Central Nervous System and Peripheral Nervous System Tumors (Student) Neuroscience and Behavior UDOS What makes primary CNS tumors different than those of other sites? • Primary CNS tumors are not staged with the TNM classification because they rarely spread outside of the CNS • Still assign CNS tumors histologic grades that correlate with prognosis and treatment • WHO classification system that divides tumors into 4 grades based on their biologic behavior • Classification system updated in 2016 to incorporate molecular features so now reported as an integrated diagnosis composed of histologic and molecular subtypes • High grade tumors can be classified as “primary” or “secondary” • Primary tumors arise de novo • Secondary tumors are those that progressed from a low grade to a high grade tumor WHO Grading System WHO Grade I Low grade/proliferation; possible cure w/ surgical resection alone II Low grade, but more infiltrative and higher tendency to recur after resection III Higher grade infiltrative tumors w/ clear malignant histologic features such as nuclear atypia and high mitotic activity IV High grade infiltrative malignant tumors with greater degree of nuclear atypia, high mitotic activity and necrosis CNS Tumor Introduction • Includes tumors that involve all parts of the CNS from the cerebral hemispheres to the end of the spinal cord • Many CNS tumors have characteristic anatomic regions they involve or age distributions • Ionizing radiation only established risk factor for non-lymphoid tumors • Histologic features and grading schemes important to differentiate b/w benign and malignant tumors. However, location is also key. A benign or low grade tumor can be fatal or lead to significant morbidity depending on its location. WHO Histologic Grading • What criteria are involved in WHO grading? • Do you remember what the definition of anaplasia is from FHD? The primary tumors of the CNS are not types we learned about in Fundamentals of Health and Disease like squamous cell carcinoma or adenocarcinoma. These are only seen as metastatic lesions in the CNS. We are going to review the main cell types found in the CNS before diving into the primary tumor types in order to understand how these tumors arise. Review of CNS Cell Types • What CNS cell type is seen in the picture below? • What role does this cell type play? Image source: http://neuropathologyweb.org/chapter1/chapter1aNeurons.html Review of CNS Cell Types • What cell types comprise the glial cells? What role do each of these cell types play? Review of CNS Cell Types Oligodendrocytes Ependyma GFAP stain of astrocytes Image source: http://neuropathologyweb.org/chapter1/chapter1cOligodendr oglia.html Review of CNS Cell Types • What are the phagocytic cells of the CNS called? What cell type do these arise from? • What cell type synthesizes myelin in the peripheral nervous system? CNS Tumor Classification 2016 WHO Classification Category Examples Diffuse astrocytic and oligodendroglial tumors (Diffuse gliomas) Diffuse astrocytoma Anaplastic astrocytoma Glioblastoma Oligodendroglioma Anaplastic oligodendroglioma Other astrocytic tumors Pilocytic astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Ependymal tumors Subependymoma Ependymoma Choroid plexus tumors Choroid plexus papilloma Choroid plexus carcinoma Neuronal and mixed neuronal-glial tumors Dysembryoplastic neuroepithelial tumor Ganglioglioma Paraganglioma Tumors of the pineal region Pineocytoma Pineoblastoma CNS Tumor Classification 2016 WHO Classification Category Examples Embryonal tumors Medulloblastoma CNS neuroblastoma Tumors of the cranial and paraspinal nerves Schwannoma Neurofibroma Meningiomas Meningioma Atypical meningioma Anaplastic (atypical) meningioma Lymphomas Diffuse large B-cell lymphoma Tumors of the sellar region Craniopharyngioma Metastatic tumors Diffuse Gliomas • Arise from a progenitor cell that differentiates into astrocytic or oligodendrocytic cell types • Most common group of primary brain tumors • Important genetic alterations include the IDH gene and 1p/19q chromosomal co-deletion • Have a tendency to infiltrate surrounding brain parenchyma, so complete surgical resection for low and high grade tumors may not always be possible IDH Mutations • • • • Isocitrate dehydrogenase Enzyme in Krebs cycle Mutation is early event in tumorigenesis Two variants (IDH1 and IDH2) • IDH1 mutations much more common • Main consequence of IDH1 mutations that lead to carcinogenesis is inhibition of enzymes that regulate DNA methylation • After determining a tumor is a glioma by histology, IDH tumor status is the next most important step Lee, Sunhee. Diffuse Gliomas for Nonneuropathologists: The New Integrated Molecular Diagnostics. Arch Pathol Lab Med. 2018;142:804–814 Diffuse Glioma Classification Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2016) World Health Organization Histological Classification of Tumours of the Central Nervous System. International Agency for Research on Cancer, France Diffuse Astrocytic Tumors • The vast majority (~80%) of primary CNS tumors in adults are considered infiltrating astrocytomas. These tumors consist of tumors diffuse astrocytomas, anaplastic