1B expression is also lower in the WNT subgroup tumors compared to other subgroups and normal cerebellar tissues that could result in haploinsufficiency. The short hairpin RNA-mediated knockdown of ARID1B expression resulted in a significant increase in the malignant potential of medulloblastoma cells. Transcriptome sequencing identified upregulation of several genes encoding cell adhesion proteins, matrix metalloproteases indicating the epithelial-mesenchymal transition. The ARID1B knockdown also upregulated ERK1/ERK2 and PI3K/AKT signaling with a decrease in the expression of several negative regulators of these pathways. The expression of negative regulators of the WNT signaling like TLE1, MDFI, GPX3, ALX4, DLC1, MEST decreased upon ARID1B knockdown resulting in the activation of the canonical WNT signaling pathway. Synthetic lethality has been reported between SWI/SNF complex mutations and EZH2 inhibition, suggesting EZH2 inhibition as a possible therapeutic modality for WNT subgroup medulloblastomas. Thus, the identification of ARID1B as a tumor suppressor and its downregulation resulting in the activation of multiple signaling pathways opens up opportunities for novel therapeutic modalities for the treatment of WNT subgroup medulloblastoma.

Nonmeningothelial Dural-Based Lesions: A Histopathological Analysis.

Introduction We report 30 cases of nonmeningothelial dural-based lesions encountered during a 3-year study period. Materials and Methods We retrospectively reviewed pathology records of patients operated for extra-axial, dural-based lesions during the years 2016 to 2018 and included nonmeningothelial lesions as a part of this study. Results Among the 3,243 neurosurgical specimens for histopathologic examination, only 30 (0.93%) were "nonmeningothelial dural-based lesions." Six (20%) patients were in the pediatric age group. Pathologic assessment identified 13 cases of solitary fibrous tumor/hemangiopericytoma (43.3%) and 7 cases of Ewing's sarcoma/primitive neuroectodermal tumor (23.3%). Two cases (6.7%) were of metastasis. Other lesions included a single case each of non-Hodgkin's lymphoma, undifferentiated sarcoma, solitary plasmacytoma, and granulocytic sarcoma. Nonneoplastic lesions included two cases each of Rosai-Dorfman disease and nonspecific inflammatory lesions. Conclusion Nonmeningothelial dural-based lesions being rare, thorough examination of morphological features is a must by the pathologist, to arrive at the accurate diagnosis. Ancillary tests, if required, should be employed in the context of the morphologic picture.

Lhermitte-Duclos disease: A series of six cases.

The Lhermitte-Duclos disease (LDD), also known as dysplastic cerebellar gangliocytoma, is a rare lesion characterized by variable enlargement of cerebellar folia. The pathological basis of LDD has long been debated, as it has overlapping features of both, a neoplasm and hamartoma. Association between LDD and Cowden syndrome (CS) has been established based on the presence of phosphatase and tensin homologue germline mutation in both. We present a series of six cases of LDD: Four females and two males, aged between 16 and 38 years, presenting with headache and imbalance on walking of 1-7 months duration. Histomorphology showed thickening and vacuolation of the molecular layer, loss of Purkinje cells, and replacement of granular cell layer by large dysplastic ganglion cells. Awareness of histological features of this rare entity and a higher level of suspicion is required for the correct diagnosis, which, in turn, should prompt thorough investigations to exclude features of associated CS. LDD is a rare entity, awareness of its histological features and correlating them with radiology is essential, especially in tiny biopsies; to render the correct diagnosis. Diagnosis of LDD warrants further clinical workup and close follow-up for the associated features of CS.

Eosinophilic meningitis due to A. Cantonensis revealed at autopsy.

Parasitic infection of the central nervous system could be fatal, and its incidence is rising due to increasing worldwide travel. Amongst the various nematodes, Angiostrongylus contonensis is the commonest and causes eosinophilic meningitis. It is a zoonotic disease produced due to the ingestion of raw or undercooked snails or slugs. Most cases of angiostrongyliasis are mild and self-limiting, but death can occur in severe cases lacking timely and proper treatment. Very few autopsy cases of A. cantonensis are reported. We present the case of a 32-year-old mentally challenged orphan male with eosinophilic meningitis at autopsy.

