Laparoscopy in the Surgical Treatment of Disorders of Sexual Development

Abstract

Introduction:

Disorder of sexual development (DSD) is a rare condition. The surgical treatment of these patients includes investigation of the internal genitalia, evaluation of the gonads, and if necessary gonadectomy. The prevention of germ cell tumors is the most important issue in the surgical treatment of this varied and special group of patients. This study aimed to evaluate the role of laparoscopy in the surgical treatment of patients with DSD.

Materials and Methods:

Over a 4-year-period, all patients presenting with DSD who underwent laparoscopic surgery at our institution were retrospectively reviewed. Operative procedure, age at the time of surgery, and histopathological results were evaluated. In addition, karyotypes and phenotypes were investigated.

Results:

Altogether, 12 patients undergoing 14 laparoscopic procedures were included. Median age at the time of surgery was 6 years with a range from 9 months to 17 years. Explorative laparoscopy was performed in all patients. In seven children, laparoscopic gonadectomy was necessary. Histopathologic examination revealed germ cell tumors in four children. In two patients, a gonadoblastoma was identified; in two patients, a dysgerminoma was found. Inguinal exploration was performed in four patients and led to removal of gonadal remnants in one case and gonadopexy in three cases. In two patients presenting with repeated urinary tract infections, laparoscopic removal of an utriculus was performed.

Conclusions:

Laparoscopic gonadal biopsy, gonadopexy, and gonadectomy can be performed successfully, even in patients with germ cell tumors. To define guidelines for the surgical treatment of patients with DSD, further prospective and multicenter studies are necessary.

Introduction

Disorder of sexual development (DSD) is a rare condition and there are only few reports in the literature. In the consensus conference on intersex, the term DSD was proposed to define congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.¹ Abnormal sexual differentiation primarily requires prevention of germ cell tumors. Furthermore, gender assignment for rearing is determined to clarify the issue of sexual ambiguity. The surgical treatment of DSD includes investigation of the internal genitalia, evaluation of gonads, and if necessary gonadectomy or relocation of gonads.² Laparoscopy has been shown to improve the cosmetic results and to reduce the psychological trauma. The lack of scars is important for this special group of patients who need reaffirmation of their body image and self-esteem.³ The aim of this study was to evaluate the role of laparoscopy in the surgical treatment of the inhomogeneous group of patients presenting with DSD.

Material and Methods

All patients presenting with DSD who underwent laparoscopic surgery between January 2010 and 2014 were included in this retrospective study. Operative procedure, intraoperative findings, age at the time of surgery, and histopathological results were evaluated. In addition, we analyzed karyotype and phenotype of these patients.

Operative procedure

All laparoscopic procedures were performed under general anesthesia and tracheal intubation. All patients were placed in a lithotomy position to perform cystoscopy and when indicated colposcopy. Afterward, the patients were placed in a supine position. One 10 mm trocar was placed in the umbilicus, and a pneumoperitoneum was created using a maximum pressure of 12 mm Hg. Two or three additional 5 mm trocars were placed in the left and right lower abdomen under visual control. First, the internal genitalia were inspected and the procedure was continued according to the actual intraoperative findings.

Results

Altogether, 12 patients undergoing 14 laparoscopic procedures were included in this retrospective study. Median age at the time of surgery was 6 years with a range from 9 months to 17 years. Phenotypically, seven patients presented as males (58.3%) and five as females (41.7%). Karyotype analysis identified two patients with 45,X/46,XY mixed gonadal dysgenesis (MGD), one patient with 46,XX/46,XY chimerism, two patients with complete gonadal dysgenesis (CGD), and one patient with 5-alpha reductase deficiency. Table 1 demonstrates karyotypes and classification of all included patients.

Table 1.