astrocytomas, and glioblastoma • Astrocytic tumors occur more often in the cerebral hemispheres • Lower grade tumors like the one pictured below are much more illdefined than higher grade glioblastomas https://www.webpathology.com/image.asp?n=9&Case=736 Astrocytic Tumors Gemistocytic https://www.webpathology.com/image.asp?n=2&Case=736 Image source: GRIPE https://www.webpathology.com/image.asp?n=5&Case=736 Case 1 A 63-year-old man presents to the emergency department following a seizure. He does not have a history of prior seizures, and only complains of recent problems with a dull, constant headache over the last few weeks. A head CT image is shown in the image. Image source: https://radiopaedia.org/articles/butterfly-glioma Case 1 • What type of primary brain tumor is most likely in this case? • GBM • What radiologic features are seen with this tumor? • Big, crosses corpus collusum • What histologic findings would you expect to find in this tumor? • Necrosis, angiogenesis • What is this patient’s prognosis? • Poor Case 1 • What immunohistochemical stain is used to target glial cells when evaluating whether a tumor is a primary CNS tumor or a metastatic lesion? • GFAP • Are the majority of glioblastomas IDH-wildtype or IDH-mutant? • Wild-type • Do IDH-wildtype or IDH-mutant tumors have a better prognosis? • Mutant have better prognosis Glioblastoma Grow more rapidly than lower grade tumors so can appear more circumscribed (may mimic metastatic lesion) Ring enhancing lesion due to abnormal vascularization and necrosis Glioblastoma Butterfly Lesion Image source: https://radiopaedia.org/articl es/butterfly-glioma Glioblastoma Histology Pseudopalisading necrosis (can have a serpentine pattern) Image source: https://webpath.med.utah.edu/CNSHTML/CNS 139.html Vascular/endothelial proliferation Case 2 • A 41 year old male presents to the emergency department following a seizure. He does not have a history of prior seizures. A non-contrast head CT is shown in the image. Additional radiologic images reveal areas of calcification within the lesion. Head CT https://radiopaedia.org/ Case 2 https://peir.path.uab.edu/library/picture.ph p?/18102/search/1250 https://peir.path.uab.edu/library/picture.p hp?/3583/search/1250 Case 2 • What is the diagnosis in this case? • Are these tumors usually IDH mutant or IDH-wild type? • What other characteristic mutation is found in these tumors? • How does the prognosis and behavior of these tumors compare to GBM’s? • What are the characteristic histologic features of an oligodendroglioma? Case 2: Oligodendroglioma • • • • WHO grade II Most common in 4th and 5th decades of life More often in white matter and in frontal lobes Commonly contain calcifications that can be seen with imaging • Additional molecular changes seen with anaplastic type (WHO grade III) has effect on both treatment and prognosis Case 3 A 12 year old boy is brought in by his parents for intermittent headache, nausea and vomiting for 3 months. Within the past 2 weeks, his symptoms have gotten much worse. His headache is now constant, dull, and a 6 out of 10. When asked about location, he pointed at his forehead and rubbed along the top of his head. Tylenol only slightly improves the headache. He notices his headache more when he wakes up in the morning. His nausea has made him unsteady on his feet a lot lately, but he denies any major falls. He normally does well at school. However, during the past 3 months, he has had a hard time concentrating and hasn’t performed well on tests. He has been a healthy child up until now. He denies any other symptoms, including visual disturbance, neck stiffness, fever, sinus issues, seasonal allergies, sensitivity to light, or neurological deficits (weakness or numbness in his arms or legs). Case 3: An MRI is performed and the images are shown below. T1 without contrast T2 T1 with contrast Based on the location and age of the patient, what tumor types are in your differential? Case 3: Pilocytic Astrocytoma • Well circumscribed • Contains both cystic and solid areas Pilocytic Astrocytoma Rosenthal fiber Eosinophilic granular bodies http://neuropathologyweb.org/chapter7/chapter7c Othergliomas.html#pa Glomeruloids of thin walled blood vessels, demonstrated here with Jones stain, are also characteristic features of pilocytic astrocytoma Pilocytic Astrocytoma • Most common CNS tumor of children • Usually found in the posterior fossa/cerebellum • Benign tumor with good prognosis (WHO grade I) • Tumors involving harder to resect areas like the optic chiasm or hypothalamus may have a poor prognosis (“location is key”) • Name comes from the hair-like processes seen within the tumor • Tumor infiltration of surrounding brain parenchyma is much less than the other infiltrating astrocytic tumors Adult vs Pediatric Patients The most common location for CNS tumors differs in adults and pediatric patients. • Where do the majority of pediatric CNS tumors arise? • Where do the majority of adult CNS tumors arise? • Are CNS tumors more common in adults or children? • Absolute numbers: adults • Percentage of tumors: children Practice Question Pilocytic astrocytoma is the most likely diagnosis