Community screening leading to the diagnosis of androgen insensitivity syndrome at the age of 65

Introduction

Androgen insensitivity syndrome (AIS) is a disease that can be X-linked recessive or sporadic in nature. Patients with complete AIS are phenotypically female individuals with an XY genotype. During embryonic development, the testicular tissue present in patients with AIS produces Mullerian Inhibiting Substance, which blocks the development of the upper one third of the vagina, uterus and ovaries, while a lack of androgen receptors results in female-appearing external genitalia. Complete AIS patients tend to present as amenorrheic females during adolescence. This case report presents a unique situation in which a public health screening campaign, for abdominal aortic aneurysms, led to an incidental finding and work-up resulting in two separate, yet related diagnoses: androgen insensitivity syndrome (AIS) and sertoli cell adenoma. This case also highlights the importance of a comprehensive physical examination with emphasis on wide differential diagnosis. It underscores the importance of considering the complicated ethics surrounding patient disclosure when dealing with a sensitive diagnosis.

Case

A 65 year-old female was in her usual state of health when she underwent an abdominal ultrasound as part of a community screening program for abdominal aortic aneurysms. The ultrasound did not show an aneurysm, but rather revealed an abdominal mass measuring 20 cm. Her primary care physician obtained a computed tomography (CT) scan of her abdomen and pelvis, which revealed an 18 cm abdominal mass without evidence of lymphadenopathy or other metastases. A uterus was not visualized (Fig. 1). She was then referred to a local gynecologist, where a pelvic ultrasound was preformed. This confirmed a large, solid hypoechoic mass with venous blood flow. Although no uterus or ovaries were appreciated on this study, there was still suspicion for a gynecologic etiology. A CA-125 level was obtained (21.6 units/mL), and she was referred to the university for further work-up.

Fig. 1.

CT scan of abdomen and pelvis. CT scan image of the abdomen and pelvis demonstrating a large pelvic mass.

At the gynecologic oncology clinic, the patient stated she had symptoms of early satiety and bloating for two weeks. She denied any nausea, vomiting, fever, night sweats or weight loss. She had normal bowel and bladder function, and denied any vaginal bleeding or discharge. Of note, her past medical history was significant for amenorrhea and a subsequent diagnosis of “congenital absence of a uterus” as a teenager. She did not recall any subsequent work up after this diagnosis and stated she went yearly to her primary care physician for a well woman exam. Of note, when speaking with her primary care doctor to discuss her case, it was mentioned that the patient consistently declined the pelvic examination portion of her yearly exam. Her past surgical history was significant for an appendectomy. She denied any family history significant for gynecologic or other malignancies. Her general appearance was one of a phenotypic female including normal breast development. However, of note, her height was 180 cm (5′ 11″) and weight was 156.4 kg (344.8 lb). The abdominal examination revealed a soft, obese abdomen without any palpable masses. Pelvic examination demonstrated a complete lack of pubic hair but otherwise normal appearing external genitalia. Upon separation of the labia and visualization of the urethra and vagina, a shallow, blind pouch was noted that measured 1 cm in depth. The clitoris was smaller than normal size. Rectal examination failed to reveal any masses.

Magnetic resonance imaging was obtained to better evaluate pelvic anatomy and characteristics of the mass. This showed a 20 × 18.2 × 13.6 cm solid pelvic mass extending into the abdomen (Fig. 2). Gonads were visualized bilaterally at the inferior aspect of the mass. No uterus or upper vagina was identified, and the tumor appeared well circumscribed without invasion into surrounding structures. Laboratory tests were ordered including a chromosomal analysis, which revealed an XY karyotype. Other abnormal assays included elevated free and total testosterone (387.6 pg/mL and > 1500 ng/dL respectively), and a markedly high Inhibin B (> 5000 pg/mL). The remainder of the patient's labs, alpha fetoprotein (181 U/L), quantitative total beta HCG (< 1.0 mIU/mL), and CEA (1.6 ng/mL), were within normal range. Upon reviewing the laboratory results and physical examination, a diagnosis of complete AIS was made without resolving the etiology of the mass.

Fig. 2.

MRI of abdomen and pelvis. MRI image of the abdomen and pelvis showing a large, solid, well circumscribed mass.

The diagnosis of AIS presented a unique and complicated situation because of the patient's age and late presentation. The patient had lived her life not knowing the medical reason behind her lack of uterus and the consequences of this diagnosis. The hospital's ethics committee was consulted to discuss the importance of diagnosis disclosure, and how to best relay the information to the patient. The committee unanimously agreed that full disclosure was essential. They added that the best way to inform the patient was not to deny her status as a female, but rather to inform her of her genetic composition and the likely etiologies of her pelvic mass. It was also agreed upon that providing the patient with sufficient support, including a health psychologist familiar with the syndrome, was imperative. The patient returned to clinic for pre-operative evaluation, was told of her diagnosis of AIS and of the importance of surgical removal of the mass as well as the gonads. She was fully consented for the procedure. She then met with an appropriate psychologist to provide emotional support.

