BACKGROUND: Histological diagnosis of patients with abnormal gonadal differentiation poses a challenge due to the rare nature of these disorders and unclear definition of pathologic findings. Herein we report two cases of gonadoblastoma misdiagnosed as ovotesticular syndrome. We present a series of immunohistochemical markers to differentiate gonadoblastoma and gonadal dysgenesis from ovotesticular syndrome. METHODS: Two patients seen in our disorders of sexual differentiation (DSD) clinic with incorrect diagnosis of 46XY ovotesticular syndrome were reviewed. Patient 1 had an initial diagnosis of ovotestis from a gonadal biopsy which was revised to streak gonad with gonadoblastoma after gonadectomy. Patient 2 had a diagnosis of ovotesticular syndrome which was revised after re-review.We obtained pathology specimens from other patients in our DSD clinic with 46XY karyotype and who had previously had gonadectomy or biopsy. Pathology specimens were sectioned and stained with markers for germ cells (SALL4, DDX4, OCT4), Sertoli cells (SOX9, Inhibin, AMH), Leydig cells (Calretinin, Cytochrome p450c17), and others (androgen receptor, smooth muscle alpha-actin). These findings were also compared to patient specimens with ovotesticular syndrome. RESULTS: In addition to the two index patients, six patients were identified from our DSD study cohort who had 46XY gonadal dysgenesis and available pathology specimens. Two of these patients had gonadoblastoma. Six specimens with ovotestis were also analyzed. Summary of findings in Table 1. Comparison between true ovotesticular, misdiagnosed gonadoblastoma, and gonadoblastoma is shown in Figure 1. Significant differences can be seen in OCT4 expression, which is clumped together in gonadoblastoma and either negative or sparse in ovotestis. Gonadoblastoma was found to have clusters of FOXL2 positive cells, whereas in ovotestis, FOXL2 positivity was limited to ovarian follicles and ovotesticular cords. Ovarian follicles were not identified in any of the gonadoblastoma tissue. Gonadal dysgenesis gonads showed minimal testicular cord structure when evaluated by inhibin staining. CONCLUSIONS:
We previously reported a series of twenty patients with ovotestis. In that study, six of the twenty ovotestis gonads did not meet criteria for ovotesticular syndrome as they did not have both testicular cords and ovarian follicles. Similarly, the two patients misdiagnosed with ovotesticular syndrome had ovarian type stroma and possible follicles on initial pathology review. On reassessment, previously noted follicles were in fact clumps of gonadoblastoma that were OCT4 and FOXL2 positive. No follicles were identified in the gonadoblastoma patients, which is a critical piece for diagnosis of ovotesticular syndrome. Based on morphology and staining we emphasis the histologic diagnosis of 1. dysgenic gonads (sparse OCT4 positivity, irregular cord structure, fibrotic stroma). 2.ovotestis (testicular cords and ovarian follicles), and 3. gonadblastoma (OCT4 positive clumps, no follicular structure).Attention to exact pathologic diagnosis as defined above will lead to the correct diagnosis and risk assessments for these complex patients.
