GERM CELL TUMORS 3/21/2017. Disclosure of Relevant Financial Relationships. Disclosure of Relevant Financial Relationships

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1 Eyas M Hattab, MD Department of Pathology and Laboratory Medicine University of Louisville eyas.hattab@louisville.edu Disclosure of Relevant Financial Relationships USAP requires that all planners (Education ommittee) in a position to influence or control the content of ME disclose any relevant financial relationship WITH OMMERIAL ITERESTS 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. Disclosure of Relevant Financial Relationships USAP requires that all planners (Education ommittee) in a position to influence or control the content of ME disclose any relevant financial relationship WITH OMMERIAL ITERESTS 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. Disclosure of Relevant Financial Relationships othing relevant to this presentation AP europath ommittee, hair WHO 2016 ongerminomatous GTs Embryonal Yolk sac tumor horio Teratoma Benign/mature teratoma Immature teratoma Teratoma with malignant transformation Mixed GTs Louis D, Ohgaki H, Wiestler OD, et al. WHO lassification of Tumours of the entral ervous System. Lyon: IAR; 2016.

2 Introduction Historical perspective Pathogenesis Largely homologues of GTs elsewhere Different from non-s GTs? Morphology o precursor lesions (GIS) o spermatocytic seminoma linical behavior Prepubertal vs postpubertal? Origin 1923 (Krabbe): Pinealoma Adenoma of the pineal body Endocrinology 1923;7: (Russel): Atypical pineal teratoma Pinealoma-Its relationship to teratoma J Pathol Bacteriol 1944;56: (Friedman and Moore): Tumors of the Testis: A report on 922 cases. Mil Surgeon 1946;99: : Ultrastructural study of histogenesis of pinealoma o To Shinkei 1976;28:41-56 Germ cell theory Primordial germ cells (PG) ommon cell of origin; totipotent Embryonic cell theory Embryonic cell; pluripotent-blastocyst stage Multiple embryonic cells at various stages of embryogenesis Teilum G: Special Tumors of the Ovary and Testis and Related Extragonadal Lesions. JB Lippincott: Philadelphia, 1976, p Sano K, Matsutani M, Seto T: So-called intracranial germ cell tumours: personal experiences and a theory of their pathogenesis. eurol Res 11: , Pathogenesis Testicular GT histogenesis Incidence Germ cell theory Embryonic cell theory Thorsten Boroviak, and Jennifer ichols Phil. Trans. R. Soc. B 2014;369: Pediatric YST Pediatric teratoma SS YST Source: Thomas M Ulbright, MD (modified with permission) Germ cell GIS Seminoma Seminoma + SynT horio Epidermoid cyst Dermoid cyst Teratoma Embryonal BTRUS Statistical Report 2016 Adults: ~0.4% of all S neoplasms 0.10/100,000 hildren: ~4% 0.21/100,000 Geographical variation: up to 15% in Far-East Asia and Japan (pediatric brain and tumors) Ostrom, et al. BTRUS Statistical Report: Primary Brain and Other entral ervous System Tumors Diagnosed in the United States in euro Oncol 2016;18 (suppl 5):v1-v75

3 Incidence: Age-Adjusted Incidence: Age-Adjusted Localization Ostrom, et al. BTRUS Statistical Report: Primary Brain and Other entral ervous System Tumors Diagnosed in the United States in euro Oncol 2016;18 (suppl 5):v1-v75 Ostrom, et al. BTRUS Statistical Report: Primary Brain and Other entral ervous System Tumors Diagnosed in the United States in euro Oncol 2016;18 (suppl 5):v1-v75 Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Localization Incidence Rate Ratios by Sex (Males:Females) Gender Distribution According to Location () Midline locations Pineal/third ventricle Suprasellar BG, thalamus, ventricles, cerebral hemispheres, S, etc Multifocal: synchronus/metachronus Holocranial variants rare s: suprasellar, BG, thalamus GGTs: other sites Ostrom, et al. BTRUS Statistical Report: Primary Brain and Other entral ervous System Tumors Diagnosed in the United States in euro Oncol 2016;18 (suppl 5):v1-v Pineal Suprasellar Synchronous BG Hattab EM, et al. Primary intracranial germinoma: a retrospective clinicopathologic analysis of 27 cases. The 94th Annual Meeting of the United States and anadian Academy of Pathology. San Antonio, TX. February 26-March 4, Published in Mod Pathol 2005;18(Suppl 1) and in Lab Invest 2005;85(Suppl1).

