Difference between revisions of "Testis"

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[[Image:Seminoma_of_the_Testis.jpg|thumb|150px|Orchiectomy specimen showing testis replaced by tumour (proven to be [[seminoma]]). (WC/Ed Uthman)]]
The '''testis''', plural '''testes''',  are important for survival of the species.  Tumours occasionally arise in 'em.  They generally are not biopsied.   
The '''testis''', plural '''testes''',  are important for survival of the species.  Tumours occasionally arise in 'em.  They generally are not biopsied.   


If the testis is biopsied, it is usually for fertility -- to understand whether the man is really azoospermic.
If the testis is biopsied, it is usually for [[male infertility|fertility]].  The [[cut-up]] of orchiectomy specimens is dealt with in ''[[orchiectomy grossing]]''.


=Normal testis=
=Normal testis=
==Gross==
===Gross===
Anatomy - deep to superficial:
Anatomy - deep to superficial:
*Tunica albuginea - fibrous layer.
*Tunica albuginea - fibrous layer.
*Tunica vaginalis - thin mesothelial layer.
*Tunica vaginalis - thin mesothelial layer.
**This layer is important in the [[cancer staging|staging]] of testicular tumours.


==Microscopic==
===Microscopic===
===Seminiferous tubules===
====Seminiferous tubules====
*Sertoli cells ([[AKA]] sustentacular cell [[AKA]] nurse cell).  
*Sertoli cells ([[AKA]] sustentacular cell [[AKA]] nurse cell).  
**Large cells with oval nucleus.  
**Large cells with oval nucleus.  
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**You don't see the tail on light microscopy.
**You don't see the tail on light microscopy.


====Images====
=====Images=====
<gallery>
<gallery>
Image:Seminiferous_tubule_and_sperm_low_mag.jpg | Seminiferous tubule and sperm - low mag. (WC/Nephron)
Image:Seminiferous_tubule_and_sperm_low_mag.jpg | Seminiferous tubule and sperm - low mag. (WC/Nephron)
Image:Seminiferous_tubule_and_sperm.jpg | Seminiferous tubule and sperm - high mag. (WC/Nephron)
Image:Seminiferous_tubule_and_sperm.jpg | Seminiferous tubule and sperm - high mag. (WC/Nephron)
Image:Intratubular_germ_cell_neoplasia_-_2_-_very_high_mag.jpg | Benign seminiferous tubules and ITGCN. (WC/Nephron)
Image:Intratubular_germ_cell_neoplasia_-_2_-_very_high_mag.jpg | Benign seminiferous tubules and GCNIS (ITGCN). (WC/Nephron)
</gallery>
</gallery>
===Interstitial===
====Interstitial====
*Leydig cell ([[AKA]] interstitial cell).
*Leydig cell ([[AKA]] interstitial cell).
**Large eosinophilic cell.
**Large eosinophilic cell.
*[[Blood vessel]]s.
*[[Blood vessel]]s.


====Image====
=====Image=====
<gallery>
<gallery>
Image:Leydig_cells_-_very_high_mag.jpg | Leydig cells - very high mag. (WC/Nephron)
Image:Leydig_cells_-_very_high_mag.jpg | Leydig cells - very high mag. (WC/Nephron)
</gallery>
</gallery>
===Associated structures===
====Associated structures====
*Epididymis - stores the sperm.
*[[Epididymis]] - stores the sperm.
**Pseudostratified epithelium with cilia.
**Pseudostratified epithelium with cilia.


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*[http://www.webpathology.com/image.asp?n=3&Case=27 Epididymis (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=3&Case=27 Epididymis (webpathology.com)].


===Rete testis===
====Rete testis====
*Receives stuff from the tubules.
*Receives stuff from the tubules.
*Occasionally afflicted by ''[[adenomatous hyperplasia of the rete testis]]''.
*Very rarely give rise to an ''[[adenocarcinoma of the rete testis]]''.
*Very rarely give rise to an ''[[adenocarcinoma of the rete testis]]''.
*May be involved by [[seminoma]] - increases risk of relapse in a univariate analysis.<Ref>{{Cite journal  | last1 = Soper | first1 = MS. | last2 = Hastings | first2 = JR. | last3 = Cosmatos | first3 = HA. | last4 = Slezak | first4 = JM. | last5 = Wang | first5 = R. | last6 = Lodin | first6 = K. | title = Observation Versus Adjuvant Radiation or Chemotherapy in the Management of Stage I Seminoma: Clinical Outcomes and Prognostic Factors for Relapse in a Large US Cohort. | journal = Am J Clin Oncol | volume =  | issue =  | pages =  | month = Dec | year = 2012 | doi = 10.1097/COC.0b013e318277d839 | PMID = 23275274 }}</ref>
*May be involved by [[seminoma]].
**Increases risk of relapse in a univariate analysis.<Ref>{{Cite journal  | last1 = Soper | first1 = MS. | last2 = Hastings | first2 = JR. | last3 = Cosmatos | first3 = HA. | last4 = Slezak | first4 = JM. | last5 = Wang | first5 = R. | last6 = Lodin | first6 = K. | title = Observation Versus Adjuvant Radiation or Chemotherapy in the Management of Stage I Seminoma: Clinical Outcomes and Prognostic Factors for Relapse in a Large US Cohort. | journal = Am J Clin Oncol | volume =  | issue =  | pages =  | month = Dec | year = 2012 | doi = 10.1097/COC.0b013e318277d839 | PMID = 23275274 }}</ref>
**More common with (sometimes subtle) intertubular pattern of seminoma.<ref name=pmid16021570>{{Cite journal  | last1 = Browne | first1 = TJ. | last2 = Richie | first2 = JP. | last3 = Gilligan | first3 = TD. | last4 = Rubin | first4 = MA. | title = Intertubular growth in pure seminomas: associations with poor prognostic parameters. | journal = Hum Pathol | volume = 36 | issue = 6 | pages = 640-5 | month = Jun | year = 2005 | doi = 10.1016/j.humpath.2005.03.011 | PMID = 16021570 }}</ref>


Microscopic:
Microscopic:
*Delicate anastomosing channels lined by cuboid epithelium.
*Delicate anastomosing channels lined by cuboid epithelium.