Cavernous Hemangioma of Cavernous Sinus: An Outcome Report of 45 Surgically Treated Patients.

OBJECTIVE: To report an outcome analysis following surgical treatment of 45 patients with cavernous hemangiomas involving cavernous sinus. METHODS: From 1992 to 2020, 45 cases of cavernous hemangiomas involving the cavernous sinus were surgically treated. These patients were retrospectively analyzed. RESULTS: Patients included 12 males and 33 females; the average age was 34 years (age range, 15-61 years). Two patients had only headache as presenting symptom, and 43 patients had headache and diplopia as presenting symptoms. Investigations showed characteristic radiological imaging and encasement of internal carotid artery (35 cases), extension toward the sella, and displacement of cranial nerves III-V. An entirely extradural surgical approach was adopted in 39 cases. Cranial nerves III-V had a discrete dural covering and were always displaced over the dome of the tumor. The sixth cranial nerve was displaced on the dome of the tumor adjacent to the floor of the cavernous sinus. Three patients died in the early postoperative period, all related to excessive bleeding. In 36 patients, ocular movement dysfunction did not recover or worsened. During an average follow-up period of 110 months (range, 6 months to 27 years), 3 patients had tumor recurrence after postoperative imaging had shown complete tumor resection. CONCLUSIONS: Surgery on cavernous hemangiomas of cavernous sinus can be a challenge owing to the vascular profile and complex anatomical location. An extradural approach provides satisfactory exposure for radical tumor resection.

Melanoma of the central nervous system: A report of three cases.

Melanomas within the Central Nervous System (CNS) are most commonly metastatic lesions, with primary melanomas comprising only 0.05-0.07% of all brain tumors. We report three cases of primary CNS melanoma. The patients were young adults. There were two females and one male. On preoperative investigations, two cases were misdiagnosed to be angiomas on Magnetic Resonance Imaging (MRI). The melanotic nature of the lesion was an intraoperative observation. Pathologic examination showed features of malignancy with invasion of tumor cells into the brain parenchyma. In two patients, presence of systemic lesions were ruled out after surgery by whole-body Positron Emission Tomography (PET) scan. These patients were subject to adjuvant radiotherapy, while one patient succumbed immediately post-surgery. Primary CNS melanomas are rare with no defined treatment protocols. Histopathology diagnosis is crucial to rule out pigmented mimics.

Endodermal cyst: rare intraaxial brainstem location. Illustrative cases.

BACKGROUND: This report detailed an extremely rare location of an endodermal cyst. Such location of the tumor can pose radiological confusion and a therapeutic dilemma. However, when identified, it can be a pleasant surprise for the surgeon and provide the possibility of a symptom-free long life for the patient. OBSERVATIONS: This report discussed two young patients who presented with relatively short-duration reports of ataxia and diplopia. Investigations revealed intraaxial brainstem lesion. During surgery, thick, pus-like fluid was evacuated and part of a wall was resected. Histology revealed that the lesion was an endodermal cyst. Both patients are well and are lesion- and symptom-free for 24 and 72 months. LESSONS: Endodermal cysts are some of the few long-standing and benign intraaxial brainstem lesions.

Glioblastoma Occurring as Second Primary in a Treated Case of Diffuse Large B-Cell Lymphoma.

Glioblastoma as second primary malignancy (SPM) has been reported after prostate cancer, meningiomas, Hodgkin's lymphoma. We report an extremely rare case of glioblastoma as SPM, occurring after remission of diffuse large B-cell lymphoma (DLBCL). Fifty-year-old male presented with loss of consciousness followed by right-sided weakness. He was treated with chemotherapy for DLBCL of the cervical lymph nodes, 5 years back. Present scans revealed well-defined intra-axial lesion in the left parietal lobe, suggestive of central nervous system (CNS) involvement by lymphoma. Left parieto-occipital craniotomy was performed and microscopic examination revealed the tumor to be Glioblastoma, WHO Grade IV. The tumor cells were positive for glial fibrillary acid protein and negative for leucocyte common antigen. He was treated by radiotherapy and temozolomide. Pathologic examination is a must for CNS lesions. Had it not been for the biopsy, the patient would have been treated as a recurrence of CNS lymphoma by chemotherapy and would have probably succumbed.