4 Incidence Rate Ratios by Race (Whites:Blacks) Ostrom, et al. BTRUS Statistical Report: Primary Brain and Other entral ervous System Tumors Diagnosed in the United States in euro Oncol 2016;18 (suppl 5):v1-v75 linical Manifestations Pineal Aqueductal compression (increased IPs; hydrocephalus) Distortion of quadrigeminal plate (mental status changes, upward gaze palsies, etc; Parinaud syndrome) Precocious puberty (hg) Suprasellar Triad: DI, loss of visual acuity, hypopituitarism Higher incidence / association Klinefelter syndrome Down syndrome Radiographic Features onspecific Well-circumscribed, lobulated lesions T1: hypointense T2/FLAIR: mainly hyperintense Enhanced intensity and heterogeneously on both T and MR alcification (usually pineal) Hydrocephalus common Often partially cystic Local invasion common Hattab EM, et al. Primary intracranial germinoma: a retrospective clinicopathologic analysis of 27 cases. The 94th Annual Meeting of the United States and anadian Academy of Pathology. San Antonio, TX. February 26-March 4, Published in Mod Pathol 2005;18(Suppl 1) and in Lab Invest 2005;85(Suppl1). Histology of S GTs Surgical europathology: a Diagnostic Approach. Second edition. Surgical europathology: a Diagnostic Approach. Second edition.

5 Embryonal arcinoma Embryonal arcinoma c-kit OT4 Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Embryonal arcinoma Yolk Sac Tumor Yolk Sac Tumor OT4 D30 Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Surgical europathology: a Diagnostic Approach. Second edition. Surgical europathology: a Diagnostic Approach. Second edition.

6 Yolk Sac Tumor horio Mature Teratoma Surgical europathology: a Diagnostic Approach. Second edition. α-fetoprotein Surgical europathology: a Diagnostic Approach. Second edition. βhg Surgical europathology: a Diagnostic Approach. Second edition. Mature Teratoma Immature Teratoma Immunohistochemistry: recent advances Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Surgical europathology: a Diagnostic Approach. Second edition.

7 PLAP Previously the marker of choice Lacks specificity (epithelial malignancies) onspecific staining 23/25 (92%) positive membranous staining (only 2 at 3+) Hattab, et al. OT4 Immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol 2005;29: ew IH Markers Glypican 3 AOG LI28A OT4 Podoplanin/aggruss SALL4 SOX2 SOX17 OT4 Transcription factor Regulates initiation, maintenance, and differentiation of pluripotent and germline cells during normal development ormally expressed in embryonic stem cells and embryonal ca High sensitivity/specificity Hattab, et al. OT4 Immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol 2005;29: Kit Tyrosine-kinase glycoprotein s 23/25 (92%), 20 at 3+ egative or weak in E o correlation with KIT mutations SALL4 Transcription factor Maintains embryonic stem cell pluripotency and self renewal (OT4, AOG, & SOX2) PanGT marker Ideal screening marker Superior to AFP and glypican 3 in YST Hattab, et al. OT4 Immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol 2005;29: Hattab EM, heng L. Expression of c-kit (D117) in primary pineal germinomas. The 93rd Annual Meeting of the United States and anadian Academy of Pathology. Vancouver, B, anada. March 6-12, Published in Mod Pathol 2004;17(Suppl 1) and in Lab Invest 2004;84(Suppl 1).

