Difference between revisions of "Germ cell tumours"

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[[Image:Mixed_Germ_Cell_Tumor_of_Testis_(3260625567).jpg|thumb|right|Testicular [[mixed germ cell tumour]]. (WC/euthman)]]
This article covers '''germ cell tumours''', often abbreviated [[GCT]], which classically arise in the gonads ([[ovary]], [[testis]]).  They are also found in the midline and make appearances in [[neuropathology]] (e.g. [[pineal gland]]) and in the [[mediastinum]].
This article covers '''germ cell tumours''', often abbreviated [[GCT]], which classically arise in the gonads ([[ovary]], [[testis]]).  They are also found in the midline and make appearances in [[neuropathology]] (e.g. [[pineal gland]]) and in the [[mediastinum]].


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===Grossing===
===Grossing===
*1 cm^2 of tumour per cm of maximal tumour dimension - guideline for testicular cancer.<ref>URL: [http://www.uroweb.org/gls/pdf/10_Testicular_Cancer.pdf http://www.uroweb.org/gls/pdf/10_Testicular_Cancer.pdf]. Accessed on: 30 October 2012.</ref>
{{Main|Orchiectomy}}
*1 cm<sup>2</sup> of tumour per cm of maximal tumour dimension - guideline for testicular cancer.<ref>URL: [http://www.uroweb.org/gls/pdf/10_Testicular_Cancer.pdf http://www.uroweb.org/gls/pdf/10_Testicular_Cancer.pdf]. Accessed on: 30 October 2012.</ref>


===IHC for GCTs===
===IHC for GCTs===
ABCDs of GCTs:
====ISUP====
An algorithmic approach based on the ISUP consensus paper by Ulbright ''et al.'':<ref name=pmid24832161>{{cite journal |author=Ulbright TM, Tickoo SK, Berney DM, Srigley JR |title=Best practices recommendations in the application of immunohistochemistry in testicular tumors: report from the international society of urological pathology consensus conference |journal=Am. J. Surg. Pathol. |volume=38 |issue=8 |pages=e50–9 |year=2014 |month=August |pmid=24832161 |doi=10.1097/PAS.0000000000000233 |url=}}</ref>
{{familytree/start}}
{{familytree | | | | | | | | | | | | | A01 | | | | | | | | | | | | | | | | | | |A01=[[Germ cell tumours]]}}
{{familytree | | | | | |,|-|-|-|-|-|-|-|^|-|-|-|-|-|-|-|.| | | | | | | | | | | |}}
{{familytree | | | | | B01 | | | | | | | | | | | | | | B02 | | | | | | | | | | |B01=OCT4 +ve | B02=OCT4 -ve}}
{{familytree | |,|-|-|-|^|-|-|-|.| | | | | |,|-|-|-|-|-|+|-|-|-|-|-|.| | | | | |}}
{{familytree | C01 | | | | | | C02 | | | | C03 | | | | C04 | | | | C05 | | | | |C01=CD117 +ve<br>CD30 -ve |C02= CD117 -ve<br>CD30 +ve|C03=[[Glypican 3]] +ve<br>AFP +ve<br>beta-hCG -ve|C04=Glypican 3 ?<br>AFP -ve<br>beta-hCG +ve|C05=Glypican 3 -ve<br>AFP -ve<br>beta-hCG -ve}}
{{familytree | |!| | | | | | | |!| | | | | |!| | | | | |!| | | | | |!| | | | | |}}
{{familytree | D01 | | | | | | D02 | | | | D03 | | | | D04 | | | | D05 | | | | |D01=[[Seminoma]]|D02=[[Embryonal carcinoma]]|D03=[[Yolk sac tumour]]|D04=[[Choriocarcinoma]] |D05= [[Spermatocytic seminoma]] }}
{{familytree/end}}
 
====ABCDs of GCTs====
*AFP - yolk sac tumour.
*AFP - yolk sac tumour.
*Beta-hCG - choriocarcinoma.
*Beta-hCG - choriocarcinoma.
*CD30 - embryonal carcinoma.
*CD30 - embryonal carcinoma.
*D2-40 - seminoma.
*D2-40 - seminoma.
====GCT versus sex cord-stromal tumour====
The ISUP recommends:<ref name=pmid25025364>{{cite journal |author=Amin MB, Epstein JI, Ulbright TM, ''et al.'' |title=Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the international society of urological pathology consensus conference |journal=Am. J. Surg. Pathol. |volume=38 |issue=8 |pages=1017–22 |year=2014 |month=August |pmid=25025364 |doi=10.1097/PAS.0000000000000254 |url=}}</ref>
*[[SALL4]] +ve (in GCTs).<ref name=pmid24525512>{{cite journal |author=Miettinen M, Wang Z, McCue PA, ''et al.'' |title=SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases |journal=Am. J. Surg. Pathol. |volume=38 |issue=3 |pages=410–20 |year=2014 |month=March |pmid=24525512 |doi=10.1097/PAS.0000000000000116 |url=}}</ref>
*Alpha-inhibin -ve (+ve in [[SCST]]).
*Calretinin -ve (+ve in SCST).
Alternates for SALL4 are:<ref name=pmid25025364/>
*OCT4 and GPC3.


