Please Silence Your Cell Phones. Thank You

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2 Please Silence Your Cell Phones Thank You

3 The three M s of human brain cancer: Morphology, Models and Molecular biology Anne F Buckley MD PhD Department of Pathology Pediatric Brain Tumor Foundation Institute, Preston Robert Tisch Brain Tumor Center Duke University, Durham, NC

4 Disclosure of Relevant Financial Relationships The USCAP requires that anyone in a position to influence or control the content of all CME activities disclose any relevant relationship(s) which they or their spouse/partner have, or have had within the past 12 months with a commercial interest(s) [or the products or services of a commercial interest] that relate to the content of this educational activity and create a conflict of interest. Complete disclosure information is maintained in the USCAP office and has been reviewed by the CME Advisory Committee. Dr. Buckley declares she has no conflict of interest to disclose.

5 Primary human brain neoplasms Mesenchymal (e.g. meningioma) Glial infiltrating (astrocytoma, oligodendroglial) non infiltrating (pilocytic astrocytomas, ependymal) Neuronal (e.g. neurocytoma) Embryonal (e.g. medulloblastoma) Germ cell (e.g. germinoma, teratoma)

6 Meningiomas

7 Meningiomas are the most common primary intracranial neoplasm autopsy brain CT with contrast Wikimedia commons

8 Meningiomas arise from arachnoid cap cells Skull Arachnoid surface Pia mater VandenBerg/missinglink.ucsf.edu

9 Common histologic features: Meningothelial variant of meningioma (WHO grade I)

10 EMA immunostaining in meningioma

11 Some other histologic variants of meningioma fibrous angiomatous secretory microcystic Wikimedia commons/jensflorian psammomatous

12 Histologic grade is the best predictor for local recurrence of meningiomas WHO Grade I 7 25% WHO Grade II (atypical) 29 52% WHO Grade III (anaplastic) 50 94%, and 19% risk of metastasis

13 WHO grade II features (atypical meningioma) Brain invasion or Increased mitotic activity (>=4/10 hpf) or 3/5 of 1. Increased cellularity 2. Small cells with increased N:C ratio 3. Prominent nucleoli 4. Sheet like growth 5. Spontaneous necrosis or Specific histologic variants: chordoid or clear cell Wikimedia commons/jensflorian

14 Chordoid meningioma Wikimedia commons/jensflorian Clear cell meningioma

15 WHO Grade III features (anaplastic meningioma) High mitotic activity (>=20/10 hpf) or Cellular anaplasia (sarcoma, carcinoma, melanoma like) or Specific histologic variants (papillary, rhabdoid)

16 Papillary meningioma Wikimedia commons/jensflorian Rhabdoid meningioma Wikimedia commons/marvin 101

17 Meningioma MIB 1 labelling indices (WHO grades I, II, III) MIB1 immunostaining of proliferation marker Ki67 WHO Grade I 1 2% WHO Grade II % WHO Grade III %

18 Treatment of meningioma Grade I: Asymptomatic or manageable symptoms: surveillance Symptomatic: maximal safe resection with post op surveillance Grade II: Maximal safe resection, followed by active surveillance if gross total resection Adjuvant external beam radiation therapy/stereotactic radiosurgery if subtotal resection Grade III: Maximal safe resection, followed by adjuvant external beam radiation therapy Chemotherapy for salvage only (anti VEGFR agents)

19 Epidemiology/etiology of meningiomas Most causes unknown Incidence increasing: environmental change/detection increase Known environmental association: ionizing radiation tinea capitis therapy in 1960 s; atomic bombs; higher dose dental x rays Younger patients More likely higher grade Structural abnormalities of 1p, 18q, 10q seen more often in radiation associated meningiomas

20 Molecular Genetics of Meningiomas NF2 gene product: Merlin Member of cell membrane/cytoskeleton associated protein 4.1 superfamily Mutated in most neurofibromatosis (NF2) meningiomas, and in 40% sporadic (fibrous, transitional, psammomatous, atypical, anaplastic) Neurofibromatosis patients have a 50 75% risk of meningioma

21 Molecular Genetics of Meningiomas Riemenschneider, Perry & Reifenberger (2006) The Lancet Neurology 5:1045

22 Meningioma: location associations Skull base and spine: slower growth, lower grade Medial skull base: non NF2 genetic profile Lateral and posterior skull base: NF2 mutations/p22 loss Non skull base: associated with higher grades

23 Infiltrating gliomas

24 Infiltrating gliomas: Astrocytomas, oligodendrogliomas, oligoastrocytomas

25 Astrocytes Oligodendrocytes podocyte astrocyte capillary Glial fibrillary acid protein (GFAP)

26 GFAP staining of astrocytes Reactive Neoplastic

27 Anaplastic astrocytoma (WHO grade III) WebPathology Glioblastoma multiforme (WHO grade IV) wikimedia commons

28 Imaging of gliomas Infiltrating brainstem glioma (WHO Grade II) MRI without contrast MRI with contrast Glioblastoma (WHO grade IV) Wikimedia commons

29 Progression of infiltrating gliomas, with worsening prognosis Diffuse astrocytoma (WHO grade II) Anaplastic astrocytoma (WHO grade III) Glioblastoma multiforme (GBM) (WHO grade IV) survival 6 8 years survival 2 3 years survival 12 months Oligodendroglioma/oligoastrocytoma (WHO grade II) Anaplastic oligodendroglioma/oligoastrocytoma (WHO grade III) GBM with oligodendroglial features (WHO grade IV) survival 4 15 years survival 3 10 years survival 12 months

