Testicular cancer pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Gertrude Djouka, M.D.[2], Shanshan Cen, M.D. [3]

## Overview

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The pathophysiology of testicular cancer depends on the histological cell subtypes and findings. Most testicular cancers derived from the lack of differentiation of primordial germ cell into spermatogonia. Germ cells testicular tumor have some genetic component while most sex cord stromal testicular cancer are hormonal dependent. Most gross pathology of testicular tumors look similar on the physical appearance. On microscopic histopathological analysis of testicular cancer, fried-egg appearance is the characteristic finding of seminoma; marked nuclear atypia is the characteristic finding of embryonal carcinoma; hyaline-type globules, and Schiller-Duval bodies are characteristic findings of yolk sac tumor  ; syncytiotrophoblasts and cytotrophoblast cells are the characteristic findings of choriocarcinoma, Polymorphism with"spirene" chromatin for spermatocytic.

## Pathogenesis

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### Normal process of testicular germ cells

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* Normal inner cell mass leads to primordial germ cell mass[1][2]

* Primordial germ cell mass leads to gonocytes through cell proliferation
* Gonocytes differentiate into spermatogonia

### Normal process of testicular sex cord stromal

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#### Leydig cells

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* Leydig cells are found in the seminiferous tubules of the testis.[3][4]
* Leydig cells secrete testosterone hormone under the signal of luteinizing hormone.
* Leydig cells are involved in the development of male secondary sexual characteristics and spermatogenesis.

## Germ cells tumors

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### Germ cell tumors derived from germ cell neoplasia in situ

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* Lack of primordial germ cell to differentiate into spermatogonia leads to germ cell neoplasia in Situ[2]
* Germ cell neoplasia in Situ may gain some abnormal chromosome(12), then it leads to seminomas and nonseminomas cancers.
* Seminomas and non seminotous germ cell tumors have similar pathogenesis.[5][6]
* Aneuploid
* Loss of chromosomes 4,5,11,13,18, and Y
* Gain of chromosomes 7,8,12, and X
* More than 90% of all testicular cancers are germ cell tumors. This type of cancer starts in germ cells, which are the cells that develop into sperms.
* About 50% of all germ cell tumors are seminomas, or seminomatous germ cell tumours. They grow slower than non-seminomas.
* Overrepresentation of short arm of chromosomes 12p may be related to invasive growth of seminomas and nonseminomatous testicular cancer.[7]
* Seminomas tumors may have both genetic and immune components due to lymphocytes infiltration in HIV patients.[8]
* Histological of seminomas tumor in HIV patients: tumor infiltrated by lymphocytes which may lead to weak immune system response.[8]
* Familial contribution:[9]
* Gene on chromosome Xq27 may be related to testicular germ cell tumors
* Some proteins such as C-kit (receptor) and placental-like alkaline phosphatase (PLAP) may be excessively expressed[10]

### Germ cell tumors unrelated to germ cell neoplasia in situ

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* Mutations from the proteins that may be involved in the maturation of the spermatogonia.[11]
* Mostly located in the testis and rarely metastases.
* Mutated proteins involved: SAGE1 and SSX2-4.
* Hypothesis of gain of chromosome 9 may be involved in the process.[12]

## Testicular sex cord stromal tumors

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### Leydig cells tumor

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* The pathogenesis of leydig cells tumors is not well understood.[3][13]
* It is hypothesized that there is a disturbance of hypothalamic-pituitary-testicular axis which lead to excess of hormone productions.
* The G proteins in the leydig cells and the structure alteration of Luteinizing hormone receptors may play role in leydig cells tumors.

