germ cell tumors - uscap · • cap neuropath committee, chair ... endocrinology 1923;7:379-414 •...

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GERM CELL TUMORSEyas M Hattab, MDDepartment of Pathology and Laboratory MedicineUniversity of [email protected]

GERM CELL TUMORS

Disclosure of Relevant Financial Relationships

USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial

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.


USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial

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.

GERM CELL TUMORS


• Nothing relevant to this presentation• CAP Neuropath Committee, Chair

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• Germinoma• Nongerminomatous GCTs

• Embryonal carcinoma• Yolk sac tumor• Choriocarcinoma• Teratoma

• Benign/mature teratoma• Immature 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.

WHO 2016

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• Largely homologues of GCTs elsewhere

• Different from non-CNS GCTs?• Morphology

• No precursor lesions (GCNIS)• No spermatocytic “seminoma”

• Clinical behavior• Prepubertal vs postpubertal

• ? Origin

Introduction

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Historical perspective

• 1923 (Krabbe): “Pinealoma” Adenoma of the pineal body Endocrinology 1923;7:379-414

• 1944 (Russel): “Atypical pineal teratoma” Pinealoma-Its relationship to teratoma J Pathol Bacteriol 1944;56:145-50

• 1946 (Friedman and Moore): “Germinoma” Tumors of the Testis: A report on 922 cases. Mil Surgeon 1946;99:573-93

• 1976: “Ultrastructural study of histogenesis of pinealoma” No ToShinkei 1976;28:41-56

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Pathogenesis

• Germ cell theory• Primordial germ cells (PGC)• Common 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 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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Thorsten Boroviak, and Jennifer Nichols Phil. Trans. R. Soc. B 2014;369:20130541

Pathogenesis

Germ cell theory Embryonic cell theory

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Germ cell

GCNIS

Seminoma

Seminoma + SynT

Chorio-carcinoma

YST

SS

Pediatric teratoma

Pediatric YST

Embryonal carcinoma

Teratoma

Dermoid cyst

Epidermoid cyst

Source: Thomas M Ulbright, MD (modified with permission)

Testicular GCT histogenesis

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Incidence

• CBTRUS Statistical Report 2016• Adults: ~0.4% of all CNS neoplasms

0.10/100,000• Children: ~4%

0.21/100,000

• Geographical variation: up to 15% in Far-East Asia and Japan (pediatric brain and tumors)

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 (suppl5):v1-v75

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Incidence: Age-Adjusted

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Incidence: Age-Adjusted

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Localization

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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• Midline locations• Pineal/third ventricle• Suprasellar

• BG, thalamus, ventricles, cerebral hemispheres, SC, etc• Multifocal: synchronus/metachronus• Holocranial variants rare

• Germinomas: suprasellar, BG, thalamus• NGGCTs: other sites

Localization

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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 5):v1-v75

Incidence Rate Ratios by Sex (Males:Females)

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Gender Distribution According to Location (Germinoma)

0

1

2

3

4

5

6

7

8

9

10

Pineal Suprasellar Synchronous BG6 9 4 01 10 1 1

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(Suppl 1).

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Incidence Rate Ratios by Race (Whites:Blacks)

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 5):v1-v75

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Clinical Manifestations

• Pineal• Aqueductal compression (increased ICPs; hydrocephalus)• Distortion of quadrigeminal plate (mental status changes, upward gaze palsies,

etc; Parinaud syndrome)• Precocious puberty (hCG)

• Suprasellar• Triad: DI, loss of visual acuity, hypopituitarism

• Higher incidence / association• Klinefelter syndrome• Down syndrome

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Radiographic Features• Nonspecific• Well-circumscribed, lobulated lesions • T1: hypointense • T2/FLAIR: mainly hyperintense • Enhanced intensity and heterogeneously on both CT and MR• Calcification (usually pineal)• Hydrocephalus common• Often partially cystic• Local invasion common


