Pathology of Differences in Sex Development

Various DSD diagnoses are usually evident from clinical evaluation and preliminary investigations including karyotype, imaging and hormonal studies. However, some may require histopathological examination of the gonads and genital ducts to clinch a final diagnosis. The role of the pathologist extends beyond establishing a diagnosis to identifying premalignant and malignant lesions in these gonads. The commonest DSDs are congenital adrenal hyperplasia and mixed gonadal dysgenesis. Gross and microscopic features of the gonads and genital ducts in various DSD, especially different forms of gonadal dysgenesis, Persistent Mullerian Duct syndrome, Androgen Insensitivity Syndrome and Ovotesticular DSD are discussed. The aberrant genesis of a streak gonad during ovarian or testicular differentiation and the pathology of an ovotestis are detailed. A partial, asymmetric, and ipsilateral development of Mullerian /Wolffian ducts is typical of both gonadal dysgenesis and ovotesticular DSD. Premalignant and frankly malignant gonadal lesions are often detected at diagnosis itself. Germ Cell Neoplasia In Situ (GCNIS) and gonadoblastomas can develop in a dysgenetic gonad, gonadoblastomas being the precursor lesions of germ cell tumors. The risk of malignancy is higher in mixed gonadal genesis, PAIS (partial androgen insensitivity syndrome), Fraiser and Denis Drash syndrome; and lower in ovotesticular DSD and in CAIS (complete androgen insensitivity syndrome). The histology of the gonad in DSD is often challenging and a final diagnosis is made with careful deliberation on paraffin sections. However, frozen section diagnosis, immunohistochemistry, and molecular studies like FISH are useful in select situations.