### Sertoli cell tumor

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* Sertoli cell arise from testicular supporting cells which regulate the spermatogenesis.
* It may due to excess production of androgen hormone.[14]

### Granulosa cell tumor

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* It involved in hyperestrogenism due to an unregulated aromatase enzyme activity that leads to excessive production of hormones.[15]

## Gross and Microscopic Pathology

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The gross and microscopic features of the most common tumors are described below:[16][17][18][19][20][21][22][19][23][24][25][26][27][3][28][29][15]

Types  | Gross pathology  | Microscopic pathology  | Images

|
|
|

Germ cell neoplasia in situ |

* Solid, fleshy nodules
* Similar to seminoma in appearance
* Well-circumscribed with hemorraghic and necrotic areas

* Hyperchromatic nuclei
* Prominent nucleoli and clear cytoplasm
* Thickened basement menbrane
* Proliferation of tumor germ cell in the seminiferous tubules

| Contributed by Nephron in wikimedia.commons
Seminoma |

* Solid, firm without cross section

* Solid fleshy tan to yellow mass in homogeneous appearance
* Well-circumscribed with small hemorraghic and necrotic areas

* Large nucleoli with clear to pale to eosinophilic cytoplasm due to the presence of glycogen
* Clonal proliferation of neoplastic germ cells
* Fried-egg appearance
* Prominent mitotic figures
* Nests and sheets of cancer cells with "squared-off" nuclei
* Granulomatous inflammation

| Contributed by Nephron in wikimedia.commons
Embryonal carcinoma |

* Poorly demarcated mass
* Soft gray on cut surface
* Large hemorraghic and necrotic foci.

* Presents with mixed histological features (solid, papular, glandular)
* Marked nuclear atypia
* Marked epithelial cells with polymorphism
* Large nuclei with abundant amphophilic cytoplasm
* Prominent mitotic activities

| Contributed by Nephron in wikimedia.commons
Yolk sac tumor |

* Solid, lobulated, soft, mucinous on cut surface
* Gray and grayish yellow mass

* May have small hemorrhagic and necrotic foci
* Heterogenous mass

* Hyaline-type globules
* Schiller-Duval bodies
* Multiple histological patterns such as recticular, microcystic, glandular, papillary, hepatoid, and solid
* Associated with myxoid stroma
* Variable cytologic atypia

| Contributed by EDDAOUALLINE Hanane in wikimedia.commons
Choriocarcinoma |

* Hemorrhagic and necrotic nodules
* May appear more cystic and calcified in homogeneous

* More Hemorrhagic and necrotic
* Made up of mononucleated trophoblast and multinucleated syncytiotrophoblast cells
* Hyperchomatic cytoplasm

| Contributed by Nephron in wikimedia.commons
Teratoma, postpubertal-type  |

* Hetereogenous, cystic and irregular calcification on appearance
* Solid, firm mass

* Arrange in disorder fashion
* Cytologic atypia
* High mitotic activities
* Presence of 3 germ cells layers
* Presence of immature elements with primitive nuclei

| Contributed by Nephron in wikimedia.commons
Mixed germ cell tumors |

* Solid and cystic mass
* More hemorhragic and necrotic.

* Microscopic findings are variable depending on the tumor type
* May have the component of yolk sac and choriocarcinoma

| Contributed by Nephron in wikimedia.commons
Spermatocytic tumor |

* Soft, gray, and gelatinous mass
* Well circumscribed with small hemorrhagic and necrotic foci.

* Atyical mitoses activities
* Eosinophilic cytoplasm without glycogen
* Tumors cells with three different sizes (small, intermediate, and large)
* Polymorphism with"spirene" chromatin find in the giant cells
* Frequent apoptosis

| Contributed by Nephron in wikimedia.commons
Teratoma, prepubertal-type,

Desmoid cyst

Epidermoid cyst

* Solid and firm mass

* Lack of cytologic atypia
* No mitotic activities
* Absence of immature elements
* Desmoid cyst has polosebaceous cells
* Epidermoist cyst is surrounded with squamous epithelial cells

| Contributed by Nephron in wikimedia.commons
Testicular lymphoma |

* Soft, gray, and gelatinous mass
* Well circumscribed with small hemorrhagic and necrotic foci.