===Tabular summary of GCTs===
===Tabular summary of GCTs===
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! Image
! Image
|-  
|-  
| Intratubular germ cell neoplasia (ITGCN)
| [[Germ cell neoplasia in situ]] (GCNIS)
| nests of small fried egg cells
| nests of small fried egg cells
| large central nucleus, clear <br>cytoplasm, squared-off nuclear membrane, nucleoli<ref name=Ref_GUP538>{{Ref GUP|538}}</ref>
| large central nucleus, clear <br>cytoplasm, squared-off nuclear membrane, nucleoli<ref name=Ref_GUP538>{{Ref GUP|538}}</ref>
| CD117
| CD117 +ve, CD30 -ve
| appearance similar to seminoma
| appearance similar to [[seminoma]]
| [[Image:Intratubular_germ_cell_neoplasia_high_mag_cropped.jpg|thumb|center|150px|ITGCN (WC/Nephron)]]
| [[Image:Intratubular_germ_cell_neoplasia_high_mag_cropped.jpg|thumb|center|150px|GCNIS (WC/Nephron)]]
|-  
|-  
| Germinoma / Seminoma / Dysgerminoma
| [[Germinoma]] / [[Seminoma]] / [[Dysgerminoma]]
| fried egg cells
| fried egg cells
| fried egg-like cells (central nucleus, clear <br>cytoplasm) with squared-off nuclear <br>membrane, nucleoli, lymphocytic infiltrate, granulomata,<br>syncytiotrophoblastic giant cells<ref name=Ref_GUP542>{{Ref GUP|542}}</ref>
| fried egg-like cells (central nucleus, clear <br>cytoplasm) with squared-off nuclear <br>membrane, nucleoli, lymphocytic infiltrate, granulomata,<br>syncytiotrophoblastic giant cells<ref name=Ref_GUP542>{{Ref GUP|542}}</ref>
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| Schiller-Duval bodies
| Schiller-Duval bodies
| Schiller-Duval b. = central blood vessel surrounded by epithelial-like cells a space and more epithelial-like cells, variable arch.  
| Schiller-Duval b. = central blood vessel surrounded by epithelial-like cells a space and more epithelial-like cells, variable arch.  
| AFP
| [[AFP]] +ve, [[Glypican 3]] +ve
| patterns: microcystic, solid, hepatoid
| patterns: microcystic, solid, hepatoid
| [[Image:Mixed_germ_cell_tumour_-_very_high_mag.jpg|thumb|center|150px|Yolk sac tumour (WC)]]
| [[Image:Mixed_germ_cell_tumour_-_very_high_mag.jpg|thumb|center|150px|Yolk sac tumour (WC)]]
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| prominent nucleoli, vescicular nuclei
| prominent nucleoli, vescicular nuclei
| var. arch.: tubulopapillary, glandular, solid, embryoid bodies (ball of cells in surrounded by empty space on three sides), +/-nuclear overlap, mitoses common
| var. arch.: tubulopapillary, glandular, solid, embryoid bodies (ball of cells in surrounded by empty space on three sides), +/-nuclear overlap, mitoses common
| CD30
| CD30 +ve, CD117 -ve
| usu. part of a mixed GCT  
| usu. part of a mixed GCT  
| [[Image:Embryonal_carcinoma_high_mag.jpg|thumb|center|150px|Embryonal carcinoma (WC/Nephron)]]
| [[Image:Embryonal_carcinoma_high_mag.jpg|thumb|center|150px|Embryonal carcinoma (WC/Nephron)]]
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| clear cytoplasm  
| clear cytoplasm  
| cells with abundant clear cytoplasm and eccentric atypical nuclei (cytotrophoblast), very large (multinucleated) cells with abundant eosinophilic cytoplasm and extreme nuclear atypia (syncytiotrophoblast)
| cells with abundant clear cytoplasm and eccentric atypical nuclei (cytotrophoblast), very large (multinucleated) cells with abundant eosinophilic cytoplasm and extreme nuclear atypia (syncytiotrophoblast)
| beta-hCG
| beta-hCG +ve
| may be preceded by a [[complete mole|complete hydatidiform mole]]
| may be preceded by a [[complete mole|complete hydatidiform mole]]
| [[Image:Choriocarcinoma_-2-_very_high_mag.jpg|thumb|center|150px|Choriocarcinoma. (WC/Nephron)]]
| [[Image:Choriocarcinoma_-2-_very_high_mag.jpg|thumb|center|150px|Choriocarcinoma. (WC/Nephron)]]
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===Molecular pathology===
===Molecular pathology===
Most common cytogenetic abnormality in GCTs:
Most common cytogenetic abnormality in GCTs:
* Isochromosome p12.<ref name=pmid10357096>{{Cite journal  | last1 = Looijenga | first1 = LH. | last2 = Oosterhuis | first2 = JW. | title = Pathogenesis of testicular germ cell tumours. | journal = Rev Reprod | volume = 4 | issue = 2 | pages = 90-100 | month = May | year = 1999 | doi =  | PMID = 10357096 }}</ref>
*[[Isochromosome 12p]].<ref name=pmid10357096>{{Cite journal  | last1 = Looijenga | first1 = LH. | last2 = Oosterhuis | first2 = JW. | title = Pathogenesis of testicular germ cell tumours. | journal = Rev Reprod | volume = 4 | issue = 2 | pages = 90-100 | month = May | year = 1999 | doi =  | PMID = 10357096 }}</ref>
** Isochromosome = one arm (p or q) is lost and replaced with a duplicate of the remaining one.
** Isochromosome = one arm (p or q) is lost and replaced with a duplicate of the remaining one.
***Example: isochromosome p12 = chromosome 12 where q is lost and two p arms are present.<ref>URL: [http://ghr.nlm.nih.gov/handbook/illustrations/isochromosomes http://ghr.nlm.nih.gov/handbook/illustrations/isochromosomes]. Accessed on: 15 February 2012.</ref>
***Example: isochromosome 12p = chromosome 12 where q is lost and two p arms are present.<ref>URL: [http://ghr.nlm.nih.gov/handbook/illustrations/isochromosomes http://ghr.nlm.nih.gov/handbook/illustrations/isochromosomes]. Accessed on: 15 February 2012.</ref>


==Germinoma==
==Germinoma==
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Image: [http://path.upmc.edu/cases/case525/images/fig02a.jpg Germinoma (upmc.edu)].<ref>URL: [http://path.upmc.edu/cases/case525.html http://path.upmc.edu/cases/case525.html]. Accessed on: 25 January 2012.</ref>
Image: [http://path.upmc.edu/cases/case525/images/fig02a.jpg Germinoma (upmc.edu)].<ref>URL: [http://path.upmc.edu/cases/case525.html http://path.upmc.edu/cases/case525.html]. Accessed on: 25 January 2012.</ref>
<gallery>
Image:Neuropathology_case_VIII_01.jpg | Germinoma  of the brain, low mag. (WC/jensflorian)
Image:Neuropathology_case_VIII_02.jpg | Germinoma intermed. mag. (WC/jensflorian)
Image:Neuropathology_case_VIII_03.jpg | Germinoma very high. mag. (WC/jensflorian)
Image:Neuropathology_case_VIII_05.jpg | Germinoma Oct3/4 staining (WC/jensflorian)
</gallery>


===Seminoma===
===Seminoma===
{{Main|Testis#Seminoma}}
{{Main|Seminoma}}
A common GCT in males.
A common GCT in males.


