ENDOCRINE SOCIETY
OXFORD
Gynecomastia in a Man With Adrenal Mass
Jasmine Saini, 10 Patrick Navin,20D Michael Rivera,3 and Irina Bancos10
1Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA 2Division of Radiology, Mayo Clinic, Rochester, MN 55905, USA
3Division of Anatomic Pathology, Mayo Clinic, Rochester, MN 55905, USA
Correspondence: Irina Bancos, MD, Msc, Division of Endocrinology and Metabolism, Department of Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA. Email: bancos.irina@mayo.edu.
Abstract
Estrogen-secreting adrenocortical carcinoma (ACC) is exceedingly rare, representing 1% to 2% of all ACCs. We present a case of a 65-year-old man diagnosed with an estrogen-secreting, 4.3-cm right adrenal mass discovered during work-up for bilateral gynecomastia. Gynecomastia and hyperestrogenism resolved after laparoscopic adrenalectomy, and pathology was reported as adrenocortical adenoma. However, 5 years later, he again developed bilateral gynecomastia because of recurrent hyperestrogenism. Imaging revealed multiple metastases in the abdomen. Urine steroid profiling demonstrated increased androgen precursors, androgen metabolites, and glucocorticoid precursors. Ultrasound-guided biopsy of one of the metastases confirmed ACC. Initial therapy included debulking surgery with removal of metastatic lesions. Mitotane therapy was initiated 4 weeks later along with hydrocortisone for anticipated mitotane-induced adrenal insufficiency. Histopathology from the adrenalectomy specimen 5 years earlier was rereviewed and confirmed ACC. Estrogen-secreting adrenal tumors are exceedingly rare, and the majority are malignant. This case underlines the importance of making an initial accurate diagnosis of adrenal malignancy that allows better surgical planning and appropriate monitoring. Indeterminate imaging characteristics of the adrenal mass, as well as the presentation with estrogen excess, suggested an elevated risk for ACC. Initial pathology-based misdiagnosis illustrates the need for an expert adrenal pathologist to review these rare tumors.
Key Words: adrenocortical carcinoma, adrenal cancer, estrogen, feminization
Abbreviations: ACC, adrenocortical carcinoma; CT, computed tomography; HU, Hounsfield unit; MRI, magnetic resonance imaging.
Introduction
Adrenocortical carcinoma (ACC) is a rare and aggressive tu- mor representing .3% of all adrenal tumors in a population setting and diagnosed at a rate of approximately 1 case per million population (1, 2). Approximately half of all patients with ACC demonstrate either overt or mild hormone excess, most commonly cortisol and/or androgen excess (3). Depending on the degree of hormone overproduction, pa- tients may develop features of overt Cushing syndrome (from excess cortisol), virilization (from excess androgen, evi- dent in women only), or hypertension with hypokalemia (from excess mineralocorticoid). Estrogen-secreting ACCs are very rare and constitute approximately 1% to 2% of ACCs (3, 4). In postmenopausal women, estrogen excess may lead to uterine bleeding, and girls may experience preco- cious puberty. In men, symptoms of estrogen excess include gynecomastia that occurs from hyperestrogenism-induced breast tissue growth and decreased libido resulting from hypo- gonadotrophic hypogonadism (4).
We present a rare case of an estrogen-secreting ACC that was initially misdiagnosed as an adenoma, but later presented with metastatic ACC.
Case Presentation
A 65-year-old man presented to the clinic in June 2022 with bilateral progressive gynecomastia and fatigue. His medical
history included dyslipidemia, hypertension, obstructive sleep apnea, gastroesophageal reflux disease, and history of gyneco- mastia and an adrenal mass 5 years earlier.
In 2017, the patient also reported progressive bilateral gynecomastia and fatigue. Laboratory work-up at that time demonstrated elevated estrogen concentrations with the rest of work-up (thyroid function tests, renal and liver func- tion tests) being unremarkable. Testosterone and prolactin measurements were not performed. Finding excess estrogen prompted adrenal imaging. Computed tomography (CT) showed a 42-mm, right adrenal mass with an unenhanced density of 32 Hounsfield units (HU). However, contrast washout characteristics were reassuring, with the absolute washout of 78% and relative washout of 36% (Fig. 1). On the magnetic resonance imaging (MRI), imaging characteris- tics were indeterminate with absence of chemical shift (Fig. 2).
The patient was treated with a right laparoscopic adrenalec- tomy locally. Postoperatively, estrogen concentrations de- creased 2.5-fold and was within the normal ranges. Two different pathologists assessed histopathology, both conclud- ing that the adrenal mass was benign, consistent with adreno- cortical adenoma. The patient was reassured and was not recommended for follow up.
