Pathology of CNS Tumors

CPC-44: 22y Sam G, Seizure. Sam Gully, 22y, previously healthy male. On bus, became agitated, combative, had a seizure and became unresponsive. From Boston, USA, on holidays, 3 days. No neck stiffness, no skin lesions/rash Pupils minimally reactive and 6mm bilaterally; fundoscopy normal.

CPC-44: 22y Sam G, Seizure. Epileptic seizure CVA, CNS infection, Brain tumour Drugs: drug withdrawal/ overdose Idiopathic (epilepsy), Genetic, Autoimmune, endocrine.. Head Injury Metabolic: uraemia, Hypoglycaemia, Neurodegenerative diseases e.g. Alzheimer’s Non epileptic: Syncope, arrythmias, Pseudoseizures, TIA,

CPC-4.3.7 – Jenna 27y teacher. Jenna is a 27 year old teacher in Ingham who collapsed in her classroom today. She was seen by her pupils to ‘shake all over’. Brought to ED by paramedics, accompanied by teaching colleague. Collapsed approx 30 mins ago. Tutors: (Aim: ..look at a broad range of differential diagnoses for a witnessed, generalized tonic- clonicseizure. Focus… on epilepsy, infection (meningitis), and braintumour. ..discuss ‘what if’ questions..

Scenario: Brain Tumor Chronic Crescendo Morning - Head ache* Pulse 62 bpm reg small volume; BP 140/90 mmHg T37.4C. GCS - variable. Localising signs – seizures, aphasia, anosmia, vision defects, paralysis (unilateral), dementia. Cushing’s reflex – Bradycardia hypertension (ICP) Papilloedema * raised ICP Lesion on imaging. Peritumoral edema – rapidly growing/inflammed. Cesc. Chron. Morn. headache*, Seizures, localizing signs

Scenario: Meningitis ABC breathing spontaneously rr 18/min 4l O2 via mask, sats 90%; pulse 110 bpm reg small volume; BP 90/60 mmHg T39.6C GCS - E2V3M4 Detailed check - petechiae non blanching rash trunk, buttocks, Neck stiffness Small contusion L temperoparietal area Capillary refill time > 3 secs, peripheral cyanosis+ Brudzinski sign positive Ix skin scraping from lesion : gram negative diplococci; CSF gram negative diplococci; FBC wcc 18 (polymorhic leucocytosis) Brudzinski sign, Kernig sign, CSF findings

Scenario: Epilepsy: ABC breathing spontaneously rr 14/min; 4l O2 via mask , sats (O2 Sat study) 96% ; pulse 100 bpm regular good volume T 36.1 C BP 148/94. GCS E2V3M4 Detailed check no neck stiffness, no skin lesions/rash Tongue has been bitten; pupils equal and reactive to light; fundoscopy normal Decreased tone R upper limb, ?normal tone other limbs Reflexes increased on R upper + lower limb; decreased on L upper +lower; Plantar reflexes upgoing Evidence of urinary incontinence All other systems : nil abnormal Ix - BSL : 5.1; toxicology screen : negative

Core Learning Issues: Pathology Major CLI: Raised ICP – Pathology & Clinical features. Pathology of common CNStumors in different age groups. Astrocytoma – grades, clinical types, presentation & complications. Meningitis – common types *Bacterial, viral, fungal. Pathology Minor CLI: Pathology of Epilepsy (note this is major clinical learning issue) Meningioma, Acoustic neuroma, Craniopharyngioma / pituitary tumors. Medulloblastoma. CJD-Creutzfeldt jakob's disease. (Mad cow disease).

In every person who comes near you look for what is good and strong; honor that; try to learn it, and your faults will drop off like dead leaves when their time comes.--John RuskinLook for good in others “No one is without faults and everyone has good qualities…!”

Pathology ofCNS Tumors Dr. Venkatesh M. Shashidhar, MD Associate Professor & Head of Pathology

CNS Tumors: General Features 10% of all tumors. Commonest solid cancers in children.(2nd to Leuk for all malignancies) Age: double peak 1st& 6th decade Adults - 70% supratentorial Children - 70% infratentorial No/very rare extraneural spread. Metastasis most common. Adults Children

Most common CNS Tumors: Glioblastoma MF

Clinical features: Slow, Progressive..* Crescendo, Chronic, Morning head ache. Local damage: Nerve & tract deficits, unilateral* Paralysis, vision defects, anosmia, seizures.. etc. Raised Intracranial Pressure* Headache, vomiting, slow pulse, papilloedema.

