Androgen producing oncocytic adrenocortical tumor in a 3.7-year-old female

Abstract

Summary

We report a 3.7-year-old female who presented with clinical features of premature adrenarche. Workup revealed significantly elevated androgen levels and advanced bone maturation, prompting abdominal imaging that identified a 6.0 cm adrenal mass. She underwent unilateral adrenalectomy, and subsequent histopathology revealed a benign oncocytic adrenocortical adenoma. Post-adrenalectomy, androgen levels returned to pre-pubertal levels. A review of the literature on pediatric oncocytic adrenocortical neoplasms (OANs) is presented, and we add our case to the growing data of this rare disease in the pediatric population.

Learning points

• A high index of suspicion is necessary when encountering a prepubertal child with clinical signs of hyperandrogenism and advanced bone age.

• Oncocytic adrenocortical neoplasms are rare in children and are often benign, although they can be malignant or of uncertain malignant potential. Adrenalectomy is necessary for histopathological diagnosis and definitive treatment.

• Pediatric oncocytic adrenocortical neoplasms are typically associated with elevated androgens; however, they can have a variety of other abnormal hormonal profiles at presentation. Return to normal hormonal levels is common post-adrenalectomy.

Background

Oncocytic tumors are epithelial neoplasms consisting of cells with abundant eosinophilic cytoplasm and rich in mitochondria. Classically, oncocytic tumors arise in kidney, salivary gland, thyroid, parathyroid and pituitary tissues (1).

An oncocytic adrenocortical neoplasm (OAN) is an extremely rare variant of adrenal tumor, initially reported by Kakimoto and colleagues in 1986 (2). While they are grossly variable in their size and weight, typical OANs are round, well-circumscribed and encapsulated (3). In 2004, Bisceglia and colleagues developed a malignancy scoring system based on the histopathological findings of OAN. This ‘Lin-Weiss-Bisceglia’ scoring system has three major criteria, including high mitotic rate, atypical mitoses or venous invasion. Minor criteria are tumor size more than 10 cm or weight more than 200 g, tumor necrosis, sinusoidal invasion or capsular invasion. Benign lesions (adenomas) do not exhibit any of these features. The presence of any one or more major criteria indicates a malignant oncocytic tumor (carcinoma). If the tumor shows at least one minor criterion, it suggests a diagnosis of uncertain malignant potential (4). The immune profile of an OAN is known to be most consistently positive for a combination of vimentin, neuron-specific enolase, Melan-A, synaptophysin and alpha-inhibin (2, 3, 4).

We present a case of a 3.7-year-old female who presented with a benign, androgen producing OAN.

Case presentation

A 3.7-year-old female was referred to the pediatric endocrinology clinic by her primary care physician for evaluation of precocious puberty. In the 4 months prior to presentation, she had developed coarse dark pubic hair, white vaginal discharge, adult-type body odor and acne. Parents denied any axillary hair growth, breast development, oily skin, vaginal spotting, nocturnal headaches, balance issues or neurologic concerns. No significant past medical history was identified. No known family history of precocious puberty or other pertinent conditions.

Investigation

Upon review of her growth data, at birth she was at the 89^th percentile length for age and the 70^th percentile weight for age. At presentation, she was above the 98^th percentile height for age with an expected mid-parental height in the 89^th percentile. In addition, she was in the 96^th percentile weight for age with a BMI at the 81^st percentile. Vital signs, including blood pressure, were appropriate for her age. Her physical exam was notable for Tanner stage 1 breast development and Tanner stage 2 pubic hair. The remainder of the exam was unremarkable, without cushingoid features, clitoral enlargement or labial fusion.

Initial workup was most notable for advanced bone age, estimated to be 2.5–3.5 standard deviations above the mean for her chronological age. In addition, she demonstrated significantly elevated DHEA and DHEAS, indicating adrenal etiology (Table 1). There were also slight elevations of androstenedione and total testosterone, and elevation of insulin-like growth factor 1 (IGF-1). Both 17-hydroxyprogesterone (17-OHP) and 17-hydroxypregnenolone were normal. Morning serum cortisol and evening salivary cortisol levels were normal. A computed tomography (CT) of adrenal glands revealed 6.0 cm left adrenal mass (Fig. 1).