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==Yolk sac tumour==
==Yolk sac tumour==
*Abbreviated ''YST''.
{{Main|Yolk sac tumour}}
*[[AKA]] ''endodermal sinus tumour''.
===General===
*Rare.
*Aggressive - especially extragonadal tumours.<ref name=pmid18767035/>
 
Epidemiology:
*Most common GCT in infants and young boys.
*Bimodal age distribution:<ref name=pmid18767035>{{Cite journal  | last1 = Shah | first1 = JP. | last2 = Kumar | first2 = S. | last3 = Bryant | first3 = CS. | last4 = Ali-Fehmi | first4 = R. | last5 = Malone | first5 = JM. | last6 = Deppe | first6 = G. | last7 = Morris | first7 = RT. | title = A population-based analysis of 788 cases of yolk sac tumors: A comparison of males and females. | journal = Int J Cancer | volume = 123 | issue = 11 | pages = 2671-5 | month = Dec | year = 2008 | doi = 10.1002/ijc.23792 | PMID = 18767035 }}</ref>
**<4 years.
**10-30 years.
 
Clinical:
*Elevated AFP.
 
===Gross===
*White/yellow mucinous infiltrative mass.<ref name=Ref_PCPBoD8_510>{{Ref PCPBoD8|510}}</ref>
 
===Microscopic===
Classic feature:<ref name=Ref_PCPBoD8_510>{{Ref PCPBoD8|510}}</ref>
*Schiller-Duval bodies.
**Look like glomerulus - central blood vessel surrounded by epithelial-like cells a space and more epithelial-like cells
*Architecure - variable.
*#Reticular - most common according to WMSP.<ref name=Ref_WMSP369>{{Ref WMSP|369}}</ref>
*#Microcystic - most common according to ''webpathology.com''.<ref name=webpath_case34>URL: [http://webpathology.com/image.asp?case=34&n=1 http://webpathology.com/image.asp?case=34&n=1]. Accessed on: March 8, 2010.</ref> 
*#*Lace-like pattern.
*#Endodermal sinus-like - has Schiller-Duval bodies.
*#Solid.
*#Papillary.
*#Glandular.
*#Alveolar.
*#Enteric.
*#Polyvesicular vitelline.
*#Hepatoid.
*+/-Eosinophilic hyaline globules (contain alpha-fetoprotein).
 
Notes:
*Has a loose stroma/vaguely discohesive -- unlike embryonal carcinoma.
*How to remember patterns ''REM PS GAPEH'' = reticular, endodermal sinus, microcystic, papillary, solid, glandular, alveolar, polyvesicular vitelline, enteric, hepatoid.
*Yolk sac tumours in adults are essentially always a component of a [[mixed germ cell tumour]], i.e. if one sees a pure yolk sac tumour in an adult, it is probably under sampled.<ref name=pmid1203848>{{Cite journal  | last1 = Talerman | first1 = A. | title = The incidence of yolk sac tumor (endodermal sinus tumor) elements in germ cell tumors of the testis in adults. | journal = Cancer | volume = 36 | issue = 1 | pages = 211-5 | month = Jul | year = 1975 | doi =  | PMID = 1203848 }}</ref>
 
Variants:
*Hepatoid pattern.<ref>URL: [http://webpathology.com/image.asp?case=34&n=6 http://webpathology.com/image.asp?case=34&n=6]. Accessed on: March 8, 2010.</ref>
**Vaguely resembles liver.
***[[Hyaline globules]] (light red well-circumscribed globs).
***Bile canaculi.
*Solid pattern.<ref>URL: [http://webpathology.com/image.asp?case=34&n=8 http://webpathology.com/image.asp?case=34&n=8]. Accessed on: March 8, 2010.</ref>
**Vaguely resembles ''seminoma''.
 
DDx:
*[[Embryonal carcinoma]].
 
====Images====
<gallery>
Image:Mixed_germ_cell_tumour_-_very_high_mag.jpg|Yolk sac tumour. (WC/Nephron)
</gallery>
www:
*[http://webpathology.com/image.asp?case=34&n=6 Hepatoid Pattern (webpathology.com)].
*[http://www.webpathology.com/image.asp?case=34&n=5 Schiller-Duval body (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=6&Case=34 Hyaline globules (webpathology.com)].
*[http://path.upmc.edu/cases/case152.html Yolk sac tumour - case 1 - several images (upmc.edu)].
*[http://path.upmc.edu/cases/case492.html Yolk sac tumour - case 2 - several images (upmc.edu)].
*[http://www.moffitt.org/CCJRoot/v11n6/pdf/374.pdf Yolk sac tumour (moffitt.org)].<ref name=pmid15625525>{{Cite journal  | last1 = Sesterhenn | first1 = IA. | last2 = Davis | first2 = CJ. | title = Pathology of germ cell tumors of the testis. | journal = Cancer Control | volume = 11 | issue = 6 | pages = 374-87 | month =  | year =  | doi =  | PMID = 15625525 }}</ref>
 
===IHC===
*AFP +ve.
*Glypican 3 +ve.
**More sensitive than AFP.<ref name=pmid20438407>{{Cite journal  | last1 = Emerson | first1 = RE. | last2 = Ulbright | first2 = TM. | title = Intratubular germ cell neoplasia of the testis and its associated cancers: the use of novel biomarkers. | journal = Pathology | volume = 42 | issue = 4 | pages = 344-55 | month = Jun | year = 2010 | doi = 10.3109/00313021003767355 | PMID = 20438407 }}</ref>
*Alpha-1 AT +ve.
*Cytokeratin +ve.{{fact}}
 
Negative stains:<ref name=pmid19396148>{{Cite journal  | last1 = Gopalan | first1 = A. | last2 = Dhall | first2 = D. | last3 = Olgac | first3 = S. | last4 = Fine | first4 = SW. | last5 = Korkola | first5 = JE. | last6 = Houldsworth | first6 = J. | last7 = Chaganti | first7 = RS. | last8 = Bosl | first8 = GJ. | last9 = Reuter | first9 = VE. | title = Testicular mixed germ cell tumors: a morphological and immunohistochemical study using stem cell markers, OCT3/4, SOX2 and GDF3, with emphasis on morphologically difficult-to-classify areas. | journal = Mod Pathol | volume = 22 | issue = 8 | pages = 1066-74 | month = Aug | year = 2009 | doi = 10.1038/modpathol.2009.66 | PMID = 19396148 }}</ref>
*OCT3/4 - positive in [[seminoma]] and embryonal carcinoma.
*CD30 - positive in [[embryonal carcinoma]].


