gonadoblastoma

Definition: The gonadoblastoma is a precancerous or in situ form of germ cell cancer unique to patients with abnormal sexual development. This tumor is composed of a mixture of germ cell and sex-cord-stromal elements that arises almost exclusively in dysgenetic gonads.

Images

 Inguinal mass, 15 yom.

• https://twitter.com/hematogones/status/863133218593263617

Digital cases (Digital slides)

 HPC:32 : Gonadoblastoma
 HPC:384 : Gonadoblastoma in 46,XY gonadal dysgenesis

Gonadoblastoma has ovarian stroma surrounding nests of germ cells and sex cord stromal cells, with frequent hyalinization and calcification. It is the most frequent tumor found in gonadal dysgenesis, usually a phenotypic female with an XY karyotype and streak gonads.

It consists of malignant germ cells that are surrounded individually or in groups or by immature cells that are of sex-cord derivation (immature Sertoli/granulosa-like cells). The tumor nearly always occurs in association with a whole or component
of a ‘Y’ chromosome, although cases are known that have arisen in tumors with a 46,XX karyotype and even where the patient has given birth.

Although most cases are detected in children or young adults, the tumor may develop prenatally.

Localization

 testicular gonadoblastoma
 ovarian gonadoblastoma

Clinical features

Most gonadoblastomas occur in phenotypic females with abnormal gonads. Some occur in phenotypic males, almost all of whom have cryptorchism or abnormal external or abnormal internal genitalia. Only the rare patient is a normal phenotypic male without apparent abnormal genitals.

Nearly all gonadoblastomas occur in patients with mixed gonadal dysgenesis (MGD). Gonadoblastoma accounts for three-fourths of the gonadal tumors arising
in dysgenetic gonads and is usually discovered during the first to fourth decades of life.

Many of the isolated reports of gonadoblastoma associated with other forms of hermaphroditism described clinically and pathologically may in actuality be
examples of MGD.

Synopsis

 One third are detected before the age of 15.
 frequent association with abnormalities in the secondary sex organs, with detection of a Y chromosome in over 90% of cases
 bilateral in at least 38% of cases
 usually develops in a phenotypic female, frequently virilized (see also gonadal dysgenesis)
 may be overgrown by dysgerminoma or by other neoplastic germ cell elements

 Patient usually sexually abnormal:

• commonly gonadal dysgenesis and carrying Y chromosome, i.e.:
  • XY gonadal dysgenesis
  • XO–XY mosaicism
  • but not XX gonadal dysgenesis

 estimated 25% risk of neoplasia in these dysgenetic gonads

 Also documented in:

• phenotypically and chromosomally normal females, even during pregnancy
• ataxia–telangiectasia

Gonadoblastoma locus

 The gonadoblastoma (GBY) locus is the only oncogenic locus on the human Y chromosome.
 It is postulated to serve a normal function in the testis, but could exert oncogenic effects in dysgenetic gonads of individuals with intersex and/or dysfunctional testicular phenotypes.
 The testis-specific protein Y-encoded (TSPY) gene could be the putative gene for GBY.
 TSPY serves normal functions in male stem germ cell proliferation and differentiation, but is ectopically expressed in early and late stages of gonadoblastomas, testicular carcinoma in situ (the premalignant precursor for all testicular germ cell tumors), seminomas, and selected nonseminomas.
 Aberrant TSPY expression stimulates protein synthetic activities, accelerates cell proliferation, and promotes tumorigenicity in athymic mice. - TSPY binds to type B cyclins, enhances an activated cyclin B-CDK1 kinase activity, and propels a rapid G(2)/M transition in the cell cycle.
 TSPY also counteracts the normal functions of its X-homologue, TSPX, which also binds to cyclin B and modulates the cyclin B-CDK1 activity to insure a proper G(2)/M transition in the cell cycle.
 Hence, ectopic expression and actions of the Y-located TSPY gene in incompatible germ cells, such as those in dysgenetic or ovarian environments and dysfunctional testis, disrupt the normal cell cycle regulation and predispose the host cells to tumorigenesis.
 The contrasting properties of TSPY and TSPX suggest that somatic cancers, such as intracranial germ cell tumors, melanoma, and hepatocellular carcinoma, with detectable TSPY expression could exhibit sexual dimorphisms in the initiation and/or progression of the respective oncogenesis.

