Dysgerminoma in Swyer Syndrome: A Rare Case Report and Review of the Literature

Introduction

Swyer syndrome or 46,XYcomplete gonadal dysgenesis (46,XY CGD) is a disorder of sex development (DSD) in which an individual is 46,XY in genotype but phenotypically a female. This entity was first recognized in 1955 when G.I.M. Swyer, FRCP, described 2 cases of sex reversal that differed from the known forms of what was then termed “male pseudohermaphroditism.” The 2 women had the 46,XY karyotype, primary amenorrhea, tall stature, female external genitalia, and normal vaginas and cervices. ¹ This condition was linked to dysgenetic gonads later and is now also known as CGD. ² These individuals are typically raised as females and have female gender identity. Swyer syndrome has been estimated to occur in ∼1 of 80,000 people. The diagnosis relies on clinical findings, gonadal history, chromosome analysis, and testing to detect changes in one of the following genes: SRY, NR5A1, DHH, NR0B1, or WNT4. Patients with Swyer syndrome show hypergonadotrophic hypogonadism with low levels of estrogens and normal female levels of androgens, and usually present with primary amenorrhea and delayed puberty. The syndrome may also present in late adulthood with gonadal tumors that are typically dysgerminomas. This article reports on a case of a dysgerminoma arising in Swyer syndrome.

Institutional ethical committee approval was obtained, and written informed consent was obtained from the patient for publication of this case report and its accompanying figures.

Case

A 16-year-old female sought care for primary amenorrhea; she presented at the endocrinology department of the Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupathi, Chittoor District, Andhra Pradesh, India. She reported experiencing thelarche at 12 years of age. She had taken oral contraceptive pills for a few months for primary amenorrhea, during which she had withdrawal bleeding. On physical examination, her height was noted to be 160 cm and weight was noted to be 42 kg. Her breast and pubic hair were consistent with Tanner stage II. She had no axillary hair. Her vagina was eutrophic. She had no clitoromegaly. There was no family history of primary amenorrhea, genital-tract tumors, or disorders of sexual development.

Hormonal analysis showed that this patient had elevated levels of serum and follicle-stimulating hormone (FSH), luteinizing hormone (LH), and lactate dehydrogenase; and a low level of estradiol; but the levels of other tumor markers and her thyroid profile were within normal ranges (Table 1). A buccal smear was negative for Barr bodies (“drumsticks”). A peripheral smear did not reveal any drumsticks in the neutrophils. Her karyotype was 46,XY (Fig. 1). Her X-ray bone age was 14 years and 4 months. An ultrasound (US) of her abdomen revealed a hypoplastic uterus and a 5 × 3.6–cm mass in the left adnexa. Magnetic resonance imaging (MRI) of her pelvis showed a 5.7 × 4.0–cm left adnexal mass with a suspicion of malignancy (Fig. 2).

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FIG. 1.

Karyotype of the patient with her 46,XY component.

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FIG. 2.

Magnetic resonance image of the patient's pelvis (T2-weighted image) showing a left-side gonadal mass.

An exploratory laparotomy was performed, and the intraoperative findings showed a 7 × 5–cm left gonadal mass with a streak gonad on the right side; her uterus appeared to be normal for her age (Fig. 3). Thus, uterus preserving surgical staging was performed.

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FIG. 3.

Intraoperative image showing a left-side gonadal tumor with a right streak gonad.

Results

Grossly, the left gonadal tumor measured 7.5 × 5.5 × 3 cm with a gray-brown, shiny lumpy surface. Upon sectioning, multiple gray-white nodules were noted. The final histopathologic report indicated that the tumor was a stage IA dysgerminoma (Fig. 4).

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FIG. 4.

Photomicrograph of the patient's left gonad showing lesional cells in the form of cords, tubules and nests (hematoxylin and eosin 20 × ).

Discussion

Individuals with Swyer syndrome show female phenotypes and are typically raised as girls; these individuals are generally diagnosed in adolescence when they seek medical assistance for amenorrhea and the absence of secondary sex characteristics. In 2006, a consensus statement was issued that recommended using the DSD classification to replace various terms that are no longer utilized, such as pseudohermaphrodite, intersex, and sex reversal, among others. ³ The exact incidence is unknown. Swyer syndrome has been estimated to occur in 1 in 80,000 births. CGD is characterized by a female phenotype, nonambiguous genitalia, the presence of Müllerian derivatives, gonadal dysgenesis, and a normal karyotype. ⁴ The existence of a uterus is important in the definition of gonadal dysgenesis. In Swyer syndrome, the uterus is present and it is generally hypoplastic but, in the current case, the uterus was appropriate for the patient's age as was noted intraoperatively (Fig. 3). The absence of a uterus has been regarded by a number of researchers as a criterion for the diagnosis of androgen insensitivity syndrome. Because of the existence of a uterus, the current case was not thought as androgen insensitivity syndrome. It was defined as Swyer syndrome.

