Germinoma pathophysiology: Difference between revisions

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==Overview==
==Overview==
On gross pathology, smooth and bosselated external surface, and soft, fleshy and either cream-colored, gray, pink or tan interior are characteristic findings of germinoma.
On microscopic histopathological analysis, uniform cells that resemble [[primordial germ cells]], consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic are characteristic findings of germinoma. Genes involved in the pathogenesis of germinoma include gains of 1p, 8p, and 12q and losses of 13q and 18q, duplication of the short arm of chromosome 12, loss of 1p and 6q, alterations in sex chromosomes in children, alterations of the ''p14'' gene, mutations of the ''c-kit'' gene, aberrations of ''CCND2'' (12P13), and ''RB1'', and gain-of-function mutations of ''KIT''. The progression to germinoma usually involves the mutations of the ''KIT/RAS'' signalling or ''AKT1''/mtor pathways and cyclin/''CDK-RB-E2F'' pathway if ''CCND2'' (12P13) and ''RB1'' genes are aberrated.<ref name="pmid11005262">{{cite journal| author=Rickert CH, Simon R, Bergmann M, Dockhorn-Dworniczak B, Paulus W| title=Comparative genomic hybridization in pineal germ cell tumors. | journal=J Neuropathol Exp Neurol | year= 2000 | volume= 59 | issue= 9 | pages= 815-21 | pmid=11005262 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11005262  }} </ref><ref name="pmid16607373">{{cite journal| author=Schneider DT, Zahn S, Sievers S, Alemazkour K, Reifenberger G, Wiestler OD et al.| title=Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. | journal=Mod Pathol | year= 2006 | volume= 19 | issue= 6 | pages= 864-73 | pmid=16607373 | doi=10.1038/modpathol.3800607 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16607373  }} </ref><ref name="pmid17285132">{{cite journal| author=Palmer RD, Foster NA, Vowler SL, Roberts I, Thornton CM, Hale JP et al.| title=Malignant germ cell tumours of childhood: new associations of genomic imbalance. | journal=Br J Cancer | year= 2007 | volume= 96 | issue= 4 | pages= 667-76 | pmid=17285132 | doi=10.1038/sj.bjc.6603602 | pmc=PMC2360055 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17285132  }} </ref><ref name="pmid19329861">{{cite journal| author=Sato K, Takeuchi H, Kubota T| title=Pathology of intracranial germ cell tumors. | journal=Prog Neurol Surg | year= 2009 | volume= 23 | issue=  | pages= 59-75 | pmid=19329861 | doi=10.1159/000210053 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19329861  }} </ref><ref name="pmid16572634">{{cite journal| author=Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H| title=C-kit gene mutation: common and widely distributed in intracranial germinomas. | journal=J Neurosurg | year= 2006 | volume= 104 | issue= 3 Suppl | pages= 173-80 | pmid=16572634 | doi=10.3171/ped.2006.104.3.173 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16572634  }} </ref><ref name="pmid15471556">{{cite journal| author=Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K| title=c-kit gene mutations in intracranial germinomas. | journal=Cancer Sci | year= 2004 | volume= 95 | issue= 9 | pages= 716-20 | pmid=15471556 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15471556  }} </ref><ref name="pmid20178649">{{cite journal| author=Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ et al.| title=Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations. | journal=BMC Genomics | year= 2010 | volume= 11 | issue=  | pages= 132 | pmid=20178649 | doi=10.1186/1471-2164-11-132 | pmc=PMC2837036 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20178649  }} </ref><ref name="pmid24249158">{{cite journal| author=Terashima K, Yu A, Chow WY, Hsu WC, Chen P, Wong S et al.| title=Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors. | journal=Pediatr Blood Cancer | year= 2014 | volume= 61 | issue= 4 | pages= 593-600 | pmid=24249158 | doi=10.1002/pbc.24833 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24249158  }} </ref>
On microscopic histopathological analysis, uniform cells that resemble primordial germ cells, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic are characteristic findings of germinoma. Genes involved in the pathogenesis of germinoma include the chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q. duplication of the short arm of chromosome 12, loss of 1p and 6q and alterations in sex chromosomes in children, alterations of the p14 gene, mutations of the c-kit gene, aberrations of CCND2 (12P13), and RB1, and and gain-of-function mutations of KIT. The progression to germinoma usually involves the mutations of the KIT/RAS signalling or AKT1/mtor pathways and cyclin/CDK-RB-E2F pathway if CCND2 (12P13) and RB1 genes are aberrated.<ref name="pmid11005262">{{cite journal| author=Rickert CH, Simon R, Bergmann M, Dockhorn-Dworniczak B, Paulus W| title=Comparative genomic hybridization in pineal germ cell tumors. | journal=J Neuropathol Exp Neurol | year= 2000 | volume= 59 | issue= 9 | pages= 815-21 | pmid=11005262 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11005262  }} </ref><ref name="pmid16607373">{{cite journal| author=Schneider DT, Zahn S, Sievers S, Alemazkour K, Reifenberger G, Wiestler OD et al.| title=Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. | journal=Mod Pathol | year= 2006 | volume= 19 | issue= 6 | pages= 864-73 | pmid=16607373 | doi=10.1038/modpathol.3800607 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16607373  }} </ref><ref name="pmid17285132">{{cite journal| author=Palmer RD, Foster NA, Vowler SL, Roberts I, Thornton CM, Hale JP et al.| title=Malignant germ cell tumours of childhood: new associations of genomic imbalance. | journal=Br J Cancer | year= 2007 | volume= 96 | issue= 4 | pages= 667-76 | pmid=17285132 | doi=10.1038/sj.bjc.6603602 | pmc=PMC2360055 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17285132  }} </ref><ref name="pmid19329861">{{cite journal| author=Sato K, Takeuchi H, Kubota T| title=Pathology of intracranial germ cell tumors. | journal=Prog Neurol Surg | year= 2009 | volume= 23 | issue=  | pages= 59-75 | pmid=19329861 | doi=10.1159/000210053 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19329861  }} </ref><ref name="pmid16572634">{{cite journal| author=Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H| title=C-kit gene mutation: common and widely distributed in intracranial germinomas. | journal=J Neurosurg | year= 2006 | volume= 104 | issue= 3 Suppl | pages= 173-80 | pmid=16572634 | doi=10.3171/ped.2006.104.3.173 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16572634  }} </ref><ref name="pmid15471556">{{cite journal| author=Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K| title=c-kit gene mutations in intracranial germinomas. | journal=Cancer Sci | year= 2004 | volume= 95 | issue= 9 | pages= 716-20 | pmid=15471556 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15471556  }} </ref><ref name="pmid20178649">{{cite journal| author=Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ et al.| title=Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations. | journal=BMC Genomics | year= 2010 | volume= 11 | issue=  | pages= 132 | pmid=20178649 | doi=10.1186/1471-2164-11-132 | pmc=PMC2837036 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20178649  }} </ref><ref name="pmid24249158">{{cite journal| author=Terashima K, Yu A, Chow WY, Hsu WC, Chen P, Wong S et al.| title=Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors. | journal=Pediatr Blood Cancer | year= 2014 | volume= 61 | issue= 4 | pages= 593-600 | pmid=24249158 | doi=10.1002/pbc.24833 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24249158  }} </ref>