30 Diffuse astrocytoma Grade II (low grade) Ki67

31 Anaplastic astrocytoma WHO grade III (high grade) Increased cytologic atypia and mitotic figures on H&E

32 Gemistocytic astrocytoma (grade III)

33 GBM (glioblastoma multiforme), WHO grade IV Atypical mitotic figures Marked cytologic atypia

34 GBM, WHO grade IV Necrosis + pseudopalisading

35 GBM, WHO grade IV Microvascular proliferation

36 NOT microvascular proliferation

37 Anaplastic oligoastrocytoma (WHO grade III) Wikimedia commons

38 Appin & Brat (2015) Adv Anat Pathol 22:50

39 The trouble with infiltrating gliomas

40 Oligodendroglioma subpial accumulation

41 Glioma: infiltrating edges

42 Glioma: infiltrating edges

43 Infiltration by neoplastic astrocytes at edge of glioma: Immunostaining for the R132H IDH1 mutation

44 Fujimaki et al (2007) WJSO Treatment of infiltrating glioma: surgery, radiation, and chemotherapy (A) Initial MRI on February 16, 2005, shows a tumor in the right and left frontal lobe as well as the right thalamus. (B) MRI after surgery, radiation and chemotherapy. The tumor has completely disappeared except for slight enhancement adjacent to the surgical margin. (C) Recurrence of the thalamic tumor despite maintenance chemotherapy on November 16, (D) Increase in size of the thalamic tumor two months after stereotactic radiotherapy. (E) After 6 cycles of TMZ therapy, the thalamic lesion enlarged, and the patient developed dysarthria and hemiparesis. (F) After 2 courses of treatment with interferon beta and TMZ, the tumor shows a partial response.

45 Molecular profiling of GBMs: clinical relevance Verhaak et al and The Cancer Genome Atlas Research Network (2010)

46 Targeting blood vessel proliferation in GBMs MRI imaging T1 and T2 before and after Avastin (anti VEGFR) Pope et al Neurology 2006

47 Progression of infiltrative astrocytomas on Avastin therapy Pope et al Curr Neurol Neurosci Rep 2011

48 Infiltration is the issue Axial FLAIR MRI wikimedia commons

49 References Appin & Brat (2015) Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis Adv Anat Pathol 22:50 58 Burger et al (1983) Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg 58: Fujimaki et al (2007) WJSO Goutagny et al (2014) High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Path 24: Janbazian et al (2014) Mouse models of glioblastoma: lessons learned and questions to be answered. J Neurooncol 118:1 8 Kalamarides et al (2010) Meningioma mouse models. J Neurooncol 99: Louis et al, eds. (2007) WHO Classification of Tumors of the Central Nervous System (IARC press, Lyon) Mellai et al (2013) The distribution and significance of IDH mutations in gliomas. In Evolution of the Molecular Biology of Brain Tumors and the Therapeutic Implications. Terry Lichtor, ed. ISBN: , InTech. Peyre & Kalamarides (2014) Molecular genetics of meningiomas: Building the roadmap towards personalized therapy. Neurochirurgie Sep 19. pii: S (14) Pope et al (2006) Neurology Pope et al (2011) Curr Neurol Neurosci Rep Riemenschneider et al (2006) Histologic classification and molecular genetics of meningiomas. The Lancet 5: Sun et al (2015) Neurosurg Focus An evidence based treatment algorithm for the management of WHO Grade II and III meningiomas. 38:1 11 Vehlow & Cordes (2013) Invasion as target for therapy of glioblastoma multiforme Biochim Biophys Acta 1836: Verhaak et al and The Cancer Genome Atlas Research Network (2010) An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1 Cancer Cell 17:

50 Important Information Regarding CME/SAMs The Online CME/Evaluations/SAM claim process will only be available on the USCAP website until October 2, No claims can be processed after that date! After October 2, 2015 you will NOT be able to obtain any CME or SAMs credits for attending this meeting.

51 Thank You! Please go to the USCAP website to complete your Evaluation of the course and claim CME and/or SAMs Credits.

52 Bone invasion does not increase the WHO grade of meningiomas

53 Meningiomas and gender Women: men : 1.1 Atypical/anaplastic more common in men Hormonal association not proven Breast cancer metastasizes to meningiomas (Progesterone receptor expression) Pregnancy related increase in meningioma growth due to hemodynamic changes rather than hormonal? Increased BMI increases risk for meningioma (women in one study, men in another)

54 Meningiomatosis (MA): Plaque like hemispheric cortical mass of small blood vessels with perivascular spindled cells

55 Meningiomatosis (MA): Trichrome stain

56 Meningiomatosis (MA): small blood vessels with perivascular spindled cells

57 Ki67 Sporadic cases: Solitary and associated with seizures Neurofibromatosis 2 (NF2) cases: Multiple, no seizures, associated with glial microhamartomas Pure MA is hamartomatous or developmental; genetic profile of benign meningothelial cells Tau

58 MA in association with meningioma (MA M) appears to be neoplastic gene deletions (NF2/4.1B) loss of merlin/protein 4.1B expression PR positivity represents a perivascular spread of the associated meningioma distinct from brain invasion

59 Astrocytoma infiltration