The etiology of 46,XY gonadal dysgenesis is thought to be a short-arm Y chromosome deletion involving SRY, a mutation in other genes that leads to inhibition of SRY function or mutation of SRY function. ⁵ To date, 20% of 46,XY pure gonad dysgenesias are explained by a mutation or a deletion in SRY. In 80% of these cases, SRY is apparently normal. A female patient with an XY karyotype who has a palpable Müllerian system, normal female testosterone levels, and a lack of sexual development is considered to have Swyer syndrome. ⁶

In the current case, this patient's breast and pubic hair were consistent with Tanner stage III. Her vagina was normal and her cervix was small; these characteristics are in accordance with the typical traits of patients with Swyer syndrome. A hormonal evaluation showed elevated gonadotropins (FSH: 159 IU/L; LH: 50 mIU/L) and low estradiol (22 pg/mL). Patients with Swyer syndrome are usually normal or, more frequently, tall in stature. ⁷ The current patient was 160 cm height and 42 kg weight.

Transabdominal US is the first choice diagnostic imaging method for investigating such lesions, with MRI restricted to cases where US is inconclusive. ³ In the present case, a US of the patient's abdomen revealed a hypoplastic uterus, a 5 × 3.6–cm mass in the left adnexa, and ovaries not visualized separately. A further investigation with an MRI of the pelvis showed a 5.7 × 4.0–cm left adnexal mass with a possibility of malignancy.

Differential diagnoses of patients with primary amenorrhea should include various possibilities, including Mayer–Rokitansky–Küster–Hauser syndrome (XX), which is the second most common cause of this condition; this syndrome is characterized by varying degrees of Müllerian-duct abnormalities and a rudimentary or absent uterus. ⁸ In addition, complete androgen insensitivity syndrome should be considered. Patients with this syndrome, which was formerly known as Morris syndrome, are XY individuals with primary amenorrhea and normal breast and vaginal development but have no uterus. ⁹

Ovarian cancer is the second most common gynecologic malignancy worldwide, and it remains one of the leading causes of gynecologic cancer–related deaths. Comprehensive global cancer statistics from the International Agency for Research on Cancer indicated that gynecologic cancers accounted for ∼28% of all the malignancies in India, of which ovarian cancers account for 5%, making this cancer the second most common gynecologic malignancy even in India next to cervical cancers. ¹⁰ According to the GLOBOCAN 2012 estimate, the incidence of ovarian cancers in India was 26,834. The age-standardized incidence rate was 4.9 per 1,00,000 women, and 5-year prevalence was 55,231 (4.9%). In the year 2012, 19,549 deaths were noted, accounting for 6% of overall cancer-related mortality in women. ¹¹

The three major types of ovarian tumors are epithelial, sex-cord (5%–8%), and germ-cell. Epithelial-cell tumors represent the majority of all ovarian neoplasms (90%). Conversely, germ-cell tumors (GCTs) are rare, comprising ∼2%–3% of all ovarian tumors, both benign and malignant. Approximately 3%–5% of ovarian GCTs are malignant. The most commonly occurring GCT is the dysgerminoma, which accounts for ∼2% of all ovarian cancers. In Swyer syndrome, the gonads are at a high risk for gonadal tumors, which are typically gonadoblastomas and/or dysgerminomas. ⁴ Dysgerminomas are generally rare, accounting for <2% of ovarian tumors, but have a high malignant potential; however, this type of tumor is found in 1 of every 3 individuals with Swyer syndrome. Dysgerminomas typically present with abdominal pain (70%–80%) and a lower abdominal mass. ¹² About 65% of dysgerminomas are stage I at diagnosis. About 85%–90% of stage I tumors are confined to one ovary; 10%–15% are bilateral.

The treatment of a patient with early dysgerminoma is primarily surgical, including resection of the primary lesion and proper surgical staging. Adjuvant chemotherapy is particularly necessary in the advanced disease.

In cases of Swyer syndrome, after surgical treatment, hormone replacement therapy to induce puberty and the development of secondary sex characteristics is indicated. ⁴ Estrogen therapy should be administered as early as possible to ensure adequate bone-mass formation and prevent reduction of bone mineral density that lead to osteopenia and osteoporosis. Cyclic estrogen and progesterone replacement is indicated until the patient reaches age 50, when hormonal therapy may be discontinued. ³ In the present case, the patient was maintained on cyclic estrogen and progesterone replacement.

Several cases of pregnancy among patients with Swyer syndrome have been described since 1988; the prognoses for these pregnancies is similar to the prognoses for the pregnancies of 46,XX patients with ovarian failure. ¹³ In the current case, the patient's uterus was preserved, per the wish of her family members in order to preserve future fertility.

The survival rates of patients with XY gonadal dysgenesis and dysgerminoma are similar to the survival rates of XX individuals with malignant ovarian germ-cell tumors.

Conclusions

The treatment of Swyer syndrome requires multidisciplinary teams who are able to provide multifaceted care in terms of prevention of malignancy and osteoporosis, induction of puberty, fertility, and psychologic support. Thus, in an adolescent patient with primary amenorrhea, karyotype analysis and investigation of gonads is recommended. The appropriate surgical staging in cases of patients with gonadoblastomas or prophylactic surgical resection of gonads is advised.