Table 1.

GRADE evaluation of literature for timing of gonadectomy

Study	Type of study	Diagnoses	Location of gonads that show malignancy: if specified	Conclusions from each study regarding timing of gonadectomy	Design limitations
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