Table 1 GRADE evaluation of literature for timing of gonadectomy

Wunsch, et al. 2012 [33]

Observational Cohort study

8 patients with CGD underwent gonadectomy:

All patients with CGD had intra-abdominal gonads

Early gonadectomy for patients with CGD

Small sample size, lack of blinding, lack of allocation concealment

-Ages ranged from 1–25 years

All patients with PGD had intra-abdominal streak gonads.

For patients with PGD and non-scrotal gonads, early gonadectomy may be warranted

-3 patients (37.5%) had evidence of in situ neoplasia (ages 3, 12, 18);

-2 of these patients also had dysgerminoma. 12 patients with PGD had gonadal tissue evaluation:

1 patient (8.3%) had gonadoblastoma at age 6

Johansen, et al. 2012 [34]

Observational Retrospective study

15 patients with PGD (45X/46,XY and variants) had gonadal samples for review:

14 year old male had left inguinal dysgenetic testis with CIS

No specific recommendations for timing, does indicate that CIS originates before puberty

Small sample size, lack of blinding, lack of allocation concealment, ascertainment bias

-3 patients (20%) had evidence of In situ Neoplasia:

2 year old male with right inguinal dysgenetic testis

4 year old female with left inguinal dysgenetic testis

-2 males (ages 2 and 14) and 1 female (age 4) had CIS

Martinerie, et al. 2012 [35]

Observational Retrospective Study

20 boys with PGD (45,X/46,XY) were studied

13 year old with intra-abdominal streak gonad

No specific recommendations for timing of gonadectomy.

Small sample size, lack of blinding, lack of allocation concealment

-2 patients (10%) had evidence of malignancy:

23 year old with intrascrotal dysgenetic testis (inguinal at birth with orchidopexy at 9 years of age).

Recommend strict surveillance of gonads and testicular function in patients with PGD raised as males

Dysgerminoma found in a 13 year old male.

Seminoma found in a 23 year old male.

Rocha, et al. 2011[20]

Observational Retrospective study

9 patients with XY CGD who had histology available.

Abdominal

Recommend gonadectomy at diagnosis

Limited sample size, lack of blinding, lack of allocation concealment

-Gonadoblastoma in 4 patients (44%) ages 14–17, Two of which also had dysgerminoma (22%)

Cools, et al. 2011[36]

Observational study

Obtained 84 gonadal samples from 39 patients with PGD who were 45,X/46, XY:

1 patient with mild undervirilization had right abdominal gonad with gonadoblastoma (age not specified)

In females with PGD, tumor risk is limited but gonads are not functional, making gonadectomy the most reasonable option.

Small sample size, lack of blinding, lack of allocation concealment, selection bias (no gonadal tissue from undiagnosed 45,X/46,XY males).

-In Situ Neoplasia found in 4 different patients (10.2%).

1 patient with ambiguous phenotype had left abdominal gonad with gonadoblastoma (age 1)

Malignancy risk in males appears inversely related to degree of virilization (more virilized, less risk).

-3 patients had gonadoblastoma, 1 had CIS.

1 patient with ambiguous phenotype had dysgenetic inguinal testis with gonadoblastoma (age 1)

Low threshold for gonadectomy in males with ambiguous genitalia.

1 patient with female phenotype had right abdominal gonad with CIS (age 16)

For mildly undervirilized males: 1 prepubertal biopsy and 1 post-pubertal biopsy

Michala, et al. 2008 [37]

Observational Retrospective study

Gonadal histology reviewed in 22 patients with Swyer syndrome:

Abdominal

Recommend bilateral gonadectomy as soon as diagnosis is made

Limited sample size, retrospective study

-45% with germ cell tumors;

-32% with dysgerminoma (ages 10–31 years)

-14% with gonadoblastoma (ages 17, 19, and 27 yrs)

Cools, et al. 2006 [14]

Observational Retrospective Study

60 gonadectomy samples from 43 patients with gonadal dysgenesis (included CGD and PGD):

Did not specify gonadal location

Gonadal histology revealing undifferentiated gonadal tissue or testicular tissue staining positive for OCT3/4 on the basal lamina contains high risk for gonadal tumors and should lead to immediate gonadectomy.