In 2022, after a 5-year symptom-free period, patient rede- veloped gynecomastia (Fig. 3) and presented for evaluation to our clinic.
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Diagnostic Assessment
Considering the patient’s previous history of estrogen-secreting adrenal mass with clinical presentation of gynecomastia, hormo- nal work-up was repeated, and indeed revealed hyperestrogen- ism (Table 1). Imaging included abdominal CT, MRI, and positron emission tomography CT (Fig. 4). Urine steroid profil- ing was consistent with ACC, demonstrating increased estrogen, androgen, and glucocorticoid precursors and metabolites (Z scores of 4 and above) (Table 2). Metastatic ACC was suspected, and the ultrasound-guided left upper quadrant mesenteric mass biopsy confirmed ACC (Fig. 5).
Considering the patient’s previous diagnosis of benign adrenal adenoma and current presentation with ACC,
pathology slides from the previous surgery were requested and reviewed by an expert adrenal pathologist. This review confirmed that the initial adrenal mass from 2017 was misinterpreted as benign and was in fact ACC, Fig. 6, reporting foci suspicious for capsular invasion, marked cytological atypia, diffuse architecture, <25% clear cells, and increased mitoses of 23/50 high power fields, with a Weiss score of 4 of 9.
Treatment
Initial therapy included debulking surgery with the removal of multiple metastatic lesions.
| Laboratory findings | Result | Reference range |
|---|---|---|
| Estrone | 345 pg/mL (1276 pmol/L) | 10-60 pg/mL (37-222 pmol/L) |
| Estradiol | 72 pg/mL (264 pmol/L) | 10-40 pg/mL (37-147 pmol/L) |
| Progesterone | 0.59 ng/ml (1.9 nmol/L) | <0.20 ng/ml (<0.64 nmol/L) |
| Total Testosterone | 157 ng/dL (5 nmol/L) | 240-950 ng/dL (8-33 nmol/L) |
| Testosterone, bioavailable | 16 ng/dL (0.6 nmol/L) | 40-168 ng/dL (1.4-5.8 nmol/L) |
| Cortisol, morning | 19 mcg/dL (524 nmol/L) | 7-25 mcg/dL (193-670 nmol/L) |
| Adrenocorticotropic hormone | 14 pg/mL (3.08 pmol/L) | 7.2-63 pg/mL (1.6-13.8 pmol/L) |
| Aldosterone | 13 ng/dL (0.36 nmol/L) | <= 21 ng/dL ( <= 0.5 nmol/L) |
| Renin plasma activity | 6.3 ng/ml/hr (6.3 mcg/L/hr) | <= 0.6-3 ng/ml/hr ( <= 0.6-3 mcg/L/hr) (Sodium-replete, upright) |
| 11 deoxycortisol | 204 ng/dL (5.9 nmol/L) | 10-79 ng/dL (0.3-2.3 nmol/L) |
| Androstenedione | 81 ng/dL (2.8 nmol/L) | 40-150 ng/dL (1.4-5.2 nmol/L) |
| Dehydroepiandrosterone Sulphate | 219 mcg/dL (5.9 mcmol/L) | 12-227 mcg/dL (0.3-6.2 mcmol/L) |
| Pregnenolone | 230 ng/dL (7.3 nmol/L) | 33-248 ng/dL (1.04-7.83 nmol/L) |
| 17-Hydroxypregnenolone | 264 ng/dL (8.3 nmol/L) | 55-455 ng/dL (1.7-14.4 nmol/L) |
| 17-Hydroxyprogesterone | 72 ng/dL (2.2 nmol/L) | <220 ng/dL (<6.6 nmol/L) |
Postoperatively, estrogen (13 pg/mL normal ranges, 10-40 pg/mL [48 pmol/L]) and urine steroid profiling (Table 2) normalized, and gynecomastia improved when reevaluated 3 months later.
Outcome and Follow-up
Imaging surveillance was initiated and planned for every 3 months during the first 12 months after adrenalectomy. Mitotane therapy was initiated 4 weeks after adrenalectomy along with hydrocortisone for anticipated mitotane-induced adrenal insufficiency. When imaging demonstrated progres- sive disease at 3 the month-follow up visit, cytotoxic chemo- therapy with etoposide, doxorubicin, and cisplatin was initiated, and mitotane was discontinued in an attempt to re- duce the overall toxicity. Following a favorable response to the 6 cycles of etoposide, doxorubicin, and cisplatin, our pa- tient demonstrated a favorable response, and at this time is under observation without further therapy. CT performed
8 months after chemotherapy initiation demonstrated no me- tastases except for 1 peritoneal nodule that decreased in size when compared with previous imaging.