====Images====
=====Images=====
<gallery>
<gallery>
Image:Rete_testis_high_mag.jpg | Rete testis (WC/Nephron)
Image:Rete_testis_high_mag.jpg | Rete testis (WC/Nephron)
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*[http://www.webpathology.com/image.asp?case=27&n=5 Rete testis (webpathology.com)].
*[http://www.webpathology.com/image.asp?case=27&n=5 Rete testis (webpathology.com)].


===Appendix of testis===
====Appendix of testis====
Muellerian duct remnant.
*Muellerian duct remnant.


Microscopic:
Microscopic:
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*[http://www.webpathology.com/image.asp?case=27&n=7 Appendix of testis (webpathology.com)].
*[http://www.webpathology.com/image.asp?case=27&n=7 Appendix of testis (webpathology.com)].


==Sign out==
===Sign out===
<pre>
<pre>
TESTICLE, RIGHT, ORCHIECTOMY:
TESTICLE, RIGHT, ORCHIECTOMY:
- TESTICLE WITHOUT APPARENT PATHOLOGY.
- TESTICLE WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR INTRATUBULAR GERM CELL NEOPLASIA.
- NEGATIVE FOR MALIGNANCY.
</pre>
====Alternate====
<pre>
RIGHT TESTICLE, ORCHIDECTOMY:
- BENIGN TESTIS WITH SPERMATOGENESIS.
- NEGATIVE FOR INTRATUBULAR GERM CELL NEOPLASIA.
- NEGATIVE FOR INTRATUBULAR GERM CELL NEOPLASIA.
- NEGATIVE FOR MALIGNANCY.
- NEGATIVE FOR MALIGNANCY.
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*Beta-hCG - choriocarcinoma.
*Beta-hCG - choriocarcinoma.
*CD30 - embryonal carcinoma.
*CD30 - embryonal carcinoma.
*D2-40 - seminoma.
*[[D2-40]] - seminoma.


===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, round ''or'' polygonal nuclear membrane, [[nucleoli]]<ref name=Ref_GUP538>{{Ref GUP|538}}</ref>
| large central nucleus, clear <br>cytoplasm, round ''or'' polygonal nuclear membrane, [[nucleoli]]<ref name=Ref_GUP538>{{Ref GUP|538}}</ref>
| CD117
| CD117
| appearance similar to seminoma
| appearance similar to seminoma
| [[Image:Intratubular_germ_cell_neoplasia_high_mag_cropped.jpg|thumb|center|150px|ITGCN (WC)]]
| [[Image:Intratubular_germ_cell_neoplasia_high_mag_cropped.jpg|thumb|center|150px|GCNIS (WC)]]
|-  
|-  
| [[Seminoma]]
| [[Seminoma]]
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| [[Image:Teratoma_2_low_mag.jpg|thumb|center|150px|Teratoma (WC)]]
| [[Image:Teratoma_2_low_mag.jpg|thumb|center|150px|Teratoma (WC)]]
|-  
|-  
| [[Spermatocytic seminoma]]
| [[Spermatocytic tumour]] (previously ''spermatocytic seminoma'')
| population of 3 cells  
| population of 3 cells  
| pop.: (1) small cell with high [[NC ratio]] (mature lymphocyte-like), (2) medium with nucleoli, (3) large cells with filamentous chromatin - few present
| pop.: (1) small cell with high [[NC ratio]] (mature lymphocyte-like), (2) medium with nucleoli, (3) large cells with filamentous chromatin - few present
| ?
| ?
| does not arise from ITGCN, no lymphocytic infiltrate (like in seminoma)
| does not arise from GCNIS, no lymphocytic infiltrate (like in seminoma)
| [[Image:Spermatocytic_seminoma_high_mag.jpg|thumb|center|150px|Spermatocytic seminoma (WC)]]
| [[Image:Spermatocytic_seminoma_high_mag.jpg|thumb|center|150px|Spermatocytic tumour (WC)]]
|-  
|-  
| [[Mixed germ cell tumour]]
| [[Mixed germ cell tumour]]
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=Benign=
=Benign=
==Testicular atrophy==
==Testicular atrophy==
:''Cryptorchidism'' redirects here.
*[[AKA]] ''atrophic testis''.
*[[AKA]] ''atrophic testis''.
*[[AKA]] ''atrophy of the testis''.
*[[AKA]] ''atrophy of the testis''.
===General===
{{Main|Testicular atrophy}}
*Microscopic appearance identical to ''cryptorchidism'' (undescended testis).<ref name=Ref_PCPBoD8_506-7>{{Ref PCPBoD8|506-7}}</ref>
 
===Gross===
*Decreased size.
 
===Microscopic===
Features:<ref name=Ref_PCPBoD8_506-7>{{Ref PCPBoD8|506-7}}</ref>
*Thickening of seminiferous tubule basement membrane.
*Intertubular fibrosis.
*Decreased sperm/no sperm present.
 
Note:
*End-stage testicle - only has Sertoli cell within the seminiferous tubules.
 
Image:
*[http://www.surgicalpathologyatlas.com/glfusion/mediagallery/media.php?f=0&sort=0&s=20080802171227609 Testicular atrophy (surgicalpathologyatlas.com)].


===Sign out===
==Male infertility==
<pre>
*This is a [[clinical diagnosis]].
TESTICLE, RIGHT, ORCHIECTOMY:
{{Main|Male infertility}}
- ATROPHIC TESTICLE.
- NEGATIVE FOR INTRATUBULAR GERM CELL NEOPLASIA.
- NEGATIVE FOR MALIGNANCY.
</pre>
 
====Micro====
The sections show seminiferous tubules surrounded by thick hyaline sleeves.  In a large number of sections only Sertoli cells are found in the tubules.
 