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Histology of CNS GCTs

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Germinoma


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Germinoma


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Germinoma


c-kit OCT4

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Embryonal Carcinoma


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Embryonal Carcinoma


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Embryonal Carcinoma

OCT4 CD30Hattab 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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Yolk Sac Tumor


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Yolk Sac Tumor


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Yolk Sac Tumor

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). α-fetoprotein

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Choriocarcinoma

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). βhCG

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Mature Teratoma


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Mature Teratoma


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Immature Teratoma


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Immunohistochemistry: recent advances

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PLAP

• Previously the marker of choice• Lacks specificity (epithelial

malignancies)• Nonspecific staining• 23/25 (92%) positive membranous

staining (only 2 at 3+)

Hattab, et al. OCT4 Immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol2005;29:368-71

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“New” IHC Markers

• Glypican 3• NANOG• LIN28A• OCT4• Podoplanin/aggruss• SALL4• SOX2• SOX17

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OCT4• Transcription factor• Regulates initiation, maintenance, and

differentiation of pluripotent and germline cells during normal development

• Normally expressed in embryonic stem cells

• Germinoma and embryonal ca • High sensitivity/specificity


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C-Kit• Tyrosine-kinase glycoprotein• Germinomas

• 23/25 (92%), 20 at 3+• Negative or weak in EC• No correlation with KIT

mutations

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. 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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SALL4• Transcription factor• Maintains embryonic stem cell

pluripotency and self renewal (OCT4, NANOG, & SOX2)

• PanGCT marker• Ideal screening marker• Superior to AFP and glypican 3

in YST

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Glypican 3• Membrane-based proteoglycan

Xq26.2• Highly expressed in fetal tissues• Regulation of cell growth and

differentiation• Highly expressed in YST and

CC• HCC, hepatoblastoma, ovarian

clear cell ca

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Useful immunohistochemical stains in intracranial GCTs


Transcription Factors PodoplaninLIN28A SALL4 OCT4 NANOG SOX2 PLAP KIT CD30 Glypican 3 AFP βhCG HPL CK AE1/3 D2-40

Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++

C/M N N N M/C M C M

Embryonal carcinoma

+++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ±

C/M N N N N M/C C M/C C C

Yolk sac tumor +++ +++ – – – ± ± – ++++ ++++ – – +++ –

C/M N C C C C

Choriocarcinoma + ± – – – ± – – + – +++ +++ +++ –

C/M C C C C

Mature teratoma – – – – ± ± – – ± ± – – +++ –

N C

Immature teratoma

± ± – – +++ – ± – ± – ± – – –

N

GERM CELL TUMORS




Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++

C/M N N N M/C M C M

Embryonal carcinoma

+++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ±


Yolk sac tumor +++ +++ – – – ± ± – ++++ ++++ – – +++ –

C/M N C C C C


C/M C C C C

Mature teratoma – – – – ± ± – – ± ± – – +++ –

N C

Immature teratoma

± ± – – +++ – ± – ± – ± – – –

N

GERM CELL TUMORS




Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++

C/M N N N M/C M C M

Embryonal carcinoma

+++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ±


Yolk sac tumor +++ +++ – – – ± ± – ++++ ++++ – – +++ –

C/M N C C C C


C/M C C C C

Mature teratoma – – – – ± ± – – ± ± – – +++ –

N C

Immature teratoma

± ± – – +++ – ± – ± – ± – – –

N

GERM CELL TUMORS




Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++

C/M N N N M/C M C M

Embryonal carcinoma

+++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ±


Yolk sac tumor +++ +++ – – – ± ± – ++++ ++++ – – +++ –

C/M N C C C C


C/M C C C C

Mature teratoma – – – – ± ± – – ± ± – – +++ –

N C

Immature teratoma

± ± – – +++ – ± – ± – ± – – –

N

GERM CELL TUMORS




Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++

C/M N N N M/C M C M

Embryonal carcinoma

+++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ±


Yolk sac tumor +++ +++ – – – ± ± – ++++ ++++ – – +++ –

C/M N C C C C


C/M C C C C

Mature teratoma – – – – ± ± – – ± ± – – +++ –

N C

Immature teratoma

± ± – – +++ – ± – ± – ± – – –

N

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Germinoma +++ +++ ++++ +++ – +++ ++++ – – – – – ± ++++

