Thymoma: an Update DR CESAR MORAN

TUEDAY SURGICAL PATHOLOGY

Thymoma: an update

DR CESAR MORAN TUEDAY SURGICAL PATHOLOGY

Glial and Glial-Neuronal Tumors

DR ARIE PERRY GLIAL AND GLIO- NEURONAL TUMORS

Arie Perry, M.D.

DISCLOSURES (Arie Perry, MD)

• I have no financial relationships to disclose. - and - • I will not discuss off label use or investigational use in my presentation

School of Medicine

NEUROPATHOLOGY AND REAL ESTATE

• Location • Location • Location • Patient Age • Neuroimaging

School of Medicine GLIOMAS

• Astrocytomas (A) • Oligodendrogliomas (O) • [Mixed oligoastrocytomas (MOA)] • Ependymomas

• Diffuse glioma = A, O, or MOA School of Medicine

GLIOMA GRADING: WHO 2016

• Grade I = Benign • Grade II = Low-grade • Grade III = “Anaplastic” • Grade IV = High-grade malignant, e.g. “GBM”

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Distribution of Primary Malignant Brain and Other CNS Tumors by CBTRUS Histology Groupings and Histology and Behavior (N = 121,277) CBTRUS Statistical Report: NPCR and SEER, 2011–2015.

Gliomas account for 26% of all primary CNS tumors, but 81% of all malignant CNS tumors

Neuro Oncol. 2018;20(suppl_4):iv1-iv86. doi:10.1093/neuonc/noy131

• Diffuse (75%) • Circumscribed / Favorable (25%) – Fibrillary – Pilocytic – Gemistocytic – PXA – Giant Cell – SEGA – Small Cell – DIA – Granular Cell – Epithelioid

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ASTROCYTOMA, IDH-mutant, WHO GRADE II • Age 30-40 • Insidious / Slow growing • Non-enhancing • Often progress to grades III or IV • Survival ~10 years

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DIFFUSE ASTROCYTOMA (WHO II)

School of Medicine ASTROCYTOMA (WHO GRADE II)

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DIFFUSE ASTROCYTOMA (II)

School of Medicine SECONDARY STRUCTURES OF SCHERER

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ANAPLASTIC ASTROCYTOMA, IDH- mutant, WHO GRADE III

• Age 40-50 • More rapid onset • Frequent progression to grade IV • Survival ~5-10 years

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ANAPLASTIC ASTROCYTOMA, WHO III

School of Medicine IDH-mutant astrocytomas

IDH1 p53 ATRX

GLIOBLASTOMA (GBM), WHO GRADE IV • Age 50-60 • Rapid onset and progression • Rim (or ring)-enhancing • IDH-wildtype (“primary”): ~90%; Survival ~1-year • IDH-mutant (“secondary”): ~10%; Survival 2-3-years

School of Medicine GLIOBLASTOMA (WHO GRADE IV)

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GLIOBLASTOMA (WHO GRADE IV)

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GBM VARIANTS / PATTERNS

• Fibrillary (Classic) • Granular Cell • Gemistocytic • Small Cell • Giant Cell • GBM with primitive • Gliosarcoma neuronal component • Adenoid / Epithelioid / • Epithelioid Metaplastic • Molecular variants • Lipidized • Inflammation-rich

School of Medicine GIANT CELL GBM

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GIANT CELL GBM

Reticulin GFAP

GIANT CELL GBM PATTERN

IDH1 ATRX p53 GC-GBM in CMMRD

MLH1 MSH2

MSH6 PMS2

GLIOSARCOMA Reticulin GFAP

SMA CD34

OLIGODENDROGLIOMA, IDHm and 1p19q-codel (WHO GRADE II or III) • Average age 30-40 years • Corticotropism / seizures common • Cerebral, especially frontal lobe • Slow progression • Survival ~15-25 years for oligo (grade II); 10-15 years for anaplastic oligo (grade III): microvascular proliferation, high mitotic index, and/or necrosis

School of Medicine OLIGODENDROGLIOMA

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OLIGODENDROGLIOMA, WHO GRADE II

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OLIGODENDROGLIOMA

School of Medicine GFAP

ANAPLASTIC OLIGODENDROGLIOMA

School of Medicine SYN

IDH-mutant + 1p/19q-codeleted oligos

IDH1 p53 ATRX

Astro, IDHm IDHwt GBM, IDHwt EGFR‐amp IDHm Preneoplastic TERTm TP53m Cell (H3 G34R/V) ATRXm IDHm TERTm CICm 9p (CDKN2A/B) LOH 1p19q‐codel FUBP1m AA, IDHm Oligo, IDHm, Diffuse midline 1p19q‐codel glioma, H3‐K27Mm

PIK3R1/PIK3CAm 4q LOH? PIK3CAm?

