A challenging case of sporadic melanocytoma of the jugular foramen.

BACKGROUND: The jugular foramen (JF) can be the site of several tumours. Paragangliomas, schwannomas and meningiomas are the most commonly reported. We describe a case of melanocytoma originating from the JF and presenting with an accessory nerve palsy. ILLUSTRATIVE CASE: A 48-year-old woman presented with a 6-month history of cervical and left shoulder pain with wasting and weakness of the left trapezius. A Magnetic Resonance Imaging (MRI) showed a T1-hyperintense, T2-isointense, heterogeneously enhancing lesion involving the left JF and extending into the cerebello-medullary and cerebello-pontine cisterns. A retrosigmoid craniotomy was performed and a near-total removal achieved. The accessory nerve was involved by tumour and could not be preserved. Given the diagnostic uncertainty between melanotic schwannoma, metastatic melanoma and meningeal melanocytoma, next generation sequencing and genome-wide DNA methylation arrays were performed, documenting a mutation in GNA11 (c.6226A>T, p. Gln209Leu) and a methylation profile consistent with melanocytoma. The patient underwent adjuvant fractionated radiotherapy of the tumour remnant. A follow-up MRI 4 years after surgery did not show any tumour recurrence. CONCLUSIONS: The differential diagnosis of skull base pigmented tumours can be challenging, particularly when they occur in unusual locations such as the JF. They can be misdiagnosed given their similar clinical, neuroradiological and pathological features if anatomy of the site of origin is not carefully considered and molecular tests are not performed, leading to erroneous treatment and follow-up planning.

Primary papillary epithelial tumour of the sella: expanding the spectrum of TTF-1-positive sellar lesions.

AIM: To describe four novel primary epithelial tumours of the sella with papillary architecture and Thyroid Transcription Factor 1 (TTF-1) expression. METHODS: Paraffin-embedded tissue from the four cases and recurrence of patient 1 was investigated with haematoxylin-eosin, special histochemical stains, immunohistochemistry with a broad panel of antibodies and next-generation sequencing. The ultrastructure of one tumour was studied in tissue retrieved from paraffin. RESULTS: The lesions occurred in three females aged 20, 26 and 42 years and a male aged 49 years. They presented with signs and symptoms secondary to pituitary stalk compression. Preoperative neuroimaging documented mixed solid and cystic, enhancing sellar masses with suprasellar extension. Histologically, the tumours showed thin papillae lined by a single layer of cytokeratin and TTF-1-positive cuboidal and cylindrical cells with mildly atypical nucleus. Next-generation sequencing performed in three cases did not identify any mutations. The main differential diagnosis included metastasis from lung or thyroid carcinoma, extraventricular choroid plexus papilloma and sellar ependymoma. CONCLUSION: We suggest the descriptive term of primary papillary epithelial tumour of the sella (PPETS) for this entity and propose that it could represent the intracranial equivalent of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma. The cell of origin of PPETS remains undetermined although the intense and ubiquitous expression of TTF-1 may suggest a derivation from the infundibulum or ventricular recess. Our study expands the spectrum of sellar TTF-1-positive tumour and challenges the view that they all derive from pituicytes.

A standardised diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a European Pituitary Pathology Group (EPPG) proposal.

The 2017 World Health Organization (WHO) classification proposes to type and subtype primary adenohypophyseal tumours according to their cell lineages with the aim to establish more uniform tumour groups. The definition of atypical adenoma was removed in favour of high-risk adenoma, and the assessment of proliferative activity and invasion was recommended to diagnose aggressive tumours. Recently, the International Pituitary Pathology Club proposed to replace adenoma with the term of pituitary neuroendocrine tumour (PitNET) to better reflect the similarities between adenohypophyseal and neuroendocrine tumours of other organs. The European Pituitary Pathology Group (EPPG) endorses this terminology and develops practical recommendations for standardised reports of PitNETs that are addressed to histo- and neuropathologists. This brief report presents the results of EPPG's consensus for the reporting of PitNETs and proposes a diagnostic algorithm.

Neurosurgical contribution within a complex NF1 supraregional service.

OBJECTIVES: The goal of this study was to review and present neurosurgical related activity within a multidisciplinary nationally commissioned specialty neurofibromatosis type I (NF1) center. PATIENTS & METHODS: We reviewed all NF1 Neurosurgical MDTs, NF1 Neurosurgical clinics and all neurosurgical procedures carried out in NF1 patients over an 8-year period. RESULTS: Since the inception of the service in 2009, 1505 cases were discussed at our NF-1 multidisciplinary meeting, 171 clinic appointments in complex NF1 patients with neurosurgical pathologies and 43(cranial and spinal) operations were performed. CONCLUSIONS: The formation of a supraregional multidisciplinary team allows for a better understanding of the disease, a comprehensive evaluation of neuroimaging findings and a steep learning curve in the management of NF1 surgical conditions. We provide holistic treatment for these patients via direct care, specialist advice and liaison with local units.

