Alston Brain Tumors PDF

Alston Brain Tumors Brain Tumors Intro — Organize by cell types — Grading >> staging — Glial — Often GFAP positive — Astrocytoma, anaplastic astrocytoma, GBM — — — — — Infiltrates into surrounding brain As grade increases (increase in mitotic rate, pleomorphism/anaplasia, cellular density), survival...

Alston Brain Tumors Brain Tumors Intro — Organize by cell types — Grading >> staging — Glial — Often GFAP positive — Astrocytoma, anaplastic astrocytoma, GBM — — — — — Infiltrates into surrounding brain As grade increases (increase in mitotic rate, pleomorphism/anaplasia, cellular density), survival decreases GBM – necrosis, vascular proliferation, often crosses midline. Pilocytic – Better prognosis; cystic; often in cerebellum; long hairlike cells Advances are leading to significant changes in how patients are categorized abd treated per their molecular profiles (e.g. IDH and MGMT status). — Oligodendrogliomas — Often localized in white matter areas — Morphology – “fried egg”/halos; satellitosis in bordering cortex; calcifications — Genetics – 1p/19q deletions - sensitivity to chemotherapy — Ependymomas — Arises from ependymal cells; located in and around ventricles and spinal cord; hydrocephalus — Morphology – perivascular rosettes (perivascular clear zones), ependymal rosettes — Choroid plexus papillomas can develop in the ventricles and result in hydrocephalus. Brain Tumors Intro — Neuronal — Rare, seizures common — Ganglion cell tumor - Binucleate neurons with ganglion cell tumors — Neuroblastoma – small, blue-cell tumor, aggressive — Neurocytoma – Appears similar to oligodendroglioma. — Medulloblastoma — Posterior fossa/cerebellar; CSF spread — Primitive, undifferentiated cells– small, blue-cell tumor CNS Lymphoma (B-cell) B-cell immunohistochemical markers positive – e.g. CD20, CD19 Epithelial Membrane Antigen (EMA)-positive Seen often in immunocompromised; evidence of EBV infection in many Angiocentric (in and around blood vessels); multifocal Meningioma Arises from meningothelial cells; often attached to dura Compresses underlying brain Morphology – nests and whorls of cells; psammoma bodies Genetics – Chromosome 22 deletion; multiple meningiomas in NF2; Estrogen and progesterone receptors Metastatic Most common brain tumor Comes from outside the brain via hematogenous spread or direct invasion Often multiple; Seen frequently at grey-white junction Stains with properties of the primary neoplasm (including immunohistochemistry) Brain Tumors Intro Peripheral nervous system tumors Schwannoma S100 positive Periphery of nerves; common in cerebellopontine angle – CN VIII (acoustic neuroma) Morphology – Areas of varying density – Antoni A (dense) and B (loose); Verocay bodies in dense areas; S-100 positive (vs. meningioma) Bilateral schwannomas in NF2 Neurofibroma S100-positivity Involves entire nerve diameter Cutaneous and peripheral nerve tumors Present in NF1 Phakomatoses – Genetic syndromes with nervous system, cutaneous, and other lesions NF1 – cafe-au-lait spots, neurofibromas, ocular abnormalities NF2 – bilateral schwannoma, multiple meningiomas, gliomas (ependymomas) Von Hippel-Lindau – hemangioblastomas (cerebellar, retinal), renal cell carcinomas, organ cysts Other – Sturge Weber, Tuberous sclerosis (Summarize features) Discussion may overlap with pediatric neuropathology coverage. Cell Types (Major) with Corresponding Tumors Cell Type Glial Astrocyte Oligodendroglial cells Ependymal Neuron Meningeal coverings Lymphocytes Undifferentiated Metastatic Schwann Cell (PNS) Neoplasm Gliomas Astrocytoma Oligodendroglioma Ependymomas Neuronal tumors Meningioma B-cell lymphoma Medulloblastoma Metastatic neoplasms Schwannoma, Neurofibroma Astrocytoma ►Most common primary brain tumor ►Location – Cerebral hemispheres most common in adults Children – Brainstem, thalamus, hemispheres Many locations possible ►Often 4th – 6th decade, but can occur at any age. See below. ►GFAP-positive cells (not exclusive to astrocytomas) ►Infiltration Poorly defined border on gross