Functional Oncocytic Adrenocortical Tumour: A Rare Case Report

The occurrence of virilisation in pre-pubertal children is an uncommon finding, marked by the development of pubic hair, enlargement of the clitoris or penis, accelerated linear growth, and advanced bone age. In our case, a 7-year-old girl showed signs of virilisation with well-developed secondary sexual characteristics, including Tanner Stage II breast bud and Tanner Stage V adrenarche and pubarche. Her testosterone level was found to be elevated. Subsequent examinations and a biopsy confirmed the existence of an oncocytic adrenocortical neoplasm. Adrenal oncocytic tumours are infrequently encountered with a handful of cases documented in literature. The majority of oncocytic tumours are typically benign, with malignancy being a rare occurrence. Surgical resection is the mainstay of treatment.

Keywords: Precocious pseudo puberty, elevated testosterone level, Neuroblastoma, Adrenarche, Pubarche, Modified Weiss criteria, Makuuchi incision.

Oncocytic Adrenocortical tumours (OACT) are infrequent in paediatric patients [1]. They can be categorized as functional or non-functional. Functional tumours may manifest as peripheral precocious puberty with a predominant display of virilisation or feminization, hypercortisolism on its own or in conjunction with peripheral precocious puberty, or, in rare instances, with hyperaldosteronism [1].

Precocious puberty is typically defined as the onset of secondary sex characteristics before the age of eight in girls (or menarche before nine years of age), and before the age of nine in boys [1]. This condition significantly influences a patient’s growth, development, and psychological well-being. Studies on untreated individuals have indicated that the long-term consequences often include stunted growth and obesity. The clinical manifestations of precocious puberty can vary by gender and encompass symptoms such as acne, early breast development, enlarged testicles, increased penile length, facial hair, deepening of the voice, the emergence of pubic or axillary hair, rapid growth, and adult body odour.

A fully immunized 7-year-old girl presented to the outpatient department with complaints of abdominal pain persisting over the past few weeks. There is no history of any drug intake, and no significant past medical, personal or family history.

On general physical examination, the child was active, afebrile having coarse facial features with pustular facial acne and hirsutism on her face, abdomen, axillary and pubic areas. She also had a deep voice. Her height was above the 25^th percentile, and her weight was above the 75^th percentile. She was hypertensive with a blood pressure of 133/79mmHg, above 95^th percentile.

Abdominal examination was unremarkable, Pubertal examination revealed Tanner Stage II breast bud development and pubic hair were compatible with Tanner Stage 4. (Image 01&02). No mass palpable no hepatosplenomegaly. The CNS and cardiovascular examinations were unremarkable.

Table 01. Laboratory tests indicated the presence of microcytic anemia.

Image 01: Facial acne observed in 8-year-old female.

Image 02: Abnormally thick pubic hair can be observed in 8-year-old female.

To help differentiate the cause of precocious puberty, and to confirm the diagnosis further investigations were conducted. Clinical laboratory tests revealed microcytic anaemia (according to Table 01). Elevated serum testosterone levels (case value 569.65 ng/dl, Normal range female 15 to 70 ng/dL) and elevated 17-hydroxyprogesterone (case value 15.44 ng/dL, Normal range <1.1 ng/dl) were also observed. Morning cortisol was 11.3ug/dl and Evening cortisol was 8ug/dl (normal range 3.7-19.4 ug/dl). Serum sodium 140mEq/L, serum potassium 4.7mEq/L, serum chloride 102mEq/L, serum HCO3 22mEq/L. These findings provide valuable information for the diagnosis and will guide us in determining the appropriate management for the girl.

On ultrasound, a large, well-circumscribed heterogeneous solid lesion (measuring 8.4-7.5 cm) with calcification was observed in the left suprarenal region. CT scan findings confirmed the presence of a well-circumscribed soft tissue calcified mass (measuring 7.4 x 7.3 cm) near the left suprarenal region, abutting the splenic hilum, pancreatic tail, and close to the abdominal aorta. A diagnosis of an adrenocortical tumour was made. Correction of general condition was done. Details about the disease, plan of management, and risks were explained to the parents. After written consent and a pre-anaesthetic check-up surgery was planned, during the surgery, a Makuuchi incision was made to the patient’s abdomen.