In some sections poorly defined paucicellular tubular structures reminiscent of seminiferous tubules composed of hyaline material are present; these probably represent obsolete seminiferous tubules.  Focally, fibrosis is seen without definite tumour outlines.  There is no significant inflammation.  The rete testis is identified.
 
Rare seminiferous tubules have spermatid within. The germ cells seen do not have appreciable nuclear atypia.
 
Numerous small Leydig cell clusters are seen in some sections.


==Spermatocele==
==Spermatocele==
===General===
{{Main|Spermatocele}}
*Benign.
*Cyst of the epididymis (classic).
**May arise in the rete testis or [[vas deferens]].<ref>URL: [http://emedicine.medscape.com/article/443432-overview http://emedicine.medscape.com/article/443432-overview]. Accessed on: 5 March 2012.</ref>


Clinical:
*Often asymptomatic.
*Excised due to pain or mass effect.<ref name=pmid18357964>{{Cite journal  | last1 = Walsh | first1 = TJ. | last2 = Seeger | first2 = KT. | last3 = Turek | first3 = PJ. | title = Spermatoceles in adults: when does size matter? | journal = Arch Androl | volume = 53 | issue = 6 | pages = 345-8 | month =  | year =  | doi =  | PMID = 18357964 }}</ref>
===Microscopic===
Features:
*Cyst lined by a simple ciliated epithelium.
*Contain sperm.
**Head: ~1/2 the size of a [[RBC]], black.
**Tail: infrequently seen. 
Note:
*Small cellular clusters may be present.
**May mimic [[small cell carcinoma]].<ref name=pmid19740515>{{Cite journal  | last1 = Lane | first1 = Z. | last2 = Epstein | first2 = JI. | title = Small blue cells mimicking small cell carcinoma in spermatocele and hydrocele specimens: a report of 5 cases. | journal = Hum Pathol | volume = 41 | issue = 1 | pages = 88-93 | month = Jan | year = 2010 | doi = 10.1016/j.humpath.2009.06.018 | PMID = 19740515 }}</ref>
DDx:
*[[Hydrocele testis]] - do not contain sperm.
====Images====
<gallery>
Image:Spermatocele_-_intermed_mag.jpg | Spermatocele - intermed. mag. (WC)
Image:Spermatocele_-_very_high_mag.jpg | Spermatocele - very high mag. (WC)
</gallery>
www:
*[http://www.webpathology.com/image.asp?n=4&Case=40 Spermatocele - low mag. (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=5&Case=40 Spermatocele - high mag. (webpathology.com)].
==Hydrocele testis==
==Hydrocele testis==
*[[AKA]] ''hydrocele''.
*[[AKA]] ''hydrocele''.
===General===
{{Main|Hydrocele testis}}
*Benign.
 
Clinical:
*Scrotal mass.
 
===Microscopic===
Features:
*Cyst lined by a simple ciliated epithelium.
*Does '''not''' contain sperm.
 
DDx:
*[[Spermatocele]] - contains sperm.


==Idiopathic granulomatous orchitis==
==Idiopathic granulomatous orchitis==
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DDx:
DDx:
*[[ITGCN]].
*[[GCNIS]] (ITGCN).
*[[Seminoma]].
*[[Seminoma]].
*Tertiary [[syphilis]] - classically, plasma cell rich.<ref name=pmid22343746>{{Cite journal  | last1 = Sekita | first1 = N. | last2 = Nishikawa | first2 = R. | last3 = Fujimura | first3 = M. | last4 = Sugano | first4 = I. | last5 = Mikami | first5 = K. | title = [Syphilitic orchitis: a case report]. | journal = Hinyokika Kiyo | volume = 58 | issue = 1 | pages = 53-5 | month = Jan | year = 2012 | doi =  | PMID = 22343746 }}</ref>
*Tertiary [[syphilis]] - classically, plasma cell rich.<ref name=pmid22343746>{{Cite journal  | last1 = Sekita | first1 = N. | last2 = Nishikawa | first2 = R. | last3 = Fujimura | first3 = M. | last4 = Sugano | first4 = I. | last5 = Mikami | first5 = K. | title = [Syphilitic orchitis: a case report]. | journal = Hinyokika Kiyo | volume = 58 | issue = 1 | pages = 53-5 | month = Jan | year = 2012 | doi =  | PMID = 22343746 }}</ref>
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*[[Lymphoma]].<ref name=pmid21458170/>
*[[Lymphoma]].<ref name=pmid21458170/>
*[[Malakoplakia]].<ref name=pmid21458170/>
*[[Malakoplakia]].<ref name=pmid21458170/>
*BCG-associated orchitis.<ref name=pmid23856256>{{Cite journal  | last1 = Parker | first1 = SG. | last2 = Kommu | first2 = SS. | title = Post-intravesical BCG epididymo-orchitis: Case report and a review of the literature. | journal = Int J Surg Case Rep | volume = 4 | issue = 9 | pages = 768-70 | month =  | year = 2013 | doi = 10.1016/j.ijscr.2013.05.017 | PMID = 23856256 }}</ref><ref name=pmid12841318>{{Cite journal  | last1 = Bulbul | first1 = MA. | last2 = Hijaz | first2 = A. | last3 = Beaini | first3 = M. | last4 = Araj | first4 = GF. | last5 = Tawil | first5 = A. | title = Tuberculous epididymo-orchitis following intravesical BCG for superficial bladder cancer. | journal = J Med Liban | volume = 50 | issue = 1-2 | pages = 67-9 | month =  | year =  | doi =  | PMID = 12841318 }}</ref>


===Stains===
===Stains===
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*[[Dieterle stain]] -ve -- for syphilis.
*[[Dieterle stain]] -ve -- for syphilis.


=Premalignant=
==Testicular scar==
==Intratubular germ cell neoplasia==
{{Main|Testicular scar}}
*Abbreviated ''ITGCN''.
 