8 Glypican 3 Membrane-based proteoglycan Xq26.2 Highly expressed in fetal tissues Regulation of cell growth and differentiation Highly expressed in YST and H, hepatoblastoma, ovarian clear cell ca Useful immunohistochemical stains in intracranial GTs Transcription Factors Podoplanin LI28A SALL4 OT4 AOG SOX2 PLAP KIT D30 Glypican 3 AFP βhg HPL K AE1/3 D ± ++++ /M M/ M M Embryonal ± ++++ ± ++++ ± /M M/ M/ Yolk sac tumor ± ± /M horio + ± ± /M Mature teratoma ± ± ± ± +++ Immature ± ± +++ ± ± ± teratoma Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Useful immunohistochemical stains in intracranial GTs Transcription Factors Podoplanin LI28A SALL4 OT4 AOG SOX2 PLAP KIT D30 Glypican 3 AFP βhg HPL K AE1/3 D ± ++++ /M M/ M M Embryonal ± ++++ ± ++++ ± /M M/ M/ Yolk sac tumor ± ± /M horio + ± ± /M Mature teratoma ± ± ± ± +++ Immature ± ± +++ ± ± ± teratoma Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Useful immunohistochemical stains in intracranial GTs Transcription Factors Podoplanin LI28A SALL4 OT4 AOG SOX2 PLAP KIT D30 Glypican 3 AFP βhg HPL K AE1/3 D ± ++++ /M M/ M M Useful immunohistochemical stains in intracranial GTs Transcription Factors Podoplanin LI28A SALL4 OT4 AOG SOX2 PLAP KIT D30 Glypican 3 AFP βhg HPL K AE1/3 D ± ++++ /M M/ M M Useful immunohistochemical stains in intracranial GTs Transcription Factors Podoplanin LI28A SALL4 OT4 AOG SOX2 PLAP KIT D30 Glypican 3 AFP βhg HPL K AE1/3 D ± ++++ /M M/ M M Embryonal ± ++++ ± ++++ ± /M M/ M/ Embryonal ± ++++ ± ++++ ± /M M/ M/ Embryonal ± ++++ ± ++++ ± /M M/ M/ Yolk sac tumor ± ± /M horio + ± ± /M Mature teratoma ± ± ± ± +++ Yolk sac tumor ± ± /M horio + ± ± /M Mature teratoma ± ± ± ± +++ Yolk sac tumor ± ± /M horio + ± ± /M Mature teratoma ± ± ± ± +++ Immature teratoma ± ± +++ ± ± ± Immature teratoma ± ± +++ ± ± ± Immature teratoma ± ± +++ ± ± ± Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series.

9 Useful immunohistochemical stains in intracranial GTs Transcription Factors Podoplanin LI28A SALL4 OT4 AOG SOX2 PLAP KIT D30 Glypican 3 AFP βhg HPL K AE1/3 D2-40 Other differential diagnosis Genetics of S Germ cell tumors ± ++++ /M M/ M M Embryonal ± ++++ ± ++++ ± /M M/ M/ Yolk sac tumor ± ± /M horio + ± ± /M Mature teratoma ± ± ± ± +++ Infiltrative glioma Lymphoma Sarcoidosis or infection Metastatic Mostly sporadic Syndromic associations: Trisomy 21 Klinefelter (47 XXY): intracranial, mediastinal? F1 12p abnormalities common Immature teratoma ± ± +++ ± ± ± Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. 12p abnormalities Treatment and prognosis Prognostic variables: histology, location, and proximity to vital structures EP12 Tel12 Isochromosome 12p 12p overrepresentation EP12 Tel12 s: SI/whole brain, plus local boost Recent trend: less radiation, in favor of cisplatin-based chemotherapy >90% 10-year survival on-gts: Mature teratomas: gross total resection Immature teratomas: GTS + radiation ongenital teratomas: invariably fatal E, YST, horio: multimodal therapy; <45% 5-year survival Hattab EM, et al. hromosome 12p abnormalities in germinoma of the central nervous system: a FISH analysis of 23 cases. The XVIth International ongress of europathology/82nd Annual Meeting of the American Association of europathologists. San Francisco, A. September 10-15, Published in Brain Pathol, 2006.