==Pathophysiology==
==Pathophysiology==
Pineal lesions occur more commonly than suprasellar lesions, at a ratio of 2:1.
Pineal lesions occur more commonly than suprasellar lesions, at a ratio of 2:1.
The location of the tumor that compromises total percentage of CNS germ cell tumors is shown below in a tabular form:<ref name="radio"> Germ cell tumors. Radiopedia(2015) http://radiopaedia.org/articles/central-nervous-system-germinoma Accessed on January 25, 2016</ref>
The location of the tumor that compromises total percentage of central nervous system (CNS) germ cell tumors is shown below in a tabular form:<ref name="radio"> Germ cell tumors. Radiopedia(2015) http://radiopaedia.org/articles/central-nervous-system-germinoma Accessed on January 25, 2016</ref>
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align=center
{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align=center
|valign=top|
|valign=top|
|+
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Location of the tumor }}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Location of the tumor}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|% of CNS GCT}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|% of CNS GCT}}
|-
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
:Pineal area
:[[Pineal]] area
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*50-60% of CNS germ cell tumors
*50-60% of CNS germ cell tumors
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Suprasellar area
:[[Suprasellar]] area
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*30-40%
*30-40%
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
:Basal ganglia, thalamus, cerebral hemisphere
:[[Basal ganglia]], [[thalamus]], cerebral hemisphere
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*5-10%
*5-10%
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|-
|}
|}
===Gross pathology===
===Gross Pathology===
On gross examination, the external surface is smooth and bosselated (knobby), and the interior is soft, fleshy and either cream-coloured, gray, pink or tan.<ref name="wiki">germinoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Germinoma Accessed on January 26, 2016</ref>  
On gross examination, the external surface is smooth and bosselated (knobby), and the interior is soft, fleshy and either cream, gray, pink, or tan colored.<ref name="wiki">germinoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Germinoma Accessed on January 26, 2016</ref>
===Microscopic pathology===
 