Often surrounds neurons and other structures ►Often shares features with normal nervous systems cells Astrocytoma – Grading (World Health Organization System (WHO)) ►Grading usually matters more than staging ►Many grading systems; none are perfect ►Rare metastases outside of CNS (negating much of the value of staging) ►Range Lowest grade* – Astrocytoma, Grade II/IV WHO Anaplastic Astrocytoma, Grade III/IV WHO Highest Grade – Glioblastoma multiforme, Grade IV/IV WHO *Note that the pilocytic astrocytoma has a more favorable prognosis than even Grade II/IV. These often occur in children. Astrocytoma Grade II Grade III Grade IV (Necrosis is usually also present) Figure 1 Role of Ki-67 labeling index as an adjunct to the histopathological diagnosis and grading of astrocytomas Thotakura, Mahathi; Tirumalasetti, Neelima; Krishna, Ravi. Journal of Cancer Research and Therapeutics10(3):641-645, Jul-Sep 2014. doi: 10.4103/0973-1482.139154 Ki-67 LI in (a) Grade I astrocytoma, (b) Grade II astrocytoma, (c) Grade III astrocytoma, and (d) Grade IV astrocytoma Ki-67 stains cells that are not in G0 (i.e. resting phase). Thus, it gives a measure of the proliferation index and how fast cells are dividing. Note the proportion of cells staining positively in relation to grade. It is similar to quantifying mitotic figures but is easier and more reliable. Copyright © 2024 Wolters Kluwer. Published by Lippincott Williams & Wilkins. 9 Astrocytoma - Grading ►Cellularity Higher grade – higher cellular density ►Necrosis Highest grade (GBM only) – necrosis is most significant factor ►Pleomorphism Higher grade – higher pleomorphism (i.e. variability/anaplasia) ►Mitotic rate (proliferation index) Higher grade – higher mitotic rate ►Vascular proliferation Highest grade (GBM) – Diagnostic feature ►Other p53 inactivation (and PDGF-A) - common in lower grade lesions and secondary GBM (i.e. tumors that progress from astrocytomas to anaplastic astrocytomas to glioblastomas. Transition to higher grade ► Inactivation of tumor suppressor genes (e.g. RB, p16/CDKN2A, tumor suppressor gene on 19Q?) ► EGFR amplification and loss of Chromosome 10 – common in primary GBM (tumors that start out as glioblastoma). Astrocytoma, Grade II/IV ►Higher cellular density, uneven distribution, increased mitotic rate, and pleomorphism distinguish astrocytoma from gliosis ►Infiltrates into surrounding brain; no margin ►GFAP-positive cells with processes; may be gemistocytic ►Absence of necrosis and vascular proliferation ►Relatively lower cellular density, mitotic rate and pleomorphism than higher grade astrocytoma ►Genetic – commonly p53 inactivation; PDGF-A and receptor overexpression can be seen ►Can show microcystic change ►Symptoms – seizures, deficits dependent on lesion ►Survival – mean, over 5 years (See prior slide). This slide highlights some of the gross features of astrocytomas. First, cerebral edema develops around the tumor. Second, it is not possible to specifically outline the tumor on the cut section; the tumor infiltrates surrounding tissues. Third, there is no obvious areas of necrosis in this tumor; necrosis would be a feature of glioblastoma multiforme or Grade IV/IV astrocytoma. Note that the tumor infiltrates into surrounding brain. There is no sharp border. A star has been placed over the tumor. Astrocytic neoplasms Ellison, David, MD PhD MA MSc BChir MRCP(UK) FRCPath FRCPCH, Neuropathology, 35, 705-728 Astrocytoma. (a) An astrocytoma diffusely invades the cerebrum producing distortion and expansion of normal structures. The neoplasm produces midline shift and is poorly demarcated. (b) CT scan. A poorly defined mass in the right frontal lobe has... Copyright © 2013 © 2013, Elsevier Limited. All rights reserved. Astrocytoma Iowa Virtual Slidebox Anaplastic Astrocytoma, Grade III/IV ►Earlier onset than GBM, later than Grade II ►Increased cellularity, mitotic rate, and pleomorphism than Astrocytoma, Grade II/IV; less than GBM ►No necrosis (vs. GBM) or vascular proliferation in WHO system; Other systems allow vascular proliferation ►Gemistocytic astrocytomas (plump with short processes) are often Grade III/IV lesions ►Shorter survival than Grade II/IV lesion; closer to but longer than GBM (30 months from prior slide). Anaplastic Astrocytoma Diffuse Gliomas : Astrocytic Yachnis, Anthony T., MD, Neuropathology, A, 72-83 Anaplastic astrocytoma. Infiltrating tumor with nuclear pleomorphism and increased mitotic activity. The latter is most important in distinguishing the anaplastic astrocytoma (WHO Grade III) from the diffuse astrocytoma (WHO Grade II). Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Anaplastic Astrocytoma - Gemistocytic Astrocytic neoplasms Ellison, David, MD PhD MA MSc BChir MRCP(UK) FRCPath FRCPCH, Neuropathology, 35, 705-728 Anaplastic astrocytoma containing many gemistocytic cells. The presence of mitoses puts this astrocytoma into the anaplastic category. Copyright © 2013 © 2013, Elsevier Limited. All rights reserved. Glioblastoma, Grade IV/IV ►Highest grade astrocytoma with shortest survival (14 month per prior slide) ►Cellular density, mitotic rate, and pleomorphism (both small and large cells) can be marked. ►Often crosses midline (butterfly lesion) ►Spread Rare metastases outside CNS Spread within CSF pathways ►Necrosis is seen; often pseudopalisading (higher density of tumor cells around necrotic area) ►Radiology – often contrast-enhancing around necrosis ►Vascular proliferation is common Glomeruloid formation Endothelial proliferation within lumen Secondary to vascular growth factor production by tumor (e.g. VEGF) Glioblastoma, Grade IV/IV ►Genetic ►Primary GBM – not arising in preexisting astrocytoma Occurs in older adults Amplification of EGFR gene MDM2 overexpression, p16 deletion, PTEN mutations ►Secondary - GBM Younger patients Arises from lower-grade tumor Shares p53 inactivation (and PDGF-A) amplifications with lower grade ►GBM can be seen with Turcot, Ollier, Maffucci, NF1, and other syndromes ►Treatment – Surgery, Radiation. Immunotherapy Chemotherapy, not very effective New treatments are being introduced. Recall the poliovirus treatment that was discussed in Molecular Medicine. ►Survival – Recent studies have shown survivals of 16-19 months (M.D. Anderson) with 5-year survival of 10%. This is a significant improvement (Link) Glioblastoma Imaging: Ring – Enhancing and Edema Gross – Butterfly Lesion ( Crossing the Midline) Robbins 7th - Fig 28-43 Glioblastoma multiforme Vascular Proliferation in Glioblastoma Diffuse Gliomas : Astrocytic Yachnis, Anthony T., MD, Neuropathology, A, 72-83 Astrocytic neoplasms Ellison, David, MD PhD MA MSc BChir MRCP(UK) FRCPath FRCPCH, Neuropathology, 35, 705-728 Glioblastoma. In addition to diverse cytologic features, the glioblastoma is characterized by a distinctive neovascularization and micronecrosis. (a) Buds of capillary endothelial proliferation are seen among neoplastic cells Copyright © 2013 © 2013, Elsevier Limited. All rights reserved. Glioblastoma. Marked “glomeruloid” microvascular proliferation. Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Pseudopalisading Necrosis - Glioblastoma Astrocytic neoplasms Ellison, David, MD PhD MA MSc BChir MRCP(UK) FRCPath FRCPCH, Neuropathology, 35, 705728 Glioblastoma. In addition to diverse cytologic features, the glioblastoma is characterized by a distinctive neovascularization and micronecrosis. (a) Buds of capillary endothelial proliferation are seen among neoplastic cells Copyright © 2013 © 2013, Elsevier Limited. All rights reserved. Diffuse Gliomas : Astrocytic Yachnis, Anthony T., MD, Neuropathology, A, 72-83 Glioblastoma. Cellular tumor with pseudopalisading necrosis. Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Diffuse Gliomas : Astrocytic Yachnis, Anthony T., MD, Neuropathology, A, 72-83 Glioblastoma. Immunohistochemistry for GFAP showing strong reactivity of tumor cells. Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Pilocytic Astrocytoma ►Occurs in children and young adults ►Often occurs in cerebellum; can occur around 3rd ventricle, optic nerves, and cerebral hemispheres ►Morphology Long, hair-like (pilocytic) cells Rosenthal fibers – protein droplets Cystic with mural nodule Often minimally invasive in brainstem ►Consider as a Grade I/IV neoplasm ►Rarely have p53 or other changes seen in astrocytomas (diffuse fibrillary) ►Optic lesions can be seen in NF1 ►Longer survival than Grade II/IV Pilocytic Astrocytoma Robbins 28-48 "© Copyright UAB and the UAB Research Foundation, 1999-2000. All rights reserved. Other Astrocytic Tumors Yachnis, Anthony T., MD, Neuropathology, C, 91-98 Pilocytic astrocytoma. Neuroimaging study showing typical appearance of a cerebellar pilocytic astrocytoma with a prominent cyst and adjacent enhancing tumor. Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Oligodendroglioma ►Arises from oligodendroglial cells ►Occurs most commonly in white matter ►Occurs in 4th or 5th decade; often with seizures ►Morphology Well-circumscribed Cells ►Surrounded by halo (artifact) – “fried eggs” ►At border with grey matter, cells surround neurons – satellitosis Delicate network of capillaries Calcifications Low mitotic rate GFAP-positive cells (especially microgemistocytes) Deletion of 1p/19q is now considered characteristic of these neoplasm. ►Mixed gliomas (oligoastrocytomas) Oligodendroglioma ►Anaplastic forms (Grade III/IV) occurs with necrosis; increased cellular density, mitotic rate, and pleomorphism; microgemistocytes ►Genetic Most characteristic – 1p/19q deletions Anaplastic – additional changes – loss of 9q and 10q, mutation in CDKN2A ►Those with 1p/19q respond well to chemotherapy and radiation ►Those without 1p/19q are refractory to chemotherapy ►Treatment Surgery Chemotherapy with higher grade ►Survival – Better prognosis than low-grade astrocytoma Oligodendroglioma - Morphology Perinuclear Halos (Clear Spaces) Satellitosis – Clustering around neurons Yachnis AT, Rivera-Zengotita ML. Neuropathology (ClinicalKey) Oligodendroglioma – Halos and Satellitosis Halos/”Fried Egg” Copyright (C) 2017 Japanese Society of Pathology all rights reserved. https://pathology.or.jp/corepicturesEN/17/c08/11.html Satellitosis Yachnis AT, Rivera-Zengotita ML. Neuropathology (ClinicalKey) Diffuse Gliomas : Oligodendroglial Yachnis, Anthony T., MD, Neuropathology, B, 84-90 Oligodendroglioma. High magnification showing monomorphous collection of neoplastic cells with prominent perinuclear “halos.” Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Changes! As noted, In the last few years, changes in how we are approaching the gliomas has begun. The 2021 WHO Classificant was the first big step. The anticipated and upcoming next WHO Classification is expected to be huge and significant. The changes will largely concern the astrocytic gliomas (from pilocytic to glioblastoma multiforme and include oligodendroglioma. Much starts with what you covered in Molecular Medicine! It stands that our grasp of natural histories and improvements in therapies will start to make significant differences. New Molecular Classifications and IDH The 2016 WHO Classification accelerated the move towards a molecular-oriented classification. A big change was inclusion of whether wild-type or mutant isocitrate dehydrogenase (IDH) was expressed. Astrocytic tumors with wild-type IDH astrocytomas have a poorer prognosis than those IDH-mutant tumors. Tumors with both IDH mutation and 1p/19q deletion (i.e. oligodendroglial tumors) have the best prognosis per Rubin’s Pathology: Mechanisms of Human Disease, 8th ed. This has also already started to become important with chemotherapeutic approaches to gliomas. See discussions in Chapter 7 and 28. I again believe this is only the start! Robbins and Cotran – Figure 7.30 Isocitrate dehydrogenae (IDH) acquires a mutation that leads to a specific amino acid substitution involving residues in its active site. As a result, the mutated protein loses its IDH function and instead acquires a new enzymatic activity that catalyzes the production of 2-hydroxyglutarate (2-HG). 