CNS Anatomy - Clinical Features

CNS Tum: Clinical Features-Pathogenesis Headaches (morning) Papilloedema Nausea or vomiting Bradycardia Seizures (convulsions). Drowsiness, Obtundation Personality or memory Changes in speech Limb weakness Balance/Stumbling eye movements or vision Increased ICP Increased ICP ICP – Medulla ob. ICP – Parasymp. Irritation. Brain Stem compress Frontal lobe Temporal lobe Motor area Cerebellum Optic tract, occipital.

CNS Tumors Classification: Secondary Tumors- Metastasis – commonest* breast, lung, GIT, Melanoma. Primary Tumors: (not from neurons…!) Glial cells:Glioma * commonest Astrocytoma (& Glioblastoma).Oligodendroma, ependymoma. Nerve sheath – Schwanoma, Neurofibroma. Meninges: Meningioma Germ cell: Medulloblastoma, neuroblastoma, teratoma, neuroma, neuroganglioma. Lymphocytes: CNS Lymphoma * Other BV: (angioma)Epithelial, Pituitary & Pineal gland tumors.

Adults: Astrocytoma & Glioblastoma. Meningioma Metastasis. Children: Astrocytoma Medulloblastoma (Metastases) Common:

Meningioma: Arachnoid granulation fibroblastsvenous sinuses (Attached to dura). Females(2:1), progesterone, cyclical/preg* Common site: parasagittal (falx), Slow growth, well differentiated & demarcated. Does not invade brain (Benign). Reactive skull Hyperostosis over the tumor.

Meningioma: Note location in the venus sinus & adherent to dura.

Meningioma Nodules Capsulated, spindle cells in whorls and psammoma bodies (common type).

Psammoma bodies (calcification)

Glioma: Gliomas are neoplasms of glial cells. Commonest both in adults and children. Benign * to Aggressively malignant. Astrocytoma(low & high grade) Ependymoma - Rare, 4th ventricle. Oligodendroglioma - Benign, adults, rare

Astrocytomas Adults: Commonest 80%, Cerebral. Low Gr: Solid, Fibrillary. High Gr: glioblastomamultiformeVarigated, Hemorrhagic - Malignant,. Children: Cystic, Low grade*, Pilocytic Infratentorial(Cerebellum),

Astrocytoma-Lowgrade fibrillary

Glioma Brain Stem – note diffuse tumor

Glioma Cerebrum cystic degeneration

Astrocytoma: * Lat. Vent. *petechial hem.

Astrocytoma (Glioma) – brain stem

Glioblastoma Multiforme (GBM): High grade Astrocytoma - Grade IV Commonest & malignant brain tumor in adults – mean survival <1y – cerebral supratentorial. Loss of heterozygosity on Chromosome 10 (80%) Most GBMs have lost one entire copy of C – 10 2 types: Primary (worst) or Secondary from low grade astrocytomas (better prog). Variants: giant cell GBM, gliosarcoma Microscopy: Necrosis, palisading, hypercellularity, nuclear atypia & vascular proliferation & mitoses.

Genetic abnormalities in Glioma:Low grade  AnaplasticGBM Note: GBM can occur alone without prior glioma

GBM: MRIEnhancement with peritumoral edema.

Glioblastoma – high grade Astrocytoma

Glioblastoma – high grade Astrocytoma Note: Looks like abscess, but it is necrosis..!

Glioblastoma Multiforme (high grade Astrocytoma)

High Gr.: Glioblastomamultiforme(high grade- Hypercellularity, necrosis, hemorrhage & palisading) Hem Hyper cel. Palis. Necro

Glioblastoma Multiforme B.V Necrosis Palisading

A Astrocytoma Low gradeB Glioblastoma Multiforme(GBM)C Necrosis with pseudopalisading in GBM.

