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Mixed germ cell - sex cord stromal tumors

Gonadoblastoma


Andreas Kontosis, M.D.
Julieta E. Barroeta, M.D.

Last author update: 16 January 2025
Last staff update: 16 January 2025

Copyright: 2002-2025, PathologyOutlines.com, Inc.

PubMed search: Ovarian gonadoblastoma

Andreas Kontosis, M.D.
Julieta E. Barroeta, M.D.
Page views in 2024: 7,743
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Kontosis A, Barroeta JE. Gonadoblastoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/ovarytumorgonadoblastoma.html. Accessed January 18th, 2025.
Definition / general
  • Type of germ cell neoplasia in situ that consists of germ cells resembling those of germ cell neoplasia in situ (GCNIS) / germinoma and incompletely differentiated sex cord cells
Essential features
  • Type of germ cell neoplasia in situ
  • Mostly occurs in patients with disorders of sex development (DSD); the presence of the Y chromosome or parts thereof plays a significant role in the pathogenesis
  • Rarely occurs in patients with normal peripheral blood karyotype and no evidence of DSD; mostly females
  • Classic gonadoblastoma consists of nests or cords of admixed germ cells and small sex cord stromal cells that surround basement membrane-like material, which can be calcified
  • Bilateral in 40% of cases; bilateral gonadectomy is practically curative and eliminates the risk of progression to invasive germ cell tumors
Terminology
  • Gonadoblastoma
ICD coding
  • ICD-10: 9073/1 - gonadoblastoma
  • ICD-11
    • 2C73.Y & XH0K61 - other specified malignant neoplasms of the ovary & gonadoblastoma
    • 2F76 & XH0K61 - neoplasms of uncertain behavior of female genital organs & gonadoblastoma
    • 2F77 & XH0K61 - neoplasms of uncertain behavior of male genital organs & gonadoblastoma
Epidemiology
  • Almost always in patients with disorders of sex development (DSD)
  • Most common karyotypes at risk
    • 46,XY complete gonadal dysgenesis
    • 45,X / 46,XY partial gonadal dysgenesis (mosaicism)
    • 46,XY DSD including partial gonadal dysgenesis and ovotesticular DSD
    • Partial androgen insensitivity syndrome (Hum Pathol 2020;100:47, World J Pediatr 2009;5:93)
  • May be associated with other chromosomal abnormalities and syndromes
    • Turner syndrome with Y chromosomal material (could be cryptic), up to 35% of patients
    • Germline or somatic mutations in genes involved in the XY developmental pathway
  • Infrequently cases have been reported in patients with normal peripheral blood karyotype and no evidence of DSD
  • Age: majority < 15 years old (1 - 38 years)
Sites
  • Gonads
Pathophysiology
  • Vast majority of gonadoblastomas are associated with disorders of sex development (DSD) and dysgenetic gonads
    • Gonadal dysgenesis: incomplete or defective formation of the gonads, due to disturbed migration of germ cells or proper organization in the fetal gonadal ridge
  • Formation and differentiation of the normal gonad is a complex process
    • Bipotential gonad develops from the urogenital ridge close to the kidney and adrenals (genes like WT1, SF1, DAX1 are involved in the process)
    • Germ cells from the yolk sac migrate to the gonads during the fifth week of pregnancy
    • If SRY gene in Y chromosome is present
      • SRY and SOX9 genes are expressed and initiate a cascade of genetic events; through a stringent time schedule and a balance of activating and inhibiting mechanisms, the gonad is gradually being differentiated into primitive testis with sex cords, first and later into more mature testis with seminiferous tubules
    • If SRY gene is absent
      • Activation of genes such as FOXL2 leads to ovarian differentiation with initiation of meiosis in the germ cells and formation of primordial follicles
  • The earlier this process is interrupted / disturbed, the less the gonad can differentiate into ovary and testis
    • Gradual continuum between well differentiated testis and well differentiated ovary
    • Combinations of these patterns can be found within the same or opposite gonad of the patient
    • Discrete patterns
      • Normal testis (with maturation delay of germ cells)
      • Dysgenetic testis
      • Primitive sex cords containing germ cells
      • Streak fibrous tissue (no germ cells) with remnants of testicular or ovarian differentiation
      • Undifferentiated gonadal tissue (UGT)
      • Normal ovary (World J Pediatr 2009;5:93)
  • Suboptimal environments, such as dysgenetic gonads or deficient androgen effects, cause reduced SOX9 expression and increased FOXL2; thus, the germ cells delay their process of maturation and start expressing OCT3/4 (J Pathol 2008;215:31)
  • Prolonged expression of OCT3/4, increased KIT / KITL signaling and strong expression of TSPY in the germ cells is hypothesized to be important in the pathogenesis of germ cell neoplasias (J Pathol 2008;216:43)
    • TSPY gene is found in the gonadoblastoma susceptibility region on the Y chromosome (GBY region), around centromere of Y chromosome and is necessary for the development of gonadoblastoma
  • If the gonad contains well differentiated testicular tissue and seminiferous tubules → carcinoma in situ (CIS)
  • If the gonad has primitive sex cords or undifferentiated gonadal tissue → gonadoblastoma (J Pathol 2008;216:43)
  • 60% of gonadoblastoma cases have an associated malignant germ cell tumor
    • 80% of cases are dysgerminomas / germinomas, while the remaining cases include other tumor types like embryonal carcinoma, teratoma, yolk sac tumor or choriocarcinoma
    • Some findings suggest that the other malignant tumors arise from dysgerminoma / germinoma (J Pathol 2008;215:31)
  • Pathogenesis of gonadoblastoma is mainly unknown in patients with normal peripheral karyotype and no evidence of DSD (J Pathol 2008;215:31)
Diagrams / tables

