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germ cell tumors

Wednesday 10 March 2004


Definition: The germ cell tumors (GCTs) are a rare and complex group of heterogenous neoplasms that comprise both benign and malignant
histologies. Despite their heterogeneity, they are all presumed to arise from totipotent primordial germ cells (PGC).


- Rx-gross-histology. Mixed testicular neoplasia. Seminoma + Yolk Sac Tumor, post-puberal

Digital cases

- JRC:18783 : Yolk sac carcinoma arising in liver.
- JRC:18767 : pineal choriocarcinoma.

Benign GCTs are called teratomas. Of the malignant GCT histologies, seminomatous tumors (testicular seminomas, ovarian dysgerminomas, and
extragonadal germinomas) recapitulate the undifferentiated and pluripotent PGC phenotype, whereas nonseminomatous tumors [e.g., yolk sac tumors (YST)] display lineage specific differentiation.

Amixture of histologic subtypes may be present within any single GCT, suggesting a close interrelationship between the different histologies and the cell of origin.

Many epidemiologic and clinical differences exist between GCTs arising in adulthood and those arising in childhood (defined in United Kingdom as 0–16 years of age), with tumors in adolescents showing a degree of overlap with GCTs in both age groups.


Germ cell tumors (GCTs) constitute a heterogeneous group of embryonal tumors, which originate in early embryonic development. They may develop at any age from the fetal period to adulthood and can arise both in the gonads and at extragonadal midline sites such as the coccyx, the mediastinum, and the pineal region (Calaminus et al.,2004; Schneider et al.,2004).

Imprinting studies have demonstrated that the cell of origin of both gonadal and nongonadal GCTs is most probably a primitive germ cell, the primordial germ cell.

Its developmental potential differs according to its stage of maturation and pattern of genomic imprinting (van Gurp et al.,1994; Schneider et al.,2001(b); Oosterhuis et al.,2005; Sievers et al.,2005).

Thus, the origin of nongonadal GCTs can be interpreted as resulting from an abnormal migration of primordial germ cells during embryogenesis.

GCTs show a distinctive age distribution that separates a group of teratomas and yolk sac tumors (YST) that arise during infancy and childhood from the more diverse GCTs of adolescent and adult patients, presenting as teratomas, germinomas (seminomas, dysgerminomas), embryonal carcinomas, choriocarcinomas, or compositions of these histological entities (Göbel et al.,2000; Schneider et al.,2004; Oosterhuis et al.,2005).

In addition, cystic ovarian teratomas and spermatocytic seminomas of the elderly are considered distinct entities (Oosterhuis et al.,2005).

Characteristically, the majority of childhood GCTs are diagnosed at nongonadal sites, while in adults gonadal tumors (dermoid cysts of the ovary and malignant GCTs of the testis) predominate (Schneider et al.,2004).

GCTs are presumed to arise from mutated primordial germ cells (PGCs) of genital ridge origin or dysfunction totipotent embryonic cells.

Investigation of the different genetic compositions in ECs and ES cells may provide clues about the reduced dependency on external cues for self-maintenance that exist among GCTs, thereby benefiting tumorigenesis research on ECs as well as applications for human ES cells.

Global gene expression studies in human embryonic stem cells and human pluripotent germ cell tumors have shown that the gene expression patterns of human ES cell lines are similar to those of the human embryonal carcinoma cell samples but are more distantly related to those of seminoma samples.

Genes that are expressed at significantly greater levels in human ES and embryonal carcinoma cell lines than in control samples were pinpointed and are possible candidates for involvement in the maintenance of a pluripotent undifferentiated phenotype.

Wnt and Notch pathway genes are overexpressed in the pluripotent human embryonal carcinoma cell line NTERA2 and in embryonic stem cells.

These include members of the frizzled gene family (FZDI, FZD3, FZD4, FZD5, FZD6), which encodes receptors for the Wnt proteins, the Frizzled Related Protein family (SFRPI, SFRP2, FRZB, SFRP4), which encode soluble Wnt antagonists and also ligands and receptors of the Notch pathway (Dlkl, Jaggedl; Notchl, Notch2, Notch3).


- benign germ cell tumors (BGCTs)

- malignant germ cell tumors (MGCTs )

  • embryonal carcinoma
  • seminoma
  • endodermal sinus tumor (yolk sac tumor )
  • choriocarcinoma
  • malignant teratomas
    • teratomas with sarcomatous component
  • mixed malignant germ cell tumor


- gonadal germ cell tumors

  • ovarian germ cell tumor
  • testicular germ cell tumor

- extragonadal germ cell tumors (EGCTs)

  • intracranial germ cell tumors (ICGCTs)
  • mediastinal germ cell tumors (MGCTs)
  • abdominal germ cell tumors (AGCTs)
  • retroperitoneal germ cell tumors (RGCTs)

According to the sex of the patient

- male germ cell tumors
- female germ cell tumors
- neonatal germ cell tumors

According to the age of the patient

- adult germ cell tumors
- pediatric germ cell tumors

Are cently proposed classification attempted to separate GCTs based upon present epidemiologic and biological evidence. In this system, GCTs of children with ages @<@5 years (typically teratomas or YSTs) are classified as type 1 tumors.