==Testicular abscess==
{{Main|Testicular abscess}}
 
==Testicular torsion==
{{Main|Testicular torsion}}
 
==Adenomatous hyperplasia of the rete testis==
{{Main|Adenomatous hyperplasia of the rete testis}}
 
==Epidermoid cyst of the testis==
{{Main|Epidermoid cyst of the testis}}
 
==Testicular trauma==
===General===
===General===
*Considered the precursor lesion for germ cell tumours.
*May lead to orchitectomy.
*Not all germ cell tumours (GCTs) arise from ''intratubular germ cell neoplasia''.  


The following testicular GCTs do not arise from ITGCN:
===Gross===
*[[Spermatocytic seminoma]].<ref>{{cite journal |author=Müller J, Skakkebaek NE, Parkinson MC |title=The spermatocytic seminoma: views on pathogenesis |journal=Int. J. Androl. |volume=10 |issue=1 |pages=147–56 |year=1987 |month=February |pmid=3583416 |doi= |url=}}</ref>
*Hemorrhagic.
*[[Yolk sac tumour]]s (endodermal sinus tumour).<ref>{{cite journal |author=Manivel JC, Simonton S, Wold LE, Dehner LP |title=Absence of intratubular germ cell neoplasia in testicular yolk sac tumors in children. A histochemical and immunohistochemical study |journal=Arch. Pathol. Lab. Med. |volume=112 |issue=6 |pages=641–5 |year=1988 |month=June |pmid=2837162 |doi= |url=}}</ref>
*Teratoma.{{Fact}}
 
Classification:<ref name=pmid11900581/>
*Undifferentiated ITGCN.
*Differentiated ITGCN.<ref name=pmid17592271>{{Cite journal  | last1 = Lau | first1 = SK. | last2 = Weiss | first2 = LM. | last3 = Chu | first3 = PG. | title = Association of intratubular seminoma and intratubular embryonal carcinoma with invasive testicular germ cell tumors. | journal = Am J Surg Pathol | volume = 31 | issue = 7 | pages = 1045-9 | month = Jul | year = 2007 | doi = 10.1097/PAS.0b013e31802b8712 | PMID = 17592271 }}</ref>
**''Intratubular embryonal carcinoma''.
**''Intratubular seminoma.''


===Microscopic===
===Microscopic===
Features:<ref>URL: [http://www.webpathology.com/image.asp?case=30&n=1 http://www.webpathology.com/image.asp?case=30&n=1]. Accessed on: 18 May 2010.</ref><ref name=pmid3328244>{{Cite journal  | last1 = Gondos | first1 = B. | last2 = Migliozzi | first2 = JA. | title = Intratubular germ cell neoplasia. | journal = Semin Diagn Pathol | volume = 4 | issue = 4 | pages = 292-303 | month = Nov | year = 1987 | doi =  | PMID = 3328244 }}</ref>
Features:
*"Large" round ''or'' polygonal nuclei.
*Necrotic seminiferous tubules.
**Size in relation to normal often not defined.
*Intratubular blood in keeping with hemorrhage.
***Rakheja ''et al.'' say >= 5x a lymphocyte for intratubular embryonal carcinoma.<ref name=pmid11900581>{{Cite journal  | last1 = Rakheja | first1 = D. | last2 = Hoang | first2 = MP. | last3 = Sharma | first3 = S. | last4 = Albores-Saavedra | first4 = J. | title = Intratubular embryonal carcinoma. | journal = Arch Pathol Lab Med | volume = 126 | issue = 4 | pages = 487-90 | month = Apr | year = 2002 | doi = 10.1043/0003-9985(2002)1260487:IEC2.0.CO;2 | PMID = 11900581 | url = http://www.archivesofpathology.org/doi/full/10.1043/0003-9985(2002)126%3C0487:IEC%3E2.0.CO;2 }}</ref>
**Polygonal nuclei = squared-off nuclear membrane.
*Prominent nucleoli - '''key feature'''.
*Clear cytoplasm.
*+/-Cells fill the tubule.


DDx:
Note:
*Sertoli cell-only syndrome - Sertoli cells also have nucleoli, wind swept appearance.<ref>URL: [http://www.webpathology.com/image.asp?n=3&Case=28 http://www.webpathology.com/image.asp?n=3&Case=28]. Accessed on: 25 March 2013.</ref>
*Normal spermatogenesis in background - if viable tissue present.


====Images====
===Sign out===
<gallery>
<pre>
Image:Intratubular_germ_cell_neoplasia_-_2_-_very_high_mag.jpg | Benign seminiferous tubules and ITGCN. (WC/Nephron)
Right Testicle Tissue, Debridement:
Image:Intratubular_germ_cell_neoplasia_high_mag_cropped.jpg | ITGCN - cropped. (WC/Nephron)
    - Hemorrhagic testicular tissue and necrotic seminiferous tubules.
Image:Intratubular_germ_cell_neoplasia_high_mag.jpg | ITGCN. (WC/Nephron)
    - Small amount of viable seminiferous tubules with spermatogenesis.
</gallery>
    - NEGATIVE for germ cell neoplasia in situ.
www:
    - NEGATIVE for malignancy.
*[http://www.webpathology.com/image.asp?case=30&n=1 ITGCN (webpathology.com)].
*[http://www.archivesofpathology.org/na101/home/literatum/publisher/pinnacle/journals/content/arpa/2002/15432165-126.4/0003-9985%282002%29126%3C0487%3Aiec%3E2.0.co%3B2/production/images/large/i1543-2165-126-4-487-f01.jpeg Intratubular embryonal carcinoma (archivesofpathology.org)].<ref name=pmid11900581/>


