Pathology of CNS Tumours - Lecture

1. Pathology of CNS Tumours - Lecture CNS Tumors CPC-44: 22y Sam G, Seizure.  Mr. SG, 22y, previously healthy male.  On bus, became agitated, combative, had a seizure and became unresponsive.  From Boston, USA, on holidays, 3 days.  No H/O neck stiffness, no skin lesions/rash  Pupils minimally reactive and 6mm bilaterally; fundoscopy normal.

2. CNS Tumors 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: ..look at a broad range of differential diagnoses for a witnessed, generalized tonic- clonic seizure. Focus… on epilepsy, infection (meningitis), and brain tumour.  ..discuss „what if‟ questions.. CNS Tumors 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: ..look at a broad range of differential diagnoses for a witnessed, generalized tonic- clonic seizure. Focus… on epilepsy, infection (meningitis), and brain tumour.  ..discuss „what if‟ questions..

3. CNS Tumors CPC-44: 22y Sam G, Seizure.  Epileptic seizure  CVA, CNS Injury, infection, tumour & Epilepsy*  Drugs: drug withdrawal/ overdose  Idiopathic (epilepsy), Genetic, Autoimmune, endocrine..  Metabolic: uraemia, Hypoglycaemia,  Neurodegenerative diseases e.g. Alzheimer‟s  Non epileptic:  Syncope* - vasovagal  Arrhythmias, Pseudoseizures (psychogenic),  Concussion, TIA CNS Tumors CPC-44: 22y Sam G, Seizure.  Epileptic seizure  CVA, CNS Injury, infection, tumour & Epilepsy*  Drugs: drug withdrawal/ overdose  Idiopathic (epilepsy), Genetic, Autoimmune, endocrine..  Metabolic: uraemia, Hypoglycaemia,  Neurodegenerative diseases e.g. Alzheimer‟s  Non epileptic:  Syncope* - vasovagal  Arrhythmias, Pseudoseizures (psychogenic),  Concussion, TIA

4. CNS Tumors 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. Cresc. Chron. Morn. headache*, Seizures, localizing signs CNS Tumors 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. Cresc. Chron. Morn. headache*, Seizures, localizing signs

5. CNS Tumors 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 CNS Tumors 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

6. CNS Tumors 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 Negative signs, family / past history CNS Tumors 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 Negative signs, family / past history

7. CNS Tumors Core Learning Issues:  Pathology Major CLI:  Raised ICP – Pathology & Clinical features.  Pathology of common CNS tumors in different age groups.  Astrocytoma – grades, clinical types, presentation & complications. – “glioblastoma multiforme”  Meningitis – common types *Bacterial – Micro-Lec*.  Pathology Minor CLI:  Pathology of Epilepsy (note this is major clinical learning issue)  Meningioma, Acoustic neuroma, Craniopharyngioma / pituitary tumors. Medulloblastoma.  CJD-Creutzfeldt jakobs disease. (Mad cow disease). CNS Tumors Core Learning Issues:  Pathology Major CLI:  Raised ICP – Pathology & Clinical features.  Pathology of common CNS tumors in different age groups.  Astrocytoma – grades, clinical types, presentation & complications. – “glioblastoma multiforme”  Meningitis – common types *Bacterial – Micro-Lec*.  Pathology Minor CLI:  Pathology of Epilepsy (note this is major clinical learning issue)  Meningioma, Acoustic neuroma, Craniopharyngioma / pituitary tumors. Medulloblastoma.  CJD-Creutzfeldt jakobs disease. (Mad cow disease).

8. 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…!” 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…!”

9. Pathology ofCNS TumorsDr. Venkatesh M. Shashidhar, MD Associate Professor & Head of Pathology Pathology ofCNS TumorsDr. Venkatesh M. Shashidhar, MD Associate Professor & Head of Pathology

10. . CNS Tumors CNS Tumors: General Features  10% of all tumors. (10 to 17 per 100,000)  Commonest solid cancers in children.(2nd to Leuk)  Age: double peak 1st & 6th decade  Adults - 70% supratentorial  Children - 70% infratentorial  Metastatic tumors are the most common (50-70%)  Primary - glial origin.  Very rare extraneural spread.  Location & not nature determines prognosis.