==Embryonal carcinoma==
==Embryonal carcinoma==
===General===
{{Main|Embryonal carcinoma}}
*Affects young adults.
**May be seen in women.
 
===Microscopic===
Features:<ref name=Ref_GUP549>{{Ref GUP|549}}</ref>
#Nucleoli - '''key feature'''.
#Vesicular nuclei (clear, empty appearing nuclei) - '''key feature'''.
#Nuclei overlap.
#[[Necrosis]] - common.
#*Not commonly present in seminoma.
#Indistinct cell borders
#Mitoses - common.
#Variable architecture:
#*Tubulopapillary.
#*Glandular.
#*Solid.
#*Embryoid bodies - ball of cells in surrounded by empty space on three sides.
 
Notes:
*Cytoplasmic staining variable (eosinophilic to basophilic).
 
DDx:
*[[Yolk sac tumour]].
 
====Images====
<gallery>
Image:Embryonal_carcinoma_-_very_high_mag_-_cropped.jpg | Embryonal carcinoma - very high mag. - cropped (WC/Nephron)
Image:Embryonal_carcinoma_-_high_mag.jpg | Embryonal carcinoma - high mag. (WC/Nephron)
</gallery>
<gallery>
Image:Embryonal_carcinoma_high_mag.jpg | Embryonal carcinoma - high mag. (WC/Nephron)
Image:Embryonal_carcinoma_intermed_mag.jpg | Embryonal carcinoma - intermed. mag. (WC/Nephron)
Image:Embryonal_carcinoma_low_mag.jpg | Embryonal carcinoma - low mag. (WC/Nephron)
</gallery>
===IHC===
*AE1/AE3 +ve.
*CD30 +ve.


==Choriocarcinoma==
==Choriocarcinoma==
===General===
{{Main|Choriocarcinoma}}
*Aggressive clinical course.
*Usually a mixed tumour, i.e. pure choriocarcinoma is rare, e.g. [[dysgerminoma]] + choriocarcinoma.
 
====Clinical====
*High beta-hCG -- usually > 10,000 IU.
*Vaginal bleeding.
*Occasionally thyrotoxicosis.<ref name=pmid8395487>{{Cite journal  | last1 = O'Reilly | first1 = S. | last2 = Lyons | first2 = DJ. | last3 = Harrison | first3 = M. | last4 = Gaffney | first4 = E. | last5 = Cullen | first5 = M. | last6 = Clancy | first6 = L. | title = Thyrotoxicosis induced by choriocarcinoma a report of two cases. | journal = Ir Med J | volume = 86 | issue = 4 | pages = 124, 127 | month =  | year =  | doi =  | PMID = 8395487 }}</ref>
 
====Epidemiology====
*May be preceded by a [[complete hydatidiform mole]].<ref name=Ref_PBoD1110-1>{{Ref PBoD|1110-1111}}</ref>
*More common in the far east.
*More common at extremes of fertile age (teens and 40-50 years).
 
===Microscopic===
Features:
*Two cell populations:
#'''C'''ytotrophoblasts - '''key feature'''.
#*'''C'''lear cytoplasm.
#*Polygonal shaped cells in cords/masses.
#*Distinct cell borders.
#*Single uniform nucleus.
#Syncytiotrophoblasts - may be absent.<ref>URL: [http://www.webpathology.com/image.asp?n=4&Case=36 http://www.webpathology.com/image.asp?n=4&Case=36]. Accessed on: 8 February 2011.</ref>
#*Large + many irreg. or lobular hyperchromatic nuclei.
#*Eosinophilic vacuolated cytoplasm (contains hCG).
*+/-Hemorrhage - classically in the centre of the lesion.
*+/-Necrosis.
 
Notes:
*No ''[[chorionic villi]]'' should be present.
**If chorionic villi are present... it is likely a type of [[hydatidiform mole]].
*The dual cell population may not be evident at first.
**Hemorrhage and marked nuclear pleomorphism are suggestive of the diagnosis.
 
DDx:
*[[Invasive hydatidiform mole]].
*[[Placental site trophoblastic tumour]] (PSTT).
 