The patient underwent exploratory laparotomy, bilateral gonadal resection which included resection of the pelvic mass, uterine remnant resection, adhesiolysis and peritoneal washings. Intra-operative findings included a large pelvic mass, arising from the left gonad, solid in consistency, with small adhesions to the right and left pelvic sidewalls (Fig. 3). The uterine remnant was found to be distally attached to the right gonad. It was transected from its distal attachment and suture ligated. Frozen section revealed a 2.8 kg homogenous solid mass, with sertoli cell proliferation and no features of carcinoma. Because of these findings, staging was not preformed. The patient tolerated the procedure well and was discharged home on post-operative day four. After an uncomplicated surgical recovery, she followed up with reproductive endocrinology and the health psychologist for long-term management of her AIS. She was found to be coping considerably well with the new diagnosis, with a solid social support system. Her main concern was why this diagnosis had not been made years prior. Final pathology revealed a left gonad with well-differentiated sertoli cell adenoma measuring 19.6 cm without surface involvement. The right gonad was composed of ovarian-type stroma with areas of fibrosis, admixed with testicular tubules containing sertoli cells but no identifiable spermatogonia. The suspected uterine remnant was found to have benign smooth muscle.

Fig. 3.

Gross image of the tumor.

Comment

The etiology of a congenitally absent uterus, blind short vaginal pouch, and lack of pubic hair is most likely complete or partial AIS. Patients with partial AIS usually have some features of masculinization (e.g., enlarged clitoris and virilization) and this patient did not. Patients with complete AIS have no androgen receptor activity and therefore are phenotypically female, as virilization requires excess androgens with functional receptors. Complete AIS patients do tend to have tall stature, lack of androgen effect in their hair distribution, shortened vagina, and infertility due to the absence of a uterus; with the latter two being a result of the presence of Mullerian Inhibiting Substance produced by the testes during development. Notably, on physical examination, all of these characteristics were present in our patient. Additional possibilities in the differential diagnosis included congenital abnormalities such as vaginal agenesis and microperforate hymen. The patient lacked classic ovaries on imaging, essentially ruling out vaginal agenesis, and the vaginal anatomy was not consistent with imperforate hymen.

AIS is a disease most commonly diagnosed in adolescents during the initial presentation of primary amenorrhea. By diagnosing AIS early, patients have more time to process the psychological and physical implications of the disease. Cases of AIS diagnosed beyond adolescence are rare. Similar to our patient, Lentz and Cappellari in 1998 reported a 67 year-old amenorrheic female diagnosed with AIS after presenting with abdominal pain, swelling and a pelvic mass (Lentz and Cappellari, 1998).

Early diagnosis allows patients to undergo the recommended preventative gonadectomy to prevent malignancy from occurring (Cassio et al., 1990). In a case series by Rutgers and Scully, 10 of their 43 patients (23%), were found to have sertoli cell adenomas (Rutgers and Scully, 1991). Seven of the cases had a uterine remnant as was also seen in this case (Rutgers and Scully, 1991). This is likely due to varying levels of Mullerian Inhibitory Substance and excess estrogen during development (Rutgers and Scully, 1991; Oka et al., 1984). Other case reports involving patients with AIS have found Sertoli–Leydig cell tumors and malignant Leydig cell tumors (Rutgers, 2011). The microscopic pathology of the gonads found in patients with AIS tends to be consistent with tubulostromal gonadal tissue with Sertoli or Leydig cells present and occasionally with spindle cell stroma representing ovarian stroma. Spermatogonia were found in 12% of cases by Rutgers and Scully (1991). This patient's gonadal tissue was found to be ovarian-type stroma with areas of fibrosis, admixed with testicular tubules containing sertoli cells but no identifiable spermatogonia, as well as small nests of steroid producing cells and Leydig cells.

With the diagnosis of AIS so late in life, disclosure becomes complex. It is challenging to inform a female adult patient that she is a genotypic male, especially when she lacked any suspicion of such a diagnosis. Conn et al. in 2005, presented the ethics regarding diagnosis disclosure of AIS (Conn et al., 2005). They concluded that because of patient justice and the right to patient autonomy, women should be told of their diagnosis of AIS immediately. Women with AIS are not men. They are women who have a Y-chromosome (Jorgensen et al., 2010). Their syndrome provides them with unique challenges both physically and psychologically that deserve attention, whether the diagnosis is made in adolescence or in late adulthood.

An intriguing feature of this case is that both the discovery of a pelvic mass and the eventual diagnosis of AIS were found incidentally due to community screening for abdominal aortic aneurysm. Public health screening campaigns are used as a strategy to detect certain diseases and conditions within target populations. While they are popular as an approach to preventive medicine, the US Preventive Services Task Force does not recommend specific screening of women for abdominal aortic aneurysms (AAA) due to lack of significant benefit and low prevalence of AAA in women (Andermann, 2012). Once again, in reviewing the literature on abdominal aortic aneurysm screening, there is paucity of data on the prevalence of incidental, but clinically significant, findings (Andermann, 2012; Darwood and Brooks, 2012). This topic needs additional study to further clarify the implications of community radiologic screenings.

In conclusion, this case demonstrates a unique situation: delayed diagnosis of complete AIS found incidentally at a community screening, with concurrent sertoli cell adenoma. It is rare for a woman beyond her teen years to be diagnosed with AIS. With late diagnosis, disclosure is just as critical. A great deal of support is required, as both the psychological and physical aspects are complex.

Consent

In accordance with University of Wisconsin's IRB policy, written informed consent was not obtained for publication of this case.

Conflict of interest statement

The authors have no conflicts of interest to declare.