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Germ Cell Tumors

Germ Cell Tumors

3/21/2017

Disclosure of Relevant Financial Relationships GERM TUMORS USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial Eyas M Hattab, MD relationship WITH COMMERCIAL INTERESTS which they or their Department of Pathology and Laboratory Medicine spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. University of Louisville [email protected]

GERM CELL TUMORS

Disclosure of Relevant Disclosure of Relevant WHO 2016 Financial Relationships Financial Relationships • • Nongerminomatous GCTs USCAP requires that all planners (Education Committee) in a position to • Nothing relevant to this presentation • Embryonal influence or control the content of CME disclose any relevant financial • CAP Neuropath Committee, Chair • tumor relationship WITH COMMERCIAL INTERESTS which they or their • spouse/partner have, or have had, within the past 12 months, which relates to • the content of this educational activity and creates a conflict of interest. • Benign/mature teratoma • • Teratoma with “malignant transformation” •Mixed GCTs

Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC; 2016.

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Introduction Historical perspective Pathogenesis

• Largely homologues of GCTs elsewhere • 1923 (Krabbe): “” Adenoma of the pineal body • Germ cell theory Endocrinology 1923;7:379-414 • Different from non-CNS GCTs? • Primordial germ cells (PGC) • 1944 (Russel): “Atypical pineal teratoma” Pinealoma-Its • Common cell of origin; totipotent • Morphology relationship to teratoma J Pathol Bacteriol 1944;56:145-50 • No precursor lesions (GCNIS) • Embryonic cell theory • No spermatocytic “” • 1946 (Friedman and Moore): “Germinoma” Tumors of the • Embryonic cell; pluripotent-blastocyst stage • Clinical behavior Testis: A report on 922 cases. Mil Surgeon 1946;99:573-93 • Multiple embryonic cells at various stages of embryogenesis • Prepubertal vs postpubertal • 1976: “Ultrastructural study of histogenesis of pinealoma” No To • ? Origin Shinkei 1976;28:41-56 • Teilum G: Special Tumors of the and Testis and Related Extragonadal Lesions. JB Lippincott: Philadelphia, 1976, p 466-469. • Sano K, Matsutani M, Seto T: So-called intracranial germ cell tumours: personal experiences and a theory of their pathogenesis. Neurol Res 11:118-126, 1989.

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Testicular GCT histogenesis Pathogenesis Incidence

Pediatric Germ cell Epidermoid YST cyst

Germ cell theory Embryonic cell theory • CBTRUS Statistical Report 2016 Pediatric GCNIS Dermoid teratoma cyst • Adults: ~0.4% of all CNS 0.10/100,000 Seminoma SS Teratoma • Children: ~4% 0.21/100,000 Seminoma Embryonal YST + SynT carcinoma • Geographical variation: up to 15% in Far-East Asia and Japan (pediatric and tumors) Chorio- carcinoma Ostrom, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013. Neuro Oncol 2016;18 (suppl Thorsten Boroviak, and Jennifer Nichols Phil. 5):v1-v75 Trans. R. Soc. B 2014;369:20130541 Source: Thomas M Ulbright, MD (modified with permission)

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Incidence: Age-Adjusted Incidence: Age-Adjusted Localization

Ostrom, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013. Neuro Oncol 2016;18 (suppl Ostrom, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013. Neuro Oncol 2016;18 (suppl Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. 5):v1-v75 5):v1-v75 Elsevier Inc, Philadelphia, PA. 2017 (in press).

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Incidence Rate Ratios by Sex (Males:Females) Localization Gender Distribution According to Location (Germinoma)

• Midline locations 10 9 • Pineal/third ventricle 8

• Suprasellar 7 • BG, , ventricles, cerebral hemispheres, SC, etc 6 5 • Multifocal: synchronus/metachronus 4 3

• Holocranial variants rare 2

1

0 Pineal Suprasellar Synchronous BG • : suprasellar, BG, thalamus Ostrom, et al. CBTRUS Statistical Report: Primary 6940 Brain and Other Central Nervous System Tumors 1101 1 Diagnosed in the United States in 2009–2013. • NGGCTs: other sites Neuro Oncol 2016;18 (suppl 5):v1-v75 Hattab EM, et al. Primary intracranial germinoma: a retrospective clinicopathologic analysis of 27 cases. The 94th Annual Meeting of the United States and Canadian Academy of Pathology. San Antonio, TX. February 26-March 4, 2005. Published in Mod Pathol 2005;18(Suppl 1) and in Lab Invest 2005;85(Suppl1).