Astrocytomas Adults: Commonest 80%, Cerebral. Low Gr: Solid, Fibrillary. High Gr: glioblastomamultiformeVarigated, Hemorrhagic - Malignant,. Children: Cystic, Low grade*, Pilocytic Astrocytoma Infratentorial(Cerebellum),

Pilocytic astrocytoma Children, slowest growth, Cerebellum, Cystic with mural nodule Micro: elongated hair-like (pilocytic) cells

Pilocytic Astrocytoma - children

Pilocytic Astrocytoma: solid, brightly contrast-enhancing mural component and associated cyst.

Pilocytic Astrocytoma: Microscopy Palisading pilocytic astrocytes – note plenty of Rosenthal fibres between cells.

Medulloblastoma: Children. Cerebellum – vermis. Primitive neuroectodermal tum. Blast cells – round scanty cytoplasm. 4th ventricle Obstruction – hydrocephalus. CSF seeding and Meningeal infiltration is common. Rosettes & neuronal or glial differentiation rarely seen.

Medulloblastoma: Primitive neuroectodermal tumor:Children, vermis of cerebellum. Spread Origin

Youtube Videos: GlioblastomaMultiforme: http://www.youtube.com/watch?v=idSos1XOi7A http://www.youtube.com/watch?v=bGawC2RJ-Sc Meningioma: http://www.youtube.com/watch?v=ddEB5ITx2fw Pyogenic Meningitis: http://www.youtube.com/watch?v=L9jpjxTSLws

CNS Lymphoma: Rare, 1%, most common CNS neoplasm in immunosuppressed (transplant recipients, AIDS), caused by Epstein-Barr Virus. High grade, large B-cell lymphomas. Poor response to chemotherapy

CNS Tumors: Summary Adults: Secondary common Lung, Skin, breast.. Primary - Supratentorial Astrocytoma / glioblastoma. Meningioma Children: 2nd common (leuk / lymph) Infratentorial Astrocytoma (cystic cerebellar) Medulloblastoma Hydrocephalus. Meningeal spread.

Learning Medicine...! Learning medicine should be a JOY, not an ordeal. Everyone learns according to their own best style. The Hippocratic oath issues of patient privacy, compassion, and FREE sharing of knowledge have to be honored. Exam and grade anxieties are the CANCERS of medical education. If your school admitted students which they feel need to be whipped, the SCHOOL has failed, not YOU! If you claim you NEED to be pushed, I do not want you as my doctor. John R. Minarcik, MD (http://www.medicalschoolpathology.com)

Pathology of Increased Intracranial Pressure

Pathogenesis: Increased intracranial pressure (ICP): - if > 40 mm Hg  cerebral hypoxia, cerebral ischemia, cerebral edema, hydrocephalus, and brain herniation. Cerebral edema: Edema - Disruption of the blood brain barrier – vasodilatation – swelling. Hydrocephalus  communicating type common in Total Body Irradiation.

Pathogenesis: Brain herniation: Supratentorial herniation common. 3 sub types Subfalcine herniation: The cingulate gyrus of the frontal lobe (commonest) Central transtentorial herniation: displacement of the basal nuclei and cerebral hemispheres downward Uncal herniation: Medial edge of the uncus and the hippocampal gyrus Cerebellar herniation: infratentorial herniation - tonsil of the cerebellum is pushed through the foramen magnum and compresses the medulla, leading to bradycardia and respiratory arrest.

Common CNS Herniations: Subfalcine:

Subfalcine Herniation: in brain trauma. Contusion of the inferior temporal lobe (blue arrow) has resulted in diffuse edema. (compressed and flattened gyri on the right). This has resulted in subfalcine herniation of the cingulate gyrus (red arrow), with a secondary hemorrhagic infarction above that (black arrow). A midline shift from right to left is also present, as is uncal herniation (yellow arrow).

Uncal Herniation: Inferior view, The herniated uncus is bulging over the position of the tentorium (black arrows) and compressing the midbrain. The two mammillary bodies (blue arrows) have been shifted to the patients right due to the pressure.

acute brain swelling + Uncal Herniation Swelling of the left cerebral hemisphere has produced a shift with herniation of the uncus of the hippocampus through the tentorium, leading to the groove seen at the white arrow.

