Testis and epididymis
Sex cord stromal tumors
Mixed germ cell - sex cord stromal tumors: gonadoblastoma

Author: Swapnil U. Rane, M.D. (see Authors page)

Revised: 17 July 2017, last major update August 2013

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PubMed Search: Mixed germ cell sex cord stromal tumors gonadoblastoma

Related topics: Mixed germ cell - sex cord stromal tumors: other

Cite this page: Mixed germ cell - sex cord stromal tumors: gonadoblastoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/testismixed.html. Accessed November 20th, 2017.
Definition / general
  • Rare benign gonadal tumor composed of germ cells and sex cord stromal derivatives resembling immature granulosa cells and Sertoli cells
Terminology
Epidemiology
  • Most cases occur within first 2 decades; nearly 94% by age 30
  • Those with with partial dysgenesis / mosaicism are diagnosed prior to puberty; those with complete androgen insensitivity are diagnosed after puberty
  • Almost always associated with disorders of sex development
  • ~10% with dysgenetic gonads develop gonadoblastoma / seminoma by age 10 (Obstet Gynecol Surv 1986;41:74)
  • ~25% with mixed gonadal dysgenesis and Y component develop gonadoblastoma and germ cell tumor by age 40 (Am J Obstet Gynecol 1976;124:293)
Sites
  • Usually abdominal / inguinal undescended gonads / testis
  • May occur in ovaries of phenotypically and genetically normal females (see ovary tumor chapter)
Pathophysiology and etiology
Disorders of sexual development (DSD) clearly associated with increased risk of gonadoblastoma include:
  • Complete androgen insensitivity (46,XY) (30 - 66% incidence)
  • Pure gonadal dysgenesis / Swyer syndrome (46,XY)
  • Mixed gonadal dysgenesis (45,X / 46,XY) (55% incidence)
  • Turner syndrome (45,XO) with XY mosaicism
    • Molecular presence of Y chromosome (6 - 9% incidence) results in 43% incidence of gonadoblastoma
  • Frasier syndrome (rare 46,XY DSD caused by mutation in WT1 gene)
  • Maternal exposure to androgens, drugs, alcohol or illness during first trimester is associated with gonadal dysgenesis and intersex disorders; however, association with gonadoblastoma development is not established
Clinical features
  • ~80% are phenotypic females with subtle abnormalities in sexual development; cases with pure gonadal dysgenesis can be completely normal females
    • Patients with clitoromegally, abnormal hirsutism, etc. are candidates for karyotype analysis to exclude intersex disorders
  • ~20% are phenotypic males with gynecomastia, hypospadias, cryptorchidism; usually 46XY or 45X / 46XY
  • 1/3 have bilateral gonadoblastoma
  • Commonly associated with primary amenorrhea, developmental delay of genitalia and secondary sexual characters
  • 50% have abdominal mass with malignant transformation into seminoma or with metastatic disease
  • Gonadoblastoma not identified during neonatal period may go undetected until puberty when patients present with primary amenorrhea
  • Features of intersex disorders:
    • Presence of inguinal hernia in phenotypically female neonates associated with male pseudohermaphrodites in 1.6%
  • Bimanual abdominal palpation can be used to confirm presence of uterus in initial few days of neonatal life (due to effects of maternal hCG)
  • Patients with complete androgen insensitivity / male pseudohermaphroditism not diagnosed during neonatal period usually go unnoticed until puberty
    • Normal breast development but secondary sexual characters like pubic and axillary hair growth are rudimentary; vagina may be hypoplastic
  • Patients with mixed gonadal dysgenesis (45XO / 46XY) have
    • Ambiguous genitalia with varying degrees of phallic enlargement
    • Undescended testis
    • Urogenital sinus with labioscrotal fusion
    • Nearly all have a uterus, vagina and fallopian tubes in addition to an ovary / streak and a contralateral testicle
    • 50% are short and ~33% appear similar to individuals with Turner syndrome
Laboratory
  • Karyotyping is most important investigation for identifying those with intersex disorders who are at increased risk of developing gonadoblastoma
  • May have abnormalities in serum electrolytes, may be life threatening
  • Hormonal evaluation is necessary to rule out other causes of abnormal sexual development and to plan hormonal replacement
Prognostic factors
  • Excellent prognosis prior to malignant transformation, with no deaths reported
  • 30% of patients have malignant germ cell tumor in dysgenetic or contralateral gonad
  • Cure rates > 80% have been reported, including those with seminomatous overgrowth or metastases
Case reports
  • 10 year old girl, Turner mosaic with Y chromosome material identified by restriction fragment analysis and unilateral microscopic gonadoblastoma (Am J Clin Pathol 1988;90:622)
  • 12 year old girl with minute Y chromosome derived marker (J Med Genet 1992;29:542)
Treatment
  • Some cases undergo spontaneous involution
  • Treatment of choice is excision of gonadoblastoma and dysgenetic gonads prior to neoplastic transformation; however, timing of surgery varies with underlying disorder of sexual development
    • For mixed gonadal dysgenesis and mosaicism, surgery recommended before puberty, as early as possible
    • For complete androgen insensitivity (pure gonadal dysgenesis), surgery recommended after completion of puberty but before age 20:
      • Allows development of female breast by peripheral conversion of testosterone by aromatase into estrogens
      • Incidence of gonadoblastoma or other germ cell tumors before age 20 is negligible in these patients
      • Patients are usually diagnosed at puberty when they present with primary amenorrhea
Clinical images

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Abnormal external genitalia

Gross description
  • Tumor size varies from microscopic to 8 cm
  • Yellow to tan nodules with gritty cut surface
  • No hemorrhage or necrosis unless transformation to malignant germ cell tumor
Gross images

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Gonadoblastoma and dysgerminoma in gonadal dysgenesis

Microscopic (histologic) description
  • Three growth patterns
    1. Most common: round / irregular clusters of immature Sertoli cells and germ cells surrounded by basement membranes, with Sertoli cells encircling rounded hyaline nodules
    2. Sertoli cells surround large germ cells
    3. Germ cells occupy center of nests with peripheral ring of Sertoli cells
  • Stroma may contain large polygonal cells indistinguishable from Leydig cells: common in postpubertal patients
  • Calcification common: may be focal involving hyaline bodies or extensive
  • 50% have coexisting or subsequent seminoma
  • 8 - 10% develop other germ cell malignancies (Am J Obstet Gynecol 1972;113:410)
Microscopic (histologic) images

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Various images - site unspecified

With ITGCN-like appearance

Ovarian tumors


Female patient

Female phenotype

Positive stains
Electron microscopy description
  • Some cells show Charcot-Böttcher filaments of Sertoli cells
Molecular / cytogenetics description
  • Germ cells are aneuploid (Histopathology 1997;30:177)
  • Tsuchiya identified gonadoblastoma locus near Y centromere; TSPY gene is most likely candidate
    • TSPY is expressed in adult spermatogonia and fetal gonocytes and has vital functions in male stem / germ cell proliferation
    • It is ectopically expressed in gonadoblastoma, seminoma, ITGCN, some nonseminomatous germ cell tumors
    • TSPY expression correlates with PLAP, c-kit, OCT3 / 4
  • Seminomas and nonseminomatous tumors arising within dysgenetic gonad are usually diploid, unlike those arising from normal gonad (Genes Chromosomes Cancer 1999;25:134, Cancer Genet Cytogenet 1991;57:219, Cancer Res 1998;58:3105)
Differential diagnosis
  • Sertoli cell tumor with nodules with entrapped germ cells in a may be mistaken for a gonadoblastoma