10 Age Distribution According to Location () Mature Teratoma Mature Teratoma Pineal 16 Suprasellar Age (years) Anatomical Location Hattab EM, et al. Primary intracranial germinoma: a retrospective clinicopathologic analysis of 27 cases. The 94th Annual Meeting of the United States and anadian Academy of Pathology. San Antonio, TX. February 26-March 4, Published in Mod Pathol 2005;18(Suppl 1) and in Lab Invest 2005;85(Suppl1). Surgical europathology: a Diagnostic Approach. Second edition. Surgical europathology: a Diagnostic Approach. Second edition. A Volume in the Pattern Recognition Series. OT4 Transcription factor Regulates initiation, maintenance, and differentiation of pluripotent and germline cells during normal development ormally expressed in embryonic stem cells and embryonal ca are undifferentiated neoplasms with pluripotential 25/25 (100%); 22 at 3+ Add D30 or Aggrus if embryonal ca is in differential Aggrus/Podoplanin Transmembrane sialoglycoprotein? Physiological role Expressed in lung type I alveolar cells, lymphatic endothelial cells (lymphatic endothelial marker) Identified on surface of some tumor cells: platelet aggregation-inducing effect that did not require plasma components ot expressed in E 19/20 (95%); 17 at 3+

11 Useful immunohistochemical stains in intracranial germ cell tumors Demographics Transcription Factors Podoplanin K OT4 AOG AP-2γ SOX2 PLAP c-kit D30 AFP β-hg HPL EMA D2-40 YM-1 AE1/ ² -² - +/ M/ M M M Embryonal / /- -² -² +/- ++ +/- - M/ M/ M Yolk sac tumor /- +/ ² -² horio / ² +++² Mature teratoma /- +/ /- -² -² M Immature teratoma ¹ - +/ /-² -² M Abbreviations: AFP: alpha-fetoprotein; β-hg: β-human chorionic gonadotropin; : cytoplasmic; HPL: human placental lactogen; M: membranous; : nuclear; PLAP: placental alkaline phosphatase. ¹staining limited to primitive neuroepithelial tissues; ²HG and HPL are positive in intermingled syncytiotrophoblast cells Age distribution: >90% younger than 25 years; peripuberty Younger: teratoma and chorio Older: pure germinoma ongenital forms Sex predilection: M:F of 3.8:1 Pineal and BG: males Suprasellar and congenital: slight female predominance Genetics of S GTs Genetics of S Germ cell tumors S vs on-s GTs 12p Abnormalities in S s 12p abnormalities common Frequent gain in D2 (12p13) and PRDM14 (8q13), and losses of RB1 (13q14) =? cyclin/dk-rb-e2f pathway Mutually exclusive somatic mutations in KIT and RAS (germinomas) =? KIT/RAS signaling pathway 8q,1q, and X gains 18q, 9q and 11q losses Variable Morphology Immunohistochemistry Ultrastructure Genetics on-s S? Similar?? % cases p OR i(12)p 12p OR +i(12p) 12p OR only Abnormality Hattab EM, et al. hromosome 12p abnormalities in germinoma of the central nervous system: a FISH analysis of 23 cases. The XVIth International ongress of europathology/82nd Annual Meeting of the American Association of europathologists. San Francisco, A. September 10-15, Published in Brain Pathol, 2006.