Intravascular papillary endothelial hyperplasia of the cavernous sinus-A rare occurrence.

Intravascular papillary endothelial hyperplasia (IPEH) is a benign, reactive proliferation of endothelial cells within areas of thrombus. It most commonly occurs in the skin and subcutaneous tissue, with less than 40 cases reported in intracranial location. Ours is the first case report from India of IPEH in the cavernous sinus. A 45-year-old male presented with headache and decreased visual acuity. Magnetic resonance imaging (MRI) revealed a well-defined, homogeneously contrast-enhancing mass in the cavernous sinus. Postoperatively, examination of tissue showed organizing thrombus within the vessel wall along with delicate, acellular, pseudopapillary cores. The fibrin-rich connective tissue of these showed blue staining with Masson's trichrome stain. These were lined by a single layer of endothelial cells without evidence of atypia; no nuclear pleomorphism, hyperchromasia, atypical mitosis, or areas of necrosis were seen. Hence, it was diagnosed to be IPEH. Follow-up MRI revealed no residual disease and the patient is disease-free at 8 months. Recognition of this entity by pathologic examination is important to rule out angiosarcoma. Gross total resection is curative. Residual lesions have the potential for recurrence, requiring adjuvant therapy.

Large lateral intraventricular tumors - Outcome of radical surgery.

This is a retrospective analysis of 145 cases of lateral intraventricular tumors that were larger than 4 cm in their maximum dimension. The aim of surgery was radical tumor resection. During the period January 2000 to December 2019, 145 cases of lateral intraventricular tumors were treated by surgery by an interhemispheric approach. There were 101 males and 44 females. The ages of the patients ranged from 2 months to 77 years (average 29 years). Histological examination of tumors identified 73 central neurocytomas, 20 choroid plexus papillomas, 23 subependymal giant cell astrocytomas (SEGA), 5 ependymomas, 21 gliomas, 2 primitive neuroectodermal tumors (PNET/embryonal tumors) and 1 atypical teratoid rhabdoid tumor (ATRT). Nineteen patients had mild to severe hemiparesis in the immediate post-operative period. Eight patients died in the postoperative period. At a follow up of 1 year 137 patients were leading active and symptom free lives. Twenty seven patients received adjuvant radiation treatment. At a follow-up of more than 3 years, 8 additional patients died of their disease. Tumor recurrence or re-growth was observed in 13 patients and 2 patients needed reoperation. Surgery on large lateral intraventricular tumors can be associated with significant postoperative morbidity and mortality. Majority of tumors in this location are relatively 'low-grade' malignant tumors and when successfully treated, the long term outcome can be gratifying.

Silent stellate ganglion paraganglioma masquerading as schwannoma: A surgical nightmare.

A 28-year-old normotensive female presented with Horner's syndrome and paresthesia over the left side of the chest. Imaging study showed a large heterogeneous enhancing lesion in short-T1 inversion recovery sequence with flow voids in T2W sequence of magnetic resonance imaging. The lesion was located in the left-sided D1 and D2 regions extending into the neural foramina and apical part of the lung. During surgery, even minimal dissection of the tumor resulted in marked fluctuation in hemodynamic parameters, requiring temporary suspension of the surgery multiple times until hemodynamic parameters were brought under control by the anesthesiologist with drugs. The massive fluctuation in hemodynamic parameters in an unprepared and unanticipated scenario was a challenge for the anesthetist and surgeon. The tumor was radically excised with improvement of paresthesia in the immediate postoperative period, but Horner's syndrome persisted. After 18-months of follow-up, she was relieved of all symptoms including Horner's syndrome. Histopathological examination confirmed our suspicion as paraganglioma.