Images hosted on other servers:
Pathogenesis of UGT and GB

Pathogenesis of UGT and GB

Germ cell tumor risk

Germ cell tumor risk

Molecular alterations and GCT risk

Molecular alterations and GCT risk

Clinical features
  • 80% phenotypically female
    • 50% develop in virilized females and 30% in nonvirilized females
  • 20% in male patients, usually with hypospadias, cryptorchidism and gynecomastia (Cancer 1970;25:1340)
  • Gonadoblastoma can be a steroid secreting tumor and may cause precocious puberty and virilization (Front Horm Res 2019;53:100)
  • Most patients present in the neonatal period for ambiguous external genitalia; later in life for primary amenorrhea or investigation of abdominal mass (Semin Diagn Pathol 2014;31:427)
Diagnosis
  • History, physical examination, imaging of internal reproductive organs and molecular / cytogenetic studies, including karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) for evidence of mosaicism and Y material, will aid in the correct diagnosis of DSD subcategory and estimate the risk for the development of germ cell tumor (Int J Mol Sci 2019;20:5017, World J Pediatr 2009;5:93)
  • Definite diagnosis is made through the histologic examination of the specimen (biopsy or gonadectomy)
  • Diagnostic criteria
    • Essential
      • Nested to corded arrangement of germ cells (similar to that seen in germinoma / dysgerminoma / seminoma) and small sex cord cells with deposits of basement membrane material
      • Immunopositivity for OCT3/4 and PLAP
    • Desirable
      • Background of a DSD
      • Germ cells positive for podoplanin
      • Sex cord cells coexpressing SOX9 (weak) and FOXL2 (strong), inhibin, calretinin and SF1
Laboratory
  • Rise in lactate dehydrogenase (LDH), alpha fetoprotein (AFP), human chorionic gonadotropin (hCG) levels could indicate that a malignant germ cell tumor developed from a pre-existing gonadoblastoma
Radiology description
  • Identification of dysgenetic gonads can be challenging due to variations in size and appearance
  • Abdomen radiographs may identify pelvic calcifications, which could be a sign of gonadoblastoma but need to be differentiated from other causes (AJR Am J Roentgenol 1976;127:1001)
  • No distinctive features to detect premalignant transformation (such as development of gonadoblastoma) (Semin Diagn Pathol 2014;31:427)
    • Normal ultrasound or MRI does not rule out neoplasm in patients with gonadal dysgenesis (J Pediatr Urol 2018;14:154.e1)
    • Surveillance in patients who want to defer gonadectomy can be challenging
Prognostic factors
  • Gonadoblastoma is an in situ malignancy and simple excision is curative
    • 5 year overall survival (OS) and recurrence free survival (RFS) > 96%, when gonadoblastoma identified during prophylactic gonadectomy (Hum Pathol 2020;100:47)
  • If not excised, 60% progress to dysgerminoma / germinoma, 4% embryonal carcinoma or yolk sac tumor and 4% teratoma (Semin Diagn Pathol 2014;31:427)
  • If invasive germ cell tumor develops, prognosis depends on the nature and the stage
Case reports
Treatment
  • Simple excision is curative; bilateral gonadectomy is indicated due to the high risk for bilateral disease
  • Malignant germ cell tumor such as dysgerminoma → treat accordingly
  • Many patient advocacy groups support a more conservative approach whenever possible towards gonadectomy in DSD individuals (Hum Pathol 2020;100:47)
  • Ideally, personalized recommendations should be given by an interdisciplinary team consisting of geneticists, endocrinologists, behavioral health specialists and urologists
  • Multiple parameters to be considered: gender identity, need for endogenous sex hormone production, desire for fertility and risk of germ cell tumor
  • If dysgenetic gonads are retained, proactive surveillance with imaging is insufficient
    • Relocating the gonads to accessible areas like inguinal canal or adjacent to the biopsy laparoscopy port site has been suggested (Front Horm Res 2019;53:100)
Gross description
Gross images