2-HG in turn acts as an inhibitor of several other enzymes that require a metabolite called α-ketoglutarate as a cofactor. Among the proteins that are inhibited by 2-HG are several members of the TET family, including TET2. TET2 is one of several factors that enhance DNA methylation, which you will recall is an epigenetic modification that controls normal gene expression and often goes awry in cancer. According to the model, loss of TET2 activity leads to abnormal patterns of DNA methylation. Abnormal DNA methylation in turn leads to misexpression of cancer genes, which drive cellular transformation and oncogenesis. Some data suggest that the net effect of TET2 loss in lineages in which TET2 is a tumor suppressor is the upregulation of RAS and receptor tyrosine kinase signaling. Thus, according to this scenario, mutated IDH acts by producing 2HG, which is considered a prototypical oncometabolite. Oncogenic IDH mutations occur in a diverse collection of cancers including a sizable fraction of cholangiocarcinomas, gliomas, acute myeloid leukemias, and sarcomas. Of clinical significance, because the mutated IDH proteins have an altered structure, it has been possible to develop drugs that inhibit mutated IDH and not the normal IDH enzyme. Glioblastomas/Grade 4 astrocytomas without the IDH mutation Due to very poor survival, much attention is being paid to those with GBM without the IDH mutation. Harrison’s states that the term glioblastoma will be restricted to those without the mutation (i.e. wild type). Treatment is also affected by mutations in MGMT. Patients whose tumor contains the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are relatively resistant to temozolomide (TMZ) and have a worse prognosis compared to those whose tumors contain low levels of MGMT as a result of silencing of the MGMT gene by promoter hypermethylation. MGMTprotects the cell genome as it repairs damaged DNA by eliminating alkyl groups produced by the action of alkylating agents such as TMZ. Robbins and Kumar Table 28.5 Features of Diffuse Gliomas Ependymoma – Related lesions Choroid plexus papilloma ►Papillary ►Hydrocephalus Noncommunicating Overproduction of CSF ►Carcinoma can occur ►Cells are often S100, cytokeratin, and transthyretin (pre-albumin) positive Ependymoma ►Arise from ependymal cells that line ventricles ►Central (in and around ventricles) ►Most common around 4th ventricles in first 2 decades and in spinal cord in adults ►Morphology Perivascular pseudorosettes – result from cells sending processes (without nuclei) to vessels; this results in clear, perivascular zone Ependymal rosettes – neoplastic cells appear to form primitive central canal-like structures Tends to push and not infiltrate Ependymoma ►Genetics Common in Neurofibromatosis type 2 (NF2) (spinal) - chromosome 22 gene ►Due to central location CSF spread Hydrocephalus ►Survival related to extent of removal; one study had 5-year survival of 50% and rising Ependymoma Note the ventricular location of this ependymoma. Noncommunicating hydrocephalus is likely. Robbins 28-46 Perivascular Pseudorosette Rosettes Neuronal Tumors ►Often with seizures ►Not common ►Neuronal markers – e.g. synaptophysin, neurofilament ►Ganglion cell tumors – mature but disorganized neurons; binucleate forms Gangliocytoma – no glial tumor Ganglioglioma – glial tumor as well Neuronal ►Cerebral neuroblastoma Cerebral hemispheres Small, blue-cell tumor – similar to medulloblastoma Homer-Wright rosettes Highly aggressive ►Cerebral neurocytoma Appearance similar to oligodendroglioma Neuronal markers positive Within and adjacent to lateral or 3rd ventricles Ganglioglioma FIGURE 9.26 Ganglioglioma with abnormally clustered ganglion cells ( A ), perivascular lymphocytic cuffing, eosinophilic granular bodies, and dysmorphic neurons including binucleate forms ( B , arrow ). The neuronal and glial components are highlighted with immunostains for synaptophysin ( C ) and glial fibrillary acidic protein ( D ), respectively. Perry A, Brat DK. Neuropathology: Foundations in Diagnostic Pathology (Clinical Key) Medulloblastoma ►Poorly differentiated/”undifferentiated” ►Arises