Familial Giant Enchondroma of Thoracic Spine: A Rare Manifestation of a Rare Disease.

We present a rare case of spinal enchondromatosis in a 15-year-old boy. The patient presented with spastic paraparesis. He also had multiple bony swellings over the long bones. On inquiry it was found that his father had enchondromatosis. Such a familial form of enchondromatosis has not been previously described in the literature.

Solitary Plasmacytoma with Amyloid - An Unusual Dural-Based Lesion.

Solitary plasmacytoma of the dura without systemic involvement are extremely rare lesions, with <15 cases reported in the literature. Among these, ours is the second case to show the presence of amyloid. Fifty-year-old male had presented with headache, sudden onset right-sided weakness, and vomiting. Magnetic resonance imaging revealed an extra-axial mass in the left fronto-parietal region measuring 10 cm × 8.7 cm × 3.9 cm, suggestive of meningioma. The left fronto-parietal craniotomy was performed and multiple tissue bits aggregating to 10 cm × 8.5 cm × 2 cm along with thinned out membrane-like bit of calvarium was sent for pathologic examination. H and E stained sections showed sheets of plasmacytoid cells along with amyloid, which showed apple-green birefringence on Congo red staining. On immunohistochemistry, tumor cells were positive for CD38, CD138, showed kappa light chain restriction and were negative for CD45, CD34. Hence, it was diagnosed as a plasma cell neoplasm. Further work-up with whole-body positron-emission tomography scan revealed no systemic involvement. Dural-based lesions can mimic meningioma radiographically as well as intraoperatively. Histopathological examination unveils the diagnosis, to guide appropriate therapeutic regimens.

Bony lesions of cranium and spine: A study of 123 cases.

CONTEXT: Bony lesions involving the cranium and spine have a wide range of etiologies, ranging from congenital, traumatic, inflammatory, to neoplastic. AIM: The aim was to analyze the histological spectrum of various bony lesions of cranium and spine received as biopsies from the neurosurgery department in our hospital. MATERIALS AND METHODS: There were 123 cases of bony lesions of cranium and spine diagnosed over a period of 5 years during 2015-2019 in the neuropathology laboratory. These cases were studied retrospectively. RESULTS: Out of the total 123 cases of bony lesions analyzed, 75 affected the cranium and 48 affected the spine. Overall, neoplastic lesions (83) were more frequent than the nonneoplastic lesions (40). In the cranium, neoplastic lesions (66/75) outnumbered the nonneoplastic ones (9/75), whereas in the spine, nonneoplastic lesions (31/48) were more common. Chordoma (40/83) was the most common neoplasm, whereas tuberculous osteomyelitis (30/40) was the most common nonneoplastic lesion encountered. Majority of the patients were adult males aged between 21 and 50 years. Rare lesions such as spinal osteochondroma, poorly differentiated neoplasm metastatic to the cervical spine from a primary salivary gland neoplasm, spinal metastasis of a glioblastoma, and intraosseous meningioma of cranium were recorded. CONCLUSIONS: The study provides epidemiological information regarding the incidence and nature of bone lesions of the spine and cranium.

Sellar surprises: a single-centre experience of unusual sellar masses.