Microscopic examination typically reveals uniform cells that resemble primordial germ cells. Typically, the [[stroma]] contains [[lymphocyte]]s and about 20% of patients have sarcoid-like [[granuloma]]s. The tumor is uniform in appearance, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic. Pure germinomas are composed of large polygonal undifferentiated cells with abundant cytoplasm arranged in nests separated by bands of connective tissue. The histologic appearance of Nongerminomatous germ cell tumors (NGGCTs) varies depending upon the specific cell types present.<ref name="wiki">germinoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Germinoma Accessed on January 26, 2016</ref>   
===Microscopic Pathology===
Microscopic examination typically reveals uniform cells that resemble primordial germ cells. Typically, the [[stroma]] contains [[lymphocyte]]s and about 20% of patients have sarcoid-like [[granuloma]]s. The tumor is uniform in appearance, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic. Pure germinomas are composed of large polygonal undifferentiated cells with abundant cytoplasm arranged in nests separated by bands of connective tissue. The histologic appearance of nongerminomatous germ cell tumors (NGGCTs) varies depending upon the specific cell types present.<ref name="wiki">germinoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Germinoma Accessed on January 26, 2016</ref>   
===Pathogenesis===
===Pathogenesis===
*Central nervous cell germ cell tumors (GCTs) are believed to arise from nests of embryonic cells arrested during their migration in fetal development in the midline structures. As a result, CNS GCTs are found in midline sites, especially in the suprasellar and pineal gland regions.
*Central nervous cell [[germ cell tumors]] (GCTs) are believed to arise from nests of embryonic cells arrested during their migration in fetal development in the midline structures. As a result, central nervous system germ cell tumors are found in midline sites, especially in the suprasellar and pineal gland regions.
*The germ cell theory has postulated that these tumors arise from primordial germ cells that have migrated aberrantly during embryonic development and subsequently undergone malignant transformation. However, the embryonic cell theory suggests that GCTs arise from a mismigrational pluripotent embryonic cell. It is postulated that pure germinomas arise from germ cells whereas mixed NGGCTs are a result of misfolding and misplacement of embryonic cells into the lateral mesoderm, causing these cells to become entrapped in different areas of the brain.
*The germ cell theory has postulated that these tumors arise from [[primordial germ cells]] that have migrated aberrantly during embryonic development and subsequently undergone [[malignant]] transformation. However, the embryonic cell theory suggests that GCTs arise from a mis migrational pluripotent embryonic cell. It is postulated that pure germinomas arise from germ cells whereas mixed non germinomatous germ cell tumors NGGCTs are a result of misfolding and misplacement of embryonic cells into the lateral [[mesoderm]], causing these cells to become entrapped in different areas of the brain.<ref name="pmid7546360">{{cite journal |vauthors=Sano K |title=So-called intracranial germ cell tumours: are they really of germ cell origin? |journal=Br J Neurosurg |volume=9 |issue=3 |pages=391–401 |date=1995 |pmid=7546360 |doi= |url=}}</ref><ref name="urlPathogenesis of intracranial germ cell tumors reconsidered in: Journal of Neurosurgery Volume 90 Issue 2 (1999)">{{cite web |url=https://thejns.org/view/journals/j-neurosurg/90/2/article-p258.xml |title=Pathogenesis of intracranial germ cell tumors reconsidered in: Journal of Neurosurgery Volume 90 Issue 2 (1999) |format= |work= |accessdate=}}</ref>
*Intracranial GCTs express germ cell–specific proteins comprising NY-ESO-1, MAGE-A4, and TSPY, which are associated with embryonic stem cell pluripotency, which indicate that GCTs may originate from primordial germ cells.<ref name="pmid10964999">{{cite journal| author=Packer RJ, Cohen BH, Cooney K, Coney K| title=Intracranial germ cell tumors. | journal=Oncologist | year= 2000 | volume= 5 | issue= 4 | pages= 312-20 | pmid=10964999 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10964999  }} </ref><ref>Teilum, Gunnar. Special tumors of ovary and testis and related extragonadal lesions : comparative pathology and histological identification. Copenhagen Philadelphia: Munksgaard J.B. Lippincott, 1976. Print.</ref><ref name="pmid11767288">{{cite journal| author=Nomura K| title=Epidemiology of germ cell tumors in Asia of pineal region tumor. | journal=J Neurooncol | year= 2001 | volume= 54 | issue= 3 | pages= 211-7 | pmid=11767288 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11767288  }} </ref><ref name="pmid2569683">{{cite journal| author=Sano K, Matsutani M, Seto T| title=So-called intracranial germ cell tumours: personal experiences and a theory of their pathogenesis. | journal=Neurol Res | year= 1989 | volume= 11 | issue= 2 | pages= 118-26 | pmid=2569683 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2569683  }} </ref>
*Intracranial GCTs express germ cell–specific proteins comprising NY-ESO-1, MAGE-A4, and TSPY, which are associated with embryonic stem cell pluripotency, which indicate that germ cell tumors (GCTs) may originate from [[primordial germ cells]].<ref name="pmid10964999">{{cite journal| author=Packer RJ, Cohen BH, Cooney K, Coney K| title=Intracranial germ cell tumors. | journal=Oncologist | year= 2000 | volume= 5 | issue= 4 | pages= 312-20 | pmid=10964999 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10964999  }} </ref><ref>Teilum, Gunnar. Special tumors of ovary and testis and related extragonadal lesions : comparative pathology and histological identification. Copenhagen Philadelphia: Munksgaard J.B. Lippincott, 1976. Print.</ref><ref name="pmid11767288">{{cite journal| author=Nomura K| title=Epidemiology of germ cell tumors in Asia of pineal region tumor. | journal=J Neurooncol | year= 2001 | volume= 54 | issue= 3 | pages= 211-7 | pmid=11767288 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11767288  }} </ref><ref name="pmid2569683">{{cite journal| author=Sano K, Matsutani M, Seto T| title=So-called intracranial germ cell tumours: personal experiences and a theory of their pathogenesis. | journal=Neurol Res | year= 1989 | volume= 11 | issue= 2 | pages= 118-26 | pmid=2569683 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2569683  }} </ref>


