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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.
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.
GERM CELL TUMORS
Disclosure of Relevant Financial Relationships
• Nothing relevant to this presentation• CAP Neuropath Committee, Chair
GERM CELL TUMORS
• 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
GERM CELL TUMORS
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
GERM CELL TUMORS
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.
GERM CELL TUMORS
Thorsten Boroviak, and Jennifer Nichols Phil. Trans. R. Soc. B 2014;369:20130541
Pathogenesis
Germ cell theory Embryonic cell theory
GERM CELL TUMORS
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
GERM CELL TUMORS
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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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
Incidence: Age-Adjusted
GERM CELL 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
Incidence: Age-Adjusted
GERM CELL TUMORS
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).
GERM CELL TUMORS
• 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
GERM CELL 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 (suppl 5):v1-v75
Incidence Rate Ratios by Sex (Males:Females)
GERM CELL TUMORS
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
GERM CELL TUMORS
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
GERM CELL TUMORS
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
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).
GERM CELL TUMORS
Histology of CNS GCTs
GERM CELL TUMORS
Germinoma
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).
GERM CELL TUMORS
Germinoma
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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Germinoma
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).
c-kit OCT4
GERM CELL TUMORS
Embryonal Carcinoma
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).
GERM CELL TUMORS
Embryonal Carcinoma
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).
GERM CELL TUMORS
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).
GERM CELL TUMORS
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).
GERM CELL TUMORS
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).
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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
GERM CELL TUMORS
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
GERM CELL TUMORS
Mature Teratoma
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).
GERM CELL TUMORS
Mature Teratoma
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).
GERM CELL TUMORS
Immature Teratoma
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).
GERM CELL TUMORS
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
GERM CELL TUMORS
“New” IHC Markers
• Glypican 3• NANOG• LIN28A• OCT4• Podoplanin/aggruss• SALL4• SOX2• SOX17
GERM CELL TUMORS
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
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
GERM CELL TUMORS
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
GERM CELL TUMORS
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).
GERM CELL TUMORS
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
GERM CELL TUMORS
Useful immunohistochemical stains in intracranial GCTs
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).
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
Useful immunohistochemical stains in intracranial GCTs
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).
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
Useful immunohistochemical stains in intracranial GCTs
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).
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
Useful immunohistochemical stains in intracranial GCTs
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).
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
Useful immunohistochemical stains in intracranial GCTs
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).
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
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Useful immunohistochemical stains in intracranial GCTs
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).
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
Other differential diagnosis
• Infiltrative glioma• Lymphoma• Sarcoidosis or infection• Metastatic carcinoma
GERM CELL TUMORS
Genetics of CNS Germ cell tumors
• Mostly sporadic• Syndromic associations:
• Trisomy 21• Klinefelter (47 XXY): intracranial, mediastinal• ? NF1
• 12p abnormalities common
GERM CELL TUMORS
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
GERM CELL TUMORS
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
GERM CELL TUMORS
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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
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).
GERM CELL TUMORS
Mature Teratoma
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).
GERM CELL TUMORS
Mature Teratoma
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).
GERM CELL TUMORS GERM CELL TUMORS
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
GERM CELL TUMORS
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
GERM CELL TUMORS
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
GERM CELL TUMORS
Genetics of CNS GCTs
GERM CELL TUMORS
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
GERM CELL TUMORS
CNS vs Non-CNS GCTsSimilar?CNSNon-CNSVariable
Morphology
Immunohistochemistry
Ultrastructure
??Genetics
GERM CELL TUMORS
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.
GERM CELL TUMORS
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
GERM CELL TUMORS
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
GERM CELL TUMORS
Outcome of CNS GCTs
GERM CELL TUMORS
Question?Do CNS germinomas share the same genetic alterations known to non-CNS GCTs (12p abnormalities)?
GERM CELL TUMORS
p
q
+
p
q
p
p
q
q
p
q
p
q
+
How i(12p) is formed
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GERM CELL TUMORS
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
GERM CELL TUMORS
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.
GERM CELL TUMORS
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
GERM CELL TUMORS
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
GERM CELL TUMORS
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.
GERM CELL TUMORS
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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GERM CELL TUMORS
GCTs and Indiana University
GERM CELL TUMORS
GCTs and Indiana University
• 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!
GERM CELL TUMORS
GCTs and Indiana University
GERM CELL TUMORS
GCTs and Indiana University
Thomas M. Ulbright, M.D.
GERM CELL TUMORS
GCTs and Indiana University
GERM CELL TUMORS
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
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