===IHC===
Comment:
Features:<ref name=pmid15221945>{{Cite journal  | last1 = Honecker | first1 = F. | last2 = Stoop | first2 = H. | last3 = de Krijger | first3 = RR. | last4 = Chris Lau | first4 = YF. | last5 = Bokemeyer | first5 = C. | last6 = Looijenga | first6 = LH. | title = Pathobiological implications of the expression of markers of testicular carcinoma in situ by fetal germ cells. | journal = J Pathol | volume = 203 | issue = 3 | pages = 849-57 | month = Jul | year = 2004 | doi = 10.1002/path.1587 | PMID = 15221945 }}</ref>
The clinical history of trauma is noted.
*PLAP +ve.<ref>{{Cite journal  | last1 = Schreiber | first1 = L. | last2 = Lifschitz-Mercer | first2 = B. | last3 = Paz | first3 = G. | last4 = Yavetz | first4 = H. | last5 = Elliott | first5 = DJ. | last6 = Kula | first6 = K. | last7 = Slowikowska-Hilczer | first7 = J. | last8 = Maymon | first8 = BB. | title = Double immunolabeling by the RBM and the PLAP markers for identifying intratubular (in situ) germ cell neoplasia of the testis. | journal = Int J Surg Pathol | volume = 11 | issue = 1 | pages = 17-20 | month = Jan | year = 2003 | doi =  | PMID = 12598912 }}</ref>
</pre>
*CD117 +ve.
**Disputed: doesn't differentiate neoplastic from non-neoplastic according to Biermann ''et al''.<ref name=pmid22340755>{{Cite journal  | last1 = Biermann | first1 = K. | last2 = Stoop | first2 = H. | last3 = Looijenga | first3 = L. | title = c-KIT protein expression does not discriminate neoplastic from non-neoplastic intratubular germ cells. | journal = Histopathology | volume = 60 | issue = 6 | pages = 1017-9 | month = May | year = 2012 | doi = 10.1111/j.1365-2559.2011.04157.x | PMID = 22340755 }}</ref>
*OCT3/4 +ve.


Note:
=Premalignant=
*Normal testis PLAP -ve, CD117 -ve.<ref name=pmid9104938>{{Cite journal  | last1 = Hawkins | first1 = E. | last2 = Heifetz | first2 = SA. | last3 = Giller | first3 = R. | last4 = Cushing | first4 = B. | title = The prepubertal testis (prenatal and postnatal): its relationship to intratubular germ cell neoplasia: a combined Pediatric Oncology Group and Children's Cancer Study Group. | journal = Hum Pathol | volume = 28 | issue = 4 | pages = 404-10 | month = Apr | year = 1997 | doi =  | PMID = 9104938 }}</ref>
==Germ cell neoplasia in situ==
*Previously ''intratubular germ cell neoplasia'' (abbreviated ''ITGCN'').
{{Main|Germ cell neoplasia in situ}}


=Germ cell tumours=
=Germ cell tumours=
Line 367: Line 306:
{{Main|Seminoma}}
{{Main|Seminoma}}


==Spermatocytic seminoma==
==Spermatocytic tumour==
{{Main|Spermatocytic seminoma}}
*Previously ''spermatocytic seminoma''.
{{Main|Spermatocytic tumour}}


==Yolk sac tumour==
==Yolk sac tumour==
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{{Main|Embryonal carcinoma}}
{{Main|Embryonal carcinoma}}
These often look like a poorly differentiated carcinoma.
These often look like a poorly differentiated carcinoma.
===General===
*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).


==Choriocarcinoma==
==Choriocarcinoma==
{{Main|Choriocarcinoma}}
{{Main|Choriocarcinoma}}
These are aggressive tumours.
These are aggressive tumours.
===Microscopic===
Features:
*Syncytiotrophoblasts:
**Large + many irreg. or lobular hyperchromatic nuclei.
**Eosinophilic vacuolated cytoplasm (contains hCG).
*'''C'''ytotrophoblasts:
**'''C'''lear cytoplasm.
**Polygonal shaped cells in cords/masses.
**Distinct cell borders.
**Single uniform nucleus.
*+/-Hemorrhage.
*+/-Necrosis.


==Teratoma of the testis==
==Teratoma of the testis==
Line 430: Line 336:
==Leydig cell tumour==
==Leydig cell tumour==
*[[AKA]] ''interstitial cell tumour''.
*[[AKA]] ''interstitial cell tumour''.
 
{{Main|Leydig cell tumour}}
===General===
*Arises from interstitial cell.
*May be associated with increased testosterone.
 
===Gross===
*Solid, lobulated.
*Red/tan.
 
Image:
*[http://www.flickr.com/photos/35441329@N05/5056465301/sizes/m/in/photostream/ Leydig cell tumour (flickr.com)].
 
===Microscopic===
Features:<ref name=Ref_GUP581>{{Ref GUP|581}}</ref>
*Vacuolization (cytoplasm) - '''key feature'''.
*Cytoplasm - clear to eosinophilic - '''important'''.
*''Reinke crystals'' - classic finding, usually not present.
**Cylindrical crystalloid eosinophilic cytoplasmic bodies.
*Nucleoli common.
*Round nuclei.
 
DDx:
*[[Spermatocytic seminoma]] - may have eosinophilic cytoplasm.
*[[Pregnancy luteoma]] - occurs during pregnancy, as the name implies.
 
====Images====
<gallery>
Image:Leydig_cell_tumour1.jpg |Leydig cell tumour - low mag. (WC)
Image:Leydig_cell_tumour2.jpg |Leydig cell tumour - intermed. mag. (WC)
Image:Leydig_cell_tumour3.jpg |Leydig cell tumour - high mag. (WC)
</gallery>
www:
*[http://path.upmc.edu/cases/case404.html Leydig cell tumour - several images (upmc.edu)].
 
