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Home , Craniopharyngioma, Elvis impersonator, Pituicytoma

DISCLOSURES (Arie Perry, MD)

• I have no financial relationships to disclose. New Immunohistochemical - and - Biomarkers in Surgical • I will not discuss off label use or Neuropathology investigational use in my presentation Arie Perry, M.D. Director, Neuropathology

School of Medicine

World map by quartiles of Human BIOMARKERS Development Index in 2013 • Types – Diagnostic – Prognostic – Predictive • Practicality issues – Cost and ease of implementation – IHC vs. FISH vs. PCR vs. genomics – Reimbursement

School of Medicine Need for surrogate immunomarkers!

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

Prognostic

School of Medicine

5

IDH-1 R132H IHC (90% of IDHm) DIAGNOSTIC EXAMPLE OF HISTOLOGIC MIMICRY: “ELVIS ” • AO (IDHm and 1p/19q codeletion) – Average survival 15 years with 1p/19q loss 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

School of Medicine School of Medicine REFLEX TO IDH1/2 SEQUENCING ATRX/H3.3 alterations  ALT • ‘Young patient’ (<55 years old) • Long clinical history • Prior history of WHO grade II or III • Non-enhancing cerebral hemispheric mass on MR imaging • Looks low-grade and/or classic oligo on histopathology • Loss of ATRX expression on IHC

School of Medicine

ATRX IHC Pediatric AA/GBM H3F3A, DAXX TP53, ATRX

Neural Pilocytic Primary Progenitor GBM EGFR, PDGFRA Cell BRAF PTEN, TP53 PXA CDKN2A/B, NF1 TERT promoter Sturm et al., IDH1,2 Cancer Cell 2012;22:425-437 IDH1-mutated infiltrating Note: no adult gliomas oligoastro! 1p/19q TP53 CIC, FUBP1 ATRX TERT promoter Diffuse astrocytoma RB1,CDK4 RB1,CDK4 CDKN2A CDKN2A, MDM2, PTEN Anaplastic Anaplastic oligodendroglioma astrocytoma, GBM Modified from Dr. Dan Brat

ADULT TYPE ASTROCYTOMA ADULT TYPE OLIGODENDROGLIOMA

IDH1 p53 ATRX IDH1 p53 ATRX DIFFUSE MIDLINE GLIOMA, H3K27M-MUTANT ADULT TYPE OLIGODENDROGLIOMA (DIPG, THAL, SC)

1p32 19p13 1q42 19q13 H3 K27M p53 ATRX School of Medicine

26-yo M H3 K27M H3 K27M

Different Case

H3 K27M H3K27me3 OTHER GLIOMA BIOMARKERS • BRAF-KIAA1549 duplication/fusion – pilocytic (~70% in ; less in other locations) – Diagnostic and predictive (MEK inhibitors?) – FISH or PCR: No IHC surrogates • BRAF V600E mutation : – PXA (~67%), GG (~20%), PA (~10%), HGGs (5-10%), E-GBM (50%) – Predictive only: BRAF inhibitors, especially in recurrent or disseminated cases? BRAF-V600E

VIRTUALLY ‘ALL’ PEDIATRIC BRAIN TUMORS EMBRYONAL Did you order BRAF testing? On this??? Really??

School of Medicine Pediatric Neuro-Oncologist Pediatric Pathologist/Neuropathologist Taylor et al., Acta Neuropathol 2012;123:465-472

School of Medicine

WNT MOL SUBTYPE SHH MOL SUBTYPE

β-catenin- β-catenin+ GAB-1 SHH MOL SUBTYPE

GAB-1

SHH-ACTIVATED, TP53-MUTANT NON-WNT/NON-SHH MOL SUBTYPE

p53 YAP1 ATYPICAL TERATOID/RHABDOID TUMOR AT/RT

Ho et al. Acta Neuropathol 99:482, 2000

School of Medicine

AT/RT WHO Rules for ATRT

• A dx of ATRT requires typical pathological features and INI1 or BRG1 loss • Tumors with typical pathology but no INI1 or BRG1 loss should be called “Embryonal tumor with rhabdoid features” • A center without BRG1 and /or INI1 testing needs to send the case out

BRG1 INI1 Brain Pathol 20:441-450, 2010 Embryonal Neoplasms CNS

WHO 2016 = Embryonal Tumors School of Medicine

SYN NFP GFAP

2 DIFFERENT CASES

OLIG2 LIN28A ETMR

Brain Pathology ETMR 22:689-97, 2012

WHO 2016 = ETMR, C19MC-altered CD99 LIN28A MOLECULAR IHC SURROGATES MENINGEAL NEOPLASMS ADULT/PEDI EMBRYONAL GLIOMAS TUMORS • IDH1 (R132H) • INI1 (SMARCB1) • p53 • BRG1 (SMARCA4) • ATRX • Beta catenin/YAP1 • H3 K27M • GAB1/YAP1 • H3K27me3 • LIN28A