in cerebellum Midline (vermis) – children Lateral – adults ►“Small blue cells”: Homer-Wright rosettes can be seen ►Positive for synaptophysin ►Often shows subarachnoid dissemination ►Genetic Commonly shows loss of 17p, sometimes with isochromosome 17q Genetic profile – prognostic value ►Survival – with radiation and chemotherapy – 75% ►Can metastasize to bone Medulloblastoma Robbins Fig 28-51 “Small, blue cells”; High mitotic rate Undifferentiated Embryonal (Primitive) Neuroepithelial Tumors Yachnis, Anthony T., MD, Neuropathology, H, 127-135 Medulloblastoma. Postcontrast T1-weighted MRI typically shows an enhancing mass filling the fourth ventricle causing obstructive hydrocephalus. Such tumor is often “fluidrestricted,” on diffusion-weighted MRI. Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Embryonal (Primitive) Neuroepithelial Tumors Yachnis, Anthony T., MD, Neuropathology, H, 127-135 Medulloblastoma. Classic histologic features include high cellularity with nuclear hyperchromasia and “molding.” Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. CNS Lymphoma ►B-cell lymphoma; usually large cell ►Associated with EBV infection (by genetic analysis) in immunocompromised ►Can see in immunocompetent elderly ►Morphology — Multifocal — Perivascular orientation; infiltration of blood vessel walls — Positive for B-cell markers (e.g. CD20) ►Poorer response to chemotherapy than peripheral lymphomas ►Poor survival; poorer in AIDS Primary CNS Lymphoma Often Multifocal Often located around blood vessels with invasions of walls Lesions can be necrotic B-cell lymphomas Associated with immunocompromised and elderly Paulus W and Perry A. Lymphomas and Histiocytic Tumors. In Perry A, Brat DJ, eds. Practical Surgical Neuropathology: A Diagnostic Approach (ClinicalKey) Meningioma ►Arises from meningothelial cells in arachnoid ►Often dural-based ►Usually benign and slow growing ►Deficits are often from compression of underlying brain ►Morphology Whorls of meningothelial cells Calcifications – psammoma bodies Many patterns of growth with similar prognosis Papillary and rhabdoid have propensity to recur Often stains positive for epithelial membrane antigen (EMA) Meningioma ►Cells have progesterone and/or estrogen receptors ►Spinal forms have higher female:male ratio ►Genetic Loss of chromosome 22 (total or 22q) Occurs in NF2; NF2 gene is located on 22q12 ►Malignant forms exist Anaplasia Brain invasion Meningioma Dura Meningioma 3:2 Female:Male (10:1 spinal) Loss of chromosome 22 frequent Estrogen/progesterone receptors EMA positive Can be seen in NF2 (bilateral acoustic neuromas) Malignant forms exist Robbins 28-52 Psammoma bodies Meningioma Note the pushing and distortion of the underlying brain by the meningioma. "© Copyright UAB and the UAB Research Foundation, 1999-2000. All rights reserved. Tumor cytogenetics shows deletion of Chromosome 22. EMA Immunohistochemistry Meningiomas (Tumors of the Meninges) Yachnis, Anthony T., MD, Neuropathology, I, 136-148 Meningioma. Meningothelial whorls and psammomatous calcifications ( left ) are classic features of the meningothelial variant. Bland oval nuclei, some of which contain prominent clearing or intranuclear cytoplasmic inclusions, are classic features... Meningioma. Meningiomas are immunoreactive for epithelial membrane antigen (EMA). Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Metastases ►Most common brain tumor ►Spread to CNS Most via hematogenous spread Some by contiguous, direct spread into CNS ►Sources Most common – lung, breast, melanoma, kidney, GI Choriocarcinoma is overrepresented; prostate cancer is underrepresented Morphology is identical with primary tumor ►Can spread within CNS via CSF pathways. ►Look at grey-white junction for small metastases. ►Often multiple lesions Metastases Peripheral Nervous System Tumors ►Neural crest origin – Schwann cells; S100-positive ►Schwannoma Attached to peripheral nerve; can be separated from nerve Morphology ►Loose and dense areas – Antoni A and Antoni B ►Verocay bodies – cells