===IHC===
*Inhibin-alpha.
*Calretinin.<ref>URL: [http://www.antibodybeyond.com/reviews/cell-markers/leydig-cell-marker.htm http://www.antibodybeyond.com/reviews/cell-markers/leydig-cell-marker.htm]. Accessed on: 18 May 2010.</ref><ref name=pmid15950053>{{cite journal |author=Bar-Shira Maymon B, Yavetz H, Yogev L, ''et al.'' |title=Detection of calretinin expression in abnormal immature Sertoli cells in non-obstructive azoospermia |journal=Acta Histochem. |volume=107 |issue=2 |pages=105–12 |year=2005 |pmid=15950053 |doi=10.1016/j.acthis.2005.02.002 |url=}}</ref>
*Melan A.<ref name=pmid12966351>{{cite journal |author=Yao DX, Soslow RA, Hedvat CV, Leitao M, Baergen RN |title=Melan-A (A103) and inhibin expression in ovarian neoplasms |journal=Appl. Immunohistochem. Mol. Morphol. |volume=11 |issue=3 |pages=244–9 |year=2003 |month=September |pmid=12966351 |doi= |url=}}</ref>
**AKA ''MART-1''.
**Expressed in [[melanoma]], [[adrenal gland|adrenal tissue]], steroid-secreting tumours.


==Sertoli cell nodule==
==Sertoli cell nodule==
*Abbreviated ''SCN''.
*[[AKA]] ''Pick's adenoma''.
*[[AKA]] ''Pick's adenoma''.
*AKA ''testicular tubular adenoma''.
*AKA ''testicular tubular adenoma''.
*AKA ''tubular adenoma of the testis''.
*AKA ''tubular adenoma of the testis''.
===General===
{{Main|Sertoli cell nodule}}
*Benign proliferation of Sertoli cells - associated with cryptorchidism (undescended testis).
*Not composed of a clonal cell population, i.e. ''not'' neoplastic; thus, technically, should not be called an ''adenoma''.<ref name=Ref_DCHH227>{{Ref DCHH|227}}</ref>
 
===Gross===
*Usually an incidental finding, rarely presents as a testicular mass.<ref name=pmid21107095>{{Cite journal  | last1 = Vallangeon | first1 = BD. | last2 = Eble | first2 = JN. | last3 = Ulbright | first3 = TM. | title = Macroscopic sertoli cell nodule: a study of 6 cases that presented as testicular masses. | journal = Am J Surg Pathol | volume = 34 | issue = 12 | pages = 1874-80 | month = Dec | year = 2010 | doi = 10.1097/PAS.0b013e3181fcab70 | PMID = 21107095 }}</ref>
 
===Microscopic===
Features:<ref name=Ref_DCHH227>{{Ref DCHH|227}}</ref><ref>{{cite journal |author=Ricco R, Bufo P |title=[Histologic study of 3 cases of so-called tubular adenoma of the testis] |language=Italian |journal=Boll. Soc. Ital. Biol. Sper. |volume=56 |issue=20 |pages=2110–5 |year=1980 |month=October |pmid=6109541 |doi= |url=}}</ref>
*Unencapsulated nodules composed of well-formed tubules.
**May contain eosinophilic (hyaline) blob in lumen (centre).
*Cells - vaguely resemble immature Sertoli cells:
**Bland hyperchromatic oval/round nuclei that are stratified.
 
DDx:<ref name=pmid21107095/>
*[[Sertoli cell tumour]].
*[[Sex cord tumour with annular tubules]].
*[[Gonadoblastoma]].
 
====Images====
<gallery>
Image:Sertoli_cell_nodule_high_mag.jpg | Sertoli cell nodule - high mag. (WC)
Image:Sertoli_cell_nodule_low_mag.jpg | Sertoli cell nodule - low mag. (WC)
</gallery>
===IHC===
Features:<ref name=pmid21107095/>
*Alpha-inhibin +ve (5/5 cases).
*OCT3/4 -ve (5/5 cases).


==Sertoli cell tumour==
==Sertoli cell tumour==
===General===
{{Main|Sertoli cell tumour}}
*Arises from ''Sertoli cells'' ([[AKA]] nurse cells).
 
May be seen in several syndrome - esp. if there is calcification:
*[[Carney complex]].<ref name=pmid21047926>{{Cite journal  | last1 = Libé | first1 = R. | last2 = Horvath | first2 = A. | last3 = Vezzosi | first3 = D. | last4 = Fratticci | first4 = A. | last5 = Coste | first5 = J. | last6 = Perlemoine | first6 = K. | last7 = Ragazzon | first7 = B. | last8 = Guillaud-Bataille | first8 = M. | last9 = Groussin | first9 = L. | title = Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype. | journal = J Clin Endocrinol Metab | volume = 96 | issue = 1 | pages = E208-14 | month = Jan | year = 2011 | doi = 10.1210/jc.2010-1704 | PMID = 21047926 }}</ref>
*[[Peutz-Jeghers syndrome]].
 
===Microscopic===
Features:
*Groups of cells in ''cords'' or ''trabeculae'' (beam-like arrangement).
*Cells have:
**Light staining bubbly cytoplasm +/- large cytoplasmic vacuoles.
**Slightly irregular nucleoli.
**Granular irregular appearing chromatin.
 
Negatives:
*Mitoses are rare.
*No significant nuclear atypia.
 
DDx:
*[[Granulosa cell tumour]] - may be very similar.  Often has nuclear grooves.
*Epithelioid [[adenomatoid tumour]].
*[[Sertoli cell nodule]].
 
====Images====
<gallery>
Image:Sertoli_cell_tumour_high_mag.jpg | Sertoli cell tumour - high mag. (WC)
Image:Sertoli_cell_tumour_low_mag.jpg | Sertoli cell tumour - low mag. (WC)
</gallery>
www:
*[http://path.upmc.edu/cases/case275/micro.html Sertoli cell tumour with calcification in Carney complex - several images (upmc.edu)].
 
===IHC===
*Alpha-inhibin +ve. (???)


