Adrenocortical tumor manifesting as virilizing in a female child: Adenoma or carcinoma? A rare case report

Abstract

Introduction

Adrenocortical tumors (ACTs) are rare endocrine neoplasms in children, with functional ACTs being more prevalent than non-functional types. Clinical manifestations typically include virilization, Cushing's syndrome, and hyperaldosteronism. Surgical intervention is the primary treatment for ACTs, with a significant risk of recurrence in adrenocortical carcinoma even after complete resection.

Presentation of Case.

This case presentation describes a 3.5-year-old female with generalized hirsutism and clitoral hypertrophy, leading to the discovery of a left adrenal tumor. The child underwent adrenalectomy, revealing a benign adrenal cortical adenoma. Unfortunately, due to loss of follow-up, the child later presented with pulmonary metastases and passed away, preventing further investigation into the source of metastases.

Discussion

Adrenocortical tumors are uncommon in children, with the classification of ACTs into adenomas and carcinomas. To our knowledge, this is the third case of an adrenocortical tumor in a child in Syria. We highlight the challenges in managing pediatric ACTs and emphasize the importance of timely intervention and close monitoring to improve outcomes. Regular follow-up is crucial to detect complications early and optimize treatment strategies, especially considering the unpredictable behavior of these tumors.

Conclusion

This case confirms that distinguishing between adrenocortical adenoma and carcinoma can be challenging even histologically. Therefore, it is necessary to follow up after treating each case of adenoma in a child to prevent major complications.

Highlights

• •Adrenocortical tumors (ACTs) in children are rare, with functional types more common.
• •Clinical manifestations include virilization, Cushing's syndrome and hyperaldosteronism.
• •Surgical intervention is the primary treatment for ACTs.
• •Challenges exist in distinguishing between adenoma and carcinoma.
• •Regular follow-up crucial for early detection of complications.

1. Introduction

Adrenocortical tumors (ACTs) are rare endocrine neoplasms in children, with an estimated incidence of 0.2–0.3 new cases per 1 million children annually. They account for 6 percent of all adrenal malignancies in children and <0.2 % of all childhood tumors [1] [2].

Functional ACTs are more prevalent than non-functional ACTs in children, in contrast to adults. The most common clinical manifestation of these tumors is virilization, characterized by pubic hair, accelerated growth and skeletal maturation, an enlarged penis or clitoris, hirsutism, and acne. Less frequently observed manifestations include Cushing's syndrome and hyperaldosteronism [2,3].

Several histopathological scoring systems have been utilized to assess malignancy, with the Wieneke index being the most beneficial in pediatrics. Therefore, distinguishing between adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC) is often difficult, especially in children [4].

Adrenocortical tumors (ACTs) are primarily managed through surgical intervention. However, despite achieving complete resection, there remains a significant risk of recurrence in ACC. The prognosis for pediatric ACC remains unfavorable, with a 5-year survival rate ranging from 30 to 90 %, despite using multiple therapeutic approaches such as mitotane, chemotherapy, and radiotherapy [5].

This paper reports a case of a 3-and-a-half-year-old girl who came to the hospital complaining of signs of virilization and was later diagnosed with adrenocortical adenoma.

The work has been reported in line with the SCARE criteria [6].

2. Presentation of case

A 3.5-year-old female was brought to the pediatric clinic by her parents due to generalized hirsutism, particularly pronounced in the genital area over the past 7 months Fig. 1. Upon examination, we noted accelerated growth, dysphonia, and clitoral hypertrophy. The child had no significant medical, surgical, allergic, family, or medication history. She did not report any urinary or respiratory complaints, and her vital signs were within normal range.

Fig. 1.

3.5-year-old female child with features of virilization (hair growth over the pubic area, clitoromegaly).

During abdominal physical examination, a palpable mass was detected on the left side, which was further confirmed by a computed tomography (CT) scan revealing a lesion around 6.5 cm in diameter in the left adrenal region Fig. 2. Bone age assessment through X-ray of the left wrist indicated a bone age of 4.5 years.

Fig. 2.

An abdominal CT scan showing lesion around 6.5 cm in diameter, seen in the left adrenal region with amorphous calcification.

However, laboratory tests revealed elevated levels of adrenal steroid hormones including dehydroepiandrosterone (DHEA), testosterone, and 17-OH-progesterone.