Table 1.

Pre- and post-adrenalectomy serum hormone concentrations.

Hormone tested	Pre-AD	Post-AD		Reference range
		At 1 month	At 4 months
17-OHP, ng/dL	24.79			≤256.00
17-HP quantitative, ng/dL	232			≤280
IGF-1, ng/mL	237	268	210	15–216
DHEA sulfate, µg/dL	1888	3	3	0–47
Testosterone, ng/dL	28	2	1	≤19
HGH, ng/mL			0.48	0.10–6.20
IGFBP-3, ng/mL		4920	4870	2169–4790
Androstenedione, ng/mL	1.470	0.075	0.035	0.020–0.210
DHEA, ng/mL	13.093	0.112	0.067	≤1.029
Morning serum cortisol, µg/dL	8:23 AM: 9.0			3.0–21.0
Serum cortisol during ACTH stimulation test, µg/dL				3.0–21.0
0 min		7.6
30 min		16.1
60 min		18.3
ACTH, pg/mL		25.2*		7.2–63.3
Evening salivary cortisol (µg/dL) ×3 days				<0.112
Day 1	0.104
Day 2	0.054
Day 3	0.108

Abnormal values are shown in bold font.

AD, adrenalectomy; DHEA, dehydroepiandrosterone; HGH, human growth hormone; IGF-1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3; ACTH, adrenocorticotropic hormone; 17-OHP, hydroxyprogesterone; 17-HP, 17-hydroxypregnenolone.

^*Collected during ACTH stimulation test at 0 min.

Figure 1.

Axial abdominal CT images of a contrast-enhancing left adrenal mass, measuring up to a 6.0 cm axial diameter.

Treatment

She underwent subsequent laparoscopic left adrenalectomy with removal of a well-defined, 6.0 cm mass weighing 79 g (Fig. 2). No adrenal vein, lymphovascular or capsular invasion was present. Pathology revealed a benign oncocytic adrenocortical adenoma with immunohistochemical positivity for Melan-A, alpha-inhibin and synaptophysin (Fig. 3).

Figure 2.

Resected left adrenal specimen weighing 79 g and measuring 6.0 × 5.0 × 5.0 cm.

Figure 3.

Histopathologic examination demonstrated an oncocytic tumorous mass of the adrenal gland composed of sheets of polygonal cells with abundant granular eosinophilic cytoplasm. (A) Scattered mildly pleomorphic nuclei with rare mitoses identified (<1/10 hpf). (B) Immunohistochemical examination showing expression of Melan-A in tumor cells. (C) Immunohistochemical examination showing expression of inhibin in tumor cells. (D) Immunohistochemical examination showing expression of synaptophysin in tumor cells.

During and after surgery, she empirically received 100 mg/m²/day intravenous hydrocortisone divided every 6 hours as a precaution to prevent any intraoperative or postsurgical adrenal crisis. This dose was transitioned to oral hydrocortisone and weaned during her hospital stay. She was discharged on postoperative day 2 on 10 mg/m²/day oral physiologic hydrocortisone. This was tapered off over the next 3 weeks, and she passed a subsequent adrenocorticotropic hormone (ACTH) stimulation test with a normal ACTH level and appropriate peak cortisol level (Table 1).

Outcome and follow-up

Post-adrenalectomy levels of DHEA, DHEAS, testosterone and androstenedione all returned within normal prepubertal ranges (Table 1). IGF-1 has normalized, although insulin-like growth factor binding protein 3 (IGF BP-3) remained slightly elevated with some improvement. Over subsequent follow-up visits, she continues to have advanced bone age with stature greater than the 98^th percentile for age. Her growth velocity has normalized for her age, and the gap between her chronological age and bone age has been narrowing. At her most recent follow-up visit, she continues to have Tanner stage 2 pubic hair without progression and Tanner stage 1 breast development.

Discussion

OAN is a rare diagnosis. In 2017, Costanzo and colleagues reported 183 cases of OANs worldwide. Most of the reported cases were adults between 40 and 50 years of age, 20% were malignant tumors and the majority of functional tumors were benign (3). Within the pediatric population, we recognize a total of 15 cases of OAN described in the literature worldwide. We add to the growing data of pediatric OAN a 3.7-year-old female, who presented with a benign, androgen-producing OAN (Table 2).