Small sample size, lack of blinding, lack of allocation concealment

-35% incidence of germ cell tumors in patients with GD (n = 16), ages ranging from 4 months-25 yrs).

Testicular tissue displaying maturation delay of germ cells can be left in situ, given that its localization allows for adequate follow-up.

-All but 1 patient with malignancy had Y chromosome material.

Ovarian tissue can be safely left in place

-Invasive germ cell tumors found in 13% (n = 6)

Streak is not functional, making its preservation controversial

Mazzanti, et al. 2005 [38]

Observational Study

Identified 14 Turner patients with Y-chromosome material:

Abdominal

Recommend bilateral gonadectomy for all Turner patients with Y chromosome material

Limited sample size, lack of blinding, lack of allocation concealment.

-12 out of 14 patients consented to gonadectomy:

33% of gonadectomized patients had gonadoblastoma (ages 2,7,11, 15 yrs)

The 15 year-old patient also had a immature teratoma, and a endodermal sinus tumor

Slowikowska-Hilczer, et al. 2003 [39]

Observational Study

Gonadal histology reviewed in 40 cases of gonadal dysgenesis:

All gonads were located in the abdomen or upper segment of the inguinal canal

No specific recommendations for timing of gonadectomy

Limited sample size, lack of blinding, lack of allocation concealment

-67.5% had 46,XY Karyotype and the remainder had numerical and structural abberations of sex chromosomes.

One patient with 46,XY karyotype had seminoma from abdominal gonad (age 17)

CIS present in 14 patients (35%) with GD

Sex cord-derived tumors including gonadoblastoma nests and unclassified mixed germ cell-sex cord-stromal tumors were present in 11 patients (27.5%) with GD

Ages of malignancy ranged from 7 months to 19 years

Mendes, et al. 1999 [40]

Observational study

36 patients with Turner syndrome were studied:

Abdominal

Recommend gonadectomy in Turner Syndrome patients who are Y positive

Limited sample size, lack of blinding, lack of allocation concealment

Two patients were found to be Y positive by PCR

Of the two Y-positive patients, one had gonadoblastoma (50%)

Gourlay, et al. 1994 [42]

Observational Retrospective Study

11 patients with PGD had gonadal tissue for review:

All but 1 patient with PGD and malignancy had abdominal gonads

Recommend early gonadectomy in all patients with XY gonadal dysgenesis as tumors can develop at an early age

Limited sample size, lack of blinding, lack of allocation concealment

Six patients (54%) had germ cell tumors; ages ranging from 1 month to 19 years

1 PGD patient (age 19) with a seminoma had scrotal gonads

One patient with 46,XY CGD had a gonadoblastoma (age 17)

The patient with CGD had abdominal gonads

Robboy, et al. 1982 [43]

Observational Retrospective Study

Obtained gonadal tissue from 21 patients with PGD:

53 year old with gonadoblastoma had abdominal gonads

Recommend early gonadectomy

Limited sample size, lack of blinding, lack of allocation concealment

-Three patients (14.2%) with XY PGD had malignancy:

One patient had a gonadoblastoma and seminoma in a scrotal-inguinal gonad 15 years after the contralateral testis was removed (age not specified)

Two patients with XY PGD had gonadoblastomas and one of these was overgrown by a seminoma.

2 week old with seminoma had an abdominal gonad

One patient with XY PGD had seminoma (age 2 weeks)

Scully, et al. 1970 [9]

Observational Retrospective Study

Reviewed clinical characteristics of 74 cases of gonadoblastoma:

Majority were abdominal gonads

Recommend early gonadectomy

Lack of blinding, lack of allocation concealment

25 phenotypic females, 35 virilized females, 13 phenotypic males.

Inguinal gonadoblastomas were seen in several of the phenotypic males (exact number not specified)

43 patients had invasive germinoma

Ages ranged from 1 to 38 years

Karyotypes were available in 30/74 patients:

57% had 46,XY karyotypes

30% with 45,X/46,XY karyotype

3% (1 patient) with 45,X karyotype

10% with other forms of mosaicism