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Incidence Rate Ratios by Race (Whites:Blacks) Clinical Manifestations Radiographic Features • Nonspecific • Pineal • Aqueductal compression (increased ICPs; hydrocephalus) • Well-circumscribed, lobulated lesions • Distortion of quadrigeminal plate (mental status changes, upward gaze palsies, • T1: hypointense etc; Parinaud syndrome) • T2/FLAIR: mainly hyperintense • Precocious puberty (hCG) • Enhanced intensity and heterogeneously on both CT and MR • Suprasellar • Calcification (usually pineal) • Triad: DI, loss of visual acuity, hypopituitarism • Hydrocephalus common • Higher incidence / association • Often partially cystic • Klinefelter syndrome Ostrom, et al. CBTRUS Statistical Report: Primary • Local invasion common Brain and Other Central Nervous System Tumors • Diagnosed in the United States in 2009–2013. Hattab EM, et al. Primary intracranial germinoma: a retrospective clinicopathologic analysis of 27 cases. The 94th Annual Meeting of the United States and Canadian Academy Neuro Oncol 2016;18 (suppl 5):v1-v75 of Pathology. San Antonio, TX. February 26-March 4, 2005. Published in Mod Pathol 2005;18(Suppl 1) and in Lab Invest 2005;85(Suppl1).

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Germinoma Germinoma

Histology of CNS GCTs

Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Elsevier Inc, A Volume in the Pattern Recognition Series. Elsevier Inc, Philadelphia, PA. 2017 (in press). Philadelphia, PA. 2017 (in press).

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4 3/21/2017

Germinoma Embryonal Carcinoma

c- OCT4

Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Elsevier Inc, Philadelphia, PA. 2017 (in press). Elsevier Inc, Philadelphia, PA. 2017 (in press). Elsevier Inc, Philadelphia, PA. 2017 (in press).

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Embryonal Carcinoma Yolk Sac Tumor Yolk Sac Tumor

OCT4 CD30 Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. Surgical Neuropathology: a Diagnostic Approach. Second edition. Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. A Volume in the Pattern Recognition Series. Elsevier Inc, A Volume in the Pattern Recognition Series. Elsevier Inc, Elsevier Inc, Philadelphia, PA. 2017 (in press). Philadelphia, PA. 2017 (in press). Philadelphia, PA. 2017 (in press).

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Yolk Sac Tumor Choriocarcinoma Mature Teratoma

Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. Surgical Neuropathology: a Diagnostic Approach. Second edition. Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Elsevier Inc, A Volume in the Pattern Recognition Series. Elsevier Inc, A Volume in the Pattern Recognition Series. Elsevier Inc, Philadelphia, PA. 2017 (in press). α-fetoprotein Philadelphia, PA. 2017 (in press). βhCG Philadelphia, PA. 2017 (in press).

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Mature Teratoma Immature Teratoma Immunohistochemistry: recent advances

Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. A Volume in the Pattern Recognition Series. Elsevier Inc, Elsevier Inc, Philadelphia, PA. 2017 (in press). Philadelphia, PA. 2017 (in press).