===Genetics===
===Genetics===
*In adult-onset extragonadal germinomas, the most common abnormality is duplication of the short arm of chromosome 12.
*In adult-onset extragonadal germinomas, the most common abnormality is duplication of the short arm of chromosome 12.<ref name="pmid11369053">{{cite journal |vauthors=Bussey KJ, Lawce HJ, Himoe E, Shu XO, Suijkerbuijk RF, Olson SB, Magenis RE |title=Chromosomes 1 and 12 abnormalities in pediatric germ cell tumors by interphase fluorescence in situ hybridization |journal=Cancer Genet. Cytogenet. |volume=125 |issue=2 |pages=112–8 |date=March 2001 |pmid=11369053 |doi= |url=}}</ref>
*Cytogenetic abnormalities in children include loss of 1p and 6q, alterations in sex chromosomes, and abnormalities in 12p. In a study involving children, a subset of patients with pineal tumors demonstrated a gain of chromosomal material at 12p.
*Cytogenetic abnormalities in children include loss of 1p and 6q, alterations in sex chromosomes, and abnormalities in 12p. In a study involving children, a subset of patients with pineal tumors demonstrated a gain of chromosomal material at 12p.<ref name="pmid11263505">{{cite journal |vauthors=Gömöri E, Halbauer DJ, Dóczi T, Balázs E, Kajtár P, Pajor L |title=Cytogenetic profile of primary pituitary germinoma |journal=J. Neurooncol. |volume=50 |issue=3 |pages=251–5 |date=December 2000 |pmid=11263505 |doi= |url=}}</ref>
*In majority of cases, the most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q.
*In majority of cases, the most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q.
*The most frequent genotype abnormality is XXY, similar to that in Klinefelter syndrome. Individuals with Klinefelter syndrome are prone to develop intracranial GCTs, as are those with neurofibromatosis, type 1 and Down syndrome.  
*The most frequent genotype abnormality is [[XXY]], similar to that in [[Klinefelter syndrome]]. Individuals with Klinefelter syndrome are prone to develop intracranial GCTs, as are those with [[neurofibromatosis type 1]] and [[Down syndrome]].<ref name="pmid3277702">{{cite journal |vauthors=Arens R, Marcus D, Engelberg S, Findler G, Goodman RM, Passwell JH |title=Cerebral germinomas and Klinefelter syndrome. A review |journal=Cancer |volume=61 |issue=6 |pages=1228–31 |date=March 1988 |pmid=3277702 |doi= |url=}}</ref><ref name="pmid2421193">{{cite journal |vauthors=Ellis SJ, Crockard A, Barnard RO |title=Klinefelter's syndrome, cerebral germinoma, Chiari malformation, and syrinx: a case report |journal=Neurosurgery |volume=18 |issue=2 |pages=220–2 |date=February 1986 |pmid=2421193 |doi= |url=}}</ref>
*Gene p14 plays an important role in the development of intracranial germ cell tumors as frequent alterations of the p14 gene have been detected, especially in intracranial pure germinomas.
*Gene p14 plays an important role in the development of intracranial germ cell tumors as frequent alterations of the ''p14'' [[gene]] have been detected, especially in intracranial pure germinomas.<ref name="pmid19329861">{{cite journal |vauthors=Sato K, Takeuchi H, Kubota T |title=Pathology of intracranial germ cell tumors |journal=Prog Neurol Surg |volume=23 |issue= |pages=59–75 |date=2009 |pmid=19329861 |doi=10.1159/000210053 |url=}}</ref>
*In approximately 23-25% of intracranial germinomas, mutations of the c-kit gene have been found. C-myc and N-myc amplifications were seen in a minority of tumors. Genomic analysis of GCTs has revealed distinct mRNA and miRNA profiles which may be correlated with clinical outcome, histological differentiation, and may serve as novel therapeutic targets in future.[20]
*In approximately 23-25% of intracranial germinomas, mutations of the ''c-kit'' gene have been found. Amplification of c-myc and n-myc have been known to be implicated in the development of intracranial germinomas.<ref name="pmid25231001">{{cite journal |vauthors=Estiar MA, Fazilaty H, Aslanabadi S, Seifi M, Varghaei P, Rezamand A |title=MYCN gene amplification in patients with neuroblastic tumors |journal=Cell. Mol. Biol. (Noisy-le-grand) |volume=60 |issue=3 |pages=23–8 |date=September 2014 |pmid=25231001 |doi= |url=}}</ref><ref name="pmid15471556">{{cite journal |vauthors=Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K |title=c-kit gene mutations in intracranial germinomas |journal=Cancer Sci. |volume=95 |issue=9 |pages=716–20 |date=September 2004 |pmid=15471556 |doi= |url=}}</ref>
*Frequent aberrations of CCND2 (12P13), and RB1 has indicated that there might be possibility of cyclin/CDK-RB-E2F pathway involvement in the pathogenesis of intracranial germ cell tumors. Gains in the transcriptional regulator PRDM14 have also been implicated in the pathogenesis of germ cell tumors. A recent study of 62 patients with intracranial GCT has shown that more than 50% had mutations of the KIT/RAS signalling or AKT1/mtor pathways.<ref name="pmid11005262">{{cite journal| author=Rickert CH, Simon R, Bergmann M, Dockhorn-Dworniczak B, Paulus W| title=Comparative genomic hybridization in pineal germ cell tumors. | journal=J Neuropathol Exp Neurol | year= 2000 | volume= 59 | issue= 9 | pages= 815-21 | pmid=11005262 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11005262  }} </ref><ref name="pmid16607373">{{cite journal| author=Schneider DT, Zahn S, Sievers S, Alemazkour K, Reifenberger G, Wiestler OD et al.| title=Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. | journal=Mod Pathol | year= 2006 | volume= 19 | issue= 6 | pages= 864-73 | pmid=16607373 | doi=10.1038/modpathol.3800607 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16607373  }} </ref><ref name="pmid17285132">{{cite journal| author=Palmer RD, Foster NA, Vowler SL, Roberts I, Thornton CM, Hale JP et al.| title=Malignant germ cell tumours of childhood: new associations of genomic imbalance. | journal=Br J Cancer | year= 2007 | volume= 96 | issue= 4 | pages= 667-76 | pmid=17285132 | doi=10.1038/sj.bjc.6603602 | pmc=PMC2360055 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17285132  }} </ref><ref name="pmid19329861">{{cite journal| author=Sato K, Takeuchi H, Kubota T| title=Pathology of intracranial germ cell tumors. | journal=Prog Neurol Surg | year= 2009 | volume= 23 | issue=  | pages= 59-75 | pmid=19329861 | doi=10.1159/000210053 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19329861  }} </ref><ref name="pmid16572634">{{cite journal| author=Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H| title=C-kit gene mutation: common and widely distributed in intracranial germinomas. | journal=J Neurosurg | year= 2006 | volume= 104 | issue= 3 Suppl | pages= 173-80 | pmid=16572634 | doi=10.3171/ped.2006.104.3.173 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16572634  }} </ref><ref name="pmid15471556">{{cite journal| author=Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K| title=c-kit gene mutations in intracranial germinomas. | journal=Cancer Sci | year= 2004 | volume= 95 | issue= 9 | pages= 716-20 | pmid=15471556 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15471556  }} </ref><ref name="pmid20178649">{{cite journal| author=Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ et al.