Next, the solid mass, encapsulated, well-circumscribed, grey-brown tumour mass measuring 8.5 x 8 x 5 cm was excised employing unilateral left adrenalectomy. Then, abdominal layers were repaired using a vicryl. The mass was sent for histopathological study. A biopsy using the Lin-Weiss-Bisceglia (LWB) system, based on the Modified Weiss criteria, reveals a neoplastic lesion exhibiting sheets of large, polygonal cells with abundant bright eosinophilic cytoplasm and rounded to irregular hyperchromatic nuclei, with occasional mitosis. No lymph/vascular invasion, sinusoidal invasion, capsular invasion, necrosis, hypercellularity and atypical mitosis was seen.

All postoperative lab values (table 02) were repeated and were markedly improved (morning cortisol 1 ug/dL, FSH 5.4 mIU/mL, LH 1.83 mIU/mL, and testosterone 9.55 ng/dl), and a CT scan without contrast revealed no recurrent mass. The patient’s symptoms were improving; she was kept on hydrocortisone for at least three months, with regular check-ups.

Adrenal adenomas and adrenocortical carcinomas (ACCs) are neoplastic growths that arise from the adrenal cortex, while neuroblastomas and pheochromocytomas develop from the adrenal medulla (PCCs). These tumours are classified into either functional or non-functional tumours, with neuroblastomas being non-functional and adenomas, ACCs, and PCCs being functional. Adrenocortical oncocytoma is an exceptionally rare tumour, with only renal oncocytoma commonly reported in children [1]. Adrenocortical tumours are infrequent in children, and they account for only 0.2% of all neoplasms. To date, only slightly over 50 cases of adrenal oncocytoma have been documented in scientific literature. Using case notes, patients admitted between January 2011 and December 2015 were examined in retrospect. Thirteen of the 29 individuals who were admitted with adrenal tumours throughout these five years also had adrenocortical cancer. At the five-year follow-up, six patients (46.2%) experienced a recurrence. Mean overall survival was 46.69 ± 22.81 (14-80) months, 92.3%, while MEAN disease-free survival was 31.0 ± 23.92 (2-63) months, 53.8% [8]. The majority of adrenocortical oncocytomas are benign and non-functioning. However, there have been reported cases of functioning adrenocortical oncocytomas, with only nine cases reported so far. Of these, seven patients were between 40 and 60 years of age, while the remaining two were between the ages of 6 and 12 years [3]. The International Paediatric Adrenocortical Tumour Registry (IPATR) has reported that 90% of childhood ACCs are functional and exhibit different clinical signs and biological behaviour as compared to adult ACCs. Virilization is the most common clinical presentation, with an incidence rate of 84.3% [4]. Other symptoms include acne, pubic hair, and clitoris enlargement [2]. Cushing’s syndrome is the second most common clinical presentation, with symptoms such as moon faces, centripetal fat distribution, striae over the skin, and a plethora occurring in one-third of patients [4]. Feminizing adrenocortical tumours (FAT) are an infrequent occurrence in pediatric medicine. These tumours typically manifest with peripheral precocious puberty- a phenomenon that can be isosexual in females and heterosexual in males. The primary biochemical feature of FAT is excessive secretion of estrogen, either alone or in combination with other adrenal hormones. Discriminating adrenal from ovarian estrogen secretion requires a combination of imaging and biochemical assessment of other adrenal hormones [2].

