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testicular germ cell tumors

Tuesday 13 June 2006

Digital case

- JRC:12774 : Classical seminoma.

Definition: Testicular germ cell tumors (TGCTs) are the most frequent solid tumor to affect young adult males and are histologically divided into seminomas and non-seminomas (NSTGCTs).

NSTGCTs comprise undifferentiated embryonal carcinoma (EC) and differentiated tumors with embryonic (teratoma) or extra-embryonic (choriocarcinoma, yolk sac tumor) features.

Testicular germ cell tumors of adolescents and adults (TGCTs; the so-called type 2 variant) are the most frequent malignancies found in Caucasian males between 20 and 40 years of age. The incidence has increased over the last decades.

TGCTs are divided into seminomas and non-seminomas, the latter consisting of the subgroups embryonal carcinoma, yolk-sac tumor, teratoma, and choriocarcinoma.

The pathogenesis starts in utero, involving primordial germ cells/gonocytes that are blocked in their differentiation, and develops via the precursor lesion carcinoma in situ toward invasiveness.

TGCTs are totipotent and can be considered as stem cell tumors. The developmental capacity of their cell of origin, the primordial germ cells/gonocyte, is demonstrated by the different tumor histologies of the invasive TGCTs.

Seminoma represents the germ cell lineage, and embryonal carcinoma is the undifferentiated component, being the stem cell population of the nonseminomas.

Somatic differentiation is seen in the teratomas (all lineages), whereas yolk-sac tumors and choriocarcinoma represent extra-embryonal differentiation.

Seminomas are highly sensitive to irradiation and (DNA damaging) chemotherapy, whereas most nonseminomatous elements are less susceptible to radiation, although still sensitive to chemotherapy, with the exception of teratoma.

To allow early diagnosis and follow up, appropriate markers are mandatory to discriminate between the different subgroups.

Epidemiology

Testicular Germ Cell Tumor (TGCT) is the most common malignant tumor in young Caucasian men with an annual increase of 3–6% in the past 50 years.

Testicular Germ Cell Tumor (TGCT) is the most common malignant tumor—accounting for up to 60% of all malignancies— in young Caucasian men aged between 20 and 40 years.

Clinically and histologically they are divided into seminomas and nonseminomas.

The worldwide incidence of TGCTs is between 6–11 per 100,000, with significant variation. It has more than doubled in the past 50 years with an annual increase of 3–6%.

Epidemiological associations suggest that TGCTs are associated with other reproductive disorders, including hypospadias, cryptorchidism and impaired
sperm production.

Therefore, these conditions may share, in part, a common aetiology and this has given rise to the term “testicular dysgenesis syndrome”.

The TDS hypothesis proposes that abnormal gonadal development (dysgenesis) along the male lineage, which can have numerous primary causes, leads secondarily to disturbed Sertoli—and Leydig cell function, resulting in reproductive disorders.

Types

Testicular germ cell tumors are divided into two broad categories, seminoma and nonseminomatous germ cell tumors (NSGCTs), which are theorized to arise from the seminomatous epithelium (germinal epithelium) of the testis.

Tumors containing both of the major types exist, and it is probably best to call these "mixed seminoma and NSGCT," with the type or a list of the types of NSGCT present and their approximate percentages.

The type of NSTGCTs, particularly choriocarcinoma (which has an aggressive course), determines the prognosis in these cases. Seminomas (the male analogue of the ovarian dysgerminoma) comprise 30-40% of all testicular tumors, and are divided into the classic and spermatocytic catagories.

- testicular teratomas

  • testicular mature teratoma
  • testicular immature teratoma

- testicular seminoma
- non-seminomatous Testicular germ cell tumors (NSTGCTs)

  • testicular yolk sac tumor
  • testicular embryonic carcinoma
  • testicular choriocarcinoma
  • malignant mixed germ cell tumor

Variants

- Wilms tumor (nephroblastoma) in a testicular germ cell tumor (15105660)
- embryonal rhabdomyosarcoma in a testicular germ cell tumor
- familial testicular germ cell tumor (15803215)
- progression to angiosarcoma (19836053)

Association

- Hodgkin disease
- colorectal adenocarcinoma

Evolution

- metastasis
- spontaneous regression (16819328)