| title=Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations. | journal=BMC Genomics | year= 2010 | volume= 11 | issue=  | pages= 132 | pmid=20178649 | doi=10.1186/1471-2164-11-132 | pmc=PMC2837036 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20178649  }} </ref><ref name="pmid24249158">{{cite journal| author=Terashima K, Yu A, Chow WY, Hsu WC, Chen P, Wong S et al.| title=Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors. | journal=Pediatr Blood Cancer | year= 2014 | volume= 61 | issue= 4 | pages= 593-600 | pmid=24249158 | doi=10.1002/pbc.24833 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24249158  }} </ref><ref name="pmid24896186">{{cite journal| author=Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK et al.| title=Novel somatic and germline mutations in intracranial germ cell tumours. | journal=Nature | year= 2014 | volume= 511 | issue= 7508 | pages= 241-5 | pmid=24896186 | doi=10.1038/nature13296 | pmc=PMC4532372 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24896186  }} </ref><ref name="pmid16572634">{{cite journal| author=Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H| title=C-kit gene mutation: common and widely distributed in intracranial germinomas. | journal=J Neurosurg | year= 2006 | volume= 104 | issue= 3 Suppl | pages= 173-80 | pmid=16572634 | doi=10.3171/ped.2006.104.3.173 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16572634  }} </ref><ref name="pmid15471556">{{cite journal| author=Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K| title=c-kit gene mutations in intracranial germinomas. | journal=Cancer Sci | year= 2004 | volume= 95 | issue= 9 | pages= 716-20 | pmid=15471556 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15471556  }} </ref>
*Frequent aberrations of ''CCND2'' (12P13), and ''RB1'' has indicated that there might be possibility of cyclin/''CDK-RB-E2F''  pathway involvement in the pathogenesis of intracranial germ cell tumors. Gains in the transcriptional regulator PRDM14 have also been implicated in the pathogenesis of germ cell tumors. A recent study of 62 patients with intracranial GCT has shown that more than 50% had [[mutations]] of the ''KIT/RAS'' signalling or ''AKT1''/mtor pathways.<ref name="pmid11005262">{{cite journal| author=Rickert CH, Simon R, Bergmann M, Dockhorn-Dworniczak B, Paulus W| title=Comparative genomic hybridization in pineal germ cell tumors. | journal=J Neuropathol Exp Neurol | year= 2000 | volume= 59 | issue= 9 | pages= 815-21 | pmid=11005262 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11005262  }} </ref><ref name="pmid16607373">{{cite journal| author=Schneider DT, Zahn S, Sievers S, Alemazkour K, Reifenberger G, Wiestler OD et al.| title=Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. | journal=Mod Pathol | year= 2006 | volume= 19 | issue= 6 | pages= 864-73 | pmid=16607373 | doi=10.1038/modpathol.3800607 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16607373  }} </ref><ref name="pmid17285132">{{cite journal| author=Palmer RD, Foster NA, Vowler SL, Roberts I, Thornton CM, Hale JP et al.| title=Malignant germ cell tumours of childhood: new associations of genomic imbalance. | journal=Br J Cancer | year= 2007 | volume= 96 | issue= 4 | pages= 667-76 | pmid=17285132 | doi=10.1038/sj.bjc.6603602 | pmc=PMC2360055 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17285132  }} </ref><ref name="pmid19329861">{{cite journal| author=Sato K, Takeuchi H, Kubota T| title=Pathology of intracranial germ cell tumors. | journal=Prog Neurol Surg | year= 2009 | volume= 23 | issue=  | pages= 59-75 | pmid=19329861 | doi=10.1159/000210053 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19329861  }} </ref><ref name="pmid16572634">{{cite journal| author=Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H| title=C-kit gene mutation: common and widely distributed in intracranial germinomas. | journal=J Neurosurg | year= 2006 | volume= 104 | issue= 3 Suppl | pages= 173-80 | pmid=16572634 | doi=10.3171/ped.2006.104.3.173 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16572634  }} </ref><ref name="pmid15471556">{{cite journal| author=Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K| title=c-kit gene mutations in intracranial germinomas. | journal=Cancer Sci | year= 2004 | volume= 95 | issue= 9 | pages= 716-20 | pmid=15471556 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15471556  }} </ref><ref name="pmid20178649">{{cite journal| author=Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ et al.| title=Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations. | journal=BMC Genomics | year= 2010 | volume= 11 | issue=  | pages= 132 | pmid=20178649 | doi=10.1186/1471-2164-11-132 | pmc=PMC2837036 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20178649  }} </ref><ref name="pmid24249158">{{cite journal| author=Terashima K, Yu A, Chow WY, Hsu WC, Chen P, Wong S et al.| title=Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors. | journal=Pediatr Blood Cancer | year= 2014 | volume= 61 | issue= 4 | pages= 593-600 | pmid=24249158 | doi=10.1002/pbc.24833 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24249158  }} </ref><ref name="pmid24896186">{{cite journal| author=Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK et al.| title=Novel somatic and germline mutations in intracranial germ cell tumours. | journal=Nature | year= 2014 | volume= 511 | issue= 7508 | pages= 241-5 | pmid=24896186 | doi=10.1038/nature13296 | pmc=PMC4532372 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24896186  }} </ref><ref name="pmid16572634">{{cite journal| author=Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H| title=C-kit gene mutation: common and widely distributed in intracranial germinomas. | journal=J Neurosurg | year= 2006 | volume= 104 | issue= 3 Suppl | pages= 173-80 | pmid=16572634 | doi=10.3171/ped.2006.104.3.173 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16572634  }} </ref><ref name="pmid15471556">{{cite journal| author=Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K| title=c-kit gene mutations in intracranial germinomas. | journal=Cancer Sci | year= 2004 | volume= 95 | issue= 9 | pages= 716-20 | pmid=15471556 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15471556  }} </ref>