BACKGROUND: Most common incidentally detected sellar-suprasellar region (SSR) masses are pituitary adenomas, followed by craniopharyngioma, rathke's cleft cyst, hypophysitis, and meningioma. Besides these, certain unusual SSR lesions can sometimes present as diagnostic challenges, where diagnosis is often made post-operatively on histopathology, the pre-operative suspicion of which might have influenced the management strategies. Series describing such masses are few. OBJECTIVE: To present clinical, biochemical, and radiological characteristics and management outcomes of rare SSR lesions other than pituitary adenomas, craniopharyngioma, rathke's cleft cyst, hypophysitis, and meningioma. DESIGN, SETTING, PATIENTS: Retrospective case record analysis of patients with uncommon SSR masses (from January 2006 to December 2016). RESULTS: Our series consisted of ten patients, five with neoplastic and five with non-neoplastic lesions. Neoplastic masses included granular cell tumor (n = 2), astrocytoma (n = 1), malignant peripheral nerve sheath tumor (MPNST, n = 1), and metastasis from occult papillary carcinoma of thyroid (n = 1), while non-neoplastic masses were aspergillus abscess (n = 1), sterile abscess (n = 1), and tubercular abscess (n = 1), aneurysm of left internal carotid artery (n = 1), and ruptured dermoid cyst (n = 1). All patients (except one) presented with headache and/or visual disturbance. Only one patient had acromegaly while most others had hypopituitarism. We describe detailed MRI characteristics of each of the lesion. Seven patients underwent trans-sphenoidal surgery. Post-operatively, five patients had permanent diabetes insipidus, while two patients died in early post-operative period. CONCLUSION: Our series expand the differential diagnostic considerations of SSR lesions. Most of the rare SSR masses present with symptoms of mass effects and hypopituitarism. Except for some non-neoplastic lesions like sellar abscesses, aneurysms, and dermoid cysts which can have some specific imaging characteristics that can provide clue to pre-operative diagnosis, most of the other neoplastic masses have overlapping radiological features, and pre-operative suspicion remains difficult.

Primary Pineal Rhabdomyosarcoma: A Rare Case.

Primary pineal rhabdomyosarcoma (RMS) is extremely rare, and only three cases have been reported so far. Here, we report a case of 12-year-old male who presented with complaints of diplopia and diminution of vision since 15 days. He also had left-sided facial paresis. Magnetic resonance imaging brain revealed a space-occupying lesion in the region of pineal gland. The patient underwent midline suboccipital craniectomy with excision of tumor. Microscopic examination revealed a highly cellular tumor with areas showing small round cells admixed with cells having abundant eosinophilic cytoplasm resembling rhabdomyoblasts and multinucleated giant cells. Differential diagnoses of pineal anlage tumor and primary RMS were considered. The tumor cells were positive for desmin while being negative for synaptophysin and glial fibrillary acidic protein. Myogenin was used to confirm the diagnosis of RMS, which showed focal nuclear positivity. INI1 was retained. All the markers for germ cell tumors were negative.

Chondrosarcoma of the dorsal spine - A rare case.

Chondrosarcomas of the spine are rare tumors and represent <10% of all chondrosarcomas. In the spine, they may arise from vertebral bodies or posterior elements. They may occur in patients ranging from 13 to 78 years of age. Here, we present a case of a 25-year-old female who presented with complaints of lower backache, stiffness in both lower limbs, and tingling sensation in the right lower limb. On examination, both power and sensations were decreased below waist. Magnetic resonance imaging spine revealed an extradural lesion at D5 vertebral body level with severe cord compression. We received the mass in multiple fragments which were grayish-white and firm to hard in consistency. Microscopically, a chondroid tumor was seen with cells arranged in lobules in abundant myxoid matrix. The neoplastic chondrocytes were large in size and had bizarre hyperchromatic nuclei. Few binucleate and multinucleate forms were also seen along with occasional atypical mitoses. There was permeation and destruction of the host bone, and the tumor was seen invading the marrow spaces. Few foci showed high cellularity. No osteoid formation was seen by the tumor. The tumor was diagnosed as Chondrosarcoma - Grade II.

Meningiomas with Collagenous Rosettes: A Report of Three Cases.

Formation of rosettes is very rarely encountered in meningiomas. The 2016 WHO classification of central nervous system tumors mentions it as a rare pattern secondarily encountered in different variants. We report three cases of meningiomas forming collagenous rosettes. Case 1 was a 60-year-old male with a right frontoparietal mass lesion. Excisional biopsy showed features of atypical meningioma (WHO Grade II) with diffusely scattered collagenous rosettes. Case 2 was a 48-year-old male with right frontoparietal space-occupying lesion. Microscopy revealed a papillary variant of meningioma (WHO Grade III) with prominent diffusely scattered collagenous rosettes. Case 3 was a 75-year-old female with left parietal convexity tumor. Microscopy revealed a clear-cell meningioma (WHO Grade II) with cerebral invasion. Focal collagenous rosettes and fibrosclerotic whorls were noted. In all three cases, Masson's trichrome was used to confirm collagenous nature of the rosettes. All three tumors were positive for epithelial membrane antigen and vimentin.

