Cytology of Extraneural Metastases of Nonhematolymphoid Primary Central Nervous System Tumors: Six Cases with Histopathological Correlation and Literature Update.

INTRODUCTION: Extraneural/-cranial metastases (ENM) of primary central nervous system (CNS) tumors are rare and may be diagnostically challenging. We describe the cytomorphological and pertinent clinical features of ENM in a case series assessed by fine-needle aspiration (FNA). A search of the laboratory information systems of 2 tertiary care centers in Toronto (2000-2015) was performed. Cases with direct extracranial/-spinal extension of CNS neoplasms were excluded. Microscopic slides of FNA and surgical specimens were reviewed. Demographic and clinicopathological data were retrieved. CASE PRESENTATION: Six cases were identified with the original diagnoses of glioblastoma, glioblastoma with primitive neuroectodermal tumor-like components, anaplastic ependymoma, myxopapillary ependymoma, atypical meningioma, and hemangiopericytoma. Median patient age at first diagnosis was 44 years (range 22-56). The time interval between initial diagnosis and first metastatic disease manifestation was 3 months to 19 years. All FNA diagnoses were rendered correctly. In 4 cases, immunohistochemistry was used to support the diagnosis. All cases had prior surgical intervention at the primary tumor site. In 4 cases, the ENM location was the ipsilateral parotid or buccal area. Two primary tumors in midline location developed ENM in the scapular area. DISCUSSION/CONCLUSION: ENM are a rare manifestation of a range of different primary CNS tumors and may involve the ipsilateral head and neck mimicking clinically a salivary gland neoplasm. FNA can rapidly discriminate ENM from other, potentially more indolent conditions. Awareness of the clinical history is paramount to avoid diagnostic confusion.

LMNA-NTRK1 rearranged mesenchymal tumor (lipofibromatosis-like neural tumor) mimicking pigmented dermatofibrosarcoma protuberans.

We present the case of a 31-year-old female with a 1.5 cm pigmented nodule on the scalp. Histopathological examination revealed a proliferation of relatively bland spindle cells and pigmented dendritic cells, with interspersed lymphoid follicles diffusely infiltrating the adipose tissue. The microscopic differential diagnosis included pigmented dermatofibrosarcoma protuberans (DFSP). The spindle cells showed S-100 and CD34 labeling but were negative for SOX-10. Immunohistochemical stain for pan-TRK was positive, while fluorescence in-situ hybridization for PDGFB gene rearrangement was negative. Targeted RNA sequencing revealed an LMNA-NTRK1 (exon2/exon10) fusion. This molecular result coupled with the histopathological findings and immunohistochemical profile supported the diagnosis of the recently characterized NTRK-rearranged spindle cell neoplasm termed "lipofibromatosis-like neural tumor (LPF-NT)." These neoplasms typically occur in superficial soft tissue and are characterized by a distinctive immunoprofile (CD34+, S-100+, SOX10-). Histopathological differential diagnosis for LPF-NT tumors includes lipofibromatosis, DFSP, low-grade malignant peripheral nerve sheath tumor, and spindle cell/desmoplastic melanoma. The pigmented dendritic cells reminiscent of pigmented DFSP and lymphoid follicles noted in our case have not been previously reported in LPF-NT, thus expanding the morphological spectrum of this entity. LMNA-NTRK1 fusion serves both as a diagnostic and therapeutic biomarker, as cases with advanced disease may be amenable to targeted therapy using tyrosine kinase inhibitors.

Neurogenic Tumors of the Mediastinum.

Neurogenic tumors represent a broad ill-defined category of neoplasms that includes tumors of Schwann cell and/or neuroblastic derivation, as well as neoplasms that typically develop in the central nervous system, but rarely present in ectopic sites including the mediastinum. Neurogenic tumors may occur at many different anatomic sites, but the mediastinum represents a uniquely challenging site given the complex anatomy. Additionally, some of these neoplasms may present with multicentric involvement in the context of genetic syndromes, including NF1, NF2 and schwanomatosis. Most of these develop in posterior structures, often in association with paraspinal structures. Fine needle biopsy/small biopsies play an important role in the diagnosis of these neoplasms, given its record of safety and the increased applicability of ancillary testing to these smaller samples at the present time. In this review we focus on the major categories of neurogenic tumors that may be encountered in the mediastinum, including schwannoma, neurofibroma, malignant peripheral nerve sheath tumors, ganglioneuroma and ganglioneuroblastoma, as well as rarer members of this category. We discuss diagnostic approaches applicable to small cytologic and tissue samples and relevant differential diagnoses.

