A CASE OF CHILDHOOD ADRENOCORTICAL CARCINOMA

A one year and seven months old girl was referred to the Endocrine department for evaluation of pubic hair growth, which was noticed by her grandmother 2 weeks prior to the initial presentation. She was otherwise healthy and had an uneventful perinatal period and age appropriate growth and development. There was no consanguinity, history of ambiguous genitalia or recent pigmentation. On examination, her height was 77cm and her weight was 11kg. She had Tanner 2 pubic hair growth without axillary hair development and clitoral hypertrophy. Breast development was Tanner 1. There were no features of Cushing syndrome and she was normotensive. The abdomen was distended but no distinct masses were felt on palpation. Her haematological and other biochemical markers were unremarkable. Ultrasound scan of the abdomen showed a 6.8 cm x 6 cm well defined, solid, hypoechoic mass in the right supra renal region consistent with a supra renal mass. Contrast enhanced CT revealed a fairly well-circumscribed, rounded lesion in the right supra renal region measuring 5.8 x 6.7 x7.2cm without any invasion into the inferior vena cava, liver or right kidney. It was hypodense and inhomogeneously enhancing without intra-lesional calcifications. Radiologically, this appearance was suggestive of a neuroblastoma arising from the right supra renal gland. Patient underwent right sided adrenalectomy and the histology confirmed the diagnosis of adrenocortical carcinoma arising from the zona glomerulosa. There were 5-10 mitotic figures per 50 high power fields examined. The resection margins were clear. However, intra-capsular lymphatics and blood vessels contained tumour emboli. Necrotic areas were also noted (<5% of the tumour). Ki 67 proliferation index and P 53 mutation analysis were not available. Following surgery, the patient was referred to an oncologist for adjuvant therapy with mitotane and further follow up. ABSTRACT


INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare malignancy with an annual incidence of 1-2/ million (1). It has a bimodal age distribution with a peak in the below 5year age group and in the 4 th and 5 th decades of life. These tumours are generally more aggressive in adults (2).

CASE REPORT
A one year and seven months old girl was referred to the Endocrine department for evaluation of pubic hair growth, which was noticed by her grandmother 2 weeks prior to the initial presentation. She was otherwise healthy and had an uneventful perinatal period and age appropriate growth and development. There was no consanguinity, history of ambiguous genitalia or recent pigmentation. On examination, her height was 77cm and her weight was 11kg. She had Tanner 2 pubic hair growth without axillary hair development and clitoral hypertrophy. Breast development was Tanner 1. There were no features of Cushing syndrome and she was normotensive. The abdomen was distended but no distinct masses were felt on palpation.
Her haematological and other biochemical markers were unremarkable. Ultrasound scan of the abdomen showed a 6.8 cm x 6 cm well defined, solid, hypoechoic mass in the right supra renal region consistent with a supra renal mass. Contrast enhanced CT revealed a fairly well-circumscribed, rounded lesion in the right supra renal region measuring 5.8 x 6.7 x7.2cm without any invasion into the inferior vena cava, liver or right kidney. It was hypodense and inhomogeneously enhancing without intra-lesional calcifications. Radiologically, this appearance was suggestive of a neuroblastoma arising from the right supra renal gland. Patient underwent right sided adrenalectomy and the histology confirmed the diagnosis of adrenocortical carcinoma arising from the zona glomerulosa. There were 5-10 mitotic figures per 50 high power fields examined. The resection margins were clear. However, intra-capsular lymphatics and blood vessels contained tumour emboli. Necrotic areas were also noted (<5% of the tumour). Ki 67 proliferation index and P 53 mutation analysis were not available. Following surgery, the patient was referred to an oncologist for adjuvant therapy with mitotane and further follow up.
Paediatric ACC occurs mostly in children below 5 years of age with a peak incidence at 3.5 years (3). It is commoner in girls and frequently (80-90%) produces adrenocortical hormones (4). Majority of the younger children (>90%) present with virilizing features, whereas adolescents and young adults tend to have Cushing syndrome or non-functional tumours at presentation (5).
The hormonal analysis of the patient revealed very high Unlike in most other carcinomas, the children with In paediatric ACCs, abdominal ultrasound should be the first line of imaging, which is also sensitive enough in detecting caval extension of tumour thrombus. If it is negative, Magnetic resonance imaging (MRI) or Computerized tomograph (CT) scan is recommended. MRI is preferred as it lacks ionising radiation. It also gives a better definition of tumour extent and invasion into adjacent structures. Exposure to repeated X-ray radiation should be minimized in view of the likely genetic predisposition and propensity to second tumours (14). And suspected ACCs should not be biopsied because of the risk of tumour seeding (3).
histopathological distinction between adrenal adenoma and carcinoma is difficult and the tumor size is considered as the best available predictor of biological behaviour of these tumours. The tumours of >100g/200cm3 are associated with a worse prognosis (15) and older age at presentation, increased urinary steroid DHEA-S and glucocorticoid hormone levels, hypertension, peri-operative tumour rupture and delay in diagnosis (16) are the other poor prognostic factors.
Treatment for ACCs includes en block tumour removal and chemotherapy. Because of the high likelihood of a genetic cancer predisposition and risk of occurrence of secondary tumours within the radiation field, radiotherapy is not advised in children (3). Postoperative adrenocortical hormone replacement may be required in selected patients. Mitotane is an adrenolytic agent that is usually effective in controlling the endocrine symptoms and tumour regression. Some studies have shown that it has a greater effectiveness in children than adults, especially if the neoplasm is hormonally active (17). Mitotane has a cytotoxic effect especially on the zona reticulosa and also zona fasciculata to a lesser extent. In contrast, its' effect on the zona glomerulosa is negligible. Other effective chemotherapeutic agents include cisplatinum, etoposide, doxorubicin, 5-Fluoruracil and cyclophosphamide (3). The tumour staging system used in paediatric age group is slightly different from adults. The size, weight and amount of resection of the tumour are vital factors that are considered in staging these tumours (3). The