Primary pineal tumors - Unraveling histological challenges and certain clinical myths.

BACKGROUND: Pineal gland tumors range from the well-differentiated "pineocytoma" [World Health Organization (WHO) grade I], which have a very good prognosis, to the aggressive and poorly differentiated "pineoblastoma" (WHO grade IV) with "pineal parenchymal tumor of intermediate differentiation" (PPTID; WHO grades II and III) occupying intermediary differentiation and prognosis. Papillary tumor of the pineal region (PTPR; WHO grades II and III) is a distinct entity with propensity for recurrence and spinal dissemination. However, the diagnostic criteria to differentiate these entities, especially between WHO grades II and III of both PPTID and PTPR, remain nebulous. OBJECTIVE: To evaluate the relative frequency of the individual entities and histomorphological (including the proliferation indices) features across the spectrum of pineal parenchymal tumors (PPTs) [including PTPRs] along their course. DESIGN: All cases of PPTs were retrieved, reviewed, and graded based on the histological criteria defined in the literature. RESULTS: PPTID, more commonly seen in young adults, was the most common subtype of PPT. This was followed by pineoblastoma which was more commonly seen in children. Clinical progression was seen in both grades II and III of PPTID; however, it was more commonly seen in cases with a MIB1 labeling index of >10%. PTPRs (both grades II and III) showed an aggressive histological transformation and also intraparenchymal metastasis. CONCLUSION: PPTIDs are the most common adult primary PPTs and have the potential to progress and disseminate in both grades II and III. Both grades of PTPRs have a metastatic potential. These findings suggest the need for postoperative adjuvant therapy in both grades of PPTID and PTPR.

Downregulation of miR-204 expression defines a highly aggressive subset of Group 3/Group 4 medulloblastomas.

Genome-wide expression profiling studies have identified four core molecular subgroups of medulloblastoma: WNT, SHH, Group 3 and Group 4. Molecular markers are necessary for accurate risk stratification in the non-WNT subgroups due to the underlying heterogeneity in genetic alterations and overall survival. MiR-204 expression was evaluated in molecularly classified 260 medulloblastomas from an Indian cohort and in 763 medulloblastomas from the MAGIC cohort, SickKids, Canada. Low expression of miR-204 in the Group 3 / Group 4 tumors identify a highly aggressive subset of tumors having poor overall survival, in the two independent cohorts of medulloblastomas. Downregulation of miR-204 expression correlates with poor survival within the Group 4 as well indicating it as a valuable risk-stratification marker in the subgroup. Restoration of miR-204 expression in multiple medulloblastoma cell lines was found to inhibit their anchorage-independent growth, invasion potential and tumorigenicity. IGF2R was identified as a novel target of miR-204. MiR-204 expression resulted in downregulation of both M6PR and IGF2R that transport lysosomal proteases from the Golgi apparatus to the lysosomes. Consistent with this finding, miR-204 expression resulted in reduction in the levels of the lysosomal proteases in medulloblastoma cells. MiR-204 expression also resulted in inhibition of autophagy that is known to be dependent on the lysosomal degradation pathway and LC3B, a known miR-204 target. Treatment with HDAC inhibitors resulted in upregulation of miR-204 expression in medulloblastoma cells, suggesting therapeutic role for these inhibitors in the treatment of medulloblastomas. In summary, miR-204 is not only a valuable risk stratification marker in the combined cohort of Group 3 / Group 4 medulloblastomas as well as in the Group 4 itself, that has paucity of good prognostication markers, but also has therapeutic potential as indicated by its tumor suppressive effect on medulloblastoma cells.