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Table 3 GRADE evaluation of literature for immunohistochemical markers that can be used to determine high risk of malignancy in GD

From: Association of immunohistochemical markers with premalignancy in Gonadal Dysgenesis

Quality assessment Summary of findings Quality
Author Study design and objective Design limitations Sample Results/Conclusions
Inconsistency of results
Indirectness of evidence
Palma (2013) Retrospective Observational Study Insufficient sample size 18 gonadal samples from 15 pediatric patients with 45,X/46,XY PGD 1 patient had GB, 1 patient had DG Low
To determine whether OCT 3/4 and β-Catenin are expressed in dysgenetic gonads before GB development and whether TSPY participates in malignant invasive behavior No inconsistencies Ages not specified 14/18 samples stained + for OCT 3/4
Head-to-Head comparison in correct population Only 3 samples stained + for β-catenin
-Seen in Dysgenetic testes, UGT, GB, and DG, not + in streak tissue or mature germ cells
Tissue expressing OCT 3/4 and TSPY is associated with a high risk for GB development.
Suggest that β-catenin is not involved in dysgenetic gonad progression to GB, participates after GB is established.
Barros (2011) Retrospective Observational Study Insufficient sample size 32 gonadal samples from 16 patients with Turner Syndrome and Y chromosome material 19 % had + nuclear OCT4 staining, suggesting the presence of germ cell tumor cells (likely GB or CIS) Low
To investigate the frequency of gonadal tumors among patients with Turner syndrome and Y-chromosome material No inconsistencies Ages 8–18 yrs. OCT4 immunohistochemistry is more sensitive than conventional H&E staining to indicate the risk of development of germ cell tumors in TS patients
Head-to-Head comparison in correct population
Palma (2008) Retrospective Observational Study Insufficient sample size 7 patients with PGD and GB OCT 3/4 was + in the nuclei of immature germ cells in GB Low
To evaluate the participation of β-catenin and OCT 3/4 in the oncogenic pathways involved in the transformation of GB into seminoma/DG No inconsistencies Ages 2–33 m Β-catenin was overexpressed in immature germ cells in GB
Head-to-Head comparison in correct population Β-catenin and OCT 3/4 co-localized in immature germ cells in GB nests in all cases
The proliferation of immature germ cells in GB may be due to an interaction between OCT 3/4 and accumulated β-Catenin in the nuclei of the immature germ cells
Cools (2006) Retrospective Observational Study Insufficient sample size 60 gonadal samples from 43 patients with GD Incidence of GCTs was 35 % Low
To define the histological origin of GB, allowing the identification of high-risk patients No inconsistencies Ages 1 m-25 yrs. Germ cells within GB were + for OCT 3/4, c-KIT, PLAP, and TSPY
Head-to-Head comparison in correct population In UGT found adjacent to GB, OCT 3/4, PLAP, and c-KIT + germ cells were found
A gonadal biopsy revealing the presence of UGT with OCT 3/4 + cells on the basal lamina contains high risk for GCT and should lead to gonadectomy.
Quality assessment Summary of findings Quality
Author Study design and objective Design limitations Sample Results/Conclusions
Inconsistency of Results
Indirectness of Evidence
Cools (2005) Retrospective Observational Study Insufficient sample size 58 gonadal samples from 30 patients with undervirilization syndromes OCT 3/4 was found in all patients <9 m of age Low
To distinguish germ cells with maturation delay from those with CIS Different populations (not looking specifically at GD patients) Ages 1 m-23 yrs. -In young patients and controls, OCT 3/4 + cells were found centrally in the tubule
-In 3 older patients with CIS, OCT 3/4 + cells were found along the basal lamina
Expression of PLAP and c-KIT was similar to OCT 3/4, but less consistent
The presence of germ cells + for OCT 3/4, PLAP, or c-KIT in patients < 1 yr is in accordance with expected maturation delay and is insufficient for the diagnosis of CIS.
The location of OCT 3/4 positive cells is important in differentiating between CIS and maturation delay
Kersemaekers (2005) Retrospective Observational Study Insufficient sample size 6 gonads from 5 patients with GD containing GB 4 patients had DG arising from GB Low
To investigate the pathogenesis of GB and evaluate its relationship to CIS. No inconsistencies
Head-to-Head comparison in correct population Ages 14–21 yrs. c-KIT was the least consistent marker
PLAP was + in all GBs and adjacent invasive components.
Most of the tumor cells in invasive DG were weakly + or - for PLAP.
OCT 3/4 was + in all GBs and DGs
Seen in more immature cells, not mature cells
The development of an invasive germ cell tumor seems to involve selection and clonal expansion of an immature germ cell + for OCT 3/4 and TSPY
Slowikowska-Hilczer (2001) Retrospective Observational Study Insufficient sample size 23 patients with XY GD On the basis of PLAP expression, CIS was detected in 10 cases (43.5 %) with GD. Low
Ages 3 m-7 yrs. GB was found in 4 cases of GD and DG was found in 1 patient with GD (17 years old)
No inconsistencies
To investigate the appearance of CIS in patients with 46,XY testicular dysgenesis in different ages and in adult patients from other groups
Head-to-Head comparison in correct population
Results showed a high prevalence of CIS in XY GD, indicating the importance of early histopathological evaluation of the gonads in these patients