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PLAP “New” IHC Markers OCT4 • Transcription factor • Previously the marker of choice • Glypican 3 • Regulates initiation, maintenance, and differentiation of pluripotent and germline • Lacks specificity (epithelial •NANOG cells during normal development ) • LIN28A • Normally expressed in embryonic stem • Nonspecific staining •OCT4 cells • 23/25 (92%) positive membranous • Podoplanin/aggruss • Germinoma and embryonal ca staining (only 2 at 3+) • High sensitivity/specificity • SALL4 •SOX2

Hattab, et al. OCT4 Immunohistochemistry is superior to placental (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol •SOX17 Hattab, et al. OCT4 Immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol 2005;29:368-71 2005;29:368-71

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C-Kit SALL4 • Tyrosine-kinase glycoprotein • Transcription factor • Germinomas • Maintains embryonic • 23/25 (92%), 20 at 3+ pluripotency and self renewal • Negative or weak in EC (OCT4, NANOG, & SOX2) • No correlation with KIT • PanGCT marker mutations • Ideal marker • Superior to AFP and glypican 3 in YST

Hattab, et al. OCT4 Immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol Hattab EM, Cheng L. Expression of c-kit (CD117) in primary pineal germinomas. The 93rd Annual Meeting of the United States and Canadian Academy of Pathology. 2005;29:368-71 Vancouver, BC, Canada. March 6-12, 2004. Published in Mod Pathol 2004;17(Suppl 1) and in Lab Invest 2004;84(Suppl 1).

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7 3/21/2017

Useful immunohistochemical stains in intracranial GCTs Useful immunohistochemical stains in intracranial GCTs

Transcription Factors Podoplanin Transcription Factors Podoplanin Glypican 3 LIN28A SALL4 OCT4 NANOG SOX2 PLAP KIT CD30 Glypican 3 AFP βhCG HPL CK AE1/3 D2-40 LIN28A SALL4 OCT4 NANOG SOX2 PLAP KIT CD30 Glypican 3 AFP βhCG HPL CK AE1/3 D2-40 • Membrane-based proteoglycan Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++ Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++ C/M N N N M/C M C M C/M N N N M/C M C M Xq26.2 Embryonal +++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ± Embryonal +++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ± carcinoma carcinoma • Highly expressed in fetal tissues C/M N N N N M/C C M/C C C C/M N N N N M/C C M/C C C Yolk sac tumor +++ +++ – – – ±± – ++++ ++++ – – +++ – Yolk sac tumor +++ +++ – – – ±± – ++++ ++++ – – +++ – • Regulation of cell growth and C/M N C C C C C/M N C C C C differentiation Choriocarcinoma + ± –– –± – – + – +++ +++ +++ – Choriocarcinoma + ± –– –± – – + – +++ +++ +++ – • Highly expressed in YST and C/M C C C C C/M C C C C CC Mature teratoma –––– ±±–– ±±– – +++ – Mature teratoma –––– ±±–– ±±– – +++ – NC NC • HCC, hepatoblastoma, ovarian Immature ±±– – +++ – ± – ± – ± –– – Immature ±±– – +++ – ± – ± – ± –– – teratoma teratoma clear cell ca N N Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Elsevier Inc, Philadelphia, PA. 2017 (in press). Elsevier Inc, Philadelphia, PA. 2017 (in press).

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Useful immunohistochemical stains in intracranial GCTs Useful immunohistochemical stains in intracranial GCTs Useful immunohistochemical stains in intracranial GCTs

Transcription Factors Podoplanin Transcription Factors Podoplanin Transcription Factors Podoplanin LIN28A SALL4 OCT4 NANOG SOX2 PLAP KIT CD30 Glypican 3 AFP βhCG HPL CK AE1/3 D2-40 LIN28A SALL4 OCT4 NANOG SOX2 PLAP KIT CD30 Glypican 3 AFP βhCG HPL CK AE1/3 D2-40 LIN28A SALL4 OCT4 NANOG SOX2 PLAP KIT CD30 Glypican 3 AFP βhCG HPL CK AE1/3 D2-40 Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++ Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++ Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++ C/M N N N M/C M C M C/M N N N M/C M C M C/M N N N M/C M C M Embryonal +++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ± Embryonal +++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ± Embryonal +++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ± carcinoma carcinoma carcinoma C/M N N N N M/C C M/C C C C/M N N N N M/C C M/C C C C/M N N N N M/C C M/C C C Yolk sac tumor +++ +++ – – – ±± – ++++ ++++ – – +++ – Yolk sac tumor +++ +++ – – – ±± – ++++ ++++ – – +++ – Yolk sac tumor +++ +++ – – – ±± – ++++ ++++ – – +++ – C/M N C C C C C/M N C C C C C/M N C C C C Choriocarcinoma + ± –– –± – – + – +++ +++ +++ – Choriocarcinoma + ± –– –± – – + – +++ +++ +++ – Choriocarcinoma + ± –– –± – – + – +++ +++ +++ – C/M C C C C C/M C C C C C/M C C C C Mature teratoma –––– ±±–– ±±– – +++ – Mature teratoma –––– ±±–– ±±– – +++ – Mature teratoma –––– ±±–– ±±– – +++ – NC NC NC Immature ±±– – +++ – ± – ± – ± –– – Immature ±±– – +++ – ± – ± – ± –– – Immature ±±– – +++ – ± – ± – ± –– – teratoma teratoma teratoma N N N

Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Elsevier Inc, Philadelphia, PA. 2017 (in press). Elsevier Inc, Philadelphia, PA. 2017 (in press). Elsevier Inc, Philadelphia, PA. 2017 (in press).

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8 3/21/2017

Useful immunohistochemical stains in intracranial GCTs

Transcription Factors Podoplanin LIN28A SALL4 OCT4 NANOG SOX2 PLAP KIT CD30 Glypican 3 AFP βhCG HPL CK AE1/3 D2-40 Other Genetics of CNS Germ cell tumors Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++ C/M N N N M/C M C M • Infiltrative • Mostly sporadic Embryonal +++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ± carcinoma C/M N N N N M/C C M/C C C • • Syndromic associations: Yolk sac tumor +++ +++ – – – ±± – ++++ ++++ – – +++ – • Sarcoidosis or infection •Trisomy 21 C/M N C C C C • Klinefelter (47 XXY): intracranial, mediastinal Choriocarcinoma + ± –– –± – – + – +++ +++ +++ – • Metastatic carcinoma •? NF1 C/M C C C C Mature teratoma –––– ±±–– ±±– – +++ – • 12p abnormalities common NC Immature ±±– – +++ – ± – ± – ± –– – teratoma N

Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Elsevier Inc, Philadelphia, PA. 2017 (in press).

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12p abnormalities Treatment and prognosis

• Prognostic variables: , location, and proximity to vital structures • Germinomas: • CSI/whole brain, plus local boost • Recent trend: less radiation, in favor of -based • >90% 10-year survival • Non-GCTs: • Mature : gross total resection CEP12 CEP12 • Immature teratomas: GTS + radiation Tel12 Tel12 • Congenital teratomas: invariably fatal Isochromosome 12p 12p overrepresentation • EC, YST, Chorio: multimodal therapy; <45% 5-year survival

Hattab EM, et al. 12p abnormalities in germinoma of the central nervous system: a FISH analysis of 23 cases. The XVIth International Congress of Neuropathology/82nd Annual Meeting of the American Association of Neuropathologists. San Francisco, CA. September 10-15, 2006. Published in Brain Pathol, 2006.

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9 3/21/2017

Age Distribution According to Location (Germinoma) Mature Teratoma Mature Teratoma

20 18.4 18 Pineal

16 Suprasellar 14 12.5 12.1 12 10 10 Age (years) Age 8

6

4

2

0 Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Anatomical Location Surgical Neuropathology: a Diagnostic Approach. Second edition. Hattab EM, et al. Primary intracranial germinoma: a retrospective clinicopathologic analysis of 27 cases. The 94th Annual Meeting of the United States and Canadian Academy A Volume in the Pattern Recognition Series. Elsevier Inc, Hattab EM. Germ cell tumors. In Perry A, Brat D (eds): Practical Surgical Neuropathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. of Pathology. San Antonio, TX. February 26-March 4, 2005. Published in Mod Pathol 2005;18(Suppl 1) and in Lab Invest 2005;85(Suppl1). Philadelphia, PA. 2017 (in press). Elsevier Inc, Philadelphia, PA. 2017 (in press).

