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:

Types Gross pathology Microscopic pathology Images
Germ cell neoplasia in situ
  • Normal size, but can be small
  • It is characterised by densely cellular sheets of cells with scant cytoplasm imparting a ‘small blue cell tumour’ appearance
  • Small cavities called Call–Exner bodies that may contain eosinophilic fluid, degenerating nuclei, hyalinised basement membrane material, or rarely basophilic fluid are seen
  • The presence of nuclear grooves and Call–Exner bodies are often considered to be pathognomonic of AGCTs
Seminoma
  • They are solid/cystic on cut sections
  • The solid areas show a tan-yellow or greyish appearance with foci of haemorrhage and/or necrosis
  • The cysts have serous or haemorrhagic contents
  • Shows a nodular or diffuse proliferation of cells embedded in an oedematous or myxoid stroma
  • Follicle-like spaces of varying sizes and shapes, containing eosinophilic or basophilic secretions, is a characteristic feature
  • Call–Exner bodies are almost never seen
Embryonal carcinoma
  • They are usually solid and yellow
  • They are characterized by simple and complex annular (ring-shaped) tubules often with calcification
  • They show tubules with Sertoli cells arranged around one or more hyaline bodies
  • These tubules may be scattered and admixed with normal ovarian tissue rather than forming a distinct mass especially, in patients with Peutz-Jegher syndrome
Yolk sac tumor, postpubertal-type
  • They are solid, lobulated, yellow on cut surfaces
  • Retiform tumours have a spongy sectioned surface
  • Poorly differentiated tumours may be extensively haemorrhagic and necrotic
  • Well differentiated tumours are characterised by Sertoli cells in a predominantly tubular pattern, and Leydig cells in the intervening stroma
  • Tumours of intermediate differentiation often show a striking so-called alveolar pattern of Sertoli cells with pale cytoplasm
  • Poorly differentiated tumors are usually dominantly sarcomatoid
  • Retiform tumors shows elongated tubules and the stroma is focally somewhat hyalinised
  • Heterologous elements include mucinous epithelial glands or rhabdomyosarcomatous and/or chondrosarcomatous elements
Choriocarcinoma
  • They are mostly solid masses with yellowish foci, edema, and cystic areas
  • A pseudolobular pattern, admixed spindled and rounded weakly luteinised cells,
  • Prominent typically ectatic branching staghorn-like blood vessels
Teratoma, postpubertal-type
  • They are bilateral with abnormal in appearance due to a hypercerebriform contour
  • often large masses having a beefy appearance with oedema and cyst formation
  • Microcytic change within the cellular neoplasm composed of admixed, spindled, and weakly luteinised cells
  • Normal ovarian elements are often present between the proliferating spindle cells
Mixed germ cell tumors
  • They are solid and cystic with solid tissue that is tan to white to rarely yellow.
  • The microscopic appearance consists of three components:
  • Microcysts (present in 60% of cases)
  • Solid cellular areas
  • Hyalinised fibrous stroma
  • The microcystic pattern is characterised by small round to oval cystic spaces, focally coalescing into larger irregular channels; intracytoplasmic vacuoles are also common
  • The solid cellular areas are usually intersected by fibrous bands and hyalineplaques
Spermatocytic tumor
  • They are solid ovarian tumors
Teratoma, prepubertal-type
  • They appear yellow on solid sectioned surface
Yolk sac tumor, prepubertal-type
  • They are large unilateral masses, often with necrosis and hemorrhage
  • Fibromas with increased cellularity and cell proliferation (mitotic activity)
  • They follow a malignant course

Germ cell Tumors[11]

  • Clonal proliferation of neoplastic germ cells
  • Fried-egg appearance
  • Non-seminomas
  • Marked nuclear atypia
  • Blander cytomorphology
  • Hyaline-type globules
  • Schiller-Duval bodies
  • Both syncytiotrophoblasts and cytotrophoblast cells
  • Hyperchromatic nuclei
  • Prominent nucleoli
  • Intact basement menbrane.

Genetics

Genes involved in the pathogenesis of testicular cancer.

  • 4q22
  • 7q22
  • 16q22.3
  • 17q22

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. ↑ 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. ↑ 11.0 11.1 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.
  12. ↑ 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.
  13. ↑ Emerson RE, Cheng L (April 2013). "Premalignancy of the testis and paratestis". Pathology. 45 (3): 264–72. doi:10.1097/PAT.0b013e32835f3e1a. PMID 23478232.
  14. ↑ 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.


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