Histopathological Results, Age at the Time of Surgery, Karyotype, and Classification of 12 Patients with DSD Undergoing Laparoscopic Surgery

Pt No.	Gender	Karyotype	Classification	Age at surgery	Pathology
1	m	45,X0/46,XY	MGD	8 month	Gonadoblastoma
2	f	46,XY	CGD (Swyer syndrome)	10 years	Dysgerminoma, streak gonad
3	f	45,X0/46,XY	MGD	17 years	Streak gonads, no tumor
4	m	46,XY		1 year	Testicular tissue, no tumor, fallopian tubes, uterus
5	f	46,XY	CGD (Swyer syndrome)	15 years	Dysgerminoma, streak gonad
6	m	46,XY inv (9), (p11q13)		2 years	Utriculus
7	f	46,XY (alpha-Reduktase mangel)	5-alpha-reductase deficiency	1 year	No germ cells, no tumor
8	m	46,XY		1 year	Immature testicular tissue, no tumor
9	f	45,X0/46,XY	MGD	15 years	Bilateral gonadoblastoma
10	m	46 XX/46 XY chimerism	Chimerism	1 year	Bilateral ovotestis
11	m	46,XY		11 years	No gonadal tissue
12	m	46,XY		2 years	Not done

CGD, complete gonadal dysgenesis; DSD, disorder of sexual development; f, female; MGD, mixed gonadal dysgenesis; m, male.

Explorative laparoscopy was performed in all patients. In 7 of 12 patients (58.3%), laparoscopic gonadectomy was necessary due to the intraoperative findings suggesting the presence of a tumor or preoperative genetic evaluation resulting in a high tumor risk. Four patients (33.3%) underwent diagnostic laparoscopy and subsequent inguinal exploration. In one patient (8.3%), removal of gonadal remnants was necessary; in three patients (25.0%), gonadopexy was performed. Gonadopexy was performed to facilitate the postoperative surveillance for tumor development. In two patients (16.7%) presenting with repeated urinary tract infections, laparoscopic removal of an utriculus (remnant of paramesonephric ducts) was performed. At our institution, explorative laparoscopy was performed in all DSD patients with uncertain diagnosis and unclear location of the gonads. Preoperatively, chromosomal analysis and cytogenetic and biochemical tests were performed by specialized pediatric endocrinologists in all patients.

Histopathological examination revealed germ cell tumors in four of seven patients (57.1%) who underwent laparoscopic gonadectomy. In two patients, a gonadoblastoma could be identified; in two patients, a dysgerminoma was found. Table 1 demonstrates patient classification, karyotype, and histopathological findings of all 12 patients included in this study. The two children with identified gonadoblastoma were found to have MGD with karyotype 45,X/46,XY and the two patients with detected dysgerminoma were found to have Swyer syndrome. In all four patients with germ cell tumors, the intraoperative findings of the gonads were highly suspicious for a tumor. The gonads could be preserved in 3 of 12 patients (25.0%).

Discussion

Patients presenting with DSD are a heterogenous group with different congenital conditions leading to atypical development of chromosomal, gonadal, or anatomic sex.¹ Surgical treatment includes gender assignment in cases with uncertain diagnosis, gonadectomy, or orchidopexy depending on the diagnosis and chromosomal analysis. In the majority of patients, the diagnosis is made on the basis of cytogenetic and biochemical tests.² The important challenge is to identify and timely treat forms of DSD who carry an increased risk for the development of germ cell tumors. The individual risk is estimated based on the molecular diagnosis and age.⁴ Already in 1976, Manuel at al. showed that tumor formation increases with age.^5,6 Undescended dysgenetic testes and streak gonads are highly predisposed to gonadal tumor formation.⁵ Tumors are primarily gonadoblastomas and dysgerminomas. Gonadoblastomas have a low malignant potential, whereas dysgerminoma is a malignant tumor commonly found in dysgenetic gonads that have even been found in young patients.⁵ There is a 20%–25% age-related risk for malignant transformation of a gonadoblastoma into a dysgerminoma.⁷ In some cases, gonadoblastomas are hormonally active and secrete estrogens or androgens, which may mask gonadal dysgenesis and retard diagnosis.⁸ The predisposition of dysgenetic gonads for tumor formation may be the result of high levels of circulation of gonadotropins.⁵ Dysgenetic gonads with the presence of a Y chromosome, or a translocated fragment of it, have a significant risk of developing gonadoblastoma.⁶ Zieliñska et al. reported gonadal tumors in six of eight (75%) patients with Swyer syndrome.⁸ Gonadoblastoma was the usual tumor identified in five of eight patients, including two cases with gonadoblastoma and dysgerminoma. Dysgerminoma was diagnosed in one patient.⁸ Swyer syndrome belongs to the group of CGD with karyotype 46,XY. Another group of DSD with increased tumor risk are patients with “classic” MGD and karyogramm 45,X/46,XY. They are the most commonly reported group of DSD to develop gonadoblastoma.⁶ Early gonadectomy is advised in this group of patients because the risk of malignancy approaches 50%–70% in the third decade and 80% at age 40.⁶