AFIP images
Bilateral tumor, with germinoma

Bilateral tumor, with germinoma

With germinoma

With germinoma

Frozen section description
  • Unknown at this time
Microscopic (histologic) description
  • Features of classic gonadoblastoma (Hum Pathol 2020;100:47)
    • Noninvasive neoplasm (germ neoplasia in situ) consisting of multiple nests or cords of admixed germ cells and small sex cord stromal cells that surround basement membrane-like material
    • Germ cells
      • Vary in appearance and number
        • Some with round nuclei with prominent nucleoli and clear / pale cytoplasm (dysgerminoma / germinoma-like cells)
        • Others with less cytoplasm, small to inconspicuous nucleoli (spermatogonia-like cells)
    • Sex cord stromal cells
      • Bland with angulated, occasionally grooved nuclei and inconspicuous cytoplasm
      • Can be arranged at the periphery of the nests (forming palisades), around the eosinophilic material deposits (Call-Exner-like pattern) or around germ cells (follicle-like pattern)
      • They are considered incompletely differentiated rather than fully granulosa or Sertoli cells
    • Eosinophilic basement membrane-like material
      • Can become calcified
      • Early calcifications have psammomatous appearance
      • Later form larger aggregates, developing mulberry-like shape
        • Involuted or burnt out gonadoblastoma: only characteristic calcifications remain due to regression of the cellular components
    • Gonadal stroma
      • Nonspecific spindle cell stroma with occasional Leydig-like cells, lacking Reinke crystals
  • Infiltrative or dissecting gonadoblastoma (DGB)
    • Term coined by Dr. Scully and further characterized by Kao et al. to describe unusual patterns of gonadoblastoma (Am J Surg Pathol 2016;40:1417)
      • Cord-like pattern: germ cells embedded in cords or small nests of sex cord cells, which are irregularly distributed in the stroma
        • Lack of basement membrane deposits and calcifications
        • When cords are thin and sparsely distributed → similar picture to undifferentiated gonadal tissue (UGT)
      • Anastomosing pattern: the nests are smaller and interconnected
      • Solid expansile pattern: large nests often separated by fibrovascular septa, with reduced sex cord cells and deposits of basement membrane-like material that is present but hard to identify
    • Mixed patterns of dissecting gonadoblastomas are present in most (76%) gonadoblastomas and need to be differentiated from dysgerminoma (solid expansile pattern)
    • The following pathogenetic model is hypothesized
  • If not excised, 60% of gonadoblastomas will develop into germinoma and 4% will develop into other germ cell tumors like embryonal carcinoma or yolk sac tumor, etc. (Semin Diagn Pathol 2014;31:427)
Microscopic (histologic) images

Contributed by Robert H. Byrd, M.D., Andreas Kontosis, M.D. and Julieta E. Barroeta, M.D.
Gonadoblastoma cells