Discussion
We describe a patient with an estrogen-secreting adrenal mass that was initially misdiagnosed as having an adrenal adenoma and who developed recurrent estrogen excess because of meta- static ACC 5 years after adrenalectomy. At the time of initial pres- entation, the patient’s imaging characteristics of adrenal mass were indeterminate and included tumor size >4 cm, unenhanced HU>20, and absence of chemical shift on MRI. However, the pa- tient had reassuring contrast washout characteristics with abso- lute washout >60% (though a relative washout of 36%).
Making an accurate diagnosis of ACC is important to as- sure appropriate management. Imaging characteristics that are concerning for malignancy include unenhanced HU>20 (or heterogenous mass) and size > 4 cm (5). Contrast washout
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| Steroid | Before debulking surgery | 2 mo after surgery | Reference ranges (mcg/24 h) | ||
|---|---|---|---|---|---|
| Value (mcg/24 h) | Z score | Value (mcg/24 h) | Z score | ||
| Androsterone | 1986 | 0 | 609 | -1.2 | 118-25389 |
| Etiocholanolone | 3135 | 1 | 1141 | -. 3 | 127-15640 |
| Dehydroepiandrosterone | 12 595 | 4 | 298 | .5 | 7-4260 |
| 16a-OH-dehydroandristepiandrosterone | 3687 | 2 | 1361 | 1.6 | 11-6183 |
| 5-Pregnenetriol | 14 475 | 6 | 480 | 1.0 | 24-2162 |
| 5-Pregnenediol | 4023 | 5 | 150 | .0 | 17-1296 |
| Tetrahydro-11-corticosterone | 637 | 2 | 145 | -. 1 | 16-1674 |
| Tetrahydro-11-deoxycorticosterone | 72 | 2 | Undetectable | — | 5-297 |
| Pregnanediol | 4336 | 4 | 165 | -. 3 | 23-1846 |
| 17a-OH-Pregnanolone | 458 | 1 | 113 | -. 6 | 18-1747 |
| Pregnanetriol | 4952 | 3 | 324 | -1.4 | 115-5432 |
| Pregnanetriolone | 29.2 | 0 | Undetectable | — | 5-221 |
| Tetrahydrodeoxycortisol | 3343 | 4 | 102 | -. 2 | 12-1277 |
| Cortisol | 228 | 2 | 149 | .9 | 12-597 |
| 6B-OH-Cortisol | 483 | 1 | 1552 | 2.4 | 22-2406 |
| Tetrahydrocortisol | 4230 | 1 | 4375 | .8 | 331-19009 |
| 5a-Tetrahydrocortisol | 3676 | 1 | 1406 | -. 6 | 155-35266 |
| B-Cortol | 1675 | 2 | 207 | -1.1 | 56-3541 |
| 11B-OH-Androsterone | 1164 | 0 | 763 | -. 8 | 142-13135 |
| 11B-OH-Etiocholanolone | 1114 | 1 | 1568 | 1.1 | 69-6805 |
| Cortisone | 225 | 1 | 123 | -. 2 | 24-732 |
| Tetrahydrocortisone | 10 650 | 1 | 6724 | .7 | 454-34576 |
| a-Cortolone | 3412 | 1 | 2872 | .5 | 211-17591 |
| B-Cortolone | 2024 | 1 | 580 | -. 7 | 114-8434 |
| 11-Oxoetiocholanolone | 467 | -1 | 657 | -. 7 | 155-7174 |
is not recommended as a second-line imaging because of scarce data and suboptimal performance (5). Combined hormone excess, androgen, or estrogen excess in a patient with indeterminate adrenal mass also strongly suggests ACC (5). Because approximately 50% of ACCs do not demonstrate abnormalities on standard of care hormonal
work-up, urine steroid profiling can aid the diagnosis of ACC (5).
Data on estrogen-secreting adrenal tumors are scarce. A lit- erature review of 21 cases of estrogen-secreting adrenal tu- mors in men published between 1970 and 2014 reported that 71% were malignant, and 2 cases of ACC were initially
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misclassified as adenoma, similar to our case (4). Since 2014, 5 additional cases of estrogen-secreting tumors in men were published, with 3 of 4 with optimal follow-up being malig- nant, and 1 case of reportedly benign adenoma that was fol- lowed for 6 months only (6-9).