GBM, IDHm AO, IDHm, 1p19q‐codel Note: no oligoastro! PILOCYTIC ASTROCYTOMA

PILOCYTIC ASTROCYTOMA

Nat Genet 45: 927-932, 2013

MAPK pathway

BRAF KIAA1549

PILOMYXOID ASTROCYTOMA, WHO? Komotar et al. Neurosurgery 54:72, 2004

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LONG-TERM EPILEPSY ASSOCIATED TUMORS (LEAT) • Glioneuronal – Ganglioglioma (GG), WHO I – Dysembryoplastic neuroepithelial tumor (DNET), WHO I – Others: mixed GG/DNET, PGNT, EVN • Gliomas – Pleomorphic xanthoastrocytoma (PXA), WHO II/III – Diffuse LGGs, WHO II – Pilocytic astrocytoma, WHO I

School of Medicine GANGLIOGLIOMA (WHO I) • Most common LEAT • Children/young adults • Temporal lobe • Benign/surgically curable • Anaplasia rare: definition? – WHO grade III (grade II eliminated in 2007) • BRAF V600E in up to half

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GANGLIOGLIOMA (WHO I)

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GANGLIOGLIOMA (WHO I)

School of Medicine SYN NFP Neu-N

CD34

Ganglioglioma

BRAF V600E ANA GG, WHO GRADE III

DNET (WHO I) • LEAT of children/young adults • Temporal lobe • Benign/surgically curable • Tumor vs. hamartoma • Simple, complex, ‘non-specific’ variants • BRAF V600E: 0-50%; FGFR1-alt: 58%?, IDHwt, no 1p19q-codeletion

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GFAP

PXA, WHO II-III

School of Medicine PXA, WHO GRADE II

PXA, WHO GRADE II

PXA, WHO GRADE II PXA, WHO GRADE II

Reticulin

PXA, WHO GRADE II

GFAP

PXA, WHO GRADE II

SYN NFP PXA, WHO GRADE II

CD34

PXA c ANA transformation, WHO GRADE III

Ki-67 BRAF-V600E

EPENDYMOMA (WHO GRADE I, II, III) • Kids: 4th ventricle, supratentorial • Adults: spinal cord • Prognostic Variables – Extent of resection / location – Patient age (poor if <2 years old) – Histologic grade? • Subependymoma or MPE, WHO grade I • Ependymoma, WHO grade II • Anaplastic ependymoma, WHO grade III – Molecular subgroups

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Subependymoma, WHO GRADE I MPE, WHO GRADE I

MPE, WHO GRADE I

PAS Trichrome

Ependymoma, WHO GRADE II

NFP Ependymoma, WHO GRADE II

Ependymoma, WHO GRADE II

Tanycytic ependymoma GFAP

EMA CD99 EPENDYMOMA: PROGNOSIS

Tihan T, et al., Mod Pathol 2008: 21, 165–177

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Pajtler et al., 2015, Cancer Cell 27, 728–743

Clear cell ependymoma Clear cell ependymoma

Clear cell (RELA fusion+) ependymoma

L1CAM

UCSF 500 NGS PF-A Ependymoma PF-B Ependymoma

H3K27me3 Oligodendroglioma Music to Ave Maria by F. Schubert, Lyrics by Arie Perry, MD

O----ligodendroglio-oh-oh-ma, diffuse cerebral tumor of adults Invading cortex, causing epilepsy; on imaging, often you are calcified And although, you tend to progress over time, for long periods your fine You're famous for your rounded nuclei, Clear haloes look like honeycombs or fried eggs With branching chicken wire capillaries, and perineuronal satellitosis

O----ligodendroglio-oh-oh-ma, genetically, you are quite unique With 1p and 19q deletions, from translocation with loss of one derivative Represents a genetically favorable set, when FISH criteria are met

Anaplastic cases grow more rapidly, assigned a W.H.O. grade III With microvascular proliferation, or increased mitotic activity O----ligodendroglio-oh-oh-ma