=Other=
=Other=
Line 544: Line 352:


==Adenocarcinoma of the rete testis==
==Adenocarcinoma of the rete testis==
===General===
{{Main|Adenocarcinoma of the rete testis}}
*Extremely rare - a few dozen cases in the world literature.<ref name=pmid3799821>{{Cite journal  | last1 = Newbold | first1 = RR. | last2 = Bullock | first2 = BC. | last3 = McLachlan | first3 = JA. | title = Adenocarcinoma of the rete testis. Diethylstilbestrol-induced lesions of the mouse rete testis. | journal = Am J Pathol | volume = 125 | issue = 3 | pages = 625-8 | month = Dec | year = 1986 | doi =  | PMID = 3799821 | PMC = 1888460 | URL = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1888460/?page=1}}</ref>
 
*Possible association of diethylstilbestrol.<ref name=pmid3799821/>
==Testicular adrenal rest tumour==
:Abbreviated ''TART''.
{{Main|Testicular adrenal rest tumour}}
 
==Fibrous pseudotumour of the paratesticular region==
{{Main|Fibrous pseudotumour of the paratesticular region}}


===Microscopic===
==Testicular metastasis==
Features:
{{Main|Testicular metastasis}}
*Adenocarcinoma:
**Tubular or papillary architecture.<ref name=pmid3799821/>
**Columnar cells with cigar-shaped nuclei.


====Images====
<gallery>
Image:Adenocarcinoma_of_the_rete_testis_-_intermed_mag.jpg | Adenocarcinoma of the rete testis - intermed. mag. (WC/Nephron)
Image:Adenocarcinoma_of_the_rete_testis_-_extra_-_high_mag.jpg | Adenocarcinoma of the rete testis - high mag. (WC/Nephron)
</gallery>
=See also=
=See also=
*[[Genitourinary pathology]].
*[[Genitourinary pathology]].
Line 565: Line 370:
*[[Vas deferens]].
*[[Vas deferens]].
*[[Spermatic cord]].
*[[Spermatic cord]].
*[[Paratesticular region]].


=References=
=References=
Line 573: Line 379:


[[Category: Genitourinary pathology]]
[[Category: Genitourinary pathology]]
[[Category: Testis]]

Latest revision as of 19:26, 9 September 2021

Orchiectomy specimen showing testis replaced by tumour (proven to be seminoma). (WC/Ed Uthman)

The testis, plural testes, are important for survival of the species. Tumours occasionally arise in 'em. They generally are not biopsied.

If the testis is biopsied, it is usually for fertility. The cut-up of orchiectomy specimens is dealt with in orchiectomy grossing.

Normal testis

Gross

Anatomy - deep to superficial:

  • Tunica albuginea - fibrous layer.
  • Tunica vaginalis - thin mesothelial layer.
    • This layer is important in the staging of testicular tumours.

Microscopic

Seminiferous tubules

  • Sertoli cells (AKA sustentacular cell AKA nurse cell).
    • Large cells with oval nucleus.
  • Primary spermatocyte.
    • Small cells with dark nucleus on basement membrane.
  • Secondary spermatocyte.
    • Rarely seen on light microscopy.
  • Spermatids.
    • Round small.
    • Usually close to the centre of the lumen.
  • Spermatozoa.
    • You don't see the tail on light microscopy.
Images

  • Seminiferous tubule and sperm - low mag. (WC/Nephron)

  • Seminiferous tubule and sperm - high mag. (WC/Nephron)

  • Benign seminiferous tubules and GCNIS (ITGCN). (WC/Nephron)

Interstitial

Image

  • Leydig cells - very high mag. (WC/Nephron)

Associated structures

  • Epididymis - stores the sperm.
    • Pseudostratified epithelium with cilia.

Image:

Rete testis

Microscopic:

  • Delicate anastomosing channels lined by cuboid epithelium.
Images

  • Rete testis (WC/Nephron)

www:

Appendix of testis

  • Muellerian duct remnant.

Microscopic:

  • Polypoid structure.

Images:

Sign out

TESTICLE, RIGHT, ORCHIECTOMY:
- TESTICLE WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR INTRATUBULAR GERM CELL NEOPLASIA.
- NEGATIVE FOR MALIGNANCY.

Alternate

RIGHT TESTICLE, ORCHIDECTOMY:
- BENIGN TESTIS WITH SPERMATOGENESIS.
- NEGATIVE FOR INTRATUBULAR GERM CELL NEOPLASIA.
- NEGATIVE FOR MALIGNANCY.

Diagnoses (overview)

IHC for GCTs

ABCDs of GCTs:

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

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, round or polygonal nuclear membrane, nucleoli[3] 		CD117 appearance similar to seminoma
GCNIS (WC)
Seminoma fried egg cells fried egg-like cells (central nucleus, clear
cytoplasm) with squared-off nuclear
membrane, nucleoli, lymphocytic infiltrate, granulomata,
syncytiotrophoblastic giant cells[4] 		D2-40 Dysgerminoma = female version of this tumour
Seminoma (WC)
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 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 usu. part of a mixed GCT
Embryonal carcinoma (WC)
Choriocarcinoma marked nuclear atypia cells with clear cytoplasm (cytotrophoblast), multinucleated cells (syncytiotrophoblast) beta-hCG not commonly pure, usu. a component of a mixed GCT
Choriocarcinoma (WC)
Teratoma skin, GI tract-like epithelium skin (epidermis, adnexal structures - sebaceous glands, hair follicles), GI tract-like glands (simple tall columnar epithelium), fat +/-primitive neuroepithelium (pseudostratified epithelium in rosettes) None testicular teratomas in post-pubertal males are all considered malignant[5]
Teratoma (WC)
Spermatocytic tumour (previously spermatocytic seminoma) population of 3 cells pop.: (1) small cell with high NC ratio (mature lymphocyte-like), (2) medium with nucleoli, (3) large cells with filamentous chromatin - few present ? does not arise from GCNIS, no lymphocytic infiltrate (like in seminoma)
Spermatocytic tumour (WC)
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)

Tabular summary of (male) SCSTs

Tumour Key feature Microscopic IHC Other Image
Leydig cell tumour intersitial cell cluster with eosinophilic cytoplasm cytoplasmic vacuolization, uniform nuclei with nucleoli MART-1, calretinin, inhibin +/-Reinke crystals (cylindrical crystalloid eosinophilic cytoplasmic bodies)
Leydig cell tumour (WC)
Sertoli cell tumour cells in cords or trabeculae light staining bubbly cytoplasm +/- large cytoplasmic vacuoles, granular chromatin ? usu. no significant nuclear atypia, no mitoses
Sertoli cell tumour (WC)

Benign

Testicular atrophy

  • AKA atrophic testis.
  • AKA atrophy of the testis.
Main article: Testicular atrophy

Male infertility

Main article: Male infertility

Spermatocele

Main article: Spermatocele

Hydrocele testis

Main article: Hydrocele testis

Idiopathic granulomatous orchitis

Granulomatous orchitis redirects here.