Table 2.

Characteristics of functional oncocytic adrenocortical tumors described in pediatric patients.

Case	Ref	Year	GL	AOP, years	Sex	Clinical presentation	Elevated hormone	Laterality: size	HSAA	Histopathology
1	(5)	2008	Switzerland	12	F	Pubic hair, acne, abdominal pain	Testosterone, androstenedione (normal DHEAS)	Left: 5 cm	Normal	Benign OAN
2	(5)	2008	Tunisia	6	F	Pubic hair, PPP	Estradiol (normal DHEAS)	Right: 3.5 cm	Normal	Benign OAN
3	(5)	2010	Korea	14	F	Pubic hair, acne, virilization	DHEAS, testosterone	Right: 17.5 cm	Normal	OAN with uncertain malignant potential
4	(5)	2012	India	3.5	F	Pubic hair, virilization	DHEAS, testosterone, cortisol	Right: 2.5 cm	Normal	Benign OAN
5	(5)	2012	India	16	F	Amenorrhea, abdominal pain, virilization	DHEAS, testosterone	Right: 12 cm	NR	OAN with uncertain malignant potential‡
6	(5)	2014	Portugal	5.8	F	Pubic hair, cushingoid features	DHEAS (ME), testosterone (ME), cortisol	Left: 4.5 cm	Normal	Benign OAN
7	(5)	2014	Japan	11	F	Fever, weight loss	Interleukin 6*	Left: 4.5 cm	Normal	Benign OAN§
8	(5)	2015	Bulgaria	9	F	Virilization	DHEAS, testosterone, androstenedione	Left: 2.2 cm	Normal	Benign OAN
9	(5)	2018	Saudi Arabia	5	M	Pubic hair, PPP, cushingoid features	DHEAS, testosterone, cortisol	Right: 3 cm	Normal	Benign OAN
10	(5)	2020	India	4	M	PPP, pubic hair, cushingoid features	DHEAS, testosterone, cortisol	Right: 3.5 cm	Normal	Benign OAN
11	(6)	2021	Turkey	18 MO	M	Virilization	DHEAS, testosterone, androstenedione	Right: 2 cm	Normal	Malignant OAN║
12	(7)	2021	Israel	6.8	F	Pubic hair, axillary hair, acne	DHEAS, androstenedione, 17-OHP	Right: 6.5 cm	Normal†	Benign OAN
13	(8)	2022	India	10	M	Abdominal mass	Testosterone (ME)*	Right:17 cm	Normal	OAN with uncertain malignant potential
14	(9)	2023	India	14	F	Cushingoid features	Cortisol*	Left: 3.5 cm	Normal	Benign OAN with myelolipomatous metaplasia
15	(10)	2024	India	13	F	Cushingoid features	DHEAS, testosterone, cortisol 17-OHP	Right: 4 cm	Normal	Benign OAN
16	Our case	2024	USA	3.7	F	Pubic hair, acne, body odor, advanced BA	DHEAS, testosterone (ME), androstenedione (ME)	Left: 6.0 cm	Normal	Benign OAN

GL, geographical location; MO, months; AOP, age at presentation; OAN, oncocytic adrenocortical neoplasm; PPP, pseudo-precocious puberty; BA, bone age; LH, luteinizing hormone; FSH, follicle stimulating hormone; 17-OHP, 17 hydroxyprogesterone; ME, minimally elevated; HSAA, hormonal status after adrenalectomy; NR, not reported; Ref, reference.

^* DHEAS level unknown, adrenal androgen levels were not reported.

^† This patient developed central precocious puberty in 3 months after surgery.

^‡ Undetermined histopathology, OAN with uncertain malignant potential as determined by the Lin-Weiss-Bisceglia scoring system (4).

^§ Undetermined histopathology, benign OAN as determined by the Lin-Weiss-Bisceglia scoring system (4).

^║ Presented in 3 months after adrenalectomy with left leg rhabdomyosarcoma and found to have positive TP53 genetic variant.