* Vascular invasion
* Pleomorphic tumor cells
* Large irregular nuclei

| Contributed by Nephron in wikimedia.commons
Leydig cells tumor |

* Homogeneous and well circumscribed mass

* Solitary and unilateral mass
* White to brown to yellow on cut surface

* Cells are arranged in nest, sheets polygonal fahsion
* Cytoplasm is eosinophilic with round nuclei and prominent nucleoli
* Presence of lipofuscin pigment and reinke crystal intracytoplasmic

| Contributed by Nephron in wikimedia.commons
Sertoli tumor |

* Homogeneous and well circumscribed mass

* White to grey on cut surface

* Cells are arranged in cords, nests and lobulated tubules
* Fibrous stroma ans septa with lymphocytes
* Elongated spaces and microscysts
* Pale lipid- rich cytoplasm
* No prominent nucleoli

| Contributed by Nephron in wikimedia.commons
Granulosa tumor |

Adult type

* No distint feature

Juvenile type

* Solid, nodule yellow-orange and cystic mass

Adult type

* Cells are arranged in elongated, microfollicular "call-Exner bodies"

Juvenile type

* Cells are presented in solid sheets and nodules and form the estatic space
* Eosinophilic cytoplasm
* Hyperchromatic, round to oval nuclei
* High mitotic activities
* Follicles are located on the periphery

| Contributed by Nephron in wikimedia.commons

## Genetics

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These are genes involved in the pathogenesis of testicular cancer:[30][31]

* Chromosome 12p
* 12q22.2

## Immunohistochemical Markers

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* Germ cell neoplastic in situ:
* +PLAP (Placenta like-alkaline phosphatase)[32]
* Seminomas:[21][33][34]
* OCT3/4 transcription factors[35]
* C-kit
* CD30
* D2-40 monoclonal antibody
* PLAP
* NANOG transcription factor

* Embryonal carcinoma:[33][34]
* PLAP
* OCT3/4[35]
* SOX2
* CD30
* +/-GpC3,keratin

* Yolk sac tumor:[12][36]
* +SALL4
* +AFP
* +GATA3
* +Glypican3
* +Keratin
* +/-C-kit

* Choriocarcinoma:[12]
* +Ck7
* +GATA3
* +HCG
* +/-SALL4

* Spermatocytic tumor:[12]
* +SALL4
* +/-C-kit

* Teratoma:[23][37][12]
* +SALL4
* +Cytokeratin
* +HCG
* +/-GATA3,SOX2,OCT4

* Testicular lymphoma:[12]
* +CD3
* +CD20
* +CD45

* Leydig cell tumor:[3][38]
* +Inhibin
* +Calretinin
* +Melan-A
* +Vimentin

* Sertoli cell tumor:[29][38][3]
* +Inhibin
* +Vimentin
* +EMA (epithelial menbrane antigen)
* +/-Cytokeratin