The aetiology of adrenal cortical tumours (ACTs) currently remains elusive. However, inherited genetic abnormalities, particularly mutations in the P53 gene, have been linked to increased ACTs frequency within familial cancer syndromes. The overexpression of steroidogenic factor-1 and insulin-like growth factor-2 also contributes significantly to ACTs pathogenesis [2].  Unfortunately, we were unable to test our patient for these known genetic associations due to a lack of facilities for genetic testing. Common associations with ACTs include Li Fraumeni syndrome, Beckwith-Wiedeman syndrome, isolated hemi-hypertrophy syndromes, congenital anomalies of the kidney, and congenital adrenal hyperplasia [2]. Notably, our patient did not exhibit any clinical evidence of such associations. In pediatric practice, precocious puberty is frequently observed for a variety of reasons, including adrenal tumours. Pseudo-precocious puberty is brought on by the androgenic hormone excess associated with the uncommon adrenocortical tumour in youngsters [2]. Adrenocortical tumors (ACTs) are uncommon in children even though they can happen at any age. In 1865, the first occurrence of ACT in children was documented. With a peak age of less than four years old, female children are more impacted than male youngsters [2]. Between 50 and 84.2% of patients have the clinical manifestation of pseudo-precocious puberty brought on by an ACT tumour [2].

This report details a case involving an 8-year-old girl who presented with pseudo-precocious puberty and was later diagnosed with an oncocytic adrenocortical tumour. This condition is a rare occurrence in children, with the youngest reported case being a 10-month-old infant who presented with symptoms of premature puberty including facial hair, acne, and increased penile length. Another case was documented by Ghazizade et al. involving a 2-year-old girl who presented with virilization since birth [9]. In a similar case, Swaminathan et al reported a 5-year-old boy in India, in 2022, who showed symptoms of abdominal distention, virilization, pubic hair, increased penile length, and hirsutism. An MRI revealed an adrenal tumour that was subsequently confirmed as an adrenocortical carcinoma on biopsy [5].

The patient presented with a history of facial acne, hirsutism, Tanner stage 2 breast bud development, and pubic and axillary hair. Based on the hormonal essay, pseudo-precocious puberty was confirmed. The patient’s testosterone levels were elevated. Excess adrenal production of androgens can occur secondary to congenital adrenal hyperplasia or adrenal tumours and present with isosexual precocious puberty in males and contra sexual precocious puberty in females [6]. Most of the adrenal tumours are sporadic; however, a fraction of them might be familial. This is supported by Mahloud JIM et al, while the family history was negative in the current case and other cases mentioned above [7]. In a similar case report of adrenocortical carcinoma with virilization, and abdominal mass presented by Sipayya et al., the palpable mass in this case due to its size (11× 9×7 cm) [7], while in the current case, the size is 8.4 -In 7.5 cm on the US. Abdominal ultrasound and CT scan showed a large well-circumcised calcified mass on the left suprarenal region. Final confirmation and definitive diagnosis were made on biopsy, confirming an oncolytic adrenocortical neoplasm of uncertain malignancy [7].

Managing this medical condition is challenging due to the limited number of documented cases. For a definitive diagnosis of precocious puberty, a thorough assessment encompassing clinical symptoms, laboratory tests, and radiological imaging is crucial. However, discriminating benign tumours from malignant tumours does not depend on hormone secretions only; further investigations are required. Using percutaneous biopsies to diagnose Adrenocortical carcinoma (ACC) is not recommended. There is a risk of metastasis in the needle tract and tumour pillage due to capsular breach. If adrenocortical carcinoma is diagnosed early, it can be curative with prompt treatment; however, in our case, the tumour was of uncertain malignant potential with no venous, capsular, or sinusoidal invasion. The surgery for left open adrenalectomy was performed, and the postoperative labs and CT scan came out to be normal. Now the patient is on hydroxy corticosteroids for the time being with continuous follow-up.

The prognosis for benign adrenocortical tumours is favourable, with the exception of the potential for recurrence, yet malignant adrenocortical tumours have a dismal prognosis, with a 5-year survival rate of 49–55%.

Non-specific congenital adrenal hyperplasia is one of the rare causes of pseudo-precocious puberty, which paediatricians can diagnose early. Virilization is an important manifestation of adrenocortical tumours. A high index of suspicion and an increased awareness of paediatricians play an important role in the early diagnosis and treatment of this disease. Prompt management and treatment can help to improve the lifestyle of the patient.

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The author(s) received no funding or financial assistance for the research, writing, or publishing of this article.

Conflict of Interest:

The author(s) disclosed no prospective conflicts of interest over the research, writing, and/or publishing of this paper.