School of Medicine TUEDAY SURGICAL PATHOLOGY

Pleural Mespthelloma

DR CESAR MORAN TUEDAY SURGICAL PATHOLOGY

Germ Cell tumors of the Ovary

DR BLAKE GILKS 8/9/19

Germ Cell Tumors of the Ovary

Blake Gilks Dept of Pathology, Vancouver General Hospital [email protected]

Case 1

Secondary information

Clinical presentation

n22F nPreviously fit and well nMedical history - nil nRecently completed degree nRecent travel to Nigeria (April) nFever and ear pain 2 weeks prior – treated with antibiotics by GP nTwo weeks of altered sense of smell, odd taste, poor appetite

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Clinical presentation

nAttended hospital 21 Sept with generalised seizures starting focally in the right arm, non-sensical speech, confusion and agitation nTemperature of 38 nInterictally odd behaviour and not verbalising nInitial CT and EEG normal nKept in for observation nFurther 7 seizures in next 24 hrs

Course

nIntubated and ventilated, loaded with phenytoin nTreated for encephalitis/meningitis empirically and malaria nTests subsequently came back negative • normal MRI brain • CSF protein 0.28, 4 WC, opening pressure 40

Secondary information

2 8/9/19

nDeveloped pneumonia and acute renal failure requiring haemofiltration

nBedside ultrasound of abdomen revealed a pelvic mass.

Investigations n EEG 21/9/2012 • The EEG is within normal limits. No focal abnormalities or epileptiform discharges are seen. n EEG 24/9/2012 • The EEG shows mild generalised slow activity suggestive of mild global cortical dysfunction. • No focal abnormalities, epileptiform discharges or periodic complexes are seen. n EEG 27/9/2012 • The EEG is abnormal with generalised slowing in keeping with mild- moderate encephalopathy. • No focal abnormalities, periodic complexes or epileptiform discharges are seen. n MRI Brain • Normal n CSF • Prot 0.28, WCC 5 (4 LC), lactate normal • OP 40 n Bloods • Routine bloods normal, ESR 30 • Lupus anticoagulant, ANA and ANCA negative • C3 and C4 in normal limits, Ammonia <13

Investigations

• NMDA Receptor antibodies POSITIVE

• NMDA Receptor antibody was first found in young female patients with ovarian tumours and prominent psychiatric symptoms, amnesia, seizures, dyskinesias, autonomic dysfunction and decreased levels of consciousness. The antibodies are now also found in males or females with no known tumour and in children. Their presence suggests an immunotherapy-responsive condition.

• Dalmau J et al Lancet Neurology 2008 7(12) p1091

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Treatment

nIVIG contraindicated because of renal failure

nIV Methylprednisolone, then Prednisolone 60mg

nTransferred to RLH for plasma exchange

nArrived intubated and ventilated

nRenal function improved – not requiring haemodialysis

Secondary information

Pathology

• Intact cystic and solid ovarian mass • 1214g • 165 x 90 x 70 mm • Externally smooth • Internally multiloculated, 60% solid areas, soft, grey to haemorrhagic

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Secondary information

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Secondary information

GFAP CD20 Ki67 CD3

Secondary information

Post tumour removal course nPeriods of abnormal movements associated with hypertension, tachycardia and tachypnoea nLow responsiveness nOccasional focal twitching of right arm and face nAxial jerks nFacial movements • Initally focal frontalis twitches • Spont eye opening • Occasional focal right sided twitching nEvolved to involve predominantly right arm posturing, oral movements with lipsmacking, biting the tube, focal dystonic spasms of the right face when sedation light

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Treatment summary nIV Methylprednisolone then 60mg oral prednisolone nPLEX (IVIG contraindicated) nSurgery, but no chemotherapy nLack of clinical improvement -> Rituximab

Further course nProminent movement disorder improved nBehavioural disturbance with agitation requiring multiple sedatives gradually improved nEarly December back to ward nNeuropsychological assessment - January

Neuropsychology results nIntellectual function nEstimated IQ = 100 (average) Current IQ • Verbal 83 (low average) • Nonverbal 63* (extremely low) nFrontal/executive function nLow/below average (unperturbed by flatulence, impulsive in responding to tests, altered a score sheet when examiner left the room)

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Memory

nEvidence of poor registration/encoding and confabulation* on verbal recall tasks

nPoor planning, perseverations and organisational difficulties evident in visual recall

nHigh number of intrusion (confabulations) and repetition (perseverative) errors on a verbal list learning task

nGood recognition memory skills

Anti-NMDA receptor encephalitis

• Autoimmune encephalitis • First described in 2005 in 4 young women with teratomas • Antibodies against a receptor highly expressed in hippocampus • Subsequently identified as N-methyl D-aspartate (NMDA) receptor, GluN1 subunit