* Granulosa cell tumor:[39][29][40]
* +Inhibin
* +Calretinin
* +Vimentin

## References

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1. ↑ Miyai, Kosuke; Ito, Keiichi; Nakanishi, Kuniaki; Tsuda, Hitoshi (2019). "Seminoma component of mixed testicular germ cell tumor shows a higher incidence of loss of heterozygosity than pure-type seminoma". Human Pathology. 84: 71–80. doi:10.1016/j.humpath.2018.09.007. ISSN 0046-8177.
2. ↑ 2.0 2.1 Kraggerud SM, Hoei-Hansen CE, Alagaratnam S, Skotheim RI, Abeler VM, Rajpert-De Meyts E, Lothe RA (June 2013). "Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: implications for pathogenesis". Endocr. Rev. 34 (3): 339–76. doi:10.1210/er.2012-1045. PMC 3787935. PMID 23575763.
3. ↑ 3.0 3.1 3.2 3.3 3.4 Al-Agha OM, Axiotis CA (February 2007). "An in-depth look at Leydig cell tumor of the testis". Arch. Pathol. Lab. Med. 131 (2): 311–7. doi:10.1043/1543-2165(2007)131[311:AILALC]2.0.CO;2. PMID 17284120.
4. ↑ Neaves WB (May 1975). "Leydig cells". Contraception. 11 (5): 571–606. PMID 1095296.
5. ↑ Bray F, Richiardi L, Ekbom A, Forman D, Pukkala E, Cuninkova M, Møller H (April 2006). "Do testicular seminoma and nonseminoma share the same etiology? Evidence from an age-period-cohort analysis of incidence trends in eight European countries". Cancer Epidemiol. Biomarkers Prev. 15 (4): 652–8. doi:10.1158/1055-9965.EPI-05-0565. PMID 16614105.
6. ↑ Linke J, Loy V, Dieckmann KP (May 2005). "Prevalence of testicular intraepithelial neoplasia in healthy males". J. Urol. 173 (5): 1577–9. doi:10.1097/01.ju.0000154348.68575.95. PMID 15821489.
7. ↑ Rosenberg C, Van Gurp RJ, Geelen E, Oosterhuis JW, Looijenga LH (November 2000). "Overrepresentation of the short arm of chromosome 12 is related to invasive growth of human testicular seminomas and nonseminomas". Oncogene. 19 (51): 5858–62. PMID 11127816.
8. ↑ 8.0 8.1 Powles T, Bower M, Daugaard G, Shamash J, De Ruiter A, Johnson M, Fisher M, Anderson J, Mandalia S, Stebbing J, Nelson M, Gazzard B, Oliver T (May 2003). "Multicenter study of human immunodeficiency virus-related germ cell tumors". J. Clin. Oncol. 21 (10): 1922–7. doi:10.1200/JCO.2003.09.107. PMID 12743144.
9. ↑ Rapley, Elizabeth A.; Crockford, Gillian P.; Teare, Dawn; Biggs, Patrick; Seal, Sheila; Barfoot, Rita; Edwards, Sandra; Hamoudi, Rifat; Heimdal, Ketil; Fosså, Sophie D.; Tucker, Kathy; Donald, Jenny; Collins, Felicity; Friedlander, Michael; Hogg, David; Goss, Paul; Heidenreich, Axel; Ormiston, Wilma; Daly, Peter A.; Forman, David; Oliver, Timothy D.; Leahy, Michael; Huddart, Robert; Cooper, Colin S.; Bodmer, Julia G.; Easton, Douglas F.; Stratton, Michael R.; Bishop, D. Timothy (2000). "Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours". Nature Genetics. 24 (2): 197–200. doi:10.1038/72877. ISSN 1061-4036.
10. ↑ Hoei-Hansen CE, Rajpert-De Meyts E, Daugaard G, Skakkebaek NE (June 2005). "Carcinoma in situ testis, the progenitor of testicular germ cell tumours: a clinical review". Ann. Oncol. 16 (6): 863–8. doi:10.1093/annonc/mdi175. PMID 15821122.
11. ↑ Looijenga LH (August 2011). "Spermatocytic seminoma: toward further understanding of pathogenesis". J. Pathol. 224 (4): 431–3. doi:10.1002/path.2939. PMID 21725972.
12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 Howitt BE, Berney DM (December 2015). "Tumors of the Testis: Morphologic Features and Molecular Alterations". Surg Pathol Clin. 8 (4): 687–716. doi:10.1016/j.path.2015.07.007. PMID 26612222.