for which one of the listed clinical situations? A. A poorly defined cystic calcified tumor in the hypothalamus of an adult B. A well-circumscribed cystic tumor in the cerebellum of a child C. A well-circumscribed noncystic tumor attached to the dura of an adult D. An infiltrative noncystic tumor in the cerebellum of a child E. An infiltrative necrotic tumor that crosses the midline in an adult Case 4 An 11-year-old girl has had increasing headaches upon awakening for the past month. On examination, papilledema is present bilaterally. An MRI of her brain reveals a 3-cm solid circumscribed mass within the fourth ventricle. There is third and lateral cerebral ventricular dilation. True rosettes and perivascular rosettes http://neuropathology-web.org/ Case 4 • What is the diagnosis? • ependymoma • Where is the most common location for this tumor to occur in children? What about in adults? • 4th ventricle, spinal cord • These tumors can obstruct the 4th ventricle. What would be an expected complicationn of this that is seen in the case presentation? • Hydrocephalus, papilledema Case 4: Ependymoma • Usually arise by the normal ependyma that lines the ventricular system • Grossly can appear solid or papillary • Complete resection not normally possible due to location • Majority are WHO grade II tumors • Myxopapillary ependymoma = special variant seen in the filum terminale • Well circumscribed and contains a large amount of mucin • More common in adults like other spinal cord ependymomas Case 4: Ependymoma Spinal cord Choroid Plexus Tumors • Choroid plexus papilloma: • More common in young children and in lateral ventricles • Adult tumors are most often in the 4th ventricle • Cause hydrocephalus from obstruction or overproduction of CSF • Friable masses commonly with calcification • Often resectable Image source: http://neuropathologyweb.org/chapter7/chapter7dEpendymoma.html#e pendymoma • Choroid plexus carcinoma: • Very rare • Histologically resembles an adenocarcinoma https://peir.path.uab.edu/library/picture.php?/19186/search/1273 Case 5 A 45 year-old female is brought to the ED after she hit her head in a car accident. A head CT scan does not show intracranial hemorrhage, but a round enhancing lesion is seen in the image. The patient does not have neurologic deficits and denies a history of headache, nausea, vomiting, or changes in her vision. Image source: https://radiopaedia.org/ Case 5 These are examples of gross images from the tumor in this patient. • What is the most likely diagnosis? Case 5 • Are these tumors more common in men or women? • Women, progesterone receptors • What is the structure in the pictures below called? What are some other tumor types these can be seen in? • Whorled pattern and psammoma bodies https://peir.path.uab.edu/libr ary/index.php?/search/1278/s tart-195 http://neuropathologyweb.org/chapter7/chapter7fMi scellaneous.html#meningioma Case 5: Meningioma Histology • Classically whorled pattern https://peir.path.uab.edu/library/pi cture.php?/20620/search/1278 Meningioma • Tumors that arise from meningothelial cells • Most considered WHO grade I • Normally attached to the dura • May have chromosome 22 deletion • Prior radiation to the head and neck region is a risk factor • Atypical meningiomas are more aggressive tumors that show more cellular atypia and mitotic figures • Can grow more rapidly during pregnancy due to expression of progesterone receptors Neuronal and Mixed Neuronal-Glial Tumors • Show neuronal differentiation • Ganglioglioma is the most common CNS neuronal tumor • Less common than pure glial tumors Ganglioglioma • • • • • Most commonly seen in the first 3 decades of life Usually slow-growing Temporal lobe is characteristic location Patients often have a history of seizures Resectable lesion with excellent prognosis https://peir.path.uab.edu/library/picture.php?/23349/ search/1272 Case 6 A 5 year-old boy presents with morning headaches, vomiting, and decreased energy that have worsened over the last few months. Recently he has started to have problems keeping his balance and falling. An MRI shows a heterogenous mass arising in the cerebellum and extending into the 4th ventricle. Medulloblastoma • Where do medulloblastomas occur? • What is the prognosis in patients whose tumors are totally resected and receive radiation? • “Drop metastases” can be seen with medulloblastomas. What does this mean? Medulloblastoma • Most common embryonal type of tumor • Lack expression of mature neural cell markers • Embryonal tumors can differentiate along neuronal, glial, or mesenchymal lines • Most common malignant CNS tumor in children • By definition involves the cerebellum • WHO grade IV • Histology: • Small anaplastic cells with scant cytoplasm • Abundant mitotic figures Medulloblastoma • Two classification systems: • Histologic classification has been used for an extended period of time • Now being classified into 4 main molecular subtypes if molecular testing available • Histologic patterns shown to have clinical utility, so worth noting that there are 2 ways to classify (no need to memorize though) Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–820. doi:10.1007/s00401-016-1545-1 