General

  • Rare.
  • Unknown etiology -- possibly trauma + immune reaction to sperm.[6]

Microscopic

Features:[6]

  • Granulomas +/- necrosis.
  • +/-Destruction of seminiferous tubules.
  • Prominent collagen fibrosis.

DDx:

Stains

Testicular scar

Main article: Testicular scar

Testicular abscess

Main article: Testicular abscess

Testicular torsion

Main article: Testicular torsion

Adenomatous hyperplasia of the rete testis

Main article: Adenomatous hyperplasia of the rete testis

Epidermoid cyst of the testis

Main article: Epidermoid cyst of the testis

Testicular trauma

General

  • May lead to orchitectomy.

Gross

  • Hemorrhagic.

Microscopic

Features:

  • Necrotic seminiferous tubules.
  • Intratubular blood in keeping with hemorrhage.

Note:

  • Normal spermatogenesis in background - if viable tissue present.

Sign out

Right Testicle Tissue, Debridement:
     - Hemorrhagic testicular tissue and necrotic seminiferous tubules.
     - Small amount of viable seminiferous tubules with spermatogenesis.
     - NEGATIVE for germ cell neoplasia in situ.
     - NEGATIVE for malignancy.

Comment:
The clinical history of trauma is noted.

Premalignant

Germ cell neoplasia in situ

  • Previously intratubular germ cell neoplasia (abbreviated ITGCN).
Main article: Germ cell neoplasia in situ

Germ cell tumours

Main article: Germ cell tumours

Seminoma

Main article: Seminoma

Spermatocytic tumour

  • Previously spermatocytic seminoma.
Main article: Spermatocytic tumour

Yolk sac tumour

Main article: Yolk sac tumour
  • Most common GCT in infants and young boys.

Microscopic

Classic feature:

  • Schiller-Duval bodies.
    • Look like glomerulus - central blood vessel surrounded by epithelial-like cells a space and more epithelial-like cells
  • Architecure - variable.
    • Most common microcystic pattern.[11]

Embryonal carcinoma

Main article: Embryonal carcinoma

These often look like a poorly differentiated carcinoma.

Choriocarcinoma

Main article: Choriocarcinoma

These are aggressive tumours.

Teratoma of the testis

Main article: Teratoma

In post-pubertal males these (testicular) tumours are considered malignant. They usually consist of all three germ layers.[12]

Sex cord stromal tumours

Leydig cell tumour

  • AKA interstitial cell tumour.
Main article: Leydig cell tumour

Sertoli cell nodule

  • Abbreviated SCN.
  • AKA Pick's adenoma.
  • AKA testicular tubular adenoma.
  • AKA tubular adenoma of the testis.
Main article: Sertoli cell nodule

Sertoli cell tumour

Main article: Sertoli cell tumour

Other

These tumours are rare.

Adenocarcinoma of the rete testis

Main article: Adenocarcinoma of the rete testis

Testicular adrenal rest tumour

Abbreviated TART.
Main article: Testicular adrenal rest tumour

Fibrous pseudotumour of the paratesticular region

Main article: Fibrous pseudotumour of the paratesticular region

Testicular metastasis

Main article: Testicular metastasis

See also

References

  1. ↑ Soper, MS.; Hastings, JR.; Cosmatos, HA.; Slezak, JM.; Wang, R.; Lodin, K. (Dec 2012). "Observation Versus Adjuvant Radiation or Chemotherapy in the Management of Stage I Seminoma: Clinical Outcomes and Prognostic Factors for Relapse in a Large US Cohort.". Am J Clin Oncol. doi:10.1097/COC.0b013e318277d839. PMID 23275274.
  2. ↑ Browne, TJ.; Richie, JP.; Gilligan, TD.; Rubin, MA. (Jun 2005). "Intertubular growth in pure seminomas: associations with poor prognostic parameters.". Hum Pathol 36 (6): 640-5. doi:10.1016/j.humpath.2005.03.011. PMID 16021570.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 6.0 6.1 6.2 6.3 Roy, S.; Hooda, S.; Parwani, AV. (May 2011). "Idiopathic granulomatous orchitis.". Pathol Res Pract 207 (5): 275-8. doi:10.1016/j.prp.2011.02.005. PMID 21458170.
  7. ↑ Sekita, N.; Nishikawa, R.; Fujimura, M.; Sugano, I.; Mikami, K. (Jan 2012). "[Syphilitic orchitis: a case report].". Hinyokika Kiyo 58 (1): 53-5. PMID 22343746.
  8. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 364. ISBN 978-0781765275.
  9. ↑ Parker, SG.; Kommu, SS. (2013). "Post-intravesical BCG epididymo-orchitis: Case report and a review of the literature.". Int J Surg Case Rep 4 (9): 768-70. doi:10.1016/j.ijscr.2013.05.017. PMID 23856256.
  10. ↑ Bulbul, MA.; Hijaz, A.; Beaini, M.; Araj, GF.; Tawil, A.. "Tuberculous epididymo-orchitis following intravesical BCG for superficial bladder cancer.". J Med Liban 50 (1-2): 67-9. PMID 12841318.
  11. ↑ URL: http://webpathology.com/image.asp?case=34&n=1. Accessed on: March 8, 2010.
  12. ↑ Moore, Keith L.; Persaud, T.V.N. (2002). The Developing Human: Clinically Oriented Embryology (7th ed.). Saunders. pp. 83. ISBN 978-0721694122.

External links

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