12 S vs on-s GTs Abnormality 12p OR i(12p) Testicular >90% 80% Ovarian 81% 76% 12p overrepresentation (aneuploidization)?precedes the formation of i(12p) FISH analysis for 12p abnormalities:?adjunct diagnostic tool S 96% 57% Genetics of Testicular GTs 12p gain: First described by Atkin and Baker, 1982 Gain of extra copies of the short arm of chromosome 12 (overrepresentation); occasionally in tandem (isochromosome 12p) Hallmark genetic marker of testicular GTs All types of GTs, except for SS? Early event in GT tumorigenesis vs progression Target genes overexpressed: 73 genes (GLUT3, REA, D2, FLJ22028, AOG, STELLA, GDF3, EBAF, TDGF1, SOX2, etc) 12p gain is a functionally relevant change leading to activation of proliferation and Genetics of Ovarian Dysgerminoma 81% of cases showed 12p abnormalities 57%: i(12)p only 5%: 12p overrepresentation only 19%: i(12)p + 12p OR reestablishment/maintenance of stem cell function through activation of key stem cell genes Hattab EM, et al. hromosome 12p abnormalities in germinoma of the central nervous system: a FISH analysis of 23 cases. The XVIth International ongress of europathology/82nd Annual Meeting of the American Association of europathologists. San Francisco, A. September 10-15, Published in Brain Pathol, ossu-rocca P, et al. hromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis. Mod Pathol. 2006;19: Poulos, et al. Analysis of ovarian teratomas for isochromosome 12p: evidence supporting a dual histogenetic pathway for teratomatous elements. Mod Pathol. 2006;19: Korkola et al, ancer Research p overrepresentation may also be seen in esophageal, pancreatic and ovarian s 12p overrepresentation may correlate with invasive growth of seminomas and nonseminomas ossu-rocca P, et al. hromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis. Mod Pathol 2006;19: How i(12p) is formed Outcome of S GTs Question? Do S germinomas share the same genetic alterations known to non-s GTs (12p abnormalities)? p q p q p q p p + + p q q q

13 Dual-color FISH Metaphase: whole isochromosome Interphase: numerical abnormality DA Probes: EP12: entromeric α satellite h12p; Vysis Tel12: Subtelomeric h12p; Vysis ontrols: Positive: classic testicular seminoma egative: internal lymphocytes FISH Scoring 100 nuclei scored for EP12 (red) and 12p (green) signals. Green : Red ratio calculated. 12p Overrepresentation: utoff: average signal number plus 3X standard deviation (3SD), which represented about 99% accuracy. Isochromosome 12p: Spatial distribution of green : red signals analyzed: specific pattern of signal aggregation. orrelation with clinical behavior? Followup available on 15/23 cases: 12p abnormalities detected (22 cases): Recurrence: 4/14; all with 12p OR and i(12)p Death: 1/14 12p abnormalities not detected (1 case): 15-year-old male Suprasellar Alive, free of disease Morphologically and immunohistochemically typical Pure s: The IU Experience 32 primary intracranial germinomas over 22 year period: Incidence: ~2% of all primary pediatric tumors at IUM One patient had mediastinal germinoma 16 years earlier (? 2nd primary) 14/28 received T + Focal XRT: 5 (36%) relapsed: 4 salvaged by SI, 1 died of disease progression 5/28 received T: 2 (40%) relapsed, 3 others are recent cases: 1 salvaged by SI, 1 died of disease progression 9/28 received SI: one relapsed 1 died of radiation complications Important Information Regarding ME/SAMs The Online ME/Evaluations/SAMs claim process will only be available on the USAP website until September 30, o claims can be processed after that date! After September 30, 2017 you will OT be able to obtain any ME or SAMs credits for attending this meeting. GTs and Indiana University is-platinum: First member of platinum antitumor agents ross links DA; triggers apoptosis 1845: M. Peyrone (Peyrone salt) Rosenberg et al: Platinum compounds: a new class of potent antitumour agents ature Apr 26;222:385-6

14 GTs and Indiana University GTs and Indiana University GTs and Indiana University is-platinum and GTs: 1974: Lawrence Einhorn Phase II study Patients with disseminated testicular GTs cisplatinum + vinblastine + bleomycin 74% complete remission 26% partial remission With postchemo surgery: 85% remission Standard therapy o phase III study conducted! GTs and Indiana University GTs and Indiana University Thomas M. Ulbright, M.D. Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005;18 Suppl 2:S61-79.

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