Cerebellar Tonsil - Herniation Note the cone shape of the herniated tonsils around the medulla in this cerebellum specimen. Results in compression and Duret hemorrhages in the pons.

Transtentorial herniation: Transtentorial herniation at the base of the brain. A prominent groove surrounds the displaced parahippocampal gyrus (arrow). The adjacent 3rd nerve (N) is compressed and distorted and the ipsilateral cerebral peduncle (P) is distorted with small areas of haemorrhage.

Cerebral Herniation: Pathogenesis

Decorticate posturing, with elbows, wrists and fingers flexed, and legs extended and rotated inward.

Look for good in others… no one is without faults and everyone has some good qualities!BK.

52y, F, morning headache 1year, mood changes: Specimen of brain. ? diagnosis Glioblastoma multiforme. Astrocytoma grade 2. Meningioma. Ependymoma. Metastases.

52y, F, CNS tumor: ? diagnosis Glioblastoma m. Astrocytoma Metastases Medulloblastoma Meningioma

52y, F, CNS tumor: ? diagnosis AV malformation. Glioblastoma multiforme Astrocytoma Meningioma Medulloblastoma

52y, F, parasagittal tum attached to falx: ? diagnosis Glioblastoma m. Astrocytoma Meningioma Ependymoma Medulloblastoma

Commonest primary CNS tumor in Adults ? Glioblastoma m. Astrocytoma Meningioma Ependymoma Medulloblastoma

52y, F, CNS tumor: ? Arrow Feature Necrosis. Psammoma body Calcification Blood vessel Epithelial pearl

60y smoker, chronic bronchitis complains of difficulty walking. PE: stiff, expressionless face. A tremor of his fingers is apparent but ceases when he tries to reach for something. Image shows brain stem . Diagnosis? Alzheimers disease Lacunar infarcts Picks disease Parkinsons disease Durett hemorrhages

Commonest primary CNS tumor in Children? Glioblastoma m. Astrocytoma Meningioma Ependymoma Medulloblastoma

7y, F, CNS tumor: ? diagnosis Glioblastoma m. Astrocytoma Meningioma Ependymoma Medulloblastoma

55y Female. Died following car crash. Coroners autopsy Image shows Brain stem-What is the likely cause of death? Herniation of cerebral tonsil Intracerebral hemorrhage. Subdural hemotoma Subarachnoid hemorrhage. Glioblastoma multiforme.

Commonest Location of CNS tumor in Children? Supratentorial Cerebellum Infratentorial Cerebrum. Brain stem

56y, F Rapidly growing parietal lobe tumor:? diagnosis Glioblastoma m. Astrocytoma Meningioma Ependymoma Medulloblastoma

49y, M, CNS tumor: ? diagnosis Metastases Astrocytoma sy. Meningiomatosis Neurofibromatosis Lipomatosis

54y woman dies 48 hours after suffering severe head injuries in an automobile accident. Just before her death, her left pupil becomes fixed and dilated. An inferior view of the patient's brain at autopsy is shown. Most likely cause of death? Diffuse axonal shearing Laminar necrosis Thrombosis of sagittal sinus Transtentorial herniation Watershed infarct

48y male, Frontal lobe tum, What is the most likely diagnosis? Glioblastoma m. Astrocytoma Meningioma Ependymoma Medulloblastoma

It has been my philosophy of life that difficulties vanish when faced boldly.--Isaac Asimov

SAQ / KFP Should seizure patients have imaging done immediately? Personality changes indicate which location? Differentials for young adult with insidious symptoms, seizures and decreased signal on T1 and increased signal on T2 weighted MRI? What is the treatment and prognosis for someone with a low-grade astrocytoma? How should the symptoms be treated? What tests could have been done in the absence of neuroimaging? Yes, 10-20% tumors. Frontal lobe Other gliomas Conservative – Poor Steroids, anti epileptic, symptomatic. EEG

SAQ / KFP Why was the child hitting his head? Why did the child have a headache? If the child does have hydrocephalus, at what level is the ventricular system being obstructed at? Should a lumbar puncture be performed? Where in the cerebellum is the lesion located? What is the radiolucent area visible along the antero-superior aspect of the radiograph? Indicating headache. Increased ICP, tum. 4th ventricle. No – coning…* Central – vermis Separation/malfusion of anterior frontoparietal suture due to hydrocephalus.