  • Spontaneous regression of testicular germ cell tumors (GCTs) is a well-recognized phenomenon but has been incompletely characterized. Many pathologists are not familiar with the findings that support a diagnosis of a "burnt-out" primary in a patient with metastatic GCT. (16819328)
  • Primitive germ cell tumors of the testis (but not those of the ovary) occasionally exhibit a remarkable phenomenon, spontaneous regression, the typical scenario being a patient who presents with metastatic disease with a clinically inapparent primary but who has at least ’ghost’ evidence of pre-existing tumor on pathologic examination of the testis.
  • In classic examples of this enigmatic phenomenon, there is no identifiable invasive neoplasm on microscopic examination but just dense, often hyaline scarring, sometimes with IGCNU in adjacent tubules.
  • In an autopsy study, about 10% of patients who died of metastatic testicular germ cell tumors had such ’burnt-out’ primary tumors.
  • Features that are helpful in establishing a diagnosis of a regressed testicular germ cell tumor include, apart from the scar formation, intratubular calcifications, IGCNU, a lymphoplasmacytic infiltrate, hemosiderin-containing macrophages, and testicular atrophy.
  • In many cases, the scarred focus still has residual, hyalinized tubular outlines, which therefore should not be misconstrued as evidence for a non-neoplastic scarring process.
  • It is likely that such tubular remnants within scars reflect regression of intertubular growth of pre-existing germ cell tumor, a relatively frequent focal pattern in seminoma.
  • That the scarring represents ’burnt-out’ neoplasm is supported by the fact that in many cases there is residual, viable tumor that is focally or extensively undergoing this retrogressive, scarring process.
  • While choriocarcinoma is probably the tumor that is most prone to spontaneous regression, seminoma is also susceptible and is responsible for the greatest number of cases, given its much greater frequency.
  • This phenomenon may also be seen with embryonal carcinoma in which instance coarse intratubular calcification may be a clue to the prior presence of viable neoplasia of that type.

Immunochemistry

- SALL4 is a diagnostic marker for testicular germ cell tumors. (19390421)
- c-kit
- OCT-3/4

Genetics

Testicular germ cell tumor (TGCT) is the most common cancer in young men and is notable for its high familial risks.

One significant genetic risk factor has been reported, the so called “gr/gr” deletion of the Y chromosome which still request further confirmation by independent studies.

A team identified SNPs at nine new loci (1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22 and 21q22.3) showing association with TGCT (P < 5 × 10-8), which together account for an additional 4-6% of the familial risk of TGCT. (23666240)

The loci include genes plausibly related to TGCT development (23666240):
- PRDM14, at 8q13.3, is essential for early germ cell specification, and
- DAZL, at 3p24.3, is required for the regulation of germ cell development.

Furthermore, PITX1, at 5q31.1, regulates TERT expression and is the third TGCT-associated locus implicated in telomerase regulation.

Cytogenetics

Testicular germ cell tumors of adolescent and young adult men (TGCTs) generally have near triploid and complex karyotypes.

- 12p rearrangements

  • gain of 12p sequences
  • isochromosome i(12p)

CGH (17167184, 14697636)

CGH gains

- 1q gains (14697636)
- 12p gain
- 7p15.2 gain (17167184)
- 21q22.2 gain (17167184)
- 6p21.33 gain (21213372)
- 10q11.21 gain (21213372)
- 20q gains (14697636)
- 22q13.32 gain (21213372)
- Chr.X gain (14697636)

CGH losses

- 4p16.3 loss (17167184)
- Chr.4 loss (14697636)
- Chr.18 loss (14697636)
- 2q loss (14697636)
- 9q loss (14697636)
- 13q loss (14697636)
- 22q13.3 loss (17167184)
- 22q12.2 loss (21213372)

Highly over-expressed genes

- CCND2, CD9, GAPD, GDF3, NANOG, and TEAD4 (17167184)

Integration of DNA copy number information to gene expression profiles

- BRCC3, FOS, MLLT11, NES, and RAC1 may act as novel oncogenes in TGCT. (17167184)

Underexpressed genes

- DDX26, ERCC5, FZD4, NME4, OPTN, and RB1 were both lost and under-expressed genes, and are putative TGCT suppressor genes. (17167184)

DNA methylation

- Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer. (20051947)

  • Several candidate genes, APOLD1, PCDH10 and RGAG1, dysregulated in TGCT.
  • APOLD1 had previously been mapped to the TGCT susceptibility locus at 12p13.1, suggesting that it may be important in TGCT pathogenesis.
  • Aberrant methylation in the loci of some non-coding RNAs (ncRNAs).
  • One of the ncRNAs, hsa-mir-199a, was downregulated in TGCT patient samples.