Anti-NMDA receptor encephalitis

• Age range: 8 months – 85 years (median 21 years) • 81% female • 38% associated with a neoplasm • 94% of associated neoplasms are ovarian teratomas

Titulaer et al (2013). Lancet Neurol

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Titulaer et al (2013). Lancet Neurol Secondary information

Secondary information Titulaer et al (2013). Lancet Neurol

Anti-NMDA receptor encephalitis

Prodrome

Acute behavioural change, psychosis, catatonia

Seizures, memory deficit, dyskinesias, speech problems, autonomic and breathing dysregulation

MRI usually normal, EEG (90%) and CSF (79%) usually abnormal

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Anti-NMDA receptor encephalitis Prognosis: • Tumour associated cases do better (removal speeds up recovery and prevents relapses) • Lower severity of symptoms (not requiring ICU) • Prompt initiation of immunotherapy and tumour removal results in substantial neurological improvement in 81% of patients • In the remainder, second line immunotherapies (cyclophosphamide and Rituximab) improve outcome and reduce relapse

Anti-NMDA receptor encephalitis: Pathology • 5 cases, 4 mature, 1 immature teratoma (control 22 sporadic cases, all with glial elements, 14 mature, 8 immature) • 0.7 to 9.5cm • 1 case bilateral, discovered at time of recurrence of neurological recurrence • Intratumoral lymphoid infiltrate, colocalising to mature glial elements • Reactive germinal centres within neuroglial matrix • Lymphoplasmacytic infiltrates within neuroglial matrix • Neuronal degeneration • Important to identify these changes as neurological symptoms may develop after tumour removal

Dabner et al, Int J Gyn Pathol, 2012; 31:429.

Immature teratoma • Diagnostic feature: Presence of embryonic-appearing tissue - usually neuroectodermal as tubules, rosettes; cellular and mitotically active glial tissue • Other immature tissues: cartilage, skeletal muscle, epithelial, hepatic

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Grading of Immature Teratoma

• Grade 1: rare foci (<1 per lpf in any one slide) • Grade 2: (2 or 3 foci per lpf in any one slide) • Grade 3: (>4 foci per lpf in one slide)

Case 2

Secondary information

Clinical presentation

• 29F • Abdominal distension over past 3 months • Shortness of breath and abdominal pain over past 3 weeks • Oligomenorrhoea, Implanon in situ • Nulliparous, keen to preserve fertility.

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Investigations and surgery

• Ascitic tap: NMCS • MRI/CT – Ascites+++, Left sided dermoid – looks benign. R adnexal mass more complex, with fat and ?tooth in it but looks more malignant. Omentum looks normal but hard to view with ascites. No nodes anywhere. • Right oophorectomy, left ovarian cystectomy, omental biopsy

Pathology

• Intact solid and cystic ovarian mass

• 150 x 100 x 80mm

• Gelatinous tan and white solid areas measuring 80 x 40 x x40mm

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Secondary information

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Secondary information

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Struma ovarii

• 5-15% MCT have thyroid tissue • When sole or dominant (>/=50%) = Struma ovarii • 1.4 – 2% of all ovarian teratomas • Most pose no clinical or pathological difficulties

Unusual clinicopathological manifestations of struma ovarii • Thyroid hyperfunction • Pseudo-Meig’s syndrome • Diffuse solid growth • Pseudotubular solid growth • Cystic tumours • Clear cells • Oxyphilic cells • Signet ring cells

Differential diagnosis • Serous cystadenoma • Endometrioid carcinoma • Granulosa cell tumour • Sertoli cell tumour • Yolk sac tumour • Clear cell carcinoma • Hepatoid carcinoma • Steroid cell tumour • Small cell carcinoma • Malignant melanoma

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Proliferative struma ovarii

• One that shows some but not all features that would suggest malignancy in eutopic thyroid: • Papillary structures as seen in hyperplastic nodules NOT associated with nuclear features of PTC • Microfollicular architecture WITHOUT vascular invasion/mitotic activity/cytological atypia

• BENIGN behaviour

Secondary information

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Secondary information

Malignant struma ovarii

• Points of uncertainty/controversy • Whether thyroid malignancy criteria are applicable to struma? • Different criteria? • Other forms of malignancy? • Relationship between morphology and biological behaviour? • Prognosis?