Gonadoblastoma cells

Psammomatous calcifications

Psammomatous calcifications

Calcifications

Calcifications

Extensive calcifications

Extensive calcifications


Gonadoblastoma in streak gonad   Gonadoblastoma in streak gonad

Gonadoblastoma in streak gonad

Focus of anastomosing pattern

Focus of anastomosing pattern

Gonadoblastoma and Leydig-like cells

Gonadoblastoma and Leydig-like cells


Inhibin IHC

Inhibin IHC

OCT3/4 IHC

OCT3/4 IHC

Virtual slides

Images hosted on other servers:
Gonadoblastoma in a dysgenetic gonad

Gonadoblastoma in a dysgenetic gonad

OCT3/4 immunostain

OCT3/4 immunostain

Inhibin immunostain

Inhibin immunostain

Cytology description
  • Intraoperative imprint cytology (touch prep) can be utilized when extensive calcifications are present, hindering frozen sections
    • Rare cases of dysgerminoma arising in gonadoblastoma with cytology description in the literature (Diagn Cytopathol 2011;39:42, Diagn Cytopathol 2019;47:1203)
      • Gonadoblastoma
        • Oval or round clusters with microcystic spaces
        • Hyaline globules of metachromatic basement membrane-like material in the spaces, magenta stained; the globules are round and homogenous
        • 2 cell types
          • Small cells with scant cytoplasm, round to oval nuclei and fine chromatin
          • Intermediate cells with elongated nuclei, fine chromatin and occasional grooves
        • Calciferous particles may be present in the background
      • Dysgerminoma
        • Classic features of atypical cells with vesicular nuclei with 1 or 2 nucleoli and pale / vacuolated cytoplasm and admixed lymphocytes
Positive stains
Molecular / cytogenetics description
  • Genetic testing plays a major role in the evaluation of patients with suspected DSD
  • Peripheral blood karyotype → detect X and Y chromosomes and other chromosomal abnormalities
  • FISH analysis with specific X and Y centromere specific probes → assess mosaicism (Best Pract Res Clin Obstet Gynaecol 2018;48:90)
  • PCR analysis → identified cryptic Y chromosomal material (Best Pract Res Clin Obstet Gynaecol 2018;48:90)
  • DSD patients who carry Y chromosomal DNA segments, especially when the critical gonadoblastoma locus is present, have an increased risk for germ cell neoplasia (Horm Cancer 2017;8:166)
Molecular / cytogenetics images

Images hosted on other servers:
Negative FISH for Y sequence

Negative FISH for Y sequence

Positive FISH for Y sequence

Positive FISH for Y sequence

Videos

Case of gonadoblastoma and Swyer syndrome

Sample pathology report
  • Left gonad, left gonadectomy:
    • Gonadoblastoma (3 cm)
    • No invasive germ cell tumor identified (see comment)
    • Comment: The whole specimen (extensively) submitted for microscopic examination.
    • Gonadoblastoma is a type of germ cell neoplasia in situ that is considered high risk for progression to invasive germ cell tumor. In 40% of cases, it is bilateral. According to the AJCC 8th edition and UICC system, gonadoblastoma is staged as pTis.
Differential diagnosis
Board review style question #1
Calcifications


A newborn is referred to the pediatric endocrinology clinic due to ambiguous genitalia noted at birth. A karyotype reveals a 46,XY genotype. Ultrasound is performed and identifies bilateral gonadal masses in the inguinal canal. Excision of the masses and histopathologic examination reveals the presence of the lesion depicted. What is the diagnosis?

  1. Adrenal cortical rest
  2. Dysgerminoma
  3. Gonadoblastoma
  4. Sex cord tumor with annular tubules (SCTAT)
Board review style answer #1
C. Gonadoblastoma. The picture shows the classic features of gonadoblastoma i.e. nests of germ cells admixed with sex cord cells, partially differentiated and eosinophilic material deposits. Calcifications are a common feature of gonadoblastoma. Answer D is incorrect because SCTAT shows a population of sex cord cells and does not have germ cells (large cells with clear cytoplasm and prominent nucleoli). Answer B is incorrect because although dysgerminoma can arise from gonadoblastoma in dysgenetic gonads, there is no evidence of invasion in the lesion. Answer A is incorrect because adrenal cortical rests refer to circumscribed nodules of (ectopic) adrenal cortical tissue, frequently found in the paratesticular tissue. However, the morphology is entirely different from the depicted lesion.

Comment Here

Reference: Gonadoblastoma
Board review style question #2
Gonadoblastoma in streak gonad


Which of the following statements is true regarding this gonadal lesion?

  1. Gonadoblastoma is a malignant tumor that commonly metastasizes to regional lymph nodes
  2. Gonadoblastoma typically occurs in individuals with a 46,XY karyotype and dysgenetic gonads
  3. It consists of a monotonous population of sex cord cells
  4. Surgical excision is not recommended due to its benign nature
Board review style answer #2
B. Gonadoblastoma typically occurs in individuals with a 46,XY karyotype and dysgenetic gonads. Gonadoblastoma typically presents in patients with disorders of sex development, such as individuals with 46,XY karyotype and dysgenetic gonads. Answer A is incorrect because gonadoblastoma is a type of germ cell neoplasia in situ and thus cannot metastasize. If not excised, up to 60% of gonadoblastoma can give rise to malignant germ cell tumors, most frequently dysgerminoma. Answer D is incorrect because gonadoblastoma is a type of carcinoma in situ. Bilateral gonadectomy is often suggested, based on the risk of developing malignant germ cell tumors. Answer C is incorrect because gonadoblastoma consists of a mixture of germ cells and sex cord cells, not fully differentiated, having features of granulosa / Sertoli cells.

Comment Here

Reference: Gonadoblastoma
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