====Images====
www:
*[http://www.webpathology.com/image.asp?n=5&Case=36 Choriocarcinoma - low mag. (webpathology.com)].
*[http://www.webpathology.com/image.asp?case=36&n=1 Choriocarcinoma (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=4&Case=36 Choriocarcinoma (webpathology.com)].
*[http://chestjournal.chestpubs.org/content/138/1/220.full Choriocarcinoma (chestjournal.chestpubs.org)].<ref>{{Cite journal  | last1 = Venkatram | first1 = S. | last2 = Muppuri | first2 = S. | last3 = Niazi | first3 = M. | last4 = Fuentes | first4 = GD. | title = A 24-year-old pregnant patient with diffuse alveolar hemorrhage. | journal = Chest | volume = 138 | issue = 1 | pages = 220-3 | month = Jul | year = 2010 | doi = 10.1378/chest.09-2688 | PMID = 20605823 }}</ref>
*[http://oac.med.jhmi.edu/Pathology/Repro/Placenta/279B_Full.html Choriocarcinoma - uterus (med.jhmi.edu)].
<gallery>
Image:Choriocarcinoma_-2-_high_mag.jpg | Choriocarcinoma - high mag. (WC/Nephron)
Image:Choriocarcinoma_-2-_very_high_mag.jpg | Choriocarcinoma - very high mag. (WC/Nephron)
</gallery>
===IHC===
*Beta-hCG +ve.
**Classically said to be produced by syncytiotrophoblasts.<ref name=pmid20735820>{{Cite journal  | last1 = Cole | first1 = LA. | title = Biological functions of hCG and hCG-related molecules. | journal = Reprod Biol Endocrinol | volume = 8 | issue =  | pages = 102 | month =  | year = 2010 | doi = 10.1186/1477-7827-8-102 | PMID = 20735820 | PMC = 2936313 | URL = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936313/ }}</ref>
***Cytotrophoblasts also produce some<ref name=pmid20735820/><ref name=pmid12242037>{{Cite journal  | last1 = Kovalevskaya | first1 = G. | last2 = Genbacev | first2 = O. | last3 = Fisher | first3 = SJ. | last4 = Caceres | first4 = E. | last5 = O'Connor | first5 = JF. | title = Trophoblast origin of hCG isoforms: cytotrophoblasts are the primary source of choriocarcinoma-like hCG. | journal = Mol Cell Endocrinol | volume = 194 | issue = 1-2 | pages = 147-55 | month = Aug | year = 2002 | doi =  | PMID = 12242037 }}</ref> - usu. no staining.
*MUC-4 +ve.<ref name=pmid18059230>{{Cite journal  | last1 = Mao | first1 = TL. | last2 = Kurman | first2 = RJ. | last3 = Huang | first3 = CC. | last4 = Lin | first4 = MC. | last5 = Shih | first5 = IeM. | title = Immunohistochemistry of choriocarcinoma: an aid in differential diagnosis and in elucidating pathogenesis. | journal = Am J Surg Pathol | volume = 31 | issue = 11 | pages = 1726-32 | month = Nov | year = 2007 | doi = 10.1097/PAS.0b013e318058a529 | PMID = 18059230 }}</ref>
*Ki-67 +ve -- typically >30%.


==Teratoma==
==Teratoma==
===General===
{{Main|Teratoma}}
*May be benign or malignant.
*Are supposed to consists of all three [[germ layers]] - this is not always true.
*May be associated with sacral agenesis.<ref name=omim176450>{{OMIM|176450}}</ref>