Secondary information

17 8/9/19

Group 1: Histologically malignant (61 cases) • 43 adenomatous (proliferative) • 18 malignant • Either follicular carcinoma, based on vascular invasion • Or nuclear features of PTC, including FVPTC

• ALL CLINICALLY BENIGN

Robboy et al. IJGP 2009, 28:405. Secondary information

Group 2: Biologically malignant: (27 cases) • Any histology with

• Penetration and growth on ovarian serosa • Extra-ovarian spread • Recurrence

17 at presentation; 10 later

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Group 2: Biologically malignant: (27 cases)

Histology Number Outcome NED AWD DOD Normal thyroid tissue (HDFCO) 2 2

Follicular adenoma 17 4 9 4

Papillary carcinoma 7 2 0 5

Follicular carcinoma 1 0 0 1

Shaco-Levy et al. IJGP 2010, 29:212.

Roth and Karseladze. IJGP 2008; 27:213.

Secondary information

Group 2: Biologically malignant: (27 cases) • Overall protracted clinical course • Time to first recurrence 2 months to 29 years (mean 6 years) • Long term survival even in cases disseminated at presentation • Greater propensity for adhesions, ascites and spread to surface • No correlation between stage and behaviour • Recurrences may occur over a decade after presentation – warrants long term follow up

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Group 2: Biologically malignant: (27 cases) • Large size >10cm • High percentage of proliferative thyroid tissue, >80% • Extensive PTC histology (all aggressive cases are PTC; NOT all PTC are clinically malignant) • mf >5/10hpf • necrosis • Anaplastic histology/marked cytological atypia is associated with aggressive course

Approach to defining malignancy in struma ovarii • Step 1 define histology:

Ovarian Extra-ovarian Terminology

Benign None Benign

Proliferative None Proliferative

Benign Benign Highly differentiated follicular carcinoma Malignant, PTC Papillary carcinoma in struma ovarii Malignant, follicular ca Follicular carcinoma in struma ovarii

Approach to defining malignancy in struma ovarii • AVOID • ‘Malignant struma ovarii’ • Peritoneal strumosis – these are low grade malignancies, • Biologically malignant behaviour is indicated by • Capsular spread • Extra-ovarian spread • Recurrence • Course usually protracted

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Approach to defining malignancy in struma ovarii • Sample well • Look for malignant features • Nuclear f/o PTC, should be widespread • VI for FC, should be unequivocal, readily identified, exclude artefact. RARE: not a great feature in the ovary overall • ALL cases with proliferative features require long term follow up • Highlight features predictive of aggressive behaviour if present.

Case 3

14F with huge abdominopelvic mass ?adnexal

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Dysgerminoma

• Commonest ovarian primitive (non-teratomatous) germ cell tumour (≈50%) • 1% of all primary ovarian malignancies; 5-10% in first 3 decades • Age range: 15-30, abdominal mass, ↑LDH, rarely ↑HCG resulting in hormonal manifestations • 1/3rd show extraovarian spread at presentation

Dysgerminoma

• Usualy solid, bosselated • Cells resembling germ cells in solid sheets, cords, nests. Rarely follicle- like spaces • Cells are monotonous round with clear or eosinophilic cytoplasm, central round nuclei with 1-2 prominent nucleoli • Variably prominent fibrous bands • Invariably present lymphocytic infiltrate, rarely granulomas • IHC: OCT3/4, CD117 +ve (minority have c-kit mutation) NOTE: AFP, CD30 –ve

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Dysgerminoma - DD

• YST - solid variant • Embryonal carcinoma – solid • Clear cell ca • Small cell and undifferentiated Ca • NHL

Case 4

22F, right ovarian mass

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Yolk Sac Tumour

• 20% of primitive GCT • Age range 16-19 years; abdominal pain, large mass ↑AFP • Extravoarian spread in ½ cases • Rarely extraovarian pelvic primary – ovaries normal • Rarely occur in elderly (epithelial origin)

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Yolk Sac Tumour • Large solid and cystic masses, teratomatous component in 15% • Typical pattern reticular microcystic • Tumour cells moderately pleomorphic, moderate amount of pale to clear cytoplasm, hyperchromatic nuclei, often prominent nucleoli, high mitotic activity • Schiller-Duval bodies chtic but seen in minority of cases • IHC: AFP+ (may be focal, rarely negative); EMA, CK7, OCT3/4, CD117 –ve • Variants: hepatoid, glandular (intestinal or endometrioid)