13. ↑ Conkey DS, Howard GC, Grigor KM, McLaren DB, Kerr GR (August 2005). "Testicular sex cord-stromal tumours: the Edinburgh experience 1988-2002, and a review of the literature". Clin Oncol (R Coll Radiol). 17 (5): 322–7. PMID 16097561.
14. ↑ Dilworth, J. Patrick; Farrow, George M.; Oesterling, Joseph E. (1991). "Non-germ cell tumors of testis". Urology. 37 (5): 399–417. doi:10.1016/0090-4295(91)80100-L. ISSN 0090-4295.
15. ↑ 15.0 15.1 Jimenez-Quintero LP, Ro JY, Zavala-Pompa A, Amin MB, Tetu B, Ordoñez NG, Ayala AG (October 1993). "Granulosa cell tumor of the adult testis: a clinicopathologic study of seven cases and a review of the literature". Hum. Pathol. 24 (10): 1120–5. PMID 8406422.
16. ↑ Boccellino M, Vanacore D, Zappavigna S, Cavaliere C, Rossetti S, D'Aniello C, Chieffi P, Amler E, Buonerba C, Di Lorenzo G, Di Franco R, Izzo A, Piscitelli R, Iovane G, Muto P, Botti G, Perdonà S, Caraglia M, Facchini G (November 2017). "Testicular cancer from diagnosis to epigenetic factors". Oncotarget. 8 (61): 104654–104663. doi:10.18632/oncotarget.20992. PMC 5732834. PMID 29262668.
17. ↑ Howitt BE, Berney DM (December 2015). "Tumors of the Testis: Morphologic Features and Molecular Alterations". Surg Pathol Clin. 8 (4): 687–716. doi:10.1016/j.path.2015.07.007. PMID 26612222.
18. ↑ Siegel RL, Miller KD, Jemal A (2016). "Cancer statistics, 2016". CA Cancer J Clin. 66 (1): 7–30. doi:10.3322/caac.21332. PMID 26742998.
19. ↑ 19.0 19.1 Krag Jacobsen G, Barlebo H, Olsen J, Schultz HP, Starklint H, Søgaard H; et al. (1984). "Testicular germ cell tumours in Denmark 1976-1980. Pathology of 1058 consecutive cases". Acta Radiol Oncol. 23 (4): 239–47. PMID 6093440.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
20. ↑ Emerson RE, Cheng L (April 2013). "Premalignancy of the testis and paratestis". Pathology. 45 (3): 264–72. doi:10.1097/PAT.0b013e32835f3e1a. PMID 23478232.
21. ↑ 21.0 21.1 Boccellino M, Vanacore D, Zappavigna S, Cavaliere C, Rossetti S, D'Aniello C, Chieffi P, Amler E, Buonerba C, Di Lorenzo G, Di Franco R, Izzo A, Piscitelli R, Iovane G, Muto P, Botti G, Perdonà S, Caraglia M, Facchini G (November 2017). "Testicular cancer from diagnosis to epigenetic factors". Oncotarget. 8 (61): 104654–104663. doi:10.18632/oncotarget.20992. PMC 5732834. PMID 29262668.
22. ↑ Talerman A, Haije WG, Baggerman L (1980). "Serum alphafetoprotein (AFP) in patients with germ cell tumors of the gonads and extragonadal sites: correlation between endodermal sinus (yolk sac) tumor and raised serum AFP". Cancer. 46 (2): 380–5. PMID 6155988.CS1 maint: Multiple names: authors list (link)
23. ↑ 23.0 23.1 Simmonds PD, Lee AH, Theaker JM, Tung K, Smart CJ, Mead GM (March 1996). "Primary pure teratoma of the testis". J. Urol. 155 (3): 939–42. PMID 8583612.
24. ↑ Shahab N, Doll DC (June 1999). "Testicular lymphoma". Semin. Oncol. 26 (3): 259–69. PMID 10375083.
25. ↑ Chuang KL, Liaw CC, Ueng SH, Liao SK, Pang ST, Chang YH, Chuang HC, Chuang CK (March 2010). "Mixed germ cell tumor metastatic to the skin: case report and literature review". World J Surg Oncol. 8: 21. doi:10.1186/1477-7819-8-21. PMC 2851696. PMID 20331874.
26. ↑ Ramón y Cajal S, Piñango L, Barat A, Moldenhauer F, Oliva H (March 1987). "Metastatic pure choriocarcinoma of the testis in an elderly man". J. Urol. 137 (3): 516–9. PMID 3820391.