Important note:
*The site of the tumour, age and sex are very important for predicting the behaviour of a teratoma:<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/GermCell_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/GermCell_11protocol.pdf]. Accessed on: 29 April 2012.</ref>
**Immature teratomas may have a benign or malignant behaviour.
**Mature teratomas may have a benign or malignant behaviour.
====Classification====
#Mature.
#*Common in females.
#*Usually benign.
#*Mature component may give rise to a malignancy like elsewhere in the body.
#**Most common malignancy arising from a mature teratoma: [[squamous cell carcinoma]].
#Immature.
#*Uncommon.
#*Often malignant.
#Monodermal.
#*Rare.
#*Highly specialized.
===Mature teratoma===
Features - three germ cell layers (usually):<ref>{{cite book |author=Moore, Keith L.; Persaud, T.V.N.|title=The Developing Human: Clinically Oriented Embryology |publisher=Saunders |location= |year=2002 |pages= 83 |edition=7th |isbn=978-0721694122 |oclc= |doi= |accessdate=}}</ref>
#Endoderm:
#*Skin, (mature) CNS.
#Mesoderm:
#*Muscle, bone, connective tissue, blood.
#Ectoderm:
#*Internal organs.
Note:
*May consist of skin only - in which case it is commonly called a ''dermoid''.
=====Images=====
<gallery>
Image:Teratoma_2_low_mag.jpg | Mature teratoma - low mag. (WC/Nephron)
Image:Teratoma_2_high_mag.jpg | Mature teratoma - high mag. (WC/Nephron)
</gallery>
====Fetus in fetu====
*Grouped with ''mature teratoma'', as it is considered a well-developed mature teratoma.<ref name=pmid3045784>{{Cite journal  | last1 = Heifetz | first1 = SA. | last2 = Alrabeeah | first2 = A. | last3 = Brown | first3 = BS. | last4 = Lau | first4 = H. | title = Fetus in fetu: a fetiform teratoma. | journal = Pediatr Pathol | volume = 8 | issue = 2 | pages = 215-26 | month =  | year = 1988 | doi =  | PMID = 3045784 }}</ref><ref name=pmid17183856>{{Cite journal  | last1 = Basu | first1 = A. | last2 = Jagdish | first2 = S. | last3 = Iyengar | first3 = KR. | last4 = Basu | first4 = D. | title = Fetus in fetu or differentiated teratomas? | journal = Indian J Pathol Microbiol | volume = 49 | issue = 4 | pages = 563-5 | month = Oct | year = 2006 | doi =  | PMID = 17183856 }}</ref>
**It has been suggested they are distinct from teratomas.<ref>{{Cite journal  | last1 = Basu | first1 = A. | last2 = Jagdish | first2 = S. | last3 = Iyengar | first3 = KR. | last4 = Basu | first4 = D. | title = Fetus in fetu or differentiated teratomas? | journal = Indian J Pathol Microbiol | volume = 49 | issue = 4 | pages = 563-5 | month = Oct | year = 2006 | doi =  | PMID = 17183856 }}</ref>
***They could be thought of as a parasitic twin.
Features:
*Discrete mass consisting of mature tissues that form well-developed structures with the normal anatomical relations.
**Separated from teratoma by the presence of a vertebral column.<ref name=pmid17334616>{{Cite journal  | last1 = Majhi | first1 = AK. | last2 = Saha | first2 = K. | last3 = Karmakar | first3 = M. | last4 = Sinha Karmakar | first4 = K. | last5 = Sen | first5 = A. | last6 = Das | first6 = S. | title = Fetus in fetu--a mystery in medicine. | journal = ScientificWorldJournal | volume = 7 | issue =  | pages = 252-7 | month =  | year = 2007 | doi = 10.1100/tsw.2007.56 | PMID = 17334616 }}</ref>
===Immature teratoma===
Features:
*Immature if neural tissue is present:<ref>RS. 2 May 2010.</ref>
**Vaguely resembles pseudostratified respiratory epithelium.
*Islands of small hyperchromatic cells - "blastema".
*+/-Cartilage.
*+/-Adipocytes.
*+/-Colonic type mucosa.
*+/-Stratified squamous epithelium (skin).
DDx:<ref>{{Ref BITFS|34}}</ref>
*[[Cerebellum]].
*[[Retina]].
=====Images=====
<gallery>
Image:Immature_teratoma_high_mag.jpg | Primitive neuroepithelium - high mag. (WC/Nephron)
Image:Primitive_neuroepithelium_intermed_mag.jpg | Primitive neuroepithelium - intermed mag. (WC/Nephron)
Image:Teratoma_intermed_mag.jpg | Teratoma - mature components (WC/Nephron)
</gallery>
Other images:
*[http://www.webpathology.com/image.asp?n=5&Case=35 Immature teratoma - myxomatous stroma (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=6&Case=35 Immature teratoma - blastema (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=7&Case=35 Immature teratoma - primitive neuroepithelium (webpathology.com)].
*[http://moon.ouhsc.edu/kfung/jty1/opaq/PathQuiz/N0C001-PQ01-M.htm Immature teratoma - primitive neuroepithelium (ouhsc.edu)].
====Grading (immature)====
Based on quantity of immature neuroepithelium:<ref name=pmid17080330>{{cite journal |author=Harms D, Zahn S, Göbel U, Schneider DT |title=Pathology and molecular biology of teratomas in childhood and adolescence |journal=Klin Padiatr |volume=218 |issue=6 |pages=296–302 |year=2006 |pmid=17080330 |doi=10.1055/s-2006-942271 |url=}}</ref><ref name=pmid15761467>{{cite journal |author=Ulbright TM |title=Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues |journal=Mod. Pathol. |volume=18 Suppl 2 |issue= |pages=S61–79 |year=2005 |month=February |pmid=15761467 |doi=10.1038/modpathol.3800310 |url=http://www.nature.com/modpathol/journal/v18/n2s/full/3800310a.html}}</ref><ref name=pmid7814189>{{cite journal |author=O'Connor DM, Norris HJ |title=The influence of grade on the outcome of stage I ovarian immature (malignant) teratomas and the reproducibility of grading |journal=Int. J. Gynecol. Pathol. |volume=13 |issue=4 |pages=283–9 |year=1994 |month=October |pmid=7814189 |doi= |url=}}</ref>
*G0 - mature teratoma; no immature neuroepithelium.
*G1 - less than one lower power field ([[LPF]]) of immature neuroepithelium; LPF defined field at 4X magnification.
*G2 - 1-3 LPFs.
*G3 - more than 3 LPFs.
Note:
*LPF not adequately defined - see [[LPFitis]]. Same BS as HPF.
====IHC (immature)====
Features:
*Primitive neuroepithelium:<ref name=pmid11598856>{{cite journal |author=Craver RD, Lipscomb JT, Suskind D, Velez MC |title=Malignant teratoma of the thyroid with primitive neuroepithelial and mesenchymal sarcomatous components |journal=Ann Diagn Pathol |volume=5 |issue=5 |pages=285–92 |year=2001 |month=October |pmid=11598856 |doi=10.1053/adpa.2001.27918 |url=}}</ref>
**Neuron-specific enolase (NSE) +ve.
**Neuron-specific B tubulin +ve.
**Synaptophysin +ve.
===Monodermal teratomas===
====Struma ovarii====
Features:
*Thyroid tissue present - colloid is seen.
**May develop pathologies seen in the [[thyroid gland]], e.g. [[papillary thyroid carcinoma]].
=====Images=====
<gallery>
Image:Struma_ovarii_-_low_mag.jpg | Struma ovarii - low mag. (WC/Nephron)
Image:Struma_ovarii_-_high_mag.jpg | Struma ovarii - high mag. (WC/Nephron)
</gallery>
====Strumal carcinoid====
Features:<ref name=pmid18509188>{{Cite journal  | last1 = Gorin | first1 = I. | last2 = Sastre-Garau | first2 = X. | title = Strumal carcinoid tumor of the ovary. | journal = J Clin Oncol | volume = 26 | issue = 16 | pages = 2780-1 | month = Jun | year = 2008 | doi = 10.1200/JCO.2008.16.1620 | PMID = 18509188 }}</ref><ref>{{Cite journal  | last1 = Tamsen | first1 = A. | last2 = Mazur | first2 = MT. | title = Ovarian strumal carcinoid in association with multiple endocrine neoplasia, type IIA. | journal = Arch Pathol Lab Med | volume = 116 | issue = 2 | pages = 200-3 | month = Feb | year = 1992 | doi =  | PMID = 1346363 }}</ref>
*Has components that suggest:
*#Carcinoid ([[neuroendocrine tumour]]).
*#*Nuclei with stippled chromatin (salt-and-pepper chromatin).
*#[[Thyroid]] - cystic spaces/follicular-like structures.
=====Images=====
<gallery>
Image:Strumal_carcinoid_-_intermed_mag.jpg | Strumal carcinoid - intermed. mag. (WC/Nephron)
Image:Strumal_carcinoid_-_high_mag.jpg | Strumal carcinoid - high mag. (WC/Nephron)
</gallery>
==Gonadoblastoma==
==Gonadoblastoma==
===General===
{{Main|Gonadoblastoma}}
*Associated with abnormal sexual development.
*Often coexist with a [[dysgerminoma]].
*A mixed tumour that consists of (1) primitive germ cells and (2) sex cord elements.