REFERENCES
Most of the young children present with virilization and the common manifestations include deepening of the voice, acne, hirsutism, increase of muscle mass and secretion and proliferation of the sebaceous glands with characteristic adult odor. In females, clitoral enlargement, facial and pubic hair with male escutcheon, amenorrhea and rarely temporal balding may occur (7). Penile enlargement and precocious isosexual pseudo-puberty occur in males and it is usually adrenal in origin when the testes are small (8). Cushing syndrome (CS) is very rare in children and in the absence of iatrogenic steroid ingestion, it is highly indicative of ACC. (9). Less commonly, ACC co-secretes glucocorticoids and androgens. Rarely patients with ACCs present with feminization and features of hyperaldosteronism (10). Our patient's tumour was considerably large (>200cm³) with very high androgen levels by the time of diagnosis. However, the only clinical feature that our patient has was the pubic hair growth indicating a short duration androgen exposure due to the rapidity of the tumour growth.
ACCs appear generally healthy due to the anabolic effects of the increased amounts of androgens and/or other steroid and the diagnosis is often delayed. The median interval between the first clinical manifestations of ACC and its diagnosis is about 10 months (6).
In young children, ACCs may arise from the fetal zone of the fetal adrenal cortex, whereas in adolescents and adults, may originate from the definitive adrenal cortex (5). Young children with ACC frequently demonstrate mutations of the p53 gene, while these mutations are relatively rare in adults (11,12). It is likely that the presence of a constitutional p53 mutation may increase the penetrance of ACCs in the fetal adrenal cortex but not in the definitive adrenal cortex. For this reason, individuals with constitutional p53 mutations (Li-Fraumeni syndrome), adreno cortical tumours usually occur only during the first decade of life (13). Various other genetic predispositions and tumour syndromes such as Beckwith-Wiedemann syndrome. MEN 1, Carney Complex are also associated with paediatric ACC (8).
In conclusion, paediatric ACCs are very rare and quite different from adult ACCs in terms of origin and its' behavior. These are mostly virilizing tumours especially in children below 5 years of age. In order to avoid delay in the diagnosis, any child less than 4 years with pubarche should be considered to have an adrenocortical tumour, until proven otherwise.