After confirmation that there were no distal metastases, adrenalectomy was performed to remove the tumor, which was found to be encapsulated and localized on the left side. The tumor appeared greyish, well-circumscribed, measuring 5.5 × 4 cm, and weighing 37.67 g Fig. 3.

Fig. 3.

Grossly, encapsulated mass, no invasion to surroundings, size 5.5 × 4 cm, and weighed 37.67g.

Histopathological examination utilizing Synaptophysin and Chromogranin staining confirmed the encapsulated nature of the tumor, with no evidence of mitosis or necrosis, indicating no malignant features. According to the Weinke index for predicting malignancy, the score was <3, suggesting a benign adrenal cortical adenoma.

Unfortunately, we lost follow-up of the child due to her living in a rural area and the situation of war in Syria at that time. She returned to us after a year in a very late stage, diagnosed with pulmonary metastases in another hospital, and she passed away in the next day befor doing any further investigations. The rapid progression of this presentation, along with the scarcity of expertise in rare tumors like ACTs, prevented us from knowing the source of the metastases and determining exactly what happened to her. The parents refused to allow an autopsy on their daughter due to cultural beliefs.

3. Discussion and conclusion

Adrenocortical tumors (ACTs) rarely occur in children [1]. ACTs can be classified into functional and non-functional tumors based on hormone secretion, and into adenomas and carcinomas based on malignancy. Adrenocortical adenoma (ACA) is the most common type of ACT, followed by carcinoma (ACC), with a higher incidence among girls, and a tendency to occur on the left side, similar to our case [7].

Many genetic factors can be a reason for the occurrence of this tumor, such as β-catenin, Insulin-like growth factor (IGF)-II/IGF-IR, and p53/Rb signaling. The p53 mutation is the most frequent in these cases, so genetic tests can be useful in investigating this tumor [8].

Symptoms vary depending on the functionality of the tumor and the hormones it secretes. The most prevalent presentation is isolated virilization, which is the main cause that makes ACTs in children clinically noticeable [9].

Signs include hirsutism, growth spurts, an increase in bone age, acne, changes in voice, axillary sweating, and the onset of secondary sexual traits like pubic hair, darkening of the genital skin, an increase in the penile or clitoral corpus cavernosum [7].

Cushing's syndrome is the second most prevalent symptom [9]. Our patient exhibited signs of virilization, including precocious puberty, without any signs of feminization or Cushing syndrome.

In our case, the patient was diagnosed based on WHO criteria, using clinical features, biochemical tests, a wrist X-ray, and a CT scan [7].

To identify the source of the symptoms, laboratory testing was necessary. Hormones like 17-hydroxyprogesterone (17-OH), dehydroepiandrosterone sulfate (DHEA), androstenedione (A4), testosterone, 11-deoxycortisol, and cortisol are used to classify and diagnose ACA [7]. The levels of DHEA, testosterone, and 17-OH progesterone were highly elevated in our patient, while cortisol remained unchanged.

CT scan for pelvic, abdomen, and chest is the most frequently used imaging technique to detect adrenal tumors. It helps in diagnosis and determining the tumor's stage, location, therapeutic strategy, and metastasis [7] [9].

It is challenging to determine whether an ACT is malignant or not. Many histopathological scoring systems, including Weiss, Wieneke, and Van Sloote, have been used to predict malignancy; however, the Wieneke index remains the most useful in pediatrics [4] (Table 1).

Table 1.

Wieneke criteria for malignancy of ACT [10].

Tumor weight > 400 g	1
Tumor size >10.5 cm	1
Invasion through periadrenal tissues and/or close organs	1
Invasion to vena cava	1
Capsular invasion	1
Venous invasion	1
Tumor necrosis	1
>15 mitoses per 20 high power field (400×)	1
Presence of atypical mitotic figures	1
When the score is 3 or less, the tumor is benign.
When the score is >3, the tumor is malignant.

However, the Wieneke index is not reliable enough to establish a prognosis, and it can be difficult to distinguish between adenoma and carcinoma, due to the unpredictable behavior of the tumor [10].

Despite the rarity of these tumors and the lack of data to guide their management, surgery is still considered the curative intervention for adenomas, with a 100 % survival rate [7] [9]. Our patient underwent adrenalectomy and based on Wieneke index, it was diagnosed as an ACA.

Metastasis in adrenal tumors has significant potential, with percentages ranging from 5 % to 81 %, especially in the liver, lungs, regional lymph nodes, kidneys, and bones, with less possibility. The percentage of recurrence rate in adults is between 60 % to 70 %, but it is uncertain in pediatrics. When recurrence occurs, new surgery should be performed followed by pharmacological therapy for a better prognosis [8].