27. ↑ Wei Y, Wu S, Lin T, He D, Li X, Liu J, Liu X, Hua Y, Lu P, Wei G (December 2014). "Testicular yolk sac tumors in children: a review of 61 patients over 19 years". World J Surg Oncol. 12: 400. doi:10.1186/1477-7819-12-400. PMC 4326497. PMID 25547829.
28. ↑ Cheville JC, Sebo TJ, Lager DJ, Bostwick DG, Farrow GM (November 1998). "Leydig cell tumor of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of nonmetastasizing and metastasizing tumors". Am. J. Surg. Pathol. 22 (11): 1361–7. PMID 9808128.
29. ↑ 29.0 29.1 29.2 Young RH (February 2005). "Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems". Mod. Pathol. 18 Suppl 2: S81–98. doi:10.1038/modpathol.3800311. PMID 15502809.
30. ↑ van Echten J, Oosterhuis JW, Looijenga LH, van de Pol M, Wiersema J, te Meerman GJ, Schaffordt Koops H, Sleijfer DT, de Jong B (October 1995). "No recurrent structural abnormalities apart from i(12p) in primary germ cell tumors of the adult testis". Genes Chromosomes Cancer. 14 (2): 133–44. PMID 8527395.
31. ↑ Bosl GJ, Motzer RJ (July 1997). "Testicular germ-cell cancer". N. Engl. J. Med. 337 (4): 242–53. doi:10.1056/NEJM199707243370406. PMID 9227931.
32. ↑ Jacobsen GK, Nørgaard-Pedersen B (September 1984). "Placental alkaline phosphatase in testicular germ cell tumours and in carcinoma-in-situ of the testis. An immunohistochemical study". Acta Pathol Microbiol Immunol Scand A. 92 (5): 323–9. PMID 6209917.
33. ↑ 33.0 33.1 Santagata S, Ligon KL, Hornick JL (June 2007). "Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors". Am. J. Surg. Pathol. 31 (6): 836–45. doi:10.1097/PAS.0b013e31802e708a. PMID 17527070.
34. ↑ 34.0 34.1 Cheng L, Sung MT, Cossu-Rocca P, Jones TD, MacLennan GT, De Jong J, Lopez-Beltran A, Montironi R, Looijenga LH (January 2007). "OCT4: biological functions and clinical applications as a marker of germ cell neoplasia". J. Pathol. 211 (1): 1–9. doi:10.1002/path.2105. PMID 17117392.
35. ↑ 35.0 35.1 de Jong J, Stoop H, Dohle GR, Bangma CH, Kliffen M, van Esser JW, van den Bent M, Kros JM, Oosterhuis JW, Looijenga LH (June 2005). "Diagnostic value of OCT3/4 for pre-invasive and invasive testicular germ cell tumours". J. Pathol. 206 (2): 242–9. doi:10.1002/path.1766. PMID 15818593.
36. ↑ Cao D, Humphrey PA, Allan RW (June 2009). "SALL4 is a novel sensitive and specific marker for metastatic germ cell tumors, with particular utility in detection of metastatic yolk sac tumors". Cancer. 115 (12): 2640–51. doi:10.1002/cncr.24308. PMID 19365862.
37. ↑ Brosman SA (June 1979). "Testicular tumors in prepubertal children". Urology. 13 (6): 581–8. PMID 377749.
38. ↑ 38.0 38.1 Iczkowski KA, Bostwick DG, Roche PC, Cheville JC (August 1998). "Inhibin A is a sensitive and specific marker for testicular sex cord-stromal tumors". Mod. Pathol. 11 (8): 774–9. PMID 9720507.
39. ↑ Ditonno P, Lucarelli G, Battaglia M, Mancini V, Palazzo S, Trabucco S, Bettocchi C, Paolo Selvaggi F (2007). "Testicular granulosa cell tumor of adult type: a new case and a review of the literature". Urol. Oncol. 25 (4): 322–5. doi:10.1016/j.urolonc.2006.08.019. PMID 17628299.
40. ↑ McCluggage WG, Shanks JH, Whiteside C, Maxwell P, Banerjee SS, Biggart JD (May 1998). "Immunohistochemical study of testicular sex cord-stromal tumors, including staining with anti-inhibin antibody". Am. J. Surg. Pathol. 22 (5): 615–9. PMID 9591732.

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