A nonmyeloablative chimeric mouse model accurately defines microglia and macrophage contribution in glioma.

AIMS: Resident and peripherally derived glioma associated microglia/macrophages (GAMM) play a key role in driving tumour progression, angiogenesis, invasion and attenuating host immune responses. Differentiating these cells' origins is challenging and current preclinical models such as irradiation-based adoptive transfer, parabiosis and transgenic mice have limitations. We aimed to develop a novel nonmyeloablative transplantation (NMT) mouse model that permits high levels of peripheral chimerism without blood-brain barrier (BBB) damage or brain infiltration prior to tumour implantation. METHODS: NMT dosing was determined in C57BL/6J or Pep3/CD45.1 mice conditioned with concentrations of busulfan ranging from 25 mg/kg to 125 mg/kg. Donor haematopoietic cells labelled with eGFP or CD45.2 were injected via tail vein. Donor chimerism was measured in peripheral blood, bone marrow and spleen using flow cytometry. BBB integrity was assessed with anti-IgG and anti-fibrinogen antibodies. Immunocompetent chimerised animals were orthotopically implanted with murine glioma GL-261 cells. Central and peripheral cell contributions were assessed using immunohistochemistry and flow cytometry. GAMM subpopulation analysis of peripheral cells was performed using Ly6C/MHCII/MerTK/CD64. RESULTS: NMT achieves >80% haematopoietic chimerism by 12 weeks without BBB damage and normal life span. Bone marrow derived cells (BMDC) and peripheral macrophages accounted for approximately 45% of the GAMM population in GL-261 implanted tumours. Existing markers such as CD45 high/low proved inaccurate to determine central and peripheral populations while Ly6C/MHCII/MerTK/CD64 reliably differentiated GAMM subpopulations in chimerised and unchimerised mice. CONCLUSION: NMT is a powerful method for dissecting tumour microglia and macrophage subpopulations and can guide further investigation of BMDC subsets in glioma and neuro-inflammatory diseases.

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

Cortical Lewy bodies and Aß burden are associated with prevalence and timing of dementia in Lewy body diseases.

AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aß plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aß plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aß plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.

Low levels of cobalamin, epidermal growth factor, and normal prions in multiple sclerosis spinal cord.

We have previously demonstrated that multiple sclerosis (MS) patients have abnormal cerebrospinal fluid (CSF) levels of the key myelin-related molecules cobalamin (Cbl), epidermal growth factor (EGF), and normal cellular prions (PrP(C)s), thus confirming that some CSF abnormalities may be co-responsible for remyelination failure. We determined the levels of these three molecules in post-mortem spinal cord (SC) samples taken from MS patients and control patients. The control SC samples, almost all of which came from non-neurological patients, did not show any microscopic lesions of any type. All of the samples were supplied by the U.K. MS Tissue Bank. The Cbl, EGF, and PrP(C) levels were determined using enzyme-linked immunosorbent assays. The SC total homocysteine level was determined using a competitive immunoenzymatic assay. CSF samples, taken from a further group of MS patients, were used for the assay of holo-transcobalamin (holo-TC) levels. The Cbl, EGF, and PrP(C) levels were significantly decreased in MS SCs in comparison with controls and, paradoxically, the decreased Cbl levels were associated with decreased SC levels of homocysteine, a biochemical marker of Cbl deficiency. The trends of EGF and PrP(C) levels paralleled those previously found in CSF, whereas that of Cbl was the opposite. There was no significant difference in CSF holo-TC levels between the MS patients and the controls. Given that we have previously demonstrated that Cbl positively regulates central nervous system EGF levels, it is conceivable that the low EGF levels in the MS SC may be causally related to a local decrease in Cbl levels. Only PrP(C) levels were invariably decreased in both the SC and CSF regardless of the clinical course of the disease. These findings suggest that the simultaneous lack of Cbl, EGF, and PrP(C)s may greatly hamper the remyelination process in MS patients, because they are key molecules of the machinery for remyelination.

Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma.