C/M N N N M/C M C M

Embryonal carcinoma

+++ +++ +++ +++ ++++ ++ ± ++++ – ± – – ++++ ±


Yolk sac tumor +++ +++ – – – ± ± – ++++ ++++ – – +++ –

C/M N C C C C


C/M C C C C

Mature teratoma – – – – ± ± – – ± ± – – +++ –

N C

Immature teratoma

± ± – – +++ – ± – ± – ± – – –

N

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Other differential diagnosis

• Infiltrative glioma• Lymphoma• Sarcoidosis or infection• Metastatic carcinoma

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Genetics of CNS Germ cell tumors

• Mostly sporadic• Syndromic associations:

• Trisomy 21• Klinefelter (47 XXY): intracranial, mediastinal• ? NF1

• 12p abnormalities common

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12p abnormalities

CEP12Tel12

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.

Isochromosome 12p

CEP12Tel12

12p overrepresentation

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Treatment and prognosis

• Prognostic variables: histology, location, and proximity to vital structures• Germinomas:

• CSI/whole brain, plus local boost• Recent trend: less radiation, in favor of cisplatin-based chemotherapy• >90% 10-year survival

• Non-GCTs:• Mature teratomas: gross total resection• Immature teratomas: GTS + radiation• Congenital teratomas: invariably fatal• EC, YST, Chorio: multimodal therapy; <45% 5-year survival

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Age Distribution According to Location (Germinoma)

12.1 12.5

18.4

10

0

2

4

6

8

10

12

14

16

18

20

Age

(yea

rs)

Anatomical Location

Pineal

Suprasellar


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Mature Teratoma


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Mature Teratoma


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OCT4• Transcription factor• Regulates initiation, maintenance, and

differentiation of pluripotent and germline cells during normal development

• Normally expressed in embryonic stem cells

• Germinoma and embryonal ca are undifferentiated neoplasms with pluripotential

• 25/25 (100%); 22 at 3+• Add CD30 or Aggrus if embryonal ca is in

differential

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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

Not expressed in EC 19/20 (95%); 17 at 3+

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Transcription Factors Podoplanin

OCT4 NANOG AP-2γ SOX2 PLAP c-KIT CD30 AFP β-HCG HPL EMACK

AE1/3D2-40 YM-1

Germinoma ++++N

+++N

+++N

- +++M/C

++++M

- - -² -² - +/-C

++++M

++++M

Embryonal carcinoma

+++N

+++N

+++N

++++N

++M/C

+/-C

++++M/C

+/- -² -² +/-M

++C

+/-C

-

Yolk sac tumor - - - - +/- +/-C

- ++++C

-² -² - +++C

- -

Choriocarcinoma - - - - +/- - - - +++²C

+++²C

+++ +++C

- -

Mature teratoma - - - +/-N

+/- - - +/- -² -² +++M

+++C

- -

Immature teratoma - - - +++¹N

- +/- - - +/-² -² - - - +M

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 syncytiotrophoblast cells

Useful immunohistochemical stains in intracranial germ cell tumors

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Demographics

Age distribution: >90% younger than 25 years; peripuberty Younger: teratoma and choriocarcinoma Older: pure germinoma Congenital forms

Sex predilection: M:F of 3.8:1 Pineal and BG: males Suprasellar and congenital: slight female predominance

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Genetics of CNS GCTs

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Genetics of CNS Germ cell tumors

• 12p abnormalities common• Frequent gain in CCND2 (12p13) and PRDM14 (8q13), and

losses of RB1 (13q14) = ? cyclin/CDK-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