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OCT4 Aggrus/Podoplanin • Transcription factor  Transmembrane sialoglycoprotein • Regulates initiation, maintenance, and  ? Physiological role differentiation of pluripotent and germline cells during normal development  Expressed in lung type I alveolar cells, lymphatic endothelial cells (lymphatic • Normally expressed in embryonic stem cells endothelial marker) • Germinoma and embryonal ca are  Identified on surface of some tumor undifferentiated neoplasms with cells: platelet aggregation-inducing pluripotential effect that did not require plasma • 25/25 (100%); 22 at 3+ components • Add CD30 or Aggrus if embryonal ca is in  Not expressed in EC differential  19/20 (95%); 17 at 3+

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10 3/21/2017

Useful immunohistochemical stains in intracranial germ cell tumors Demographics

Transcription Factors Podoplanin

CK  Age distribution: OCT4 NANOG AP-2γ SOX2 PLAP c-KIT CD30 AFP β-HCG HPL EMA D2-40 YM-1 AE1/3  >90% younger than 25 years; peripuberty Germinoma ++++ +++ +++ - +++ ++++ - - -² -² - +/- ++++ ++++  Younger: teratoma and choriocarcinoma N N N M/C M C M M Embryonal +++ +++ +++ ++++ ++ +/- ++++ +/- -² -² +/- ++ +/- -  Older: pure germinoma Genetics of CNS GCTs carcinoma N N N N M/C C M/C M C C  Congenital forms Yolk sac tumor - - - - +/- +/- - ++++ -² -² - +++ -- C C C Choriocarcinoma - - - - +/- - - - +++² +++² +++ +++ --  Sex predilection: C C C Mature teratoma - - - +/- +/- - - +/- -² -² +++ +++ --  M:F of 3.8:1 N M C  Pineal and BG: males Immature teratoma - - - +++¹ -+/-- - +/-² -² - - - + N M  Suprasellar and congenital: slight female predominance Abbreviations: AFP: alpha-fetoprotein; β-HCG: β-human chorionic gonadotropin; C: cytoplasmic; HPL: human placental lactogen; M: membranous; N: nuclear; PLAP: placental alkaline phosphatase. ¹staining limited to primitive neuroepithelial tissues; ²HCG and HPL are positive in intermingled cells

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Genetics of CNS Germ cell tumors CNS vs Non-CNS GCTs 12p Abnormalities in CNS Germinomas

R O

Variable Non-CNS CNS Similar? p • 12p abnormalities common 2 100 1 ) p 2 1 • Frequent gain in CCND2 (12p13) and PRDM14 (8q13), and ( Morphology    80 p i ) + y 2 l 1 R n losses of RB1 (13q14) = ? cyclin/CDK-RB-E2F pathway ( i O o 60 p R 2 O • Mutually exclusive somatic mutations in KIT and RAS 1 Immunohistochemistry    p 40 2 (germinomas) = ? KIT/RAS signaling pathway % cases 1 20 • 8q,1q, and X gains Ultrastructure    • 18q, 9q and 11q losses 0 Abnormality

Genetics  ? ? Hattab EM, et al. Chromosome 12p abnormalities in germinoma of the central nervous system: a FISH analysis of 23 cases. The XVIth International Congress of Neuropathology/82nd Annual Meeting of the American Association of Neuropathologists. San Francisco, CA. September 10-15, 2006. Published in Brain Pathol, 2006.

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CNS vs Non-CNS GCTs Genetics of Testicular GCTs Genetics of Ovarian