Arginine deprivation, either by nutritional starvation or exposure to ADI-PEG20, induces adaptive transcriptional upregulation of ASS1 and ASL in glioblastoma multiforme ex vivo cultures and cell lines. This adaptive transcriptional upregulation is blocked by neoplasia-specific CpG island methylation in either gene, causing arginine auxotrophy and cell death. In cells with methylated ASS1 or ASL CpG islands, ADI-PEG20 initially induces a protective autophagic response, but abrogation of this by chloroquine accelerates and potentiates cytotoxicity. Concomitant methylation in the CpG islands of both ASS1 and ASL, observed in a subset of cases, confers hypersensitivity to ADI-PEG20. Cancer stem cells positive for CD133 and methylation in the ASL CpG island retain sensitivity to ADI-PEG20. Our results show for the first time that epigenetic changes occur in both of the two key genes of arginine biosynthesis in human cancer and confer sensitivity to therapeutic arginine deprivation. We demonstrate that methylation status of the CpG islands, rather than expression levels per se of the genes, predicts sensitivity to arginine deprivation. Our results suggest a novel therapeutic strategy for this invariably fatal central nervous system neoplasm for which we have identified robust biomarkers and which overcomes the limitations to conventional chemotherapy imposed by the blood/brain barrier.

Characterization of MENX-associated pituitary tumours.

AIMS: The aim of this study is to evaluate the pathological features, serum hormone levels and ex vivo cultures of pituitary adenomas that occur in rats affected by MENX syndrome. MENX is multiple endocrine neoplasia syndrome caused by a germline mutation in the cell cycle inhibitor p27. Characterization of MENX adenomas is a prerequisite to exploit this animal model for molecular and translational studies of pituitary adenomas. METHODS: We investigated MENX pituitary adenomas with immunohistochemistry, double immunofluorescence, electron microscopy, reverse transcription polymerase chain reaction (RT-PCR), measurement of serum hormone levels and ex vivo cultures. RESULTS: Adenomas in MENX rats belong to the gonadotroph lineage. They start from 4 months of age as multiple neoplastic nodules and progress to become large lesions that efface the gland. Adenomas are composed of chromophobic cells predominantly expressing the glycoprotein alpha-subunit (αGSU). They show mitotic activity and high Ki67 labelling. A few neoplastic cells co-express gonadotropins and the transcription factor steroidogenic factor 1, together with growth hormone or prolactin and Pit-1, suggesting that they are not fully committed to one cell lineage. Ex vivo cultures show features similar to the primary tumour. CONCLUSIONS: Our results suggest that p27 function is critical to regulate gonadotroph cells growth. The MENX syndrome represents a unique model to elucidate the physiological and molecular mechanisms mediating the pathogenesis of gonadotroph adenomas.

A report of the natural history of leptomeningeal gliomatosis.

Primary leptomeningeal gliomatosis (PLG) is a rare condition, with fewer than 50 patients reported. Our report illustrates the natural history of PLG in full, from the prodromal phase of subacute meningitis to the final stages characterised by extensive nerve root infiltration, cranial nerve palsies and widespread peripheral neurogenic muscle wasting. We provide correlative neuroimaging with serial MRI, and present the first published positron emission tomography imaging of this condition. We emphasise the importance of considering PLG in the differential diagnosis of chronic aseptic meningitis, the difficulties of making the diagnosis ante mortem, and the utility and potential limitations of early meningeal biopsy in this condition.

Myopathy secondary to intravascular large B-cell lymphoma.

We report a case of a 78-year-old woman presenting with progressive proximal muscle weakness mainly to lower limbs and myopathic EMG associated with intravascular large B-cell lymphoma. Muscle biopsy showed myopathic changes, intravascular large B-cell lymphoma but no inflammation or fibre necrosis; the patient's serum cross-reacted with an unidentified nuclear antigen of approximately 45 kDa present in muscle and lymphoma cells. Our case illustrates a myopathy associated with intravascular large B-cell lymphoma probably mediated by antibodies cross-reacting with a nuclear protein expressed by neoplastic cells and normal muscle. The nature of this nuclear antigen remains unidentified.

Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra.

The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be up-regulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly(ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.

Comparative study of commercially available anti-alpha-synuclein antibodies.