Out of the 15 reported pediatric cases, 10 were summarized by Narayanan and colleagues in 2021 (5). Almost 75% of the cases affected female patients. The right adrenal gland was affected in 10 out of 15 cases. According to the Lin-Weiss-Bisceglia malignancy scoring system, when considering their gross and histopathological features, 11 of the 15 cases were benign, three were of uncertain malignant potential and one was malignant. (4) Approximately 40% (six out of 15) of the cases presented with hypercortisolism, with or without elevated adrenal androgens.

Interestingly, case 2 is one of the benign OAN cases summarized by Narayanan and coworkers described as an unusual presentation of pseudo-precocious puberty based on the significantly elevated estradiol, suppressed gonadotropins and normal adrenal androgens (5). Similarly summarized by Narayanan and coworkers, case 7 describes an interleukin-6 producing OAN. This case is notable because the patient did not have any reported clinical signs of hyperandrogenism, virilization or cushingoid features. The patient instead presented with fever of unknown origin and weight loss. This case may be considered a nonfunctional OAN, lacking hormonal production, as adrenal androgens were not reported (5).

Akin and colleagues reported the youngest case of OAN to date (case 11). It was described as an oncocytic variant adrenocortical carcinoma in an 18-month-old male who had elevated adrenal androgens but normal cortisol. This toddler then presented 3 months after adrenalectomy with a new diagnosis of rhabdomyosarcoma in his leg. Upon further evaluation, he was found to have a variant of a tumor suppressor gene, TP53, during DNA sequencing of his peripheral blood (6). In case 12, Madi and colleagues reported a 6-year-old female with a benign, androgen-producing OAN. In this case, the patient developed central precocious puberty 3 months after tumor resection (7). In 2022, Ramamoorthi and colleagues reported case 13, an OAN of uncertain malignant potential in a 10-year-old male who presented with only minimal elevation of testosterone (8). In 2023, Bhardwaj and colleagues reported case 14, a cortisol-producing OAN with a pair of unique histopathological characteristics, including both oncocytic and myelolipomatous differentiation (9). Most recently, Meher and colleagues added case 15, a benign and functional OAN in a 13-year-old girl. It was a multihormonal OAN producing cortisol, adrenal androgens and testosterone (10).

Our patient is the 16^th reported pediatric OAN case, as per our review of the literature. Clinically, she presented at 3.7 years of age with classic clinical features of premature adrenarche, without indication of virilization, clitoromegaly or cushingoid features. However, her DHEA and DHEAS levels were extremely elevated, with minimal elevation in testosterone, androstenedione, normal 17-OHP and cortisol levels. She demonstrated significant growth acceleration, and her bone age was advanced. Such remarkable findings were enough to consider adrenal gland imaging to investigate for adrenal neoplasm. This patient’s presentation was attributed to a functional, androgen-producing oncocytic adrenocortical adenoma. This diagnosis was supported by histopathological findings and immunohistochemistry staining and further confirmed by normalization of androgen levels post-adrenalectomy.

In addition to elevated adrenal androgens, our patient demonstrated elevated levels of IGF-1 and IGF BP-3. Following adrenalectomy and subsequent normalization of DHEA and DHEAS levels, her IGF-1 level returned to normal and IGF BP-3 level was down-trending near the upper limits of normal. Elevated IGF-1 levels have been previously reported in girls with premature adrenarche (11). Meanwhile, DHEA supplementation is known to significantly increase IGF-1 levels in adults (12). These findings suggest an association between increased adrenal androgens and elevated IGF-1 levels. Although further studies are warranted to elucidate the exact mechanism linking adrenal androgen excess and IGF-1 production, this interaction likely contributes to the growth acceleration observed in children with premature adrenarche, such as our patient.

Declaration of interest

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

Funding

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

Patient consent

Written informed consent was obtained from the patient/patient’s mother for publication of this case report.

Author contribution statement

All authors made individual contributions to authorship. KM and MC were involved in the case presentation, diagnosis and management of the patient. KM and GE were responsible for the discussion and tables. JB was responsible for the histopathology images and interpretation. KM prepared the manuscript for submission. All authors reviewed, edited and approved the final draft.