YST - DD

Embryonal carcinoma • Rare in ovary in pure form, <1% • Greater pleomorphism, lack of typical YST patterns, CD30 and OCT3/4 +ve; usually AFP negative, CD117 –ve CCC Endometrioid ca

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Case 5

• 36 year old 6 months post TAH + BSO for granulosa cell tumour ovary Stage 1A. • Now pelvic recurrence

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Small cell carcinoma of ovary (hypercalcemic type) • Solid architecture, sheets of malignant cells • Variably sized follicle like spaces typical • Tumour cells small, round, scanty cytoplasm, hyperchromatic nuclei, single small nucleoli • Frequent mitotic figures • Large cells seen focally but may predominate • Minor foci of the following may occur: spindle cells, mucinous epithelium, clear cells • Vascular invasion ++ • IHC: CK, EMA, WT1, CD10, p53 positive • 1/2 - 2/3rd of cases have hypercalcaemia

Small cell carcinoma of hypercalcemic type– Differential diagnosis • Granulosa cell tumour (adult or juvenile) • Lymphoma • Small cell ca of pulmonary type • Dysgerminoma • Melanoma • Primitive round cell tumours eg PNET • Undifferentiated/ poorly differentiated ca

SMALL CELL CARCINOMA – HYPERCALCEMIC TYPE

• Rare • Young women • Hypercalcemia in 50-70% of cases • Typically stage I at presentation, but aggressive

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jGCT Small cell carcinoma, hypercalcemic type

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SMARCA4 Mutations • 11/14 tumours (79%) • 2/7 germlines (29%) • 2/2 cell lines

Germline 15 3 2 A G T * * * 3C> - Gln215 Arg381* Leu409Glyfs* Gln555 R1005 Gly1080Asp Leu1161Alafs* Lys1213Argfs* 722_735delGTCCCGGCCCGGCA 2935C> c.4071+1G> 2617

QLQ HSA BRK DEXDc SNF2_N HELICc Bromo * * * * * * 82 I542fs L388fs L762fs G836* S147N K414Q Q331* R397fs Q847* R1005* S1855fs Arg979* Arg381 Arg978 Thr187* Gln215 Gln555 Trp922* Gly241fs Glu667fs Glu952fs Leu729fs Arg1093* Arg1189* Gln1166 Gln1226 Ser1591fs Leu972Pro * Glu1254Ter K587_splice K953_splice Gly1080Asp Ser78Tyrfs*3 K1390_splice ETVN1300del Q1182_splice R978* Leu409Glyfs*2 Tyr731Valfs*10 Lys711Serfs*63 Phe947Leufs*3 Val343Cysfs*68 Val684Trpfs*90 Ser442Argfs*59 Lys1213Argfs*3 Asn563Glyfs* Met749Asnfs*75 Trp1178Glyfs*38 Leu1161Alafs*15 Q1166 Phe1082Leufs*24 Arg1093Ter Leu1161fs R1093*

Ramos, Karnezis, Nature Genetics 2014. Tumor Witkowski, Nature Genetics 2014. Jelinic, Nature Genetics 2014. Kupryjanczyk, Polish J Pathol 2013.

SWI/SNF ATP-Dependent Chromatin Remodeling Complex

Riccio, Nat Neurosci 2010.

BRG1 LOSS • 20/23 tumours (87%) • 2/2 cell lines • 0/50 GCT, DG, YST • 2 CCC/~1000 (0.2%) ovarian tumours Diagnostic marker

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SMARCA4/BRG1 SMARCA2/BRM Small cell region cell Small Large cell region cell Large

H&E SMARCA4/BRG1

SMARCA2/BRM SMARCB1/INI1

Figure 2, Karnezis et al.

H&E SMARCA4/BRG1 SMARCA2/BRM SMARCA4/A2intact SMARCA4loss

32 8/9/19

THANK YOU!