Histopathology is considered the gold standard for diagnos- ing ACC. Guidelines recommend review of all suspected ACC specimens by an expert adrenal pathologist because of the fre- quent risk of misdiagnosis: 26 (9%) of cases were misdiagnosed in 1 study of 300 patients with ACC and in another study of 161 patients with ACC, initial diagnosis was revised by refer- ence pathologist in 21 (13%) patients (10). Weiss score is a histological criterion of 9 parameters (nuclear grade, mitosis per 50 high-power field, atypical mitotic figure, % of clear cells, diffuse architecture, necrosis, vascular invasion, sinusoidal in- vasion, capsular invasion) that can help differentiate malignant from benign adrenal tumors. The score is calculated on hema- toxylin and eosin-stained slides, and score of 3 or greater indi- cates ACC. Ki67 immunohistochemistry index can help make a diagnosis of ACCs as well as stratify the prognosis of ACC and guide management. Our patient’s resected histopathology spe- cimen was labeled as benign in 2017. Five years later, when the patient presented with recurrent hyperestrogenism, the initial histopathology was reviewed by an adrenal expert pathologist who confirmed ACC with a Weiss score of 4/9.
Although open adrenalectomy is recommended for an ad- renal mass suspected to be ACC, minimally invasive
adrenalectomy could be considered by an expert high-volume adrenal surgeon in ACCs < 6 cm without evidence of local in- vasion. The recommended standard of care approach to local- ized ACC is imaging follow up for at least 5 years after adrenalectomy and mitotane therapy if the patient is at sub- stantial risk of recurrence (10).
Learning Points
· Estrogen-secreting adrenocortical carcinomas (ACCs) re- present 1% to 2% of all ACCs.
· Establishing an accurate adrenal malignancy diagnosis before adrenalectomy is important and includes review of imaging characteristics (size, Hounsfield Unit, homo- geneity) and interpretation of hormonal work-up.
· The resected specimen in suspected ACC cases should be reviewed by an expert adrenal pathologist.
Contributors
All authors made individual contributions to authorship. J.S. participated in drafting the manuscript. P.N., M.R., and I.B. par- ticipated in the diagnosis and management of this patient and drafting of the manuscript. M.R. undertook histopathology sec- tion and preparation of histology images. P.N. undertook radio- logical imaging and preparation of radiology reports. All authors critically reviewed and approved the final draft.
Funding
No public or commercial funding.
Disclosures
I.B. reports consulting and advisory board participation out- side this work (fees to institution) from Spruce, Diurnal, Neurocrine, Corcept, Sparrow, Recordati, Adrenas, HRA Pharma, and research grant for investigator-initiated award to institution outside this work from Recordati.
Informed Patient Consent for Publication
Signed informed consent obtained directly from patient.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
References
1. Sharma E, Dahal S, Sharma P, et al. The characteristics and trends in adrenocortical carcinoma: a United States population based study. J Clin Med Res. 2018;10(8):636-640.
2. Ebbehoj A, Li D, Kaur RJ, et al. Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study. Lancet Diabetes Endocrinol. 2020;8(11):894-902.
3. Sada A, Asaad M, Bews KA, et al. Comparison between functional and non-functional adrenocortical carcinoma. Surgery. 2020; 167(1):216-223.
4. Chentli F, Bekkaye I, Azzoug S. Feminizing adrenocortical tumors: lit- erature review. Indian J Endocrinol Metab. 2015;19(3):332-339.
5. Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European net- work for the study of adrenal tumors. Eur J Endocrinol. 2023;189(1):G1-G42.
6. Vogt EC, Hammerling K, Sorbye H, et al. Feminizing adrenal tumor identified by plasma steroid profiling. Endocrinol Diabetes Metab Case Rep. 2021; doi: 10.1530/EDM-21-0104
7. Ahmad RM, Ingram K, Corsetti R. Benign feminizing adrenal tu- mor in an adult male. Ochsner J. 2020;20(3):311-314.
8. Jeong Y, Cho SC, Cho HJ, et al. Estrogen-secreting adrenocortical carcinoma. Yeungnam Univ J Med. 2019;36(1):54-58.
9. Chentli F, Chabour F, Bouchibane D, Nouar N. Feminizing adreno- cortical carcinoma without gynecomastia. Oman Med J. 2017;32(4):349-351.
10. Fassnacht M, Dekkers OM, Else T, et al. European society of endo- crinology clinical practice guidelines on the management of adreno- cortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2018;179(4):G1-G46.