School of Medicine • BRAF V600E • OLIG2 School of Medicine

H&E

EMA

SSTR2a SFT/HPC

SFT/HPC MIII EMA CD34

Genetics

• Translocations and inversions of Chr 12q13

• NAB2-STAT6 fusion

Nat Genet. 2013;45(2):131-2. Acta Neuropathol. 2013;125(5):651-8. Acta Neuropathol. 2013;125(5):651 -8. STAT6 NERVE SHEATH TUMORS

HPC Giant Cell SFT

School of Medicine ANA ANA Meningioma S100 Neurofibromin

Cellular SOX10 MPNST Cellular p16 MPNST Schwannoma

Ki-67 EGFR

66-yo M H3K27me3

Beware mosaic pattern!

H3K27me3 ADENOHYPOPHYSEAL DEVELOPMENT PITUITARY NEOPLASMS

Corticotroph Somatotroph ACTH GH *Tpit

GH Oral Rathke pouch *Pit-1 Somatotroph ERMammo- ER Lactotroph endoderm Stem cell Stem cell somatotroph PRL GH PRL repressor *SF-1 TEF ER GH repressor FSH Gonadotroph Thyrotroph LH TSH

*Diagnostically useful transcription factors School of Medicine Modified from: Asa SL, Ezzat S. Annu Rev Pathol Mech Dis 2009:4:97-126

GONADOTROPH ADENOMA

LH MIXED GH-PRL ADENOMA

SF-1 Pit1

PITUICYTOMA

GFAP S100 TTF1 GRANULAR CELL TUMOR GRANULAR CELL TUMOR

Smear Alpha-AT AMA

SPINDLE CELL ONCOCYTOMA

TTF1 SPINDLE CELL ONCOCYTOMA

AMA TTF1

ADAMANTINOMATOUS CRANIOPHARYNGIOMA

School of Medicine ADAMANTINOMATOUS CRANIOPHARYNGIOMA PAPILLARY CRANIOPHARYNGIOMA

Beta catenin

PAPILLARY CRANIOPHARYNGIOMA PAPILLARY CRANIOPHARYNGIOMA

BRAF V600E Tumor + ± - Astrocytomas (diffuse and circumscribed / favorable S-100, GFAP, OLIG2, SOX10, MAP2, IDH1 R132H 1, H3 SYN, BRAF V600E (mostly PXAs), p53 (often CK 2, LCA, HMB-45 variants) K27M 1, ATRX loss in IDH-mutant cases strong in IDH-mutant cases), CD34 (stellate cells in PXA) Oligodendroglioma S-100, GFAP 3, OLIG2, SOX10, MAP2, IDH1 R132H 1 SYN CK 1, LCA S-100, GFAP, VIM, EMA (dot-like), CD99 and D2-40 CK 2 LCA, SYN, OLIG2, SOX10, NFP (axons displaced peripherally rather than (membrane and dot-like), L1CAM 4 entrapped) Tumors S-100, CK, CK7, VIM, Transthyretin 5, Kir7.1 GFAP, CK20, SYN EMA, CEA Neuropathology CD Recording Metastatic Carcinoma 12 EMA and CK, CK7, Napsin A, and TTF1 (lung), CK20, CEA, S-100, SYN, CG GFAP, LCA, HMB-45 MUC2, and CDX2 (colon), CK7, GATA3, GCDFP-15, and mammaglobin (breast), CD10, PAX2, PAX8, CA IX, and RCC (renal), CK5/6 and p40 (squamous cell) Melanoma and melanocytoma S-100, HMB-45, Melan-A (MART-1), MITF, SOX10 GFAP, CK, LCA