<gallery>
File:Germinoma1.jpg|Histopathology specimen of a germinoma located on the floor of the IIIrd ventricle in the brain - HE stain low magnification
File:G2.jpg|Histopathology specimen of a germinoma located on the floor of the IIIrd ventricle in the brain -HE stain intermediate magnification
File:G3.jpg| Histopathology specimen of a germinoma located on the floor of the IIIrd ventricle in the brain - HE stain very high magnification
File:G4.jpg|Histopathology specimen of a germinoma located on the floor of the IIIrd ventricle in the brain OCT 3/4
</gallery>
==References==
==References==
{{reflist|2}}
{{reflist|2}}
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Overview

On microscopic histopathological analysis, uniform cells that resemble primordial germ cells, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic are characteristic findings of germinoma. Genes involved in the pathogenesis of germinoma include gains of 1p, 8p, and 12q and losses of 13q and 18q, duplication of the short arm of chromosome 12, loss of 1p and 6q, alterations in sex chromosomes in children, alterations of the p14 gene, mutations of the c-kit gene, aberrations of CCND2 (12P13), and RB1, and gain-of-function mutations of KIT. The progression to germinoma usually involves the mutations of the KIT/RAS signalling or AKT1/mtor pathways and cyclin/CDK-RB-E2F pathway if CCND2 (12P13) and RB1 genes are aberrated.[1][2][3][4][5][6][7][8]