Example of a Sellar Region Tumor: Craniopharyngioma • Most common supratentorial tumor in children • Arises from Rathke pouch remnants • Can compress pituitary, so can present with pituitary hormone deficiencies (will cover more in ERMD) • Physical exam may show evidence of pituitary hormone deficiency like short stature with loss of growth hormone. Also can reveal visual changes, specifically bitemporal hemianopsia Craniopharyngioma • Calcifications common, and can be seen with radiologic imaging • Cyst fluid can be viscous and look like “motor oil” and contains cholesterol crystals Metastatic Tumors • Very common (up to ½ of intracranial tumors) • Gray-white matter junction or watershed regions • Sharply demarcated lesions Schwannoma • Example from the “tumors of the cranial and paraspinal nerves” WHO category • Benign tumor that often arises from a nerve • Well-circumscribed and encapsulated • Do not actually invade into the nerve • Schwan cells are spindled with wavy nuclei • Classically involve cranial nerves VII and VIII • Tumors involving cranial nerve VIII = vestibular schwannoma Schwannoma Histologic Features • Biphasic with alternating areas of hyper- and hypo-cellularity • Antoni A = hypercellular areas that often contain Verocay bodies • Antoni B = hypocellular areas with myxoid matrix Verocay bodies Schwannoma • What immunhistochemical stain that targets neural crest cells is positive in schwannomas? • GFAP • What symptoms would you expect a patient with a vestibular schwannoma to present with? Case 7 A 17 year-old boy presents to his physician with progressive hearing loss and ringing in both ears over the last few months. A physical exam reveals multiple hyperpigmented macules on the patient’s arms and legs. A head CT shows bilateral enhancing masses filling the internal acoustic canals. Histologic examination of the lesions confirm that they are acoustic neuromas (schwannomas). What genetic disorder does this patient have? Neurofibromatosis type 2 Neurofibromatosis Type 2 • What is the underlying genetic abnormality in this disorder? • These patients develop multiple types of neoplasms. What are some of these characteristic lesions? • What are the hyperpigmented macules seen on this patient called? • What are some other signs/symptoms that can be seen in NF2 patients? Neurofibromatosis Type 1 This is a related disorder and needs to be differentiated from NF2. It is also referred to as von Recklinghausen disease, and is more common than NF2. • What is the genetic abnormality in this disease? • What dermatologic findings are present in these patients? • What eye finding can be seen in NF1 patients? • What CNS tumor are NF1 patients at increased risk of developing? • What are some other clinical features that can be seen not listed above? Neurofibromatosis Type 1 Neurofibroma Café-au-lait spot Neurofibroma • Benign tumor of the nerve sheath composed of neoplastic Schwann cells, perineurial-like cells, fibroblasts, mast cells, and CD34+ spindle cells • Occur mostly in the superficial dermis and subcutaneous tissue • Can be sporadic as well as occurring in NF1 • Special growth pattern involving nerve roots or larger nerves called a plexiform neurofibroma is only seen in NF1. This variant has a higher risk of malignant transformation to a higher grade tumor called a malignant peripheral nerve sheath tumor. Familial Tumor Syndromes With CNS Tumors • Neurofibromatosis • Tuberous sclerosis • Von Hippel-Lindau • Cowden syndrome • Li-Fraumeni syndrome • Turcot syndrome • Gorlin syndrome Tuberous Sclerosis • Autosomal dominant syndrome involving TSC1 or TSC2 • Patients develop multiple types of hamartomas and benign tumors involving the CNS, kidneys, heart, lungs, retina, and skin • Lesions involving the CNS lead to seizure disorders, autism, and mental retardation • CNS hamartomas = cortical firm hamartomas (“tubers”) and subependymal nodules • Subependymal nodules can bulge into the ventricles and give the surface a characteristic appearance called “candle guttering” • Low grade neoplasm can develop from the subependymal nodules called a subependymal giant-cell astrocytoma (unique to tuberous sclerosis) • Other characteristic cutaneous lesions: • Shagreen patches = area of leathery thickening • Ash-leaf patch = area of hypopigmentation Von Hippel-Lindau Syndrome • Autosomal dominant disease involving the VHL tumor suppressor gene • CNS hemagioblastomas: • Usually cerebellar or retinal • Composed of thin-walled capillaries w/ some intervening parenchyma • Other associated neoplasms: • Renal cell carcinoma • Pheochromocytoma • Can see secondary polycythemia due to erythropoietin production Putting It All Together…. • What tumors are in your differential of a posterior fossa tumor in a child? • Metastatic tumors to the brain are very common. What about the reverse? Is it common to see primary CNS tumors metastasize outside of the CNS? • Recurrent tumors often are of higher grade than previous tumor. This does not represent new disease, but a “clonal evolution of the same tumor” Putting It All Together: Clinical Findings • What are the different ways patients can present with brain tumors?