11. . CNS Tumors Most common CNS Tumors: Adults children

12. . CNS Tumors CNS Tumors Classification: Secondary Tumors - Metastasis – commonest >50%* 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.

13. . CNS Tumors 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.

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

15. . CNS Tumors CNS functional anatomy – localizing signs

16. . CNS Tumors Common:  Adults:  Astrocytoma & (Metastases) Glioblastoma.  Meningioma  Metastasis.  Children:  Astrocytoma  Medulloblastoma

17. . CNS Tumors Meningioma:  Arachnoid granulation fibroblasts venous 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.

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

19. . CNS Tumors Meningioma: multiple

20. . CNS Tumors Meningioma Tumor MCAQ Pituitary

21. . CNS Tumors Meningioma

22. . CNS Tumors Meningioma high grade: (rare)

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

24. . Psammoma bodies(calcification)

25. . CNS Tumors 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

26. . CNS Tumors Astrocytomas - Glioma  Adults:  Commonest 80%, Cerebral.  Low Gr: Solid, Fibrillary glioma  High Gr: glioblastoma multiforme Varigated, Hemorrhagic - Malignant,.  Children:  Cystic, Low grade*, Pilocytic  Infratentorial (Cerebellum), mutations of the metabolic enzyme Isocitrate DeHydrogenase (IDH1 and IDH2) are common in lower-grade astrocytomas. As a result, immunostaining for the mutated form of IDH1 has become an important diagnostic tool for low grade gliomas.

27. . CNS Tumors Astrocytoma-Lowgrade fibrillary

28. . CNS Tumors Astrocytoma

29. . CNS Tumors Glioma Brain Stem – note diffuse tumor

30. . CNS Tumors Glioma Cerebrum cystic degeneration

31. . CNS Tumors Glioma:

32. . CNS Tumors Astrocytoma: * Lat. Vent. *petechial hem.

33. . CNS Tumors Astrocytoma (Glioma) – brain stem

34. . CNS Tumors Glioma Brain Normal

35. . CNS Tumors Astrocytomas  Adults:  Commonest 80%, Cerebral.  Low Gr: Solid, Fibrillary.  High Gr: glioblastoma multiforme Varigated, Hemorrhagic - Malignant,.  Children:  Cystic, Low grade*, Pilocytic  Infratentorial (Cerebellum),

36. . CNS Tumors 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.

37. . CNS Tumors Genetic abnormalities in Glioma: Low grade  Anaplastic  GBM * GBM can occur alone without prior glioma In glioblastoma, loss-of-function mutations in the p53 and Rb tumor suppressor pathways and gain-of-function mutations in the oncogenic PI3K pathways have central roles in tumorigenesis.

38. . CNS Tumors Glioma: high grade

39. . CNS Tumors GBM: MRI Enhancement with peritumoral edema.

40. . CNS Tumors Glioblastoma – high grade Astrocytoma

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

42. . CNS Tumors Glioblastoma Multiforme (high grade Astrocytoma)

43. . CNS Tumors Glioblastoma Cerebrum

44. . CNS Tumors High Gr.: Glioblastoma multiforme (high grade- Hypercellularity, necrosis, hemorrhage & palisading) Hyper cel. Hem Necro

45. . CNS Tumors Glioblastoma Multiforme Necrosis Palisading

46. . CNS Tumors Glioblastoma Multiforme

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

48. . CNS Tumors Astrocytomas  Adults:  Commonest 80%, Cerebral.  Low Gr: Solid, Fibrillary.  High Gr: glioblastoma multiforme Varigated, Hemorrhagic - Malignant,.  Children:  Cystic, Low grade*, Pilocytic Astrocytoma  Infratentorial (Cerebellum),

49. . CNS Tumors Pilocytic astrocytoma  Children, slowest growth,  Cerebellum,  Cystic with mural nodule  Micro: elongated hair-like (pilocytic) cells Mutations in IDH1 and IDH2 (common in low-grade diffuse astrocytomas) are not found in pilocytic tumors. These genetic distinctions support the division of these astrocytomas into two diagnostic categories.

50. . CNS Tumors Pilocytic Astrocytoma - children