33 TUEDAY SURGICAL PATHOLOGY

Germ Cell tumors of the Ovary

DR BLAKE GILKS TUESDAY SURGICAL PATHOLOGY WHO 2016 and cIMPACT- NOW UPDATES OF GLIOMAS

DR. ARIE PERRY WHO 2016 and cIMPACT-NOW UPDATES OF GLIOMAS

Arie Perry, M.D. Director, Neuropathology

DISCLOSURES (Arie Perry, MD)

• I have no financial relationships to disclose. - and - • I will not discuss off label use or investigational use in my presentation

School of Medicine

PATTERN RECOGNITION

School of Medicine

3 IMPERSONATORS

School of Medicine

PATTERN RECOGNITION

School of Medicine

6 Sturm et al., Cancer Cell 2012;22:425-437

Prognostic Diagnostic Both

“WHO’s Next?” A Colloquium to Guide Next Steps in Brain Tumor Classification and Grading

Sponsored by the International Society of Neuropathology

Made possible through generous support from the STOPbraintumors Foundation

Organizers: David Louis Pieter Wesseling Arie Perry

Program Committee: Peter Burger David Ellison Guido Reifenberger Andreas von Deimling

9 10

Brain Pathology 24: 429-435, 2014 ISN-Haarlem format of “layered diagnoses”

• Integrated Diagnosis (incorporating all aspects of tissue diagnosis) • Histological Classification • WHO Grade (natural history) • Molecular information (see parameters from previous slide)

“ISN-Haarlem layered diagnosis format”

I II III IV

12 13

To provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications, cIMPACT‐ NOW will at regular intervals facilitate input and consensus review of novel diagnostically relevant data and determine how such information can be practically incorporated into CNS tumor classifications. While it is understood that the major impact on international brain tumor classification comes about through the WHO classification update process, it is anticipated that this additional process will “see impact” in selected tumor types and in time periods between the WHO classification updates. The cIMPACT‐NOW updates are not intended to supplant the existing WHO classification, but to provide possible guidelines for practicing diagnosticians and future WHO classification updates.

cIMPACT‐NOW cIMPACT‐NOW (cont.) Ken Aldape Andreas von Deimling Dan Brat Pieter Wesseling David Capper David W. Ellison cIMPACT‐NOW Clinical Advisory Panel Dominique Figarella‐Branger Tracy Batchelor Cynthia Hawkins J. Gregory Cairncross David N. Louis Stefan Pfister Werner Paulus Stefan Rutkowski Arie Perry Michael Weller Guido Reifenberger Wolfgang Wick

15 BIOMARKER CONCEPTS • Types – Diagnostic – Prognostic – Predictive • Practicality issues – Cost and ease of implementation – IHC vs. FISH vs. PCR vs. genomics – Reimbursement

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GBM BIOMARKERS: EGFR/PTEN (+7/-10)

CEP7 PTEN EGFR DMBT1 School of Medicine

OLIGODENDROGLIOMA 1p19q FISH

1p32 19p13 1q42 19q13

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18 321(5897):1807-12, 2008

IDH-1 R132H IHC

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DIAGNOSTIC EXAMPLE OF HISTOLOGIC MIMICRY: “ELVIS IMPERSONATOR” • AO (IDHm and 1p/19q codeletion) – Average survival 15 years if treated with combined PCV chemo and radiation – What about chemo alone up front? • SC-GBM (IDHwt, EGFR-AMP 70%, -10q 95%) – Average survival 1 year – Typically treated with combined radiochemotherapy – Different set of clinical trials than the high-grade oligodendrogliomas

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21 REFLEX TO IDH1/2 SEQUENCING

• ‘Young patient’ (<55 years old) • Long clinical history • Prior history of WHO grade II or III glioma • Non-enhancing cerebral hemispheric mass on MR imaging • Looks low-grade and/or classic oligo on histopathology • Loss of ATRX expression on IHC

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CANCER CELLS ESCAPING SENESCENCE

Shay JW et al. Science 15:1388-1390, 2012

Reitman et al. Acta Neuropathol (2013) 126:789–792

24 Killela et al. PNAS 2013; 110: 6021–6026 25

ATRX/H3.3 alterations  ALT

ATRX IHC

27 IDH-mutant Astrocytomas

But not true for most pedi cases

IDH1 p53 ATRX

But not true for most pedi cases IDHm 1p/19q-codel Oligodendrogliomas

1p32 1q42

19p13 19q13 IDH1 p53 ATRX

(Oligo-like)

(Diffuse Astro) (GG)

30 DIFFUSE MIDLINE GLIOMA (DIPG, THAL, SC)

H3K27me3

H3 K27M p53 ATRX

Sturm et al., Cancer Cell 2012;22:425-437

33 High-grade glioma, H3 G34R/V-mutant ≠ WHO Dx (subtype of “IDH-wildtype”)

OLIG2 H3 G34R/V p53 ATRX

PIK3R1/PIK3CAm 4q LOH? PIK3CAm?

GBM, IDHm AO, IDHm, 1p19q‐codel Note: no oligoastro!