Decision Making in Retroperitoneal Nerve Sheath and Nerve-Associated Tumors: A Modular Approach.

BACKGROUND: Surgical treatment of retroperitoneal nerve and nerve-associated tumors is challenging, especially in cases with large extent. A single surgical access may have limitations and jeopardize patients. OBJECTIVE: To present a series of patients to illustrate our individually tailored treatment concept and decision pathway. METHODS: Retrospectively, clinical findings and imaging were related to surgical features and outcome. An algorithm for choice of approach was established. RESULTS: From 2012 to 2017, we operated on n = 13 patients with retroperitoneal tumors, of these n = 9 were included (n = 6 female, n = 3 male). Histological findings included n = 2 schwannomas, n = 2 malignant peripheral nerve sheath tumors, n = 1 non-origin sarcoma, n = 1 perineurioma, n = 1 intraneural ganglion cyst, n = 1 lymphoma, and n = 1 paraganglioma. In n = 6 patients, we used a monoportal (retroperitoneal/transperitoneal) approach; in n = 2 patients, a biportal retroperitoneal to inguinal/transperitoneal to dorsal approach; and in n = 1 patient, a triportal transperitoneal to dorsal to gluteal approach. In n = 2 patients, we performed an open biopsy only; in n = 2 patients, a tumor enucleation; in n = 3 patients, a subtotal function-sparing resection; in n = 1 patient, a complete resection; and in n = 1 patient, intraneural decompression. In n = 1 patient, a new motor deficit appeared. n = 4 patients required further radio-oncological treatment. n = 8/9 patients are alive without tumor progress or recurrence. CONCLUSION: Retroperitoneal nerve or nerve-associated tumors encompass multiple entities. Depending on suspected histology and tumor extension, extensile or combined surgical approaches may be necessary. We present our algorithm for assessment and decision-making regarding surgical access ports and pathways.

A systematic review reporting quality of radiomics research in neuro-oncology: toward clinical utility and quality improvement using high-dimensional imaging features.

BACKGROUND: To evaluate radiomics analysis in neuro-oncologic studies according to a radiomics quality score (RQS) system to find room for improvement in clinical use. METHODS: Pubmed and Embase were searched up the terms radiomics or radiogenomics and gliomas or glioblastomas until February 2019. From 189 articles, 51 original research articles reporting the diagnostic, prognostic, or predictive utility were selected. The quality of the methodology was evaluated according to the RQS. The adherence rates for the six key domains were evaluated: image protocol and reproducibility, feature reduction and validation, biologic/clinical utility, performance index, a high level of evidence, and open science. Subgroup analyses for journal type (imaging vs. clinical) and biomarker (diagnostic vs. prognostic/predictive) were performed. RESULTS: The median RQS was 11 out of 36 and adherence rate was 37.1%. Only 29.4% performed external validation. The adherence rate was high for reporting imaging protocol (100%), feature reduction (94.1%), and discrimination statistics (96.1%), but low for conducting test-retest analysis (2%), prospective study (3.9%), demonstrating potential clinical utility (2%), and open science (5.9%). None of the studies conducted a phantom study or cost-effectiveness analysis. Prognostic/predictive studies received higher score than diagnostic studies in comparison to gold standard (P < .001), use of calibration (P = .02), and cut-off analysis (P = .001). CONCLUSIONS: The quality of reporting of radiomics studies in neuro-oncology is currently insufficient. Validation is necessary using external dataset, and improvements need to be made to feature reproducibility, demonstrating clinical utility, pursuits of a higher level of evidence, and open science.

68Ga-DOTANOC PET/CT in an Atypical Extraskeletal Paravertebral Hemangioma Mimicking as Neurogenic Tumor in a Known Case of Breast Cancer.

Ga-DOTANOC PET/CT is well documented in evaluation of well-differentiated neuroendocrine tumors and in other lesions with somatostatin receptor expression such as pheochromocytoma, paraganglioma, neuroblastoma, meningioma, and mesenchymal tumors causing oncogenic osteomalacia. Causes of interpretative pitfalls include prominent pancreatic uncinate process activity, inflammation, osteoblastic activity (degenerative bone disease/fracture/vertebral hemangioma), splenunculi/splenosis, and others. We present a case of extraskeletal paravertebral lesion detected in a known case of breast cancer with increased Ga-DOTANOC uptake later proved to be hemangioma. This is a novel finding and should be kept as a rare benign differential in evaluation of lesions with somatostatin receptor expression.

Surgical treatment of posterior mediastinal neurogenic tumors.