Gene variants

- Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. (20543847)

  • Genome-wide association study (GWAS)
  • three new susceptibility loci (two of which include genes involved in telomere regulation)
  • ATF7IP is a regulator of TERT expression.
  • Locus on chromosome 9, containing the sex determination gene DMRT1, which has been linked to teratoma susceptibility in mice.

See also

- germ cell tumors

Open access references

- Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Ulbright TM. Mod Pathol. 2005 Feb;18 Suppl 2:S61-79. PMID: 15761467

References

Molecular biology

- Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Ruark E, Seal S, McDonald H, Zhang F, Elliot A, Lau K, Perdeaux E, Rapley E, Eeles R, Peto J, Kote-Jarai Z, Muir K, Nsengimana J, Shipley J; UK Testicular Cancer Collaboration (UKTCC), Bishop DT, Stratton MR, Easton DF, Huddart RA, Rahman N, Turnbull C. Nat Genet. 2013 May 12. doi : 10.1038/ng.2635 PMID: 23666240

- Dissecting the molecular pathways of (testicular) germ cell tumour pathogenesis; from initiation to treatment-resistance. Looijenga LH, Gillis AJ, Stoop H, Biermann K, Oosterhuis JW. Int J Androl. 2011 Aug;34(4 Pt 2):e234-51. PMID: 21564133

- Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer. Cheung HH, Lee TL, Davis AJ, Taft DH, Rennert OM, Chan WY. Br J Cancer. 2010 Jan 19;102(2):419-27. PMID: 20051947

- Molecular biology of testicular germ cell tumors. Vilar E, Calvo E, Tabernero J. Clin Transl Oncol. 2006 Dec;8(12):846-50. PMID: 17169757

- Recent developments in testicular germ cell tumor research. van de Geijn GJ, Hersmus R, Looijenga LH. Birth Defects Res C Embryo Today. 2009 Mar;87(1):96-113. PMID: 19306344

- Looijenga LH, Gillis AJ, Stoop HJ, Hersmus R, Oosterhuis JW. Chromosomes and expression in human testicular germ-cell tumors: insight into their cell of origin and pathogenesis. Ann N Y Acad Sci. 2007 Dec;1120:187-214. PMID: 17911410

Immunochemistry

- Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Turnbull C, Rapley EA, Seal S, Pernet D, Renwick A, Hughes D, Ricketts M, Linger R, Nsengimana J, Deloukas P, Huddart RA, Bishop DT, Easton DF, Stratton MR, Rahman N; UK Testicular Cancer Collaboration. Nat Genet. 2010 Jul;42(7):604-7. PMID: 20543847

- Immunohistochemical expression analysis of Cx43, Cx26, c-KIT and PlAP in contralateral testis biopsies of patients with non-seminomatous testicular germ cell tumor. Steiner M, Weipoltshammer K, Viehberger G, Meixner EM, Lunglmayr G, Schöfer C. Histochem Cell Biol. 2011 Jan;135(1):73-81. PMID: 21161545

- SALL4 is a novel diagnostic marker for testicular germ cell tumors. Cao D, Li J, Guo CC, Allan RW, Humphrey PA. Am J Surg Pathol. 2009 Jul;33(7):1065-77. PMID: 19390421

- Zynger DL, Dimov ND, Luan C, Teh BT, Yang XJ. Glypican 3: a novel marker in testicular germ cell tumors. Am J Surg Pathol. 2006 Dec;30(12):1570-5. PMID: 17122513

Morphology

- Clonal evidence for the progression of a testicular germ cell tumor to angiosarcoma. Idrees MT, Kuhar M, Ulbright TM, Zhang S, Agaram N, Wang M, Grignon DJ, Eble JN, Cheng L. Hum Pathol. 2010 Jan;41(1):139-44. PMID: 19836053

- Balzer BL, Ulbright TM. Spontaneous regression of testicular germ cell tumors: an analysis of 42 cases. Am J Surg Pathol. 2006 Jul;30(7):858-65. PMID: 16819328

- Oosterhuis JW, Looijenga LH. Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer. 2005 Mar;5(3):210-22. PMID: 15738984

- Michael H, Lucia J, Foster RS, Ulbright TM. The pathology of late recurrence of testicular germ cell tumors. Am J Surg Pathol. 2000 Feb;24(2):257-73. PMID: 10680894

- Ulbright TM. Germ cell neoplasms of the testis. Am J Surg Pathol. 1993 Nov;17(11):1075-91. PMID: 8214253

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