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CNS vs Non-CNS GCTsSimilar?CNSNon-CNSVariable

Morphology

Immunohistochemistry

Ultrastructure

??Genetics

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12p Abnormalities in CNS Germinomas

12p

OR

i(12)

p

12p

OR +

i(12p

)12

p OR

onl

y

0

20

40

60

80

100

% c

ases

AbnormalityHattab 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 GCTsCNSOvarianTesticularAbnormality

96%81%>90%12p OR

57%76%80%i(12p)

• 12p overrepresentation (aneuploidization) ?precedes the formation of i(12p)• FISH analysis for 12p abnormalities: ?adjunct diagnostic tool

• 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.

• Cossu-Rocca P, et al. Chromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis. Mod Pathol. 2006;19:611-5.• Poulos C, et al. Analysis of ovarian teratomas for isochromosome 12p: evidence supporting a dual histogenetic pathway for teratomatous elements. Mod Pathol.

2006;19:766-71.

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Genetics of Testicular GCTs• 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 GCTs• All types of GCTs, except for SS• ? Early event in GCT tumorigenesis vs progression

• Target genes overexpressed: 73 genes (GLUT3, REA, CCND2, FLJ22028, NANOG, STELLA, 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” Korkola et al, Cancer Research 2006

• 12p overrepresentation may also be seen in esophageal, pancreatic and ovarian carcinomas• 12p overrepresentation may correlate with invasive growth of seminomas and nonseminomas

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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

Cossu-Rocca P, et al. Chromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis. Mod Pathol 2006;19:611-615

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Outcome of CNS GCTs

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Question?Do CNS germinomas share the same genetic alterations known to non-CNS GCTs (12p abnormalities)?

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p

q

+

p

q

p

p

q

q

p

q

p

q

+

How i(12p) is formed

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Dual-color FISH

• Metaphase: whole isochromosome• Interphase: numerical abnormality• DNA Probes:

• CEP12: Centromeric α‐satellite – Ch12p; Vysis• Tel12: Subtelomeric – Ch12p; Vysis

• Controls:• Positive: classic testicular seminoma• Negative: internal lymphocytes

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FISH Scoring

• 100 nuclei scored for CEP12 (red) and 12p (green) signals.• Green : Red ratio calculated.• 12p Overrepresentation:

• Cutoff: 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.

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Correlation 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

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Pure Germinomas: The IU Experience• 32 primary intracranial germinomas over 22 year period:

• Incidence: ~2% of all primary pediatric tumors at IUMC• One patient had mediastinal germinoma 16 years earlier (? 2nd primary)

• 14/28 received CT + Focal XRT:• 5 (36%) relapsed:

• 4 salvaged by CSI, 1 died of disease progression• 5/28 received CT:

• 2 (40%) relapsed, 3 others are recent cases:• 1 salvaged by CSI, 1 died of disease progression

• 9/28 received CSI:• None relapsed• 1 died of radiation complications

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Important Information Regarding CME/SAMs

The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, 2017.

No claims can be processed after that date!

After September 30, 2017 you will NOT be able to obtain any CME or SAMs credits for attending this meeting.

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GCTs and Indiana University

• Cis-platinum:• First member of platinum antitumor agents• Cross links DNA; triggers apoptosis• 1845: M. Peyrone (Peyrone salt)

Rosenberg et al: “Platinum compounds: a new class of potent antitumour agents” Nature. 1969 Apr 26;222:385-6

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• Cis-platinum and GCTs:• 1974: Lawrence Einhorn

• Phase II study• Patients with disseminated testicular GCTs• cisplatinum + vinblastine + bleomycin• 74% complete remission• 26% partial remission• With postchemo surgery: 85% remission

• Standard therapy• No phase III study conducted!

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Thomas M. Ulbright, M.D.

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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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germ cell tumors - uscap · • cap neuropath committee, chair ... endocrinology 1923;7:379-414 •...

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