BACKGROUND: Posterior mediastinal neurogenic tumors are among the most frequent mediastinal masses in adults. These tumors may be dumbbell shaped, extending into the spinal canal, exclusively paraspinal or apical tumors extending in the cervical region. In this report, we present our experience in the surgical resection of these tumors and discuss the surgical strategies for such tumors. METHODS: A retrospective analysis was performed of 121 patients who underwent surgery for posterior mediastinal neurogenic tumors at our department during the period 2009 to 2016. Seventy-four tumors were excised via video-assisted thoracic surgery (VATS). Other approaches included thoracotomy, supraclavicular incision, supraclavicular incision plus thoracotomy/VATS, and a posterior approach with laminectomy combined with thoracotomy/VATS. RESULTS: Tumors were resected completely in 119 cases and partially in two. The majority of the tumors were benign nerve sheath tumors. No recurrence developed during postoperative median follow-up period of 31 months. CONCLUSION: Most posterior neurogenic tumors can be resected via VATS. Thoracotomy is the appropriate surgical approach for large tumors. A supraclavicular approach is recommended for tumors extending in the cervical region, and this can be combined with VATS or thoracotomy in case of larger masses. A posterior approach could be used for patients with dumbbell tumors.

Demographic, Clinical and Histopathological Features of Oral Neural Neoplasms: A Retrospective Study.

Intraoral neural neoplasms though unusual may be clinically significant. The aim of this study was to categorize and evaluate oral neural tumors in a large oral pathology biopsy service. With IRB approval, a retrospective search of all neural neoplasms of the oral cavity in the archives of the University of Florida Oral Pathology Biopsy Service spanning from 1994 to 2015 was performed. Extraoral cases as well as cases with insufficient patient information were excluded. A total of 340 out of 164,578 submitted specimens in a 22 year period (0.2%) were included with a mean age of 43.3 years (range: 6-89), and 44% male and 56% female. The most commonly affected locations were: tongue (37.5%), palate (22%), lip (19%), and gingiva (14%). The microscopic diagnoses rendered, in descending order of frequency were: neurofibromas (NFs): 123 (36%), granular cell tumor (GCT): 108 (32%), schwannomas: 61 (17%), palisaded encapsulated neuromas: 39 (11%), benign neural lesion not otherwise specified: 8 (2%), and mucosal neuroma c/w multiple endocrine neoplasia type 2B (MEN 2B): 1 (< 0.5%). Six cases of NF reported a history of neurofibromatosis Type 1 (NF 1). Four cases showed multifocal lesions. Immunohistochemical staining was performed on equivocal cases (25% of the lesions) and all were confirmed by their S-100 positivity. Intraoral neural neoplasms, though uncommon should be in the differential diagnosis of oral soft tissue entities and specific consideration to syndromal linkage is paramount as this may impact patient management.

Primary mediastinal melanotic schwannian tumors: A clinicopathological and immunohistochemical study of 5 cases.

Mediastinal neurogenic tumors are unusual and more so is the presence of melanotic neurogenic tumors. We present five cases of mediastinal melanotic neurogenic tumors. The patients are five men between the ages of 34 and 43 years (average: 38.5 years). All patients presented with non-specific symptoms that included back pain and cough. Diagnostic imaging revealed the presence of a posterior mediastinal mass without connection to the spinal canal, and surgical resection was accomplished in all of the patients. Histologically, the five tumors showed a spindle epithelioid cellular proliferation, nuclear atypia, mitotic activity, and melanin deposition. Histochemical stain for Fontana Masson clearly demonstrated the presence of melanin pigment in all the cases, while S-100 protein was only focally positive in tumor cells. Other immunohistochemical stains including SOX-10, MITF, HMB-45, and Melan A were negative. Clinical follow-up showed that two patients died 22 and 30 months after initial diagnosis; one remains alive, 6 months after initial diagnosis; two patients were lost to follow up. Melanotic neurogenic tumors represent a diagnostic challenge for pigmented thoracic tumors and careful analysis of the morphology and immunohistochemistry is required to lead to proper diagnosis.

Redefining Perineural Invasion: Integration of Biology With Clinical Outcome.