SAQ / KFP Name the location of tumor? What cranial nerves are involved? List differential diagnosis Explain pathogenesis of headache and papilledema? What does the histological pattern represent in slide 1? slide 2? Cerebellopontine angle Cranial Nerves 5,7 & 8 Teratoma, meningioma, acoustic neuroma. Increased intracranial tension. Tumor attempting to form Arachnoid grannulations. Origin of tumor.

50y Female smoker - Headache. This 50 year-old female smoker known for hypertension and diabetes mellitus type 2 was in her usual state of health until 2 years ago, when she began to have morning headaches that would usually go away by themselves. Year later began to have hearing problem on her left side. Recently, she noticed intermittent loss of sensation of the left side of her face. She is taking a thiazide diuretic, captopril, glyburide, and metformin. She has no known allergies. Physical exam: Slight drooping in the left mouth and lower eyelid. Incomplete closure of the left eyelid with corneal touch. Reduced pain and light touch on the left side. Fundoscopic exam revealed bilateral papilledema.

What is the most likely diagnosis? Glioblastoma m. Astrocytoma Meningioma Ependymoma Medulloblastoma

35y Male, depression 2-year history of loss of initiative, depression. He had slowly lost his drive to win all the big deals he always done so well at work. 3 months ago he began to experience headache, which did not respond to acetaminophen or aspirin. His wife noticed that his lethargic state had increased in the past few months. 3 days ago his right arm began to convulse uncontrollably for 1 minute. 1 day ago the patient began again violently shaking his right arm, and the right side of face began to twitch at the dinner table. No fever. Physical exam: Bilateral papilledema, increased deep tendon reflexes of the right bicep, tricep, +ve babinski sign on the right foot, reduced leg strength on the right.

35y Male, depression Axial T2 weighted MRI Axial T1 weighted MRI

35y Male, depression Coronal T2 weighted MRI Coronal T1 weighted MRI

3y Male, constant cry…. Constant crying and not interacting with other children at daycare since 1m. Mother noticed that he was pointing to his head often. Family physician who stated that he was developing normally, and that the “ terrible two’s” are difficult period for parents. Recently started vomiting on a daily basis and started wobbling even though he learned to walk 6 months ago. Physical: Bilateral papilledema and gait ataxia was noted on the physical exam.

Axial T1 weighted MRI Axial T2 weighted MRI 3y Male, constant cry….

Coronal T1 weighted MRI 3y Male, constant cry….

65y Fem morning headache. Morning headache 2y, Progressive right upper limb weakness. She woke up this morning obtunded, and did not initially respond to her husband’s cries. She screamed to her husband that she could not see anything to her right, and that she that her left arm and leg were very weak. At this point her husband rushed her to the nearest hospital. Physical Exam: left lid ptosis, left-pupillary dilation, and failure of her left eye to constrict to light directly or consenually. Patient had bilateral lower limb weakness, with increased deep tendon reflexes on the left side, and a +ve babinski on the left side. Bilateral Papilledema. Homonymous hemianopia of the right side. Visual acuity was corrected to 20/20 with glasses.

Brain Metastasis: Lung, Breast, Skin, Kidney, GIT. Prostate – never..! Well demarcated, usually multiple with surrounding rim of inflammation. Carcinomatosis: Meningeal CSF spread of malignant cells.

Brain Metastases: Surrounding edema.

SAQ / KFP Are there clinical signs of nerve compression? What is the most likely cause of the homonymous hemianopia? Why does the patient have progressive right upper limb weakness, and paroxysmal left upper and lower limb weakness? Should a lumbar puncture be performed? Why was the patient obtunded? Why was an-x-ray taken? Yes, ptosis, pupils 3rd Optic pathway -occipital. Motor cortex compression – tum. Risky. Brainstem compression. Meningioma hyperostosis.

CPC-3.7– KFP Questions: Meningitis Types, classification & comparison. Septic, Viral & TB meningitis. Morphology, complications. Laboratory diagnosis, CSF findings. CNS tumours: common features. Adult and childhood CNS tumors. Common Types & features. Increased intracranial pressure – Pathologic basis of clinical features.