Pathophysiology

Pineal lesions occur more commonly than suprasellar lesions, at a ratio of 2:1. The location of the tumor that compromises total percentage of central nervous system (CNS) germ cell tumors is shown below in a tabular form:[9]

Location of the tumor % of CNS GCT
Pineal area
  • 50-60% of CNS germ cell tumors
Suprasellar area
  • 30-40%
Basal ganglia, thalamus, cerebral hemisphere
  • 5-10%
Both pineal and suprasellar region
  • 6-13%

The relationship of the gender with location of the CNS germ cell tumors is shown below in a tabular form:[10]

Sex Location of the tumor
Males
  • 70% of the tumors occur in the pineal area
Females
  • 75% of the CNS germ cell tumors occur in the suprasellar area

Gross Pathology

On gross examination, the external surface is smooth and bosselated (knobby), and the interior is soft, fleshy and either cream, gray, pink, or tan colored.[11]

Microscopic Pathology

Microscopic examination typically reveals uniform cells that resemble primordial germ cells. Typically, the stroma contains lymphocytes and about 20% of patients have sarcoid-like granulomas. The tumor is uniform in appearance, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic. Pure germinomas are composed of large polygonal undifferentiated cells with abundant cytoplasm arranged in nests separated by bands of connective tissue. The histologic appearance of nongerminomatous germ cell tumors (NGGCTs) varies depending upon the specific cell types present.[11]

Pathogenesis

  • Central nervous cell germ cell tumors (GCTs) are believed to arise from nests of embryonic cells arrested during their migration in fetal development in the midline structures. As a result, central nervous system germ cell tumors are found in midline sites, especially in the suprasellar and pineal gland regions.
  • The germ cell theory has postulated that these tumors arise from primordial germ cells that have migrated aberrantly during embryonic development and subsequently undergone malignant transformation. However, the embryonic cell theory suggests that GCTs arise from a mis migrational pluripotent embryonic cell. It is postulated that pure germinomas arise from germ cells whereas mixed non germinomatous germ cell tumors NGGCTs are a result of misfolding and misplacement of embryonic cells into the lateral mesoderm, causing these cells to become entrapped in different areas of the brain.[12][13]
  • Intracranial GCTs express germ cell–specific proteins comprising NY-ESO-1, MAGE-A4, and TSPY, which are associated with embryonic stem cell pluripotency, which indicate that germ cell tumors (GCTs) may originate from primordial germ cells.[14][15][16][17]

Genetics

  • In adult-onset extragonadal germinomas, the most common abnormality is duplication of the short arm of chromosome 12.[18]
  • Cytogenetic abnormalities in children include loss of 1p and 6q, alterations in sex chromosomes, and abnormalities in 12p. In a study involving children, a subset of patients with pineal tumors demonstrated a gain of chromosomal material at 12p.[19]
  • In majority of cases, the most common chromosomal imbalance comprises gains of 1p, 8p, and 12q and losses of 13q and 18q.
  • The most frequent genotype abnormality is XXY, similar to that in Klinefelter syndrome. Individuals with Klinefelter syndrome are prone to develop intracranial GCTs, as are those with neurofibromatosis type 1 and Down syndrome.[20][21]
  • Gene p14 plays an important role in the development of intracranial germ cell tumors as frequent alterations of the p14 gene have been detected, especially in intracranial pure germinomas.[4]
  • In approximately 23-25% of intracranial germinomas, mutations of the c-kit gene have been found. Amplification of c-myc and n-myc have been known to be implicated in the development of intracranial germinomas.[22][6]
  • Frequent aberrations of CCND2 (12P13), and RB1 has indicated that there might be possibility of cyclin/CDK-RB-E2F pathway involvement in the pathogenesis of intracranial germ cell tumors. Gains in the transcriptional regulator PRDM14 have also been implicated in the pathogenesis of germ cell tumors. A recent study of 62 patients with intracranial GCT has shown that more than 50% had mutations of the KIT/RAS signalling or AKT1/mtor pathways.[1][2][3][4][5][6][7][8][23][5][6]