Our retrospective study includes two patients with gonadoblastoma and two patients with dysgerminoma. The two patients with gonadoblastoma had MGD with karyotype 45,X/46,XY. One of these two patients was 8 months old, the other one 15 years old. The two patients diagnosed with dysgerminoma had Swyer syndrome. They underwent laparoscopic gonadectomy at the age of 10 and 15 years. In the literature, early gonadectomy is warranted to prevent tumor development in patients with CGD and MGD with the presence of Y chromosomal material.^4,2 In some other forms of DSD, early gonadectomy is not mandatory according to the current literature published by Wünsch et al.⁴ According to their recommendation, patients with complete androgen insensitivity syndrome may benefit immensely from preservation of the gonads beyond puberty.⁴ However, they are at increased risk for the development of tubular in situ neoplasia, and close surveillance is mandatory. Further follow-up of these patients is necessary to decide on the recommendation of gonadectomy after puberty in this group of patients.

In 1992, the first laparoscopic bilateral gonadectomy in an intersex patient was reported by Wilson et al.⁹ Minimal-invasive surgery provides several advantages, especially for this special group of patients. Magnification and illumination enable excellent visualization of even small pelvic structures. The lack of scars is another very important aspect for these infants and children, who need reaffirmation of their body image and self-esteem.³ Generally, gonadal evaluation, biopsy, fixation, and even gonadectomy are straightforward operations.³ In addition, laparoscopy can also be used to identify internal ductal derivates and to remove structures contrary to the assigned gender.^3,9,10

In the past, reports about the surgical management of patients presenting with DSD have already been published. Nevertheless, until today, no surgical guidelines are available. The main causes are the rareness of these disorders and the variety of chromosomal, gonadal, or anatomic combinations. Therefore, individualized care is necessary and should be based on exact diagnosis and best possible assessment of the phenotype.⁴ Certainly, prevention of germ cell tumors is the most important challenge in this group of patients. Early gonadectomy is advised in patients presenting CGD karyotype 46,XY, in patients with MGD and the presence of Y chromosomal material. Laparoscopic gonadal biopsy, gonadopexy, gonadectomy, and other procedures have already been performed, but reports are scarce.^4,10–14 Until today, large series or prospective studies are not available. The present study also includes only few patients undergoing laparoscopy in the surgical treatment of DSD. This is a limitation of the present study, as well as the retrospective study design. In the future, prospective multicenter studies, including a large number of patients, are necessary to define guidelines for the surgical treatment of DSD patients. In the United States and in Europe, prospective registries (DSD-TRN and iDSD) have already been established for the long-term follow-up of this special group of patients.

Finally, a recommendation is made that patients should be followed long term. That is true and there are prospective registries in the United States (DSD-TRN) and in Europe (iDSD) that are doing just that.

Conclusion

Minimally invasive surgery provides several advantages for the heterogenous group of patients presenting with DSD. Magnification and illumination of pelvic structures and almost scarless surgery are the most important beneficial factors. Laparoscopic gonadal biopsy, gonadopexy, and gonadectomy are feasible and safe. Minimal-invasive gonadectomy can also be performed in patients with germ cell tumors. In the future, further studies are necessary to define guidelines for the surgical treatment of this special group of patients.

Footnotes

Disclosure Statement

No competing financial interests exist.

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