Lymphoma (mostly diffuse large B-cell) LCA, CD20 (L26), CD79a, PAX-5 EMA 6, CD30 and ALK (+ in ALCL), EBV/EBER CK, GFAP, HMB-45, SYN, CD3 Meningioma EMA, VIM, PR, SSTR2a S-100, CD34, CK 7 GFAP, HMB-45 • Neuropathology Solitary fibrous tumor/ (SFT/HPC) VIM, CD99, bcl-2, CD34 (diffuse in SFT pattern), STAT6 EMA, CK, GFAP, S-100 (nuclear) songs Primary meningeal melanocytic tumors S100, HMB-45, Melan-A, MITF, SOX10 Col IV (less than nerve sheath tumors), BAP1 EMA, CK, SSTR2a, GFAP, NFP (often lost in melanomas) SYN, beta catenin (nuclear in WNT), GAB1 (SHH), YAP1 S-100, GFAP, NFP, Neu-N CK, LCA, EMA (nuclear in WNT and SHH), INI1 (retained), p53 (SHH, TP53-mutant subtype) • Common disorders Atypical teratoid / rhabdoid tumor VIM, EMA, CK, actin SYN, GFAP, desmin, AFP INI1(loss of nuclear expression) 11 , PLAP, β-hCG, LCA Embryonal tumor with multilayered rosettes, C19MC- LIN28A, SYN, NFP, and Neu-N (neuropil-rich regions), CK, GFAP, dot-like EMA, CD99, and/or D2-40 OLIG2 altered INI1 (retained) (in rosettes) nd SYN, NFP, CG, GFAP, CD34, BRAF V600E (30-50%) Neu-N, MAP2 (glial cells weak to negative) CK, EMA, PLAP, IDH1 R132H • 2 Year medical Dysembryoplastic Neuroepithelial Tumor OLIG2 (oligo-like cells), BRAF V600E (0-50%) CD34 (stellate cells), MAP2 (glial cells weak to IDH1 R132H negative) Central SYN, Neu-N GFAP, S-100 NFP, CG, CK, LCA students Schwannoma S-100 8, Col IV 8, SOX10 8 GFAP, calretinin, CD34 EMA, NFP, CK S-100/Col IV (patchy), CD34 (fibroblast network), NFP GFAP EMA, CK, calretinin (entrapped axons) Perineurioma EMA, Col IV, GLUT1 NFP (axons in intraneural type), CD34, Claudin 1 S-100, CK, SOX10 • Memorization aid Melanotic schwannoma (malignant melanotic S100, HMB-45, Melan-A, MITF, SOX10, Col IV, INI1 PRKAR1A (loss of expression in 30-50%) GFAP, EMA, CK schwannian tumor) (retained) MPNST VIM, CD99, Col IV, loss of H3K27me3, loss of S-100, SOX10, CD34, GFAP, Leu-7, CK actin, desmin, and myogenin (except in Triton tumor) neurofibromin, INI1 (retained except in epithelioid variant) • Fun way to learn! SYN, CG, S-100 9, SOX10 9, GATA-3 NFP, CK GFAP, HMB-45 S-100, Inhibin, PR, brachyury GFAP, GLUT1, D2-40 CK, EMA, CD10 SYN, CG (~60%), hormones (PRL, GH, ACTH, FSH, LH, CK S-100, GFAP, CK7, CK20, TTF1, CD99, germ cell tumor markers TSH), transcription factors (SF-1, Pit-1) www.neuropathsongs.com Pituicytoma / Spindle cell oncocytoma (SCO) / Granular TTF1, S100, Anti-mitochondrial antigen (SCO), lysosomal GFAP, EMA SYN, CG, CK, Pituitary hormones cell tumor (GCT) stains (GCT) Craniopharyngioma CK, CK5/6, nuclear beta catenin (adamantinomatous), School of Medicine BRAF V600E (papillary) iTunes or amazon.com Germinoma PLAP, c-kit (CD117), OCT 3/4, D2-40, SALL4, LIN28A β-hCG 10 , CK AFP, EMA, HMB-45, LCA, Glypican-3 Yolk sac tumor AFP, SALL4, Glypican-3, CK PLAP, EMA CD30, OCT 3/4, β-hCG, GFAP

Pituitary Adenoma PITUITARY ADENOMA SONG Music to Danny’s Song by Kenny Loggins, Lyrics by Arie Perry, MD Patient presents to you with bitemporal , prolonged amenorrhea, and galactorrhea MR imaging reveals a sellar , pushing up the optic chiasm, from forming cytoplasm Chorus : Pituitary adenoma, with your disrupted reticulin stroma You’ve lost the microacinar pattern of the normal gland Your cells appear so monomorphic, with nuclei so round and perfect And salt and pepper nuclear chromatin In Cushing’s syndrome, the adenoma’s often very small The neurosurgeon’s who you better call, don’t you know he’ll try to get it all Excess ACTH causes cortisol to spin, out of control but feeding back again Corticotrophs build up Crooke’s hyaline (Chorus) Somatotrophic tumors lead to , or gigantism more rarely, in patients exposed before puberty Gonadotrophs present most commonly in elderly, with few hormonal symptoms typically So macroadenoma’s what you see (Chorus) Though most pituitary adenomas are benign, patients often suffer endocrine, Manifestations that are scarcely fine Atypical adenomas may be challenging, carcinoma’s the malignant king Better treatment’s what we strive to bring (Chorus) School of Medicine School of Medicine