Pathogenesis

Microscopic structures resembling gonadoblastoma found incidentally in some ovaries of normal children in association with follicular cysts may represent precursor.

Macroscopy

 Usually small
 Often impossible to determine nature of gonad bearing tumor

• sometimes identified as:
  • a streak gonad (many become apparent only on microscopic examination)
  • cryptorchid testis
• never a normal ovary
   ≈36% bilateral

The gross appearance of the gonad with gonadoblastoma varies according to the size of the neoplasm, the presence of calcification , and whether the gonadoblastoma has been overgrown by a malignant form of germ cell tumor
(usually germinoma).

Most gonadoblastomas, if macroscopically visible, are small. About 20% of gonadoblastomas arise in a streak gonad and another 20% arise
in a dysgenetic testis.

A very rare case is found with ovarian tissue or at least dysgenetic gonads with rare primordial follicles.

In the remaining cases, the nature of the underlying gonad cannot be determined with certainty because tumor replaces it. Abut a fifth of gonadoblastomas are discovered solely because a streak gonad was examined microscopically.

The contralateral gonad also contains a gonadoblastoma in more than one-third of patients.

Immunochemistry

 placental alkaline phosphatase+ (PLAP+)
 c-kit (CD117+)
 FOXL2+

Microscopy

On microscopic examination, the gonadoblastoma appears as circumscribed nests of neoplastic germ cells having the cytologic properties of germinoma (dysgerminoma and seminoma) and are encompassed individually or in groups by sex-cord derivatives with inconspicuous cytoplasm and small round to
oval nuclei resembling immature Sertoli cells.

The germ cells are of two forms, one of which is an immature small cell form with a high nuclear : cytoplasmic ratio resembling gonocytes/oogonia and believed to be the cell that can progress to dysgerminoma. The small cell also gives rise to the larger and mature form of germ cells which resemble prespermatogonia/oocytes and have copious amounts of light to clear cytoplasm, usually with a distinct cytoplasmic membrane.

The mature large cell is not precancerous. Both types of germ cell have centrally placed nuclei in the cell and obvious macronucleoli that are one to several in number.

Histologically, these precancerous germ cells resemble the carcinoma in situ (CIS) germ cells often found in seminiferous tubules that are adjacent to seminomas which develop in genetically normal 46,XY men.

Recent immunohistochemical studies provide some insight into the progression of precancerous germ cells into invasive malignancy, especially in the form of seminoma/dysgerminoma.

OCT 3/4 (OCT4), an octamer binding transcription factor, is present diffusely and strongly in the immature form of precancerous germ cell, in malignant germ cells at the junction of gonadoblastoma and seminoma/dysgerminoma, and in the seminoma/dysgerminoma distant from the gonadoblastoma. It is not present in the mature form of gonadoblastoma germ cell.

TSPY, the testis Y specific protein, is present in the larger mature gonadoblastoma germ cell, but minimally noticeable to absent in the precancerous immature form. While it is variably present in the early invasive component of seminoma/dysgerminoma, it is absent from the malignant germ cells
deep within the invasive cancer. These data suggest that TSPY may be involved in the initial selection of tumorigenic cells, but once the process has begun and the malignant germ cells are duplicating as a seminoma/dysgerminoma, TSPY dependency is lost. Neither PLAP nor c-kit (CD117), both markers of germ cells, reliably demonstrates the malignant germ cells, nor do they help explain the pathogenetic process.

Inhibin reactivity and AMH are commonly demonstrable in the surrounding cells, which is in keeping with the sex-cord cells (immature Sertoli/granulosa cells) being an integral part of the tumor.

Hyaline, composed of basement membrane material, is found along the margin or as nodules within the nests of gonadoblastoma. In four-fifths of cases, the hyaline material is calcified, initially appearing as small, laminated spheres, which eventually fuse and coalesce into large mulberry-like masses.

Not infrequently, the only evidence that a dysgerminoma originated in a gonadoblastoma is the presence focally of mulberry-like calcifications.

