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

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. 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; blander cytomorphology, hyaline-type globules, and Schiller-Duval bodies are characteristic findings of yolk sac tumor  ; syncytiotrophoblasts and cytotrophoblast cells are the characteristic findings of choriocarcinoma.

Pathogenesis

Normal process

  • 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

Germ cells tumors

Germ cell tumors derived from germ cell neoplasia in situ

  • 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[3][4]
  • 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.[5]
  • Seminomas tumors may have both genetic and immune components due to lymphocytes infiltration in HIV patients.[6]
  • Histological of seminomas tumor in HIV patients: tumor infiltrated by lymphocytes which may lead to weak immune system response.[6]
  • familial contribution:[7]
    • 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[8]

Germ cell tumors unrelated to germ cell neoplasia in situ

  • Mutations from the proteins that may be involved in the maturation of the spermatogonia.[9]
  • Mostly located in the testis and rarely metastases
  • Mutated proteins invovloved:SAGE1 and SSX2-4
  • Hypothesis of gain of chromosome 9 may be involved in the process[10]

Gross and Microscopic Pathology

The gross and microscopic features of the most common tumors are described below:[11][12][13][14][15][16][17][14][18][19][20][21][22]

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 york salk 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 activiyies
  • 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

Genetics

Immunohistochemical Markers

Germ cell Neoplastic in situ:

  • +PLAP (Placenta like-alkaline phosphatase)[23]

Seminomas

Stain positively for:[16][24][25]

  • OCT3/4 transcription factors[26]
  • C-kit
  • CD30
  • D2-40 monoclonal antibody
  • PLAP
  • NANOG transcription factor

Embryonal carcinoma

Stain positively for:[24][25]

  • PLAP
  • OCT3/4[26]
  • SOX2
  • CD30
  • +/-GpC3,keratin

Yolk sac tumor:[10][27]

  • +SALL4
  • +AFP
  • +GATA3
  • +Glypican3
  • +Keratin
  • +/-C-kit

Choriocarcinoma:[10]

  • +Ck7
  • +GATA3
  • +HCG
  • +/-Sall4

Spermatocytic tumor:[10]

  • +Sall4
  • +/-C-kit

Teratoma:[18][28][10]

  • +Sall4
  • +Cytokeratin
  • +HCG
  • +/-GATA3,SOX2,OCT4

Testicular lymphoma:[10]

  • +CD3
  • +CD20
  • +CD45

References

  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. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 6.0 6.1 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Looijenga LH (August 2011). "Spermatocytic seminoma: toward further understanding of pathogenesis". J. Pathol. 224 (4): 431–3. doi:10.1002/path.2939. PMID 21725972.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 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.
  11. ↑ 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.
  12. ↑ 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. ↑ 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.
  14. ↑ 14.0 14.1 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.
  15. ↑ Emerson RE, Cheng L (April 2013). "Premalignancy of the testis and paratestis". Pathology. 45 (3): 264–72. doi:10.1097/PAT.0b013e32835f3e1a. PMID 23478232.
  16. ↑ 16.0 16.1 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.
  17. ↑ 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.
  18. ↑ 18.0 18.1 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.
  19. ↑ Shahab N, Doll DC (June 1999). "Testicular lymphoma". Semin. Oncol. 26 (3): 259–69. PMID 10375083.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 24.0 24.1 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.
  25. ↑ 25.0 25.1 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.
  26. ↑ 26.0 26.1 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.
  27. ↑ 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.
  28. ↑ Brosman SA (June 1979). "Testicular tumors in prepubertal children". Urology. 13 (6): 581–8. PMID 377749.


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