The remaining GCTs of childhood, and most GCTs of adulthood, are deemed type 2. An invariable feature of the type 2 tumors is reported to be gain of 12p, which occurs infrequently in type 1 tumors and, when present, is restricted to 12p13.


- malignant transformation


These distinct epidemiological, clinical, and pathologic patterns correlate with differences in chromosomal alterations.

Postpubertal malignant GCTs are characterized by an isochromosome 12p or 12p amplification, gain of the chromosomes 7, 8, and 21q, loss of 11, 13, and 18, and other less frequent imbalances (Oosterhuis et al.,2005).

Prepubertal malignant GCTs demonstrate imbalances at chromosome 1 (loss at 1p, gain at 1q), loss at 6q, and gain of 20q, whereas the genetic changes characteristic of postpubertal tumors are lacking (Perlman et al.,1994,2000; Bussey et al.,1999; Mostert et al.,2000; Schneider et al.,2001(a),2002; van Echten et al.,2002).

Notably, in these reports no other recurrent aberration has been reported at such considerably variable frequency as loss at 1p, with reported frequencies ranging from less than 10% to more than 80%. It is unclear, whether this variability is attributable to technical or biological differences.

Thus, it should be noted that although the loss of a chromosome leads to LOH in diploid cells, a chromosome copy number loss in triploid or high-ploidy tumors such as GCTs may not lead to LOH.

- i(12)p

  • 90% of adult patients (all histologic subtypes - gonadal and extragonadal localization) (2177638)
  • few i(12)p in pediatric patients (11528555)

- recurring complex chromosomal translocations t(6p21), t(6p22), t(6q23), and t(11q13) (8174069)

- constitutional translocation t(12q13) (12752256)

- 1p loss

  • 1p loss in pediatric and adult germ cell tumors are caused by true 1p allelic loss (1p LOH)

CGH (15880464)

distal 1p 4q 6q24-qter 18q21-qter
1q32-qter Ch.7 Ch.8 12p 20q

Expression profile: 14595015

Global gene expression studies have only been performed in adult testicular GCTs (TGCT). These suggested that expression profiles can distinguish malignant TGCTs from other adult malignancies and can separate TGCTs of different histologic types. These studies included cases with pure seminoma and YST histology.

Limited expression data suggested that ovarian YSTs of adolescence
(and adulthood) differed from ovarian dysgerminomas based on overexpression of genes in the Wnt/h-catenin pathway, a
determinant of differentiation in embryonal carcinoma cell development in vitro and in adult malignant TGCTs.

miRNA: 17893849


Because of signicative differences, GCTs of identical histology are treated differently depending on patient age and country of residence. Despite overall success in managing children with GCTs, there are subgroups of patients in whom the prognosis is less favorable.

Moreover, adoption of adult derived chemotherapeutic schedules in the treatment of pediatric malignant GCTs has resulted in significant toxicity and long-term morbidity, which may be avoidable.

It is therefore essential to obtain a greater understanding of the biology of pediatric malignant GCTs, not least so that children can be given the most
appropriate treatment.



- High-throughput microRNAome analysis in human germ cell tumours. Gillis AJ, Stoop HJ, Hersmus R, Oosterhuis JW, Sun Y, Chen C, Guenther S, Sherlock J, Veltman I, Baeten J, van der Spek PJ, de Alarcon P, Looijenga LH. J Pathol. 2007 Nov;213(3):319-28. PMID: 17893849

Gene expression

- Sperger JM, Chen X, Draper JS, Antosiewicz JE, Chon CH, Jones SB, Brooks JD, Andrews PW, Brown PO, Thomson JA. Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13350-5. Epub 2003 Oct 31. PMID: 14595015


- Chaganti RS, Houldsworth J. Genetics and biology of adult human male germ cell tumors. Cancer Res. 2000 Mar 15;60(6):1475-82. PMID: 10749107


- Pediatric germ cell tumors: protocol update for pathologists. Perlman EJ, Hawkins EP. Pediatr Dev Pathol. 1998 Jul-Aug;1(4):328-35. PMID: 10463297

- Germ cell tumors. Hawkins EP. Am J Clin Pathol. 1998 Apr;109(4 Suppl 1):S82-8. PMID: 9533752