Neuroectodermal Tumors Origin from primitive blast cells. Rosettes - attempted nerve formation. Medulloblastoma – Cerebellum Retinoblastoma - Retina Neuroblastoma – Adrenal glands Ganglioneuroma - Mediastinum

Nerve Sheath Tumors: Neurofibroma: Epi & endoneurial fibroblasts. Form whorls of fibroblasts with nerves Well differentiated, benign, capsulated. Schwannoma: Schwann cells, elongated form whorls Nuclear palisading

Bilateral 8th nerve schwannomas.

Neurofibromatosis: Café-au-lait spot

Summary: Children – 70% INFRAtentorial Adults – 70% SUPRAtentorial Common Malignant - adults, metastatic tumors (Lungs) Common - adults – glioblastomamultiforme Intracerebral Common Benign - children – cerebellar astrocytoma. Common Mal - children – cerebellar medulloblastoma Very rare – meninges and schwann cells (meningiomas and schwannomas) – usu. found in adults

A 26-year old female Headache,vomiting, an epileptic attack, weakness of legs. Now drowsy. Two weeks before admission she gave her second birth. CT and NMR revealed a huge parasagittal tumor (80x67x65 mm), enhanced by contrast, compressed corpus callosum and ventricles.

Histopathology: Bifrontal parasagittal tumor, craniectomy and tumor was totally removed. Well demarcated, firm white lobular.

37 yr Female Serious automobile accident and sustained a close head injury,she does not immediately seek medical attention, but is brought to the emergency room two hours later by her brother,on physical examination there is mydriasis and loss of pupillary light reflex,several hours later she is unable to follow a flash light with her eyes,which of the following herniation is most likely occuring in this patient???? A)cerebellar tonsils into the forman magnum B)cerebellum upward past the tentorium C)singulate gyrus under the falx D)medulla into the foramen magnum E)temporal lobe under the tentorium

32y Female Fleshy pappules: Several fleshy papules on face, trunk, and upper extremities. Since 10y of age. Increased & Irritation over the past 5 y. Previous excision have recurred. No other significant history.

Neurofibromatosis: Autosomal dominant, NF1- Peripheral/Von Recklinghausen’s NF2- known as central NF. However, NF1 may cause central characteristics. About 50% familial, 50% sporadic gene mutation. NF1/ von Recklinghausen disease, gene mutation on chromosome 17, 1 in every 3000-4000 births. Diagnosis of NF1 if > 2 of 6 or more café au lait spots (irregularly shaped, evenly pigmented, brown macules), 2 or more neurofibromas, axillary or inguinal freckling, Lisch nodules on the iris or optic glioma, various types of osseous lesions, a first-degree relative with the condition.

Neurofibromatosis: NF2 – Gene mutation chromosome 22. 1 in every 33,000-40,000 births Typically present with acoustic neuromas or vestibular schwannomas. Tinnitus, balance disorders, and progressive hearing loss May also have meningiomas and juvenile cataracts. First-degree relative and on any 2 of the conditions listed for NF1. Patients with NF1 are at increased risk of malignancy. Annual ocular examinations are recommended. Genetic testing is also advocated in patients with NF who wish to have children. Surgery has been a successful treatment for the lesions themselves; however, recurrence often occurs, and nerve damage is a risk when tumors are located along neural pathways (National Institute of Neurologic Disorders and Stroke, 2006).

7th nerve palsy: Cerebellopontine angle tumours. Acoustic neuroma, epidermoid cysts, medulloblastoma meningioma Affected cranial nerves: 5 trigeminal - masticatio 7 facial –face muscles 8 auditory – hearing

Brudzinski Sign of Meningitis:

Scenario: Brain Tumor ABC as for scenario 1 GCS E3V4M5 Detailed check no neck stiffness, no rash Tongue has been bitten; small contusion L temperoparietal area PEARL fundoscopy normal L sided weakness arm > leg with increased tone and reflexes L plantar reflex equivocal; R plantar reflex downgoing Evidence urinary incontinence All other systems : no abnormalities Ix - as per scenario 1; MRI scan ?gliobalstoma multiforme R fronto-parietal region

Pathology of CNS Tumors

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Pathology of CNS Tumors