Virilizing adrenocortical carcinoma in a female child of Li-Fraumeni syndrome
Vishnu Sankar K V1, Debansu Sarkar1, Dilip Kumar Pal1, Uttara Chatterjee2
Departments of 1Urology and 2Pathology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
Address for correspondence:
Dr. Dilip Kumar Pal, Department of Urology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India. E-mail: urologyipgmer@gmail.com
ABSTRACT
Adrenocortical carcinoma is a rare malignancy and even rarer in infancy. Most of these tumors in the pediatric age group are hormonally active and predominantly present with virilization. We report a case of a 1-year-3-month-old female child presenting with virilization. She presented with hypertension, hypertrichosis, clitoromegaly (virilization), and elevation of plasma testosterone and dehydroepiandrosterone. A discussion of this case and a review of the literature on this entity are presented.
KEY WORDS: Adrenocortical carcinoma, insulin-like growth factor-2, Li-Fraumeni syndrome
INTRODUCTION
Adrenocortical carcinomas (ACCs) are rare tumors that have bimodal distribution with the first peak in children less than 5 years and the second around the fifth decade.[1] Their reported annual incidence is 0.2-0.3 per million/year. Although most adult ACCs are nonfunctional, in the pediatric age group, 95% are functional.[2] Virilization is the most common abnormality, and Cushing’s syndrome and hyperaldosteronism are less frequent. Studies have identified overexpression of insulin-like growth factor 2(IGF2) and constitutive activation of beta-catenin as the key factors involved in the development of ACC.[3] Most patients present with steroid hormone excess, for example, Cushing’s syndrome or virilization or abdominal mass effect, but a growing proportion of patients with ACC is initially diagnosed incidentally. In patients with suspected ACC, a thorough endocrine and imaging workup is recommended to guide surgical approaches aimed at complete resection of the tumor. To establish an adequate basis of treatment decision, pathology reports include the Weiss score to asses malignancy, the resection status, and ki 67 index. As recurrence is frequent, close follow-up initially every 3 months is mandatory. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the corner stone of initial treatment.[4]
CASE REPORT
A 1-year-3-month-old baby reared as female was bought to the pediatrician as her mother noticed excessive hair growth all over the body and pubic area along with clitoral enlargement with vaginal introitus present at 8 to 9 months of age [Figure 1]. She was born out of consanguinous marriage, second order by birth, with a birthweight of 3.5 kg. She was conceived by IVF and delivered by LSCS at full term. The baby cried immediately after delivery. There was no h/o any perinatal complication.
On examination, her height was 76 cm (75th-97th centile), the weight was 12.5 kg (>97th centile), and the blood pressure was 120/80 mm (SBP, SDP >95 percentile
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Hg) (normal is 88/50 mm Hg); multiple antihypertensives were given (prazosin, amlodipine, spironolactone). She had cushingoid facies, signs of virilization in the form of hypertrichosis, clitoromegaly (2.5 cm), and deepening of voice. There were no neurocutaneous markers. There was no family history of malignancy. Karyotyping was done, 1.e 46 XX. Laboratory investigation revealed morning cortisol was 4.5 mcg/dl and it was nonsuppressible with
Submitted: 16-Nov-2023 Revised: 10-Feb-2024 Accepted: 23-Apr-2024 Published: 13-Jul-2024
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How to cite this article: Sankar KVV, Sarkar D, Pal DK, Chatterjee U. Virilizing adrenocortical carcinoma in a female child of Li-Fraumeni syndrome. Indian J Pathol Microbiol 2025;68:603-5.
dexamethasone (ONDT), 4.5 mcg/dl. Other hormone levels were as follows: Dehydroepiandrosterone sulfate (DHES) >1000 mcg/dl, testosterone 381 ng/dl, 17(OH) progesterones >20 ng/ml, S. ACTH 1.43 pg/ml, LH <0.12 mIU/ml, and FSH 0.37 mIU/ml.
USG whole abdomen showed solid calcified retroperitoneal mass of left adrenal gland origin. Uterus and ovary were present. Computed tomography (CT) of the abdomen showed a large heterogeneously enhancing mass (45 × 43 mm) arising from left adrenal gland with calcification in the parenchyma. Contrast-enhanced CT thorax showed no evidence of lung metastasis. Plasma metanephrine and normetanephrine were provided, and pheochromocytoma was ruled out. A medical board was held involving multiple disciplines and planned for surgical removal of the tumor. Then the patient underwent surgery and left adrenal mass was removed [Figure 2]. Histopathology revealed diagnosis of ACC (adrenocortical carcinoma) [Figure 3a and 3b]. In the postoperative period, the patient was on replacement dose of steroid, which was later tapered to maintenance dose. Amlodipne and prazosin were continued in the postoperative period, and blood pressure was under control. The patient was discharged in stable conditions. After 3 months of follow-up, morning cortisol 0.10 mcg/dl, DHEAS <15 mcg/dl, androstenedione <0.300 ng/dl, S. testosterone <4.9 ng/dl, and free testosterone 2.85 pg/ml.
In the postoperative period, hirsutism and clitoromegaly decreased [Figure 1] and voice improved. On follow-up, she underwent genetic study and was found to have a heterozygous mutation in the TP53 gene on chromosome 17p 13. Hence, she was diagnosed to be a case of Li-Fraumeni syndrome (LFS).
DISCUSSION
ACCs are a rare pediatric neoplasm with poor prognosis. Adrenocortical adenoma and ACC are two ends of spectrum that need to be differentiated. These carcinomas are also seen with increased frequency in children with LFS, Beckwith-Widemann syndrome, and multiple endocrine neoplasia type 1 or Carney complex.[5] The etiopathogenesis of ACC is not completely understood. A slight preponderance in female population has been noted.
ACC could be diagnosed by Weiss criteria on at least three of the nine histological features.
a. High nuclear grade (Fuhrman III or IV)
b. High mitosis grade (>5 mitoses per 50 high power field)
C. Atypical mitosis figures
d. ≤25% clear cells
e. Diffuse architecture
f. Tumor confluent necrosis
g. Venous invasion
h. Sinusoidal invasion
i. Capsular invasion
ACC can be associated with Cushing’s syndrome and mineralocorticoid production, although >75% do not have
Zorex DELUX
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12
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5
2
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a
b
any hormone overproduction.[4,6] Most ACCs present with virilization (84.2%), with pure virilizing in 55%. Isolated Cushing’s syndrome in the pediatric age group is seen in about 5% (without virilization). This is in contrast to adults where most of the ACCs are nonfunctional, and if functional, most of them tend to be Cushing’s syndrome. All ACCs are highly malignant tumors, and hence, they need to be resected. Surgery is the single most important procedure for the successful treatment of ACC. The role of chemotherapy in the management of childhood ACC has not been established.[7]
Our patient was one of the rare cases where glucocorticoid and androgen excess were started simultaneously as she had cushingoid facies along with hypertricosis and clitoromegaly along with deepening of voice. ACC tends to grow and metastasize rapidly if untreated. Fortunately for this patient, evaluation was done early and she underwent surgery early. After 3 months, she is doing well without any signs of metastasis.
CONCLUSION
ACC should be part of differential diagnosis in children with precocious puberty. Clinical, biochemical, and imaging features are important for diagnosing a virilizing adrenocortical tumor. Molecular genetic testing is important to ascertain whether an ACT is related to a specific genetic tumor syndrome, including LFS. Early identification of phenotypical changes is imperative in early management and better prognosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship Nil.
Conflicts of interest
There are no conflicts of interest.
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