(WHO NOS = Not Otherwise Specified)

36 37

IDHwt

39 OTHER GLIOMA BIOMARKERS • BRAF-KIAA1549 duplication/fusion – pilocytic astrocytomas (~70% in cerebellum; less in other locations) – Diagnostic and predictive (MEK inhibitors?) – FISH or PCR: No IHC surrogates • BRAF V600E mutation – PXA (~67%), GG (20-60%), PA (~10%), HGG/GBM (5%), E-GBM (50%) – Predictive only: BRAF inhibitors, especially in recurrent or disseminated cases?

Ganglioglioma

BRAF V600E 41

LGG of unknown type post‐RX (PXA‐like signature) UCSF500

42 Nat Genet 45: 927-932, 2013

MAPK pathway

BRAF KIAA1549

Pajtler et al., 2015, Cancer Cell 27, 728–743

45 Clear cell (RELA fusion+) ependymoma

L1CAM 46

PF-A Ependymoma PF-B Ependymoma

H3K27me3 48 EMBRYONAL NEOPLASMS

School of Medicine

Taylor et al., Acta Neuropathol 2012;123:465-472

School of Medicine

WNT MOL SUBTYPE

β-catenin- β-catenin+ 51 WNT MOL SUBTYPE

YAP1 52

WNT MOL SUBTYPE

ALK LEF1 53

SHH (TP53-WILDTYPE) VARIANT

GAB-1 YAP1 54 55

ANA/LC, SHH and TP53-mutant Medulloblastoma

p53 57 Classic non-WNT non-SHH Medullo (~60% of cases)

NON-WNT/NON-SHH MOL SUBTYPE

YAP1 59

ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT)

Ho et al. Acta Neuropathol 99:482, 2000

School of Medicine

60 AT/RT

BRG1 INI1 61

EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES (ETMR)

UCSF500 NGS Panel

C19MC FISH Courtesy of Dr. David Ellison St. Jude Hospital, Memphis, TN

WHO 2016 = ETMR, C19MC-altered (ETANTR, Ependymoblastoma, subset of ME) 63 64

WHO 2016

CNS Embryonal Tumor, NOS School of Medicine

CASE

• 34 yo man • Presents with confusion • MRI: 6-cm hypodense left frontal mass with patchy enhancement • Resection performed

School of Medicine

66 67

POSSIBLE INITIAL REPORT

1. Integrated Diagnosis: pending 2. Histologic diagnosis: oligoastrocytoma (or ambiguous diffuse glioma) with atypia, mitoses, MVP, and necrosis 3. WHO grade: at least III 4. Molecular studies: pending

69 POSSIBLE FINAL REPORT

1. Integrated Diagnosis: AO, IDH-mutant and 1p/19q codeleted, WHO III (ATRX intact) 2. Integrated Diagnosis: GBM, IDH-mutant, WHO grade IV (1p/19q intact, ATRX loss) 3. Integrated Diagnosis: GBM, IDH-wildtype, WHO grade IV (1p/19q intact, ATRX intact, +/- EGFR-AMP, +7/- 10, pTERT-mut) 4. Diagnosis: GBM, NOS, WHO grade IV or AOA, NOS, WHO grade III (molecular not performed)

POSSIBLE FINAL REPORT

72 EXAMPLES

• Anaplastic oligoastrocytoma, NOS, WHO grade III • Glial or glioneuronal neoplasm, NEC • High-grade glioma, IDH-wildtype and H3 G34-mutant, NEC • High-grade glial neoplasm with ETV6- NTRK3 fusion, NEC

School of Medicine

ATRX and p53 IHC vs. 1p/19q

75 EXAMPLE

• 44-yo F • New onset seizures • MRI: R frontotemporal lesion visible only on T2-weighted images • CSF negative for oligoclonal bands • Paraneoplastic syndrome autoantibody panel negative

School of Medicine

78 IDH1 R132H ATRX 79

p53 Ki-67 80

Additional Testing

• IHC: CD34 and BRAF V600E stains negative • IDH1/2 sequencing negative • FISH: 1p and 19q intact

School of Medicine

81 DX: Diffuse astrocytoma, IDH- wildtype, at least WHO GRADE II

School of Medicine

UCSF500

Integrated Dx: Diffuse astrocytic neoplasm with molecular features of GBM, IDH-wildtype, WHO grade IV

School of Medicine

84 85

Performance of ‘Brain Tumor Rhapsody’ by Musaic (https://www.youtube.com/watch?v=FfP4HTuu6V)