Our patient was lost to follow-up, which prevented us from identifying the source of the complications that led to her death. It is not clear what the actual cause of death was: metastases of the same tumor or a new tumor, especially given the parents' refusal to allow an autopsy. Therefore, we advise regular monitoring of ACT patients to avoid such occurrences.

To our knowledge, this is the third case in Syria of an adrenocortical tumor in a child. Clinical manifestations within if associated with other syndromes and the onset of ACT differ in every case. Our patient did not exhibit any syndromes typically associated with ACTs like Li-Fraumeni, Beckwith-Wiedemann syndrome (BWS), isolated hemihypertrophy, congenital adrenal hyperplasia, and kidney abnormalities [7].

Doya LJ et al. [11] reported an 18-month-old female case that suffered from ACA combined with BWS. The other case is a 10-month-old female with Cushing syndrome reported by Al-Ghotani B et al. [7] In this case, a 3-year-old female has ACA with isolated virilization. The descriptions of these cases are detailed in (Table 2).

Table 2.

The three cases of adrenocortical tumors in Syria.

	Our case	Doya LJ et al. [11]	Al-Ghotani B et al. [7]
Age and Sex	42-month-old-girl	18-month-old-girl	10-month-old-girl
Chef Complaint	Generalized hirsutism	Excessive pubic hair (pubarche)	Mass on the right adrenal gland and Cushing's syndrome symptoms
Signs and Symptoms	Growing spurts, voice changes, pubic hair, Clitoris enlargement	Left-sided hemihypertrophy, umbilical hernia, ear lobe creases	Gradual weight gain, cushingoid face, central obesity genital hirsutism, severe genital rash, fachial acne, vascular lesions cough, hoarseness, dyspnea
Associated diseases	None	Beckwith–Wiedemann syndrome (BWS)	None
Elevated hormones	Testosterone, DHEAS,17-OH progesterone	Testosterone, DHEAS, LDH	Cortisol
Investigations	Left wrist X-ray, CT-scan with contrast	Echocardiography, Left wrist X-ray, Abdominal US, CT-scan NSE, VMA	Echocardiography, Chest X-ray, Abdominal US, Multislice CT, Echo-guided biopsy
Imaging findings	Bone age of 4.5 years. Left suprarenal mass	Bone age of 3 years. Well-circumscribed solid mass with tiny calcifications in the left suprarenal region	Large perfused mass on the top pole of the right kidney that pushes down and deviates the kidney's longitudinal axis, as well as the inferior vena cava and abdominal aorta, all to the left without invasion
Mass characteristic	Irregular, gray, soft mass, Size 2 × 4 × 5.5 cm, Weight 37.67 g	Outer glistening nodular surface, no invasion to surroundings Size 5 × 4 × 2.8 cm, weight 23.5 g	Well-encapsulated mass, Size 8 × 6 cm, weight 118 g
Wieneke score	3>	2/9	Not mentioned
Histopathologic result	Adrenocortical adenoma ACA	Adrenocortical adenoma (ACA)	Adrenocortical neoplasm
Treatment	Left adrenalectomy	Right open adrenalectomy	Right adrenalectomy
Follow-up	No follow-up was applied. The patient died after one year of lung metastases	For 2 years postoperatively, the patient is still healthy	Serum cortisol levels immediately decreased after surgery, The patient died after 16 days of surgery due to an acute pulmonary hemorrhage and Uncompensated circulation shock

This case confirms that distinguishing between adrenocortical adenoma and carcinoma can be challenging. ACTs should be considered malignant until proven otherwise through adequate follow-up, especially in children who may have genetic mutations as an ongoing cause for tumor recurrence. Therefore, regular follow-up should be added to the post-surgery treatment protocol due to the unusual behavior of this tumor.

Registration of research studies

Not applicable.

Guarantor

Fatima Breim.

Authors' contributions.

Mohamad Morjan supervised and helped in writing the manuscript. Fatima Breim, Amal Jaweesh, Amir Sleibi, Lama Kanaa, and Hanin Sattout wrote the manuscript. Fatima Breim critically revised the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not required for case reports at our hospital. Single case reports are exempt from ethical approval in our institution.

Consent for publication

Written informed consent was obtained from the patient's parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Funding

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

Declarations of interest

None.

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.