Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

Abstract

Patients with complete androgen insensitivity syndrome are at an increased risk for the development of gonadal germ cell cancer. Residual androgen receptor (AR) activity and abnormal gonadal location may influence the survival of atypical germ cells and the development of other histopathological features. To assess this, we evaluated 37 gonads from 19 patients with complete androgen insensitivity (ranging in age from 3 months to 18 years). Histological abnormalities were examined using hematoxylin and eosin-stained sections and sections stained for POU5F1 and KITLG, markers of early changes in germ cells at risk for malignant transformation. Hamartomatous nodules (HNs), Leydig cell hyperplasia (LCH), decreased germ cells, tubular atrophy and stromal fibrosis were more pronounced as age increased (Po0.001). Expected residual AR activity acted as a positive predictor only for non-malignant germ cell survival in (post)pubertal patients (Po0.05). Immunohistochemical studies indicated that delayed maturation of germ cells was present in three patients, whereas intermediate changes that occurred between delayed maturation and intratubular germ cell neoplasia, designated pre-intratubular germ cell neoplasia, were identified in four cases. Intratubular germ cell neoplasia was observed in one patient. Neither POU5F1 nor KITLG expression was dependent on expected residual AR activity. An independent effect of inguinal versus abdominal position of the gonads was difficult to assess because inguinal gonads were present primarily in the youngest individuals. In conclusion, many histological changes occur increasingly with age. Expected residual AR activity contributes to better survival of the general germ cell population in (post)pubertal age; however, it did not seem to have an important role in the survival of the germ cells at risk for malignant transformation (defined by POU5F1 positivity and KITLG overexpression) in complete androgen insensitivity. Comparison of the high percentage of patients in our study that were carrying germ cells with delayed maturation or pre-intratubular germ cell neoplasia with previously reported cumulative risk of tumor development in adult patients indicates that not all such precursor lesions in complete androgen insensitivity will progress to invasive germ cell cancer.

Androgen Insensitivity Syndrome at Prepuberty: Marked Loss of Spermatogonial Cells at Early Childhood and Presence of Gonocytes up to Puberty

“…The same was observed for the percentage of tubules with at least 1 germ cell. The early onset of germ cell loss observed in our patients is congruent with previous publications [Rutgers and Scully, 1991;Hannema et al, 2006;Kaprova-Pleskacova et al, 2014]. The number of germ cells per tubule and the percentage of MAGE-A4 positive tubules in testes of prepubertal and pubertal patients were very similar, further indicating that the damage in germ cells is established early in prepubertal life.…”

Management of Gonads in Adults with Androgen Insensitivity: An International Survey

“…In countries where the diagnosis of CAIS is rarely made early and/or gonadectomy is not commonly performed due to socioeconomic or cultural reasons, invasive or clinically manifest GGCC are seldomly reported [19]. In line with this observation, it has been found that only few in situ lesions progress to invasiveness in individuals who have AIS [20]. A small number of studies report a positive effect of retained gonads on bone mineral density in women with CAIS, which cannot always be obtained by hormone replacement therapy (HRT) [21, 22].…”

“…However, it is unclear to what extent these lesions will show invasive progression later in life [16, 18-20, 26-28]. To the best of our knowledge, no invasive GGCC had occurred so far in the 166 adult women included in our survey.…”

A novel inactivating mutation of the LH/chorionic gonadotrophin receptor with impaired membrane trafficking leading to Leydig cell hypoplasia type 1

“…This is most probably due, on one hand, to the limited AR stimulation. In a recent study, Kaprova-Pleskacova et al (18) found that survival of germ cells in CAIS patients was significantly related to the residual AR activity. On the other hand, germ cell numbers in CAIS patients decrease with age, with a rapid decline after the first year of life (19).…”