Immunohistochemistry for alpha-synuclein has become the histological technique of choice for the diagnosis for Parkinson's disease, Dementia with Lewy bodies and Multiple System Atrophy (http://www.ICDNS.org). Nevertheless, no standardised protocol has been proposed. We have reviewed 242 of the 270 studies published until June 2005 that mentioned immunohistochemistry for anti-alpha synuclein on human tissue and we found that only 75 (31%) used commercial antibodies. We also noted that protocols, particularly dilution and antigen unmasking, varied between studies, even when the same antibody was employed. In order to establish a standardised protocol for alpha-synuclein immunohistochemistry, which can be applied in diagnostic neuropathology we tested seven commercial monoclonal antibodies in brains of subjects with Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, multiple sclerosis with incidental Lewy bodies and aged-matched normal brain and determined for each antibody the best suited protocol for antigen unmasking. We evaluated the intensity of immunolabelling in Lewy bodies, neuropil threads, dendrites, pre-synaptic terminals, granular cytoplasmic positivity, peri-axonal positivity, glial inclusions and non-specific immunolabelling. Although our results showed that all the antibodies detected alpha-synuclein inclusions, differences were noted between antibodies, particularly with regard to the detection of glial inclusions. From our study, the best antibodies of the seven tested appeared to be those directed against amino acids 116-131 and 15-123 and we suggest them to be used in routine diagnostic practice for alpha-synucleinopathies.

[A case of cerebral coenurosis]. / Su di un caso di cenurosi cerebrale.

In this article the authors describe a case of cerebral coenurosis, a rare infection caused by the larval stage of the tapeworm Taenia multiceps, encountered during their professional practice. The specific epidemiological elements, linked to the parasitic lifecycle in dogs, will also be covered. The authors consider the diagnostic, pathologic and clinical elements that allow differential diagnosis with respect to neurocysticercosis, a parasitic infection caused by the larval form of other Cestoda, discussing possible medical therapeutic approaches (albendazole or praziquantel) and neurosurgical intervention. They emphasize the need to obtain a correct hystopathological diagnosis in order to achieve a differential diagnosis versus the other larval parasitosis. According to current public health regulations this diagnosis must be reported to the Health Official to allow the necessary epidemiological interventions to be planned.

Glubran 2: a new acrylic glue for neuroradiological endovascular use. Experimental study on animals.

SUMMARY: A new acrylic glue, Glubran 2, is now available on the European market. It bears the CE mark with several surgical indications and the specific indication for neuroradiological endovascular use. Despite this approval, to our knowledge its use is still limited to surgery and no injections have been made in human patients. This study was designed to evaluate the behavior of Glubran 2 in endovascular injection in a simulation of brain AVM. Six sheep were operated on opening a fistula between the right common carotid artery and the jugular vein. This fistula modifies blood flow in the skull base rete mirabilis, which then functions as an AVM. In two sheep, the rete mirabilis was occluded by injection of 1.5 ml of Histoacryl diluted 1:1 and 1:3 with Lipiodol. In two sheep, the rete was embolized by injection of 1.5 ml of Glubran 2 diluted 1:1 with Lipiodol. The last two sheep were embolized by injection of Glubran 2 diluted 1:3 with Lipiodol. The procedures were documented by DSA angiographic acquisitions and by fluoroscopic VHS. The sheep were killed immediately after the procedures and the rete mirabilis isolated for histologic examination. Embolization was obtained with both kinds of glue. Glubran 2 diffuses in a very similar way to Histoacryl with an apparently more complete diffusion. Reflux in the ascending pharyngeal artery showed that Glubran 2 tended not to produce bubbles but diffused more homogeneously. The subjective conclusion of this work is that Glubran 2 can be used in endovascular embolizations. Before approaching brain AVMs, a further study will investigate embolization of the external carotid territory.

Occipital aneurysmal bone cyst secondary to eosinophilic granuloma.

We describe the case of a 2-year-old male patient with an aneurysmal bone cyst (ABC) of the occiput secondary to unifocal eosinophilic granuloma (EG). The lesion presented as a painless mass of the scalp which had grown rapidly over the 2 weeks prior to admission. Radiologically, the lesion was osteolytic and multicystic with fluid-fluid levels. On histology, the cyst wall contained hemosiderin-laden histiocytes, spindle cells, multinucleated giant cells, Langerhans' cells and eosinophils. Surgical treatment consisted of en bloc resection. Fourteen months after surgery, the patient was well with no local recurrence. Association between EG and ABC is rare. To our knowledge, this is the first case involving the skull.

Primary polymorphous hemangioendothelioma of the spinal cord. Case report.

A case of polymorphous hemangioendothelioma of the spinal cord is described. This 55-year-old woman presented with an 18-month history of lower-extremity sensorimotor deficit. A magnetic resonance image revealed an enhancing, intradural, extramedullary nodule at the T 1-2 level. On gross inspection, the lesion measured 3.5 cm and was firmly attached to spinal cord parenchyma and adjacent nerve roots. It was completely removed. Fourteen months after surgery the patient's neurological deficit had resolved. Polymorphous hemangioendothelioma is a rare vascular tumor of borderline malignancy. Most occur in lymph nodes. None has been reported to occur in the central and peripheral nervous system. Based on current experience, resection and close follow up seems the best therapeutic approach.