References

  1. ↑ 1.0 1.1 Rickert CH, Simon R, Bergmann M, Dockhorn-Dworniczak B, Paulus W (2000). "Comparative genomic hybridization in pineal germ cell tumors". J Neuropathol Exp Neurol. 59 (9): 815–21. PMID 11005262.
  2. ↑ 2.0 2.1 Schneider DT, Zahn S, Sievers S, Alemazkour K, Reifenberger G, Wiestler OD; et al. (2006). "Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization". Mod Pathol. 19 (6): 864–73. doi:10.1038/modpathol.3800607. PMID 16607373.
  3. ↑ 3.0 3.1 Palmer RD, Foster NA, Vowler SL, Roberts I, Thornton CM, Hale JP; et al. (2007). "Malignant germ cell tumours of childhood: new associations of genomic imbalance". Br J Cancer. 96 (4): 667–76. doi:10.1038/sj.bjc.6603602. PMC 2360055. PMID 17285132.
  4. ↑ 4.0 4.1 4.2 Sato K, Takeuchi H, Kubota T (2009). "Pathology of intracranial germ cell tumors". Prog Neurol Surg. 23: 59–75. doi:10.1159/000210053. PMID 19329861.
  5. ↑ 5.0 5.1 5.2 Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H (2006). "C-kit gene mutation: common and widely distributed in intracranial germinomas". J Neurosurg. 104 (3 Suppl): 173–80. doi:10.3171/ped.2006.104.3.173. PMID 16572634.
  6. ↑ 6.0 6.1 6.2 6.3 Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K (2004). "c-kit gene mutations in intracranial germinomas". Cancer Sci. 95 (9): 716–20. PMID 15471556.
  7. ↑ 7.0 7.1 Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ; et al. (2010). "Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations". BMC Genomics. 11: 132. doi:10.1186/1471-2164-11-132. PMC 2837036. PMID 20178649.
  8. ↑ 8.0 8.1 Terashima K, Yu A, Chow WY, Hsu WC, Chen P, Wong S; et al. (2014). "Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors". Pediatr Blood Cancer. 61 (4): 593–600. doi:10.1002/pbc.24833. PMID 24249158.
  9. ↑ Germ cell tumors. Radiopedia(2015) http://radiopaedia.org/articles/central-nervous-system-germinoma Accessed on January 25, 2016
  10. ↑ Villano JL, Propp JM, Porter KR, Stewart AK, Valyi-Nagy T, Li X; et al. (2008). "Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries". Neuro Oncol. 10 (2): 121–30. doi:10.1215/15228517-2007-054. PMC 2613814. PMID 18287340.
  11. ↑ 11.0 11.1 germinoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Germinoma Accessed on January 26, 2016
  12. ↑ Sano K (1995). "So-called intracranial germ cell tumours: are they really of germ cell origin?". Br J Neurosurg. 9 (3): 391–401. PMID 7546360.
  13. ↑ "Pathogenesis of intracranial germ cell tumors reconsidered in: Journal of Neurosurgery Volume 90 Issue 2 (1999)".
  14. ↑ Packer RJ, Cohen BH, Cooney K, Coney K (2000). "Intracranial germ cell tumors". Oncologist. 5 (4): 312–20. PMID 10964999.
  15. ↑ Teilum, Gunnar. Special tumors of ovary and testis and related extragonadal lesions : comparative pathology and histological identification. Copenhagen Philadelphia: Munksgaard J.B. Lippincott, 1976. Print.
  16. ↑ Nomura K (2001). "Epidemiology of germ cell tumors in Asia of pineal region tumor". J Neurooncol. 54 (3): 211–7. PMID 11767288.
  17. ↑ Sano K, Matsutani M, Seto T (1989). "So-called intracranial germ cell tumours: personal experiences and a theory of their pathogenesis". Neurol Res. 11 (2): 118–26. PMID 2569683.
  18. ↑ Bussey KJ, Lawce HJ, Himoe E, Shu XO, Suijkerbuijk RF, Olson SB, Magenis RE (March 2001). "Chromosomes 1 and 12 abnormalities in pediatric germ cell tumors by interphase fluorescence in situ hybridization". Cancer Genet. Cytogenet. 125 (2): 112–8. PMID 11369053.
  19. ↑ Gömöri E, Halbauer DJ, Dóczi T, Balázs E, Kajtár P, Pajor L (December 2000). "Cytogenetic profile of primary pituitary germinoma". J. Neurooncol. 50 (3): 251–5. PMID 11263505.
  20. ↑ Arens R, Marcus D, Engelberg S, Findler G, Goodman RM, Passwell JH (March 1988). "Cerebral germinomas and Klinefelter syndrome. A review". Cancer. 61 (6): 1228–31. PMID 3277702.
  21. ↑ Ellis SJ, Crockard A, Barnard RO (February 1986). "Klinefelter's syndrome, cerebral germinoma, Chiari malformation, and syrinx: a case report". Neurosurgery. 18 (2): 220–2. PMID 2421193.
  22. ↑ Estiar MA, Fazilaty H, Aslanabadi S, Seifi M, Varghaei P, Rezamand A (September 2014). "MYCN gene amplification in patients with neuroblastic tumors". Cell. Mol. Biol. (Noisy-le-grand). 60 (3): 23–8. PMID 25231001.
  23. ↑ Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK; et al. (2014). "Novel somatic and germline mutations in intracranial germ cell tumours". Nature. 511 (7508): 241–5. doi:10.1038/nature13296. PMC 4532372. PMID 24896186.


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