A diagnosis of perineural invasion (PNI), defined as cancer within or surrounding at least 33% of the nerve, leads to selection of aggressive treatment in squamous cell carcinoma (SCC). Recent mechanistic studies show that cancer and nerves interact prior to physical contact. The purpose of this study was to explore cancer-nerve interactions relative to clinical outcome. Biopsy specimens from 71 patients with oral cavity SCC were stained with hematoxylin and eosin and immunohistochemical (IHC; cytokeratin, S100, GAP43, Tuj1) stains. Using current criteria, PNI detection was increased with IHC. Overall survival (OS) tended to be poor for patients with PNI (P = .098). OS was significantly lower for patients with minimum tumor-nerve distance smaller than 5 µm (P = .011). The estimated relative death rate decreased as the nerve-tumor distance increased; there was a gradual drop off in death rate from distance equal to zero that stabilized around 500 µm. In PNI-negative patients, nerve diameter was significantly related to OS (HR 2.88, 95%CI[1.11,7.49]). Among PNI-negative nerves, larger nerve-tumor distance and smaller nerve diameter were significantly related to better OS, even when adjusting for T-stage and age (HR 0.82, 95% CI[0.72,0.92]; HR 1.27, 95% CI[1.00,1.62], respectively). GAP43, a marker for neuronal outgrowth, stained less than Tuj1 in nerves at greater distances from tumor (OR 0.76, 95% CI[0.73,0.79]); more GAP43 staining was associated with PNI. Findings from a small group of patients suggest that nerve parameters other than presence of PNI can influence outcome and that current criteria of PNI need to be re-evaluated to integrate recent biological discoveries.

Granular cell tumour of the tongue treated by radiofrequency ablation.

AIM: To report on a case of granular cell tumour occurring in the tongue surgically removed by surgical radiofrequency, with histological examination. MATERIAL OF STUDY: Discussion on the clinico-pathological characteristics of the granular cell tumour and the surgical treatment by surgical radiofrequency: the differential diagnosis is also discussed. RESULTS: Histological examination is mandatory for the final diagnosis. Surgical radiofrequency is an useful medical device to achieve good quality surgery with minimal post-operative course. DISCUSSION CONCLUSIONS: Although rare, granular cell tumour should be always considered in the differential diagnosis of nodular lesions of the oral mucosa above all when the tongue is involved and a yellow appearance is detectable. The surgery will be guided by the clinical diagnosis and accurately performed to prevent recurrence. A medical device promoting reduction of the intra-operative bleeding is suggestable for such surgical treatments. KEY WORDS: Granular cell tumour, surgical radiofrequency, neurogenic tumour.

Neural and neurogenic tumours of the gastroenteropancreaticobiliary tract.

Neural lesions occur uncommonly in the gastroenteropancreaticobiliary tract. However, due to the growing number of screening colonoscopy procedures, polypoid neural lesions of the colon are being recognised increasingly and range from benign tumours to high-grade malignant neoplasms. Morphological variability of neural tumours can be wide, although some entities share pathological features, and, as such, these lesions can be diagnostically challenging. We review the spectrum of pathology of neural tumours in the gastroenteropancreaticobiliary tract, with the goal of providing a practical approach for practising surgical pathologists.

Multinodular and vacuolating neuronal tumor of the cerebrum. A rare entity. New case and review of the literature.

BACKGROUND: Multinodular and vacuolating neuronal tumor has been recently described and included in the World Health Organization Classification of Tumors of The Central Nervous System, even though its consideration as a true tumor is controversial. Patients with these lesions usually present with refractory seizures and inconclusive imaging findings that may be confused with other more common diagnoses such as dysembryoplastic neuroepithelial tumors or low-grade gliomas. Therefore, surgical resection is warranted to reach a pathologic diagnosis and seizure control. To the best of our knowledge, only 16 cases have been published in the English literature. CASE DESCRIPTION: We present the case of a 52-year-old male who presented at our institution with a 2-year-history of absence of seizures. Brain MRI showed a T2-hyperintense lesion with no contrast enhancement affecting his temporal lobe. Temporal craniotomy and microsurgical resection was scheduled. The procedure was uneventful and a grayish, gluey mass was sent for pathologic analysis. The tumor was formed by immature neuronal cells organized in nodules with a vacuolated matrix. A thorough immunohistochemical analysis showed positivity for: Protein Gene Product 9.5. ATRX. OLIG2. SOX10. p16. Nestin. Synaptophysin. The findings were consistent with multinodular and vacuolating neuronal tumor. The patient has been seizure-free after surgery and with no signs of tumor progression. CONCLUSION: We present a thorough review addressing this uncommon tumor along with a description of the 17th reported case of MVNT, a tumor that was described for the first time in 2013. Further studies and case studies are necessary to establish a well-defined morphological and immunohistochemical profile along with knowledge about its natural history.

Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

Multinodular and vacuolating neuronal tumor (MVNT) is a new pattern of neuronal tumour included in the recently revised WHO 2016 classification of tumors of the CNS. There are 15 reports in the literature to date. They are typically associated with late onset epilepsy and a neoplastic vs. malformative biology has been questioned. We present a series of ten cases and compare their pathological and genetic features to better characterized epilepsy-associated malformations including focal cortical dysplasia type II (FCDII) and low-grade epilepsy-associated tumors (LEAT). Clinical and neuroradiology data were reviewed and a broad immunohistochemistry panel was applied to explore neuronal and glial differentiation, interneuronal populations, mTOR pathway activation and neurodegenerative changes. Next generation sequencing was performed for targeted multi-gene analysis to identify mutations common to epilepsy lesions including FCDII and LEAT. All of the surgical cases in this series presented with seizures, and were located in the temporal lobe. There was a lack of any progressive changes on serial pre-operative MRI and a mean age at surgery of 45 years. The vacuolated cells of the lesion expressed mature neuronal markers (neurofilament/SMI32, MAP2, synaptophysin). Prominent labelling of the lesional cells for developmentally regulated proteins (OTX1, TBR1, SOX2, MAP1b, CD34, GFAPδ) and oligodendroglial lineage markers (OLIG2, SMI94) was observed. No mutations were detected in the mTOR pathway genes, BRAF, FGFR1 or MYB. Clinical, pathological and genetic data could indicate that MVNT aligns more with a malformative lesion than a true neoplasm with origin from a progenitor neuro-glial cell type showing aberrant maturation.

Assessment of paraspinal neurogenic tumors with diffusion-weighted MR imaging.

PURPOSE: To assess paraspinal neurogenic tumors with diffusion-weighted MR imaging. METHODS: Retrospective analysis was done upon 34 patients with paraspinal neurogenic tumors that underwent diffusion-weighted MR imaging. The ADC values of the mediastinal neurogenic tumors were calculated and correlated with biopsy results. RESULTS: The ADC of benign paraspinal neurogenic tumors (1.5 ± 0.28 × 10-3 mm2/s) was significantly higher (P = 0.001) than that of malignant peripheral nerve sheath tumors (0.995 ± 0.198 × 10-3 mm2/s). Selection of 1.15 × 10-3 mm2/s as a cut-off point for differentiating malignant from benign neurogenic tumors revealed an area under the curve of 0.885, an accuracy of 91.1%, a sensitivity of 90.9%, and specificity of 91.3%. There was significant difference (P = 0.04) in the ADC of schwannomas (1.55 ± 0.29 × 10-3 mm2/s) from neurofibromas (1.33 ± 0.08 × 10-3 mm2/s). The cut-off ADC value of 1.44 × 10-3 mm2/s was used to differentiate schwannomas and neurofibromas with an area under the curve of 0.86, an accuracy of 82.6%, a sensitivity of 100%, and a specificity of 76.5%. CONCLUSION: Diffusion-weighted MR imaging is imaging parameter that can be used for differentiation of benign from malignant paraspinal neurogenic tumors.

Ancient Schwannoma of Radial Nerve: A Report of Two Cases.

Ancient schwannoma is a rare variant of schwannoma associated with a longstanding course. They differ from classical schwannomas in the long duration for this subtype of schwannoma to develop and also by demonstrating haemorrhagic and degenerative changes with nuclear atypia. It is because of these histologic hallmarks that they are frequently misdiagnosed as malignant tumours. They usually involve the major nerves of flexor surfaces in upper extremity such as the ulnar and median nerve but schwannomas of the radial nerve are a rare entity. We report two cases of ancient schwannoma involving the radial nerve at mid arm and dorsum of the hand. The differential diagnoses included atypical soft tissue sarcomas and tumours of neural origin. Imaging and histopathology are crucial in diagnoses of these tumours.

Glycolipids: Essential regulator of neuro-inflammation, metabolism and gliomagenesis.

Gene knockout mice of glycosyltransferases have clearly showed roles of their products in the bodies, while there are examples where phenotype of knockout was much less severe than expected probably due to functional redundancy. The most striking novel finding obtained from ganglioside-deficient mice was that progressive inflammatory reaction took place, leading to neurodegeneration. In particular, dysfunction of complement-regulatory proteins due to deteriorated architecture of lipid rafts seemed to be essential mechanisms for the inflammation. Furthermore, roles of gangliosides in neurons were demonstrated by neuron-specific transgenic of B4galnt1 with genetic background of B4galnt1 deficiency. From study of gene knockout mice of St8sia1, new roles of b-series gangliosides in leptin secretion from adipocytes, and roles of a-series gangliosides in leptin receptor, ObR in hypothalamus were demonstrated, leading to apparent intact balance of energy. Essential roles of b-series gangliosides in malignant properties of gliomas were also shown, suggesting their roles in the regulation of inflammation and proliferation in nervous tissues. How to apply these findings for the control of newly discovered patients with ganglioside deficiency remains to be investigated. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.