===Gross===
*+/-Cystic.
===Microscopic===
Features:<ref name=Ref_PBoD1104>{{Ref PBoD|1104}}</ref>
*Immature germ cells resembling Sertoli cells or granulosa cells.
**Sertoli cells = moderate cytoplasm in a trabecular or tubular architecture.
**Granulosa cells = form follicle-like structures.
***May form nests.
*Primitive germ cells resemble those of a [[dysgerminoma]].
**Polygonal cells with a central nucleus, squared-off nuclear membrane and clear cytoplasm.
*+/-Calcification (very common).
*+/-Eosinophilic basement membrane material between the (primitive) germ cells and support cells.<ref>URL: [http://www.flickr.com/photos/ckrishnan/3972432044/in/photostream/ http://www.flickr.com/photos/ckrishnan/3972432044/in/photostream/]. Accessed on: 11 September 2011.</ref>
====Images====
www:
*[http://www.webpathology.com/image.asp?n=40&Case=532 Gonadoblastoma - low mag. (webpathology.com)].
*[http://www.webpathology.com/image.asp?case=532&n=42 Gonadoblastoma - high mag. (webpathology.com)].
*[http://www.webpathology.com/image.asp?case=532&n=44 Gonadoblastoma - high mag. (webpathology.com)].
*[http://www.flickr.com/photos/ckrishnan/3972431774/in/photostream/ Gonadoblastoma - low mag. (flickr.com)].
*[http://www.flickr.com/photos/ckrishnan/3972432404/in/photostream/ Gonadoblastoma - intermed. mag. (flickr.com)].
*[http://www.flickr.com/photos/ckrishnan/3972432044/in/photostream/ Gonadoblastoma - high mag. (flickr.com)].
*[http://path.upmc.edu/cases/case356.html Gonadoblastoma - several cases (upmc.edu)].
<gallery>
Image:Gonadoblastoma_-_intermed_mag.jpg | Gonadoblastoma - intermed. mag. (WC/Nephron)
Image:Gonadoblastoma_-_b_-_high_mag.jpg | Gonadoblastoma - high mag. (WC/Nephron)
</gallery>
==Polyembryoma==
==Polyembryoma==
===General===
{{Main|Polyembryoma}}
*Poor prognosis.
*Almost never in pure form, i.e. usu. a component of a [[mixed germ cell tumour]].<ref>{{Cite journal  | last1 = Young | first1 = RH. | title = Testicular tumors--some new and a few perennial problems. | journal = Arch Pathol Lab Med | volume = 132 | issue = 4 | pages = 548-64 | month = Apr | year = 2008 | doi = 10.1043/1543-2165(2008)132[548:TTNAAF]2.0.CO;2 | PMID = 18384207 }}</ref>
 
===Microscopic===
Features:
*Disc shaped structure (embryo-like) with:
**The one side endoderm.
***Skin/CNS.
**The other side ectoderm.
***Internal organs - GI tract.
 
Images:
*[http://www.webpathology.com/image.asp?case=37&n=6 Polyembryoma - low mag. (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=7&Case=37 Polyembryoma - high mag. (webpathology.com)].


==Mixed germ cell tumour==
==Mixed germ cell tumour==
===General===
{{Main|Mixed germ cell tumour}}
*60% of GCTs are mixed.
 
Common combinations:
# Teratoma + embryonal carcinoma + endodermal sinus tumour (yolk sac tumour) (TEE).
# Seminoma + embryonal (SE).
# Teratoma + embryonal +(TE).
 
Memory device: ''TEE'' + all combinations have embryonal carcinoma.
===Microscopic===
Features:
*Depends on components.
 
Notes:
*If one cannot identify the component... it is probably yolk sac as this has so many different patterns.
 
====Images====
<gallery>
Image:Mixed_germ_cell_tumour_-_intermed_mag.jpg | Mixed germ cell tumour - intermed mag. (WC/Nephron)
</gallery>
www:
*[http://path.upmc.edu/cases/case192/micro.html Mixed germ cell tumour - several images (upmc.edu)].
*[http://path.upmc.edu/cases/case356.html Mixed germ cell tumour - several cases (upmc.edu)].
 
===IHC===
*Beta-hCG +ve - if syncytiotrophoblasts are present.
*AFP +ve - a yolk sac tumour component is present.
*GFAP +ve - if neuroepithelium is present.


==See also==
==See also==
Line 496: Line 177:
*[[Ovarian tumours]].
*[[Ovarian tumours]].
*[[Trophoblast]].
*[[Trophoblast]].
*[[Sex cord-stromal tumours]].


==References==
==References==
Line 502: Line 184:
[[Category:Gynecologic pathology]]
[[Category:Gynecologic pathology]]
[[Category:Genitourinary pathology]]
[[Category:Genitourinary pathology]]
[[Category:Germ cell tumours|Germ cell tumours]]

Latest revision as of 16:36, 13 October 2023

Testicular mixed germ cell tumour. (WC/euthman)

This article covers germ cell tumours, often abbreviated GCT, which classically arise in the gonads (ovary, testis). They are also found in the midline and make appearances in neuropathology (e.g. pineal gland) and in the mediastinum.

Overview

Germ cell tumour - types

Precusor:

Germ cell tumours (GCTs):

Grossing

Main article: Orchiectomy
  • 1 cm2 of tumour per cm of maximal tumour dimension - guideline for testicular cancer.[1]

IHC for GCTs

ISUP

An algorithmic approach based on the ISUP consensus paper by Ulbright et al.:[2]

 
 
 
 
 
 
 
 
 
 
 
 
Germ cell tumours
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCT4 +ve
 
 
 
 
 
 
 
 
 
 
 
 
 
OCT4 -ve
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD117 +ve
CD30 -ve
 
 
 
 
 
CD117 -ve
CD30 +ve
 
 
 
Glypican 3 +ve
AFP +ve
beta-hCG -ve
 
 
 
Glypican 3 ?
AFP -ve
beta-hCG +ve
 
 
 
Glypican 3 -ve
AFP -ve
beta-hCG -ve
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Seminoma
 
 
 
 
 
Embryonal carcinoma
 
 
 
Yolk sac tumour
 
 
 
Choriocarcinoma
 
 
 
Spermatocytic seminoma
 
 
 
 

ABCDs of GCTs

  • AFP - yolk sac tumour.
  • Beta-hCG - choriocarcinoma.
  • CD30 - embryonal carcinoma.
  • D2-40 - seminoma.

GCT versus sex cord-stromal tumour

The ISUP recommends:[3]

  • SALL4 +ve (in GCTs).[4]
  • Alpha-inhibin -ve (+ve in SCST).
  • Calretinin -ve (+ve in SCST).

