Massive adrenal incidentalomas and late diagnosis of congenital adrenal hyperplasia in prostate cancer

Background

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of the steroid synthesis pathways. The most common form of CAH is 21-hydroxylase deficiency, representing 90–95% of CAH patients and causes a spectrum of adrenal insufficiency and virilization. Non-classical or partial CAH results from a milder enzyme deficiency compared to the classic form with an incidence estimated at approximately 1 in 1000 worldwide (1). The diagnosis may be suspected clinically but relies on genetic testing for confirmation. Although most patients are diagnosed in their childhood, there are reports of diagnosis of classical CAH in the sixth and seventh decades of life (2). There exist increasing evidence of its association with adrenal tumors (3).

Prostate cancer is the most common cancer among Canadian men (excluding non-melanoma skin cancer) accounting for 21% of all new cancer cases in men in 2016 (4). Abiraterone has been used for the treatment of castration-resistant prostate cancer, and there is emerging evidence for its use in castration-sensitive prostate cancer (5). Abiraterone inhibits 17α-hydroxylase/C17,20-lyase to decrease not only adrenal androgen production but also cortisol production (6).

Case presentation

A 61-year-old Caucasian male with prostate cancer was unresponsive to leuprolide and bicalutamide with persistent testosterone levels of 8–14 (nmol/L). Initial cancer staging imaging noted bilateral adrenal masses 18.2 × 16.2 × 14 cm on the left and 6.4 × 8.7 × 7.8 cm on the right diagnosed as myelolipomas (Fig. 1). These were determined to be non-functioning with normal serum-free metanephrines (0.34, normal: <0.49 nmol/L) and normal serum-free normetanephrines (0.74, normal: <0.89 nmol/L). There was no clinical evidence of cortisol excess, and there was no history of hypertension or hypokalemia. He was admitted to hospital for lethargy and fatigue thought to be due to excessive narcotic use. Dexamethasone was initiated as an adjunctive pain management therapy, to which he responded rapidly with improved mentation and feeling of well-being. The serum testosterone decreased to 1.5 nmol/L after the introduction of dexamethasone. He was started on abiraterone and the dexamethasone was subsequently tapered to prednisone 5 mg daily; repeat testosterone levels were suppressed below the limit of detection.

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CT scan of abdomen (coronal and axial). Arrows indicate adrenal masses.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2017, 1; 10.1530/EDM-17-0108

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Investigation

At referral to endocrinology, the patient was noted to have short stature at 151 cm (height potential: 171.5 cm based on mid-parental height) with his siblings 18–23 cm taller than him. He provided school photographs demonstrating initial tall stature and precocious puberty at age 9 years with early masculinizing features and presence of longstanding hyperpigmentation. However, by the end of high school, he recalled being the shortest person in the class. Later in life when presenting with infertility, he was noted to be azoospermic although no diagnosis was provided. At the present evaluation, he declined testicular examination but reported a history of small testes.

Genetic testing demonstrated bi-allelic mutations in CYP21A2; one complete gene deletion and the other having a C518T > A (I172N) mutation. The diagnosis of simple virilizing 21α-hydroxylase deficiency (CAH) was made. Measurements of 17-hydroxyprogesterone and ACTH were not taken due to his required use of abiraterone and prednisone as it would not have altered management.

Treatment

The patient continued on prednisone 5 mg by mouth daily in conjunction with abiraterone to suppress endogenous androgen production as well as to prevent adrenal insufficiency.

Outcome and follow-up

Unfortunately, the patient deceased due to metastatic prostate cancer shortly after the diagnosis of congenital adrenal hyperplasia was made.

Discussion

We present the first reported case of a patient presenting with massive adrenal incidental myelolipomas in the context of castration-resistant prostate cancer.

Congenital adrenal hyperplasia presents as a spectrum of disease depending on the residual enzyme activity. There can be multiple abnormalities in the adrenal hormone synthesis pathways. The most common form involves mutation in CYP21A2, resulting in variable deficiency of 21-hydroxylase (21OHD). The majority of cases of classic 21OH deficiency are detected on routine newborn screening or with evidence of virilization, ambiguous genitalia and elevated 17-OH-progesterone. However, it is more difficult to detect males with mild forms of this condition, as the 17OH progesterone may not be significantly elevated at birth and partial deficiencies may not present with adrenal insufficiency or salt wasting.

Our patient presented to medical attention diagnosed with castration-resistant prostate cancer. His short stature and precocious puberty suggests the presence of excess adrenal androgens from an early age. CAH has a strong genotype–phenotype correlation, which highlights the importance of genetic testing and counseling. Patients with del/I172N mutations (such as our patient) present most commonly as simple virilizing (53/72 cases) (7) as compared with salt wasting (18/72 cases) (7) or non-classic (1/72) (7). The delayed diagnosis in his sixth decade of life is unusual given his genetic mutation. Biochemical screening would not have been done at the time of his birth.

Suppression of endogenous testosterone is vital to managing prostate cancer to reduce tumor growth. His persistently elevated testosterone was likely from adrenal overproduction due to undiagnosed CAH. This elevation in testosterone was glucocorticoid responsive, which would decrease endogenous ACTH and thus decrease androstenedione and testosterone production (8). The decreased testosterone levels after dexamethasone therapy likely reflects this. Furthermore, abiraterone was later used for his second-line management of castration-resistant prostate cancer, which can itself precipitate adrenal insufficiency via inhibition of cortisol biosynthesis. It is crucial to treat patients on abiraterone concurrently with physiologic glucocorticoid replacement to prevent this. It was especially important that our patient received replacement as he was at risk of developing adrenal insufficiency due to undiagnosed CAH and potentially compromised cortisol biosynthesis at baseline.

This case also shows the importance of considering the diagnosis of CAH in apparent ‘castration-resistant’ prostate cancer, especially in the presence of adrenal myelolipomas, due to the important therapeutic considerations noted earlier. There are numerous reports of men with simple virilizing CAH undiagnosed until later in the sixth and seventh decades (2). While ours is the second case of CAH in the context of castration-resistant prostate cancer reported in the literature (8), it is the first reported case to our knowledge of CAH and prostate cancer treated with abiraterone. This is especially relevant given the recent trials demonstrating the efficacy of abiraterone in castration-sensitive prostate cancer (5) where patients with undiagnosed CAH may not be identified prior to prostate cancer therapy.

Adrenal myelolipomas are a type of rare benign mesenchymal and stromal tumor of the adrenal cortex composed of adipose tissue and bone marrow elements that accounts for approximately 6% of adrenal incidentalomas (9). Those greater than 10 cm are termed giant, and only 12% of adrenal myelolipomas are bilateral (9). These masses are usually hormonally inactive but have been associated with androgen production and hypertension (9). There is a higher incidence of bilateral myelolipomas in patients with longstanding and untreated CAH (10) with over 40 reported cases (3), which supports the theory that chronically elevated endogenous ACTH acts to stimulate growth of the adrenal tissue (9). There have been reports of adrenal nodules regressing in size with improved control in patients with 21OH deficiency (11). Patients presenting with incidentally found adrenal myelolipomas should be screened for classic CAH.

Case conclusion

Simple virilizing congenital adrenal hyperplasia was the likely cause of the difficult to suppress androgens in this patient. This clinical scenario also demonstrates the importance of considering CAH in patients with large myelolipomas.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agencies in the public, commercial or not-for-profit sector.

Author contribution statement

G K is the named physician of the patient and was involved in conceiving, editing and submission of the work. X F is an endocrine trainee who was responsible for writing the initial manuscript, editing and submission of the work.