lining nuclear-free area (Antoni A area) ►Common in cerebellopontine angle off of CN VIII (acoustic schwannoma) Genetic ►Mutations of NF2 gene ►NF2 frequently shows bilateral schwannomas Schwannoma (Acoustic neuroma) Verocay Body Antoni A Robbins 28-53 Antoni B Peripheral Nervous System Tumors ►Neurofibroma Cutaneous and nerve (plexiform) forms Plexiform neurofibroma cannot be separated from nerve (Tumor is throughout the nerve and not mainly peripheral) Appears as “bag of worms” S-100 and often CD34 positivity. Schwann cells (and other cell types – fibroblasts, mast cells) within myxoid background Strong association with NF1 Malignant peripheral nerve sheath tumors arise from neurofibromas and are linked to NF1 Neurofibroma Neurocutaneous Syndromes/Phakomatoses ►Genetic diseases ►Often with skin, nervous system, and other organ system involvement (neurocutaneous syndromes) ►Mental retardation and/or seizures can occur ►Types Neurofibromatosis, type 1 Neurofibromatosis, type 2 Tuberous Sclerosis Von Hippel-Lindau Sturge-Weber Phakomatoses ►Types Neurofibromatosis, type 1 ►Neurofibromas ►Gliomas of optic nerve, pigmented lesions of iris (Lisch nodules) and café-au-lait spots ►NF1 gene at 17q11.2 – neurofibromin – tumor suppressor gene Neurofibromatosis, type 2 ►Bilateral schwannomas and multiple meningiomas may occur ►Gliomas (ependymomas of spinal cord) ►NF2 gene at 22q12 - merlin Phakomatoses ►Types Von Hippel-Lindau ►Hemangioblastoma – cerebellum, retina, brain, spinal cord) ►Pancreas, liver, kidney cysts ►Renal cell carcinoma ►Gene on chromosome 3p25-26 coding pVHL ►Hemangioblastoma cells produce erythropoietin – polycythemia Sturge-Weber Syndrome Angiomas of face (port-wine stain) and underlying leptomeninges (often large) Often with intellectual disability. Sturge-Weber (Encephalofacial Angiomatosis) See Chapter 32 in Rubin’s Pathology. Sturge–Weber syndrome is a rare, nonfamilial (i.e. due to a somatic mutation) congenital disorder characterized by angiomas of the brain and face. The facial lesion is usually unilateral and is called a port wine stain (nevus flammeus). The leptomeninges contain large angiomas, which in severe cases may occupy an entire hemisphere. Cerebral calcification and atrophy often underlie the intracranial angiomas (Fig. 32-138). The link between angiomas of the face and brain may reflect the continuity of the embryologic vascular supply to the telencephalon, the eye and the overlying skin. In most instances, Sturge–Weber syndrome is associated with mental deficiency. See https://medlineplus.gov/genetics/condition/sturge-webersyndrome/#inheritance. Sturge-Weber syndrome is caused by a mutation in the GNAQ gene. This gene provides instructions for making a protein called guanine nucleotide-binding protein G(q) subunit alpha (Gαq). The Gαq protein is part of a group of proteins (complex) that regulates signaling pathways to help control the development and function of blood vessels. Hemangioblastoma (Von Hippel-Lindau Syndrome) "© Copyright UAB and the UAB Research Foundation, 1999-2000. All rights reserved. Oil Red Oil Hemangioblastoma Yachnis, Anthony T., MD, Neuropathology, N, 172-174 Hemangioblastoma. Stromal cells may have homogeneous eosinophilic cytoplasm and random nuclear atypia. Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc. Sturge-Weber Asadi S. (2019) The Role of Genetic Mutations in Gene GNAQ in Sturge-Weber Syndrome. J Cell Signal Damage Assoc Mol Patterns, 1(1): 14-13. Phakomatoses Tuberous Sclerosis Hamartomas of brain (disorganization of grey and white matter), retina, and viscera. Subependymal giant cell astrocytoma and other tumors (facial angiofibromas, cardiac rhabdomyomas, mesenchymal tumors of the kidney (angiomyolipomas). Most patients have seizures and are mentally retarded. Mutations in TSC1 and TSC2are responsible: TSC1 (9q34) encodes a protein called hamartin, and TSC2 (16p13) encodes tuberin, which is homologous to a GTPase-activating protein. Both are tumor suppressors. (per Rubin’s Pathology LWW Medical Education Library)