Adrenal cortical carcinoma in a child, a rare cause of paediatric endocrinopathy: Case report and literature review
Sugeshnee Pather,1 Biance Rowe,2 and Dawn van der Byl1
1 Anatomical Pathology, National Health Laboratory Service; 2 Paediatric Oncology, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences, University of the Witwatersrand, Gauteng, South Africa
Adrenal cortical carcinomas (ACC) are rare tumours, most commonly reported in adult patients. However, an important peak in incidence occurs in paediatric patients. ACC is a rare cause of pae- diatric endocrinopathy which may masquerade as a non-neoplastic disease process. Herein we present ACC in a five-year-old female patient. Histopathological features associated with poor outcome included tumour weight >500 g, tumour size >10.5 cm, invasive properties, confluent tumour necrosis, high nuclear grade and high proliferation index assessed by Ki67 immunohisto- chemistry. This article focuses on clinical features, treatment, pathological characteristics, evolving classification and genetic significance of ACC in paediatric patients.
Keywords paediatric adrenal cortical carcinoma, histopathologic diagnostic criteria, P53
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INTRODUCTION
Adrenal cortical carcinomas (ACC) are rare tumours which are most commonly re- ported in adult patients. However, an important peak in incidence occurs in the paedi- atric population. The worldwide annual incidence ranges from 0.3 to 0.38 per million children below the age of 15 years, with 65% of these tumours occurring in children below the age of 5 years [1, 2]. Of significance is the higher incidence (10-15%) of ACC in Southern Brazilian paediatric patients [3, 4, 5, 6]
Although ACC are very rare in the paediatric population, this tumour is an im- portant cause of paediatric endocrinopathy [4] which may masquerade as a non- neoplastic process, resulting in potential delays in diagnosis and definitive treatment.
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CASE HISTORY
A five-year-old female child presented with seizures to the Chris Hani Baragwanath Hospital in Gauteng, South Africa. Physical examination confirmed the child to be obese and hypertensive. The patient had features of precocious puberty, virilisation, hirsutism and acne. There was no premature breast development and dysmorphism
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was not evident. Thorough examination of the patient’s abdomen revealed the pres- ence of a palpable unilateral (left sided) flank mass.
Biochemical investigations were performed and elevated levels of oestrogen, testosterone, cortisol, aldosterone, DHEAS and 17-alpha-hydroxyprogesterone were confirmed.
Radiological investigations revealed advanced bone age which was twice the pa- tient’s chronological age. Computed tomography (CT) of the abdomen confirmed the presence of a large unilateral suprarenal mass.
Thereafter the patient was surgically treated by left sided adrenalectomy and nephrectomy. Macroscopic examination of the resected specimen confirmed the presence of a solid circumscribed neoplasm weighing close to 800 g. The tumour di- mensions were 17 x 12.5 x 8.5 mm3. The cut surfaces revealed multi-lobulation and a partially variegated appearance due to areas of necrosis. Infiltration of the adjacent kidney was macroscopically evident (Figure 1).
Microscopic examination of haematoxylin and eosin stained sections confirmed a neoplasm which displayed predominantly diffuse architecture with focal areas of tra- becular and alveolar growth patterns. There were distinct areas of confluent coagula- tive tumour necrosis. The tumour cells had abundant eosinophilic, intermittently vac- uolated, cytoplasm and round to oval nuclei. In some areas, there was marked nuclear pleomorphism and the Fuhrman nuclear grade was 4/4 (Figure 2). The average mi- totic count was 12/50 high power fields and no atypical mitotic figures were identified. The tumour had invaded the capsule and invasion of the adjacent kidney was evident (Figure 3). In addition, foci of lymphovascular invasion were identified. No sarcoma- tous components were present.
The tumour cells displayed immunoreactivity for pankeratin AE1/AE3 (weakly pos- itive), vimentin, alpha inhibin and p53. Chromogranin A, EMA and calretinin im- munostains were negative. Ki67 immunohistochemistry was used to assess the pro- liferative index which was approximately 20%.
These features confirmed the presence of ACC.
OUTCOME
Following surgical excision of the tumour, the patient was commenced on a chemotherapy regimen comprising Mitotane, Cisplatinum, Doxorubicin and Etoposide [20]. The patient completed six cycles with granulocyte colony stimulating factor support. The hormonal abnormalities had completely resolved two months after surgery with the DHEAS, aldosterone and testosterone levels normalising for age. The hormonal levels were monitored three monthly whilst on chemotherapy and remained normal. The clinical features of precious puberty, namely pubic hair and acne, subsequently resolved. However, the patient remained hypertensive whilst on treatment.
Following completion of the above-mentioned chemotherapy protocol, the patient was started on Mitotane maintenance treatment. Due to challenges associated with drug availability, Mitotane was only available to our patient intermittently and even- tually discontinued six months into maintenance therapy.