Alternates for SALL4 are:[3]

  • OCT4 and GPC3.

Tabular summary of GCTs

Tumour Key feature Microscopic IHC Other Image
Germ cell neoplasia in situ (GCNIS) nests of small fried egg cells large central nucleus, clear
cytoplasm, squared-off nuclear membrane, nucleoli[5] 		CD117 +ve, CD30 -ve appearance similar to seminoma
GCNIS (WC/Nephron)
Germinoma / Seminoma / Dysgerminoma fried egg cells fried egg-like cells (central nucleus, clear
cytoplasm) with squared-off nuclear
membrane, nucleoli, lymphocytic infiltrate, granulomata,
syncytiotrophoblastic giant cells[6] 		D2-40 seminoma = male version of this tumour; dysgerminoma = female version of this tumour
Seminoma (WC/Nephron)
Yolk sac tumour (endodermal sinus tumour) Schiller-Duval bodies Schiller-Duval b. = central blood vessel surrounded by epithelial-like cells a space and more epithelial-like cells, variable arch. AFP +ve, Glypican 3 +ve patterns: microcystic, solid, hepatoid
Yolk sac tumour (WC)
Embryonal carcinoma prominent nucleoli, vescicular nuclei var. arch.: tubulopapillary, glandular, solid, embryoid bodies (ball of cells in surrounded by empty space on three sides), +/-nuclear overlap, mitoses common CD30 +ve, CD117 -ve usu. part of a mixed GCT
Embryonal carcinoma (WC/Nephron)
Choriocarcinoma clear cytoplasm cells with abundant clear cytoplasm and eccentric atypical nuclei (cytotrophoblast), very large (multinucleated) cells with abundant eosinophilic cytoplasm and extreme nuclear atypia (syncytiotrophoblast) beta-hCG +ve may be preceded by a complete hydatidiform mole
Choriocarcinoma. (WC/Nephron)
Teratoma, immature primitive neuroepithelium pseudostratified epithelium in rosettes (gland-like arrangement) None testicular teratomas in post-pubertal males are all considered malignant[7]
Primitive neuroepithelium (WC/Nephron)
Mixed germ cell tumour NA common combinations: teratoma + embryonal carcinoma + endodermal sinus tumour (yolk sac tumour) (TEE); seminoma + embryonal (SE); embryonal + teratoma (TE) NA -
Mixed GCT (WC/Nephron)
Gonadoblastoma primitive germ cells (central nucleus, moderate (eosinophilic) cytoplasm); sex cord element sex cord element may be either granulosa cells (follicle-like arch.) or Sertoli cells (trabecular arch.) ? often abnormal karyotype; usu. Y chromosome present
Gonadoblastoma (WC/Nephron)

Molecular pathology

Most common cytogenetic abnormality in GCTs:

  • Isochromosome 12p.[8]
    • Isochromosome = one arm (p or q) is lost and replaced with a duplicate of the remaining one.
      • Example: isochromosome 12p = chromosome 12 where q is lost and two p arms are present.[9]

Germinoma

Comes in three flavours:

  • Germinoma.
  • Seminoma.
  • Dysgerminoma.

Germinoma

Is the generic version of this tumour. It is found in the midline (brain, mediastinum).

Image: Germinoma (upmc.edu).[10]

  • Germinoma of the brain, low mag. (WC/jensflorian)

  • Germinoma intermed. mag. (WC/jensflorian)

  • Germinoma very high. mag. (WC/jensflorian)

  • Germinoma Oct3/4 staining (WC/jensflorian)


Seminoma

Main article: Seminoma

A common GCT in males.

Dysgerminoma

Main article: Ovarian tumours#Dysgerminoma

A common GCT in females.

Yolk sac tumour

Main article: Yolk sac tumour

Embryonal carcinoma

Main article: Embryonal carcinoma

Choriocarcinoma

Main article: Choriocarcinoma

Teratoma

Main article: Teratoma

Gonadoblastoma

Main article: Gonadoblastoma

Polyembryoma

Main article: Polyembryoma

Mixed germ cell tumour

Main article: Mixed germ cell tumour

See also

References

  1. ↑ URL: http://www.uroweb.org/gls/pdf/10_Testicular_Cancer.pdf. Accessed on: 30 October 2012.
  2. ↑ Ulbright TM, Tickoo SK, Berney DM, Srigley JR (August 2014). "Best practices recommendations in the application of immunohistochemistry in testicular tumors: report from the international society of urological pathology consensus conference". Am. J. Surg. Pathol. 38 (8): e50–9. doi:10.1097/PAS.0000000000000233. PMID 24832161.
  3. ↑ 3.0 3.1 Amin MB, Epstein JI, Ulbright TM, et al. (August 2014). "Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the international society of urological pathology consensus conference". Am. J. Surg. Pathol. 38 (8): 1017–22. doi:10.1097/PAS.0000000000000254. PMID 25025364.
  4. ↑ Miettinen M, Wang Z, McCue PA, et al. (March 2014). "SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases". Am. J. Surg. Pathol. 38 (3): 410–20. doi:10.1097/PAS.0000000000000116. PMID 24525512.
  5. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 538. ISBN 978-0443066771.
  6. ↑ Zhou, Ming; Magi-Galluzzi, Cristina (2006). Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 542. ISBN 978-0443066771.
  7. ↑ Carver, BS.; Al-Ahmadie, H.; Sheinfeld, J. (May 2007). "Adult and pediatric testicular teratoma.". Urol Clin North Am 34 (2): 245-51; abstract x. doi:10.1016/j.ucl.2007.02.013. PMID 17484929.
  8. ↑ Looijenga, LH.; Oosterhuis, JW. (May 1999). "Pathogenesis of testicular germ cell tumours.". Rev Reprod 4 (2): 90-100. PMID 10357096.
  9. ↑ URL: http://ghr.nlm.nih.gov/handbook/illustrations/isochromosomes. Accessed on: 15 February 2012.
  10. ↑ URL: http://path.upmc.edu/cases/case525.html. Accessed on: 25 January 2012.
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