Abnormality Testicular Ovarian CNS • 12p gain: • First described by Atkin and Baker, 1982 • 81% of cases showed 12p abnormalities 12p OR >90% 81% 96% • Gain of extra copies of the short arm of chromosome 12 (overrepresentation); occasionally in tandem (isochromosome 12p) • 57%: i(12)p only • Hallmark genetic marker of testicular GCTs • 5%: 12p overrepresentation only i(12p) 80% 76% 57% • All types of GCTs, except for SS • ? Early event in GCT tumorigenesis vs progression • 19%: i(12)p + 12p OR • Target genes overexpressed: 73 genes (GLUT3, REA, CCND2, FLJ22028, NANOG, STELLA, • 12p overrepresentation (aneuploidization) ?precedes the formation of i(12p) • FISH analysis for 12p abnormalities: ?adjunct diagnostic tool GDF3, EBAF, TDGF1, SOX2, etc) • “12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes” • Hattab EM, et al. Chromosome 12p abnormalities in germinoma of the central nervous system: a FISH analysis of 23 cases. The XVIth International Congress of Neuropathology/82nd Annual Meeting of the American Association of Neuropathologists. San Francisco, CA. September 10-15, 2006. Published in Brain Pathol, 2006. Korkola et al, Research 2006 • Cossu-Rocca P, et al. Chromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis. Mod Pathol. 2006;19:611-5. • 12p overrepresentation may also be seen in esophageal, pancreatic and ovarian • Poulos C, et al. Analysis of ovarian teratomas for isochromosome 12p: evidence supporting a dual histogenetic pathway for teratomatous elements. Mod Pathol. Cossu-Rocca P, et al. Chromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis. Mod Pathol 2006;19:611-615 2006;19:766-71. • 12p overrepresentation may correlate with invasive growth of and nonseminomas

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How i(12p) is formed

p p p +

q q q Outcome of CNS GCTs Question? Do CNS germinomas share the same genetic alterations known to

q non-CNS GCTs (12p abnormalities)? p p + p q q

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12 3/21/2017

Dual-color FISH FISH Scoring Correlation with clinical behavior?

• Metaphase: whole isochromosome • 100 nuclei scored for CEP12 (red) and 12p (green) signals. • Followup available on 15/23 cases: • Interphase: numerical abnormality • Green : Red ratio calculated. • 12p abnormalities detected (22 cases): • Recurrence: 4/14; all with 12p OR and i(12)p • DNA Probes: • 12p Overrepresentation: • Death: 1/14 • CEP12: Centromeric α‐satellite – Ch12p; Vysis • Cutoff: average signal number plus 3X standard deviation (3SD), which • 12p abnormalities not detected (1 case): • Tel12: Subtelomeric – Ch12p; Vysis represented about 99% accuracy. • 15-year-old male • Controls: • Isochromosome 12p: • Suprasellar • Spatial distribution of green : red signals analyzed: specific pattern of • Alive, free of disease • Positive: classic testicular seminoma • Morphologically and immunohistochemically typical • Negative: internal signal aggregation.

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Important Information Pure Germinomas: The IU Experience GCTs and Indiana University Regarding CME/SAMs • 32 primary intracranial germinomas over 22 year period: • Cis-platinum: • Incidence: ~2% of all primary pediatric tumors at IUMC • First member of platinum antitumor agents • One patient had mediastinal germinoma 16 years earlier (? 2nd primary) The Online CME/Evaluations/SAMs claim process will only be • Cross links DNA; triggers • 14/28 received CT + Focal XRT: available on the USCAP website until September 30, 2017. • 1845: M. Peyrone (Peyrone salt) • 5 (36%) relapsed: • 4 salvaged by CSI, 1 died of disease progression No claims can be processed after that date! • 5/28 received CT: • 2 (40%) relapsed, 3 others are recent cases: • 1 salvaged by CSI, 1 died of disease progression After September 30, 2017 you will NOT be able to obtain any • 9/28 received CSI: CME or SAMs credits for attending this meeting. • None relapsed • 1 died of radiation complications Rosenberg et al: “Platinum compounds: a new class of potent antitumour agents” Nature. 1969 Apr 26;222:385-6

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GCTs and Indiana University GCTs and Indiana University GCTs and Indiana University

• Cis-platinum and GCTs: • 1974: Lawrence Einhorn • Phase II study • Patients with disseminated testicular GCTs • cisplatinum + vinblastine + • 74% complete remission • 26% partial remission • With postchemo surgery: 85% remission • Standard therapy • No phase III study conducted!

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GCTs and Indiana University GCTs and Indiana University

Ulbright TM. Germ cell tumors of the gonads: a selective Thomas M. Ulbright, M.D. review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005;18 Suppl 2:S61-79.

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