Hormonally active cells that resemble lutein and Leydig cells are found interspersed among the nests of tumor in about two-thirds of cases. These hormonally active cells are found least frequently in non-virilized phenotypic females, more often in virilized females, and most frequently in phenotypic males. To some degree, their appearance may reflect the postpubertal age of the patient when the gonad is examined.

 germ cells, similar to those of dysgerminoma or seminoma
 sex cord derivatives resembling immature sertoli or granulosa cells
 stromal derivatives mimicking luteinized or Leydig cells devoid of Reinke crystals mnay be present

 solid nests of inimately admixed germs cells and sex cord derivatives, the latter arranged in 3 typical patterns :

• coronal pattern at the periphery of the nests
• surrounding individual or collections of germ cells
• surrounding speces containing an eosinophilic PAS-positive material, resembling Call-Exner bodies
• sharply outlined tumor nests
• heavy calcification

 Admixture of:

• primitive germ cells:
  • resembling those of dysgerminoma
• sex cord–stromal cells:
  • resembling morphologically and immunohistochemically immature Sertoli and granulosa cells

 Steroid hormone-producing cells:

• may be present (especially after puberty)
• have capacity for steroidogenesis

 additional processes :

• hyalinization
• calcification
  • originating in the Call-Exner-like bodies
  • when abundant may be obvious on plain abdominal radiograph
• overgrowth by a malignant germ cell component, usually dysgerminoma (50% of cases) or another malignant germ cell element (in an additional 10%)

 if the nature of the gonad is identified it is either a streak or a testis (contralateral gonad : idem)

Immunohistochemistry

 Hyaline material reacts strongly with anti-laminin antibodies, indicating basement membrane deposition.

Associations

 30% of patients with mixed gonadal dysgenesis
 less than 3% of patients with true hermaphrodism
 50% of patients with 46XY pure gonadal dysgenesis
 very high frequency of associated malignant germ cell tumor
 dysgerminoma (malignant germ cell tumor most commonly associated with gonadoblastoma)

Differential Diagnosis

 dysgerminoma
 sex cord tumor with annular tubules

Prognosis

Germ cell component may overgrow stromal elements and result in formation of:
 a dysgerminoma
 exceptionally, another type of germ cell tumor

Much more unusually overgrowth of sex cord–stromal component may result in features of a Sertoli cell tumor.

Variants

 bilateral gonadoblastoma

Physioopathology

The role of the Y chromosome in the development of cancer is controversial. Since much of the Y chromosome (except for the pseudoautosomal regions at both ends of the chromosomes, initialed PAR) neither pairs with nor recombines with the X chromosome during meiosis, it has been difficult to study this chromosome and identify its oncogenic genes and tumor-suppressor
genes.

The gonadoblastoma Y gene locus (GBY) appears to be located on the short or long arm of the Y chromosome near the centromere. It may be that more than one gene is involved.

Possibly the gonadoblastoma gene functions as an oncogene only in the dysgenetic gonad, and otherwise has a normal function in the normally developing testis. A multicopy gene, called TSPY (testis specifi c protein Y), which is an oncogene located in the GBY critical region, has emerged as the most likely GBY candidate.This oncogene is expressed in spermatogonial cells in normal testis, suggesting a function early in spermatogenesis, and is drastically reduced
in the gonads of patients with androgen insensitivity, a syndrome not associated with gonadoblastoma.

Currently, it is not yet clear how and why the oncogenic function of TSPY predisposes the abnormal gonad to cancer development. In gonadoblastoma, the Y chromosome signal is significantly higher in the tumor cells than in adjacent non-tumor cells.

Tumorigenesis

Gonadoblastoma (GB) is the precursor of invasive GCTs in dysgenetic gonads, predominantly dysgerminoma (DG).

Carcinoma in situ (CIS) is the precursor of malignant testicular germ cell tumors (GCTs) of adolescents and young adults, being the neoplastic counterpart of primordial germ cells/gonocytes.

Carcinoma in situ cells will develop into invasive seminoma/nonseminoma.

In this process, part of the Y chromosome (GBY region) is involved, for which TSPY is a candidate gene.

GB is a heterogeneous mix of germ cells, in which the OCT3/4-positive cells have the potential to undergo progression to an invasive tumor.

These early invasive stages are initially also positive for TSPY (like CIS), supporting a positive selection mechanism.

Therefore, OCT3/4 in combination with TSPY is valuable to identify malignant germ cells in dysgenetic gonads. This could allow better prediction of the risk of progression to a GCT.

GB represents the earliest accessible developmental stage of malignant GCTs.

See also

 gonadal tumors
 intersex disorders

Links

 PathConsult

References

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