Three months after discontinuing Mitotane maintenance, follow-up ultrasound of the abdomen was performed, revealing a heterogeneous mass in the left renal bed, as well as a splenic mass. CT-scan of the chest and abdomen confirmed relapsed dis- ease with multiple pulmonary masses, as well as para-aortic and mesenteric nodal masses. The spleen was diffusely infiltrated with hypodense lesions. The DHEAS level was >27 umol/L, which was essentially similar to pre-treatment levels.
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Palliative care was commenced in view of the disease relapse with extensive multi- system involvement. The patient is currently on supportive care only.
DISCUSSION
Due to the functional nature of ACC in the paediatric population, these tumours are an important, though rare, cause of endocrinopathy. In contrast, those occurring in the adult population are less frequently hormonally functional. [4]. The spectrum of
endocrine dysfunction associated with ACC includes Cushing’s syndrome due to glu- cocorticoid production, severe systemic hypertension due to Conn’s syndrome from mineralocorticoid production and precocious puberty, virilisation or hirsutism due to excessive sex steroid production [1]. All of these were evident in our young patient.
Several research groups have proposed the use of a combination of histopatho- logic criteria to reliably distinguish benign from malignant adrenal cortical neoplasms in adult patients [7, 8, 9, 10]. However, in the paediatric population, some of the
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proposed criteria have been found to be less predictive of poor outcome. Cagel et al. [11] reviewed 23 cases of paediatric adrenocortical neoplasms and 42 adult cases and subsequently proposed that criteria which are predictive of biologic behaviour, differ in paediatric and adult tumours. In support thereof, the tumour size appeared to be the only reliable predictor of biologic behaviour in childhood. All paediatric adrenal cortical tumours weighing greater than 500 g behaved in a malignant manner. Weineke et al. [3] further contributed that confirmation of malignancy in paediatric adrenocor- tical tumours requires a constellation of pathological features which are additionally inclusive of tumour size (>10.5 cm) and invasive properties. Moreover, in multivari- ate analysis, these researchers demonstrated that invasion of the vena cava, tumour necrosis and mitoses in excess of 15/20HPF were independently suggestive of malig- nant clinical behaviour.
By modifying the criteria proposed by Weiss et al [7], Ribeiro et al. [12] subdivided paediatric ACC into low and high grades. The latter was defined by mitotic count in excess of 20/50HPF. In combination with tumour weight, the high-grade tumours were found to be reliable predictors of poor outcome.
Dehner and Hill [13] furthermore proposed risk groups for adrenocortical neo- plasms in children using tumour weight, invasion into surrounding soft tissue or or- gans, completeness of resection and metastatic spread. The tumour in our patient would be considered high risk as the weight exceeded 400 g.
In further contrast of the adult counterpart, ACC occurring in the paediatric popu- lation may be associated with less aggressive behaviour and outcome [3, 14]. Unfortu- nately, the tumour in our patient had several poor prognostic features which included weight of close to 800 g, greatest tumour dimension of 17 cm, invasion of the adjacent kidney and confluent tumour cell necrosis.
p53 immunohistochemical expression occurred diffusely within the nuclei of this ACC. From a genetic point of view, somatic p53 mutations occur in 30-50% of ACC [4, 15]. Importantly, germline p53 mutations also occur in association with Li Fraumeni syndrome and Beckwith-Wiedemann syndrome [4]. The former is an autosomal dom- inant condition characterised by multiple primary tumours such as breast carcinoma, osteosarcoma, soft tissue sarcomas, brain tumours, leukaemia and ACC which occur in children and young adults. Researchers have suggested that the occurrence of ACC in children, may be diagnostic of germline p53 mutations [16, 17].
The unusually higher incidence of paediatric ACC in Southern Brazilian, prompted further investigation by Reibero et al. [18]. The 35 of 36 Brazilian paediatric patients with ACC, were subsequently found to demonstrate germ-line point mutation of p53 encoding an R337H amino acid substitution. However, unlike that which occurs in Li- Fraumeni syndrome, there was no increase in malignancy in close family members of these patients. Hence, the study proposed that the inherited R337H p53 mutation rep- resented a low-penetrance p53 allele, which likely contributes to the development of paediatric ACC in a tissue-specific manner. Unfortunately, at present the aetiology of this mutation remains elusive. Figueiredo et al. [19] suggested that there is possibly an environmental influence or factor responsible for introducing the p53 mutation into the genetic pool in the Southern Brazilian region.
Our patient has no history of previous malignancy and there is no known history of associated malignancies in close family members. The patient and family have con- sulted a geneticist. Unfortunately, testing for p53 mutations is not available in South Africa at present and sending the sample overseas would be prohibitively expensive. As such, a blood sample was collected for DNA banking should the test become avail- able in future in South Africa.
In summary, the histopathological features associated with poor outcome in our patient included tumour weight exceeding 500 g, tumour size >10.5 cm, invasive
properties (renal and lymphovascular invasion), confluent tumour cell necrosis, high nuclear grade and high proliferation index assessed by Ki67 immunohistochemistry.
Declaration of Interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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