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Expression of Endothelin-1 by Adrenocortical Carcinoma: a New Target for Anti-Cancer Therapy ?
J. E. Donckiei, L. Michel, M. Delas & X. Havaux
To cite this article: J. E. Donckiei, L. Michel, M. Delas & X. Havaux (2004) Expression of Endothelin-1 by Adrenocortical Carcinoma: a New Target for Anti-Cancer Therapy ?, Acta Chirurgica Belgica, 104:5, 581-583, DOI: 10.1080/00015458.2004.11679619
To link to this article: http://dx.doi.org/10.1080/00015458.2004.11679619
Published online: 14 Mar 2016.
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Case reports
Acta chir belg, 2004, 104, 581-583
Expression of Endothelin-1 by Adrenocortical Carcinoma : a New Target for Anti-Cancer Therapy ?
J. E. Donckier1, L. Michel2, M. Delos2, X. Havaux3
Departments of ‘Internal Medicine and Endocrinology, 2Surgery and Pathology and 3Cardiovascular Unit, University Hospital of Mont-Godinne and Faculty of Medicine, Université Catholique de Louvain. Yvoir and Brussels, Belgium
Key words. Adrenocortical carcinoma ; Cushing’s syndrome ; endothelin-1.
Abstract. Adrenocortical carcinoma is a rare neoplasm with poor prognosis. Endothelin-1 (ET-1) has been implicated in carcinogenesis, but has never been studied in this neoplasm. A 76-year-old woman with Cushing’s syndrome due adrenocortical carcinoma was operated on and the tumour removed was studied by immunohistochemistry for ET-1. Patient history illustrates the poor prognosis of this cancer that became metastatic after one year. Immunohistochemical studies disclosed a strong expression of ET-1 by adrenocortical carcinoma cells. As shown in other cancers, ET-1 expres- sion by adrenocortical carcinoma may suggest a pathogenic role of ET-1 in tumorigenesis that possibly could be coun- tered by ET-1 receptor antagonists. These agents could open new therapeutic perspectives to treat a carcinoma known to have a poor prognosis.
Introduction
Adrenocortical carcinoma is a rare neoplasm with poor prognosis (1). Despite complete tumoral removal, patients may still develop local recurrences or metas- tases. Adjuvant therapy, consisting in local radiation therapy, mitotane and cytotoxic chemotherapy unfortu- nately yields low remission rates in patients with metas- tases (1, 2) implying the search for innovative treat- ments.
Endothelin-1 (ET-1), a vasoconstrictive and mito- genic peptide released by the endothelium (3, 4) has recently found a new role as a progression factor in can- cer cells (5, 6). ET-1 can be produced by various cancers including notably those arising in prostate, lung, colon, breast, kidney and thyroid (5-12). The development of ET-1 receptor antagonists has thus opened new thera- peutic perspectives to treat metastatic or refractory can- cers expressing ET-1 (5-13). Because this question has never been addressed in adrenocortical carcinoma, we studied the expression of ET-1 in the case of a patient with Cushing’s syndrome due this cancer.
Case Report
Patient history
A 76-year-old woman was admitted to hospital in June 2003 for a poor glycaemic control of type 2 diabetes and
an ulceration of the left shin, caused by a bump on the leg. She gave a past history of hypertension, a diver- ticulitis requiring surgery, a cholecystectomy, a thy- roidectomy and a left adrenalectomy in 1993 with a diagnosis of oncocytoma. A mass in the right kidney was also evidenced in 1993 without being removed. On admission, she complained of polydipsia, polyuria and breathlessness. Clinically, she had bruises on the arms and her face appeared plethoric. Her pulse rate was 60/min and blood pressure 130/80 mm Hg. There was a marked proximal myopathy. A 3-cm ulcer was found on the left shin.
Laboratory investigations revealed a C-reactive pro- tein of 161600 µg/l (normal < 5000), white blood count 12.5 × 109/1, fasting sugar 7.16 mmol/l, glycated hemo- globin Ale 14.6% (normal range : 4 - 6), potassium 3.1 mmol/l and bicarbonate 31.8 mmol/l. Thyroid func- tion tests were normal (on thyroxine replacement thera- py). A initial diagnostic assessment showed a high urine free cortisol of 1302 nmol/d (normal range : 55-248). At 08.00 and 20.00 hr, serum cortisol levels were raised at 974 nmol/l (normal range : 193-690) and 919 nmol/l (normal range : 55-248) respectively with low plasma ACTH (0.62 and 0.53 pmol/l) (normal range : 2.20- 13.21 at 08.00 hr and 1.32 - 6.60 at 20.00 hr). Cortisol did not suppress on dexamethasone 2 mg/day for 48 hours. Abdominal computed tomography (CT) demonstrated an inhomogeneous 15-cm tumour of the left adrenal (Fig. 1) as well as a 3-cm right renal tumour.
The latter was unchanged compared with that of 1993. A lung scanning performed because of hypoxaemia showed several perfusion defects consistent with pulmonary thromboembolism. Treatment was then commenced with low molecular weight heparin and insulin to control diabetes. After stabilization for a week, the patient was operated on and a 1.5 kg adrenal tumour was removed, using a transabdominal approach. Invasion into the spleen also required en bloc excision of the spleen. Post-operative endocrine assessment showed a cortisol of 303 nmol/l at 08.00 hr, that suppressed to 165 nmol/l on dexamethasone 2 mg/day for 48 hours.
Urine free cortisol was 99 nmol/d. Histological findings were consistent with a diagnosis of adrenocortical carci- noma. The tumour exhibited a high number of atypical mitoses, necrosis areas and lymphatic invasions. A lym- phnode was found negative but pathohistological exam- ination of the spleen disclosed a massive invasion by adrenocortical cancer cells. Therefore, the patient received a course of mitotane that had to be discontinued after a week because of confusion, lethargy, severe dizziness and nausea. The patient then recovered pro- gressively, could be discharged and remained stable for one year. Unfortunately, a CT Scan performed in July 2004 showed peritoneal and hepatic metastases. Nevertheless, her overall clinical condition was satisfac- tory 13 months after surgery.
A
B
Immunohistochemical studies of adrenocortical carcinoma showing a lack of labelling with the preimmune serum (A) and a red labelling of carcinoma cells with the immune antiserum raised against endothelin-1 (ET-1) (B). Diffuse ET-1 immuno- reactivity is detected in the cytoplasm of carcinoma cells. Scale bar for A and B : 100 um.
Immunohistochemistry (Fig. 2)
Immunohistochemical studies for ET-1 were performed as previously described (12). Briefly, the anti-ET-1 anti- serum was home-made and has been well characterized (12). In the present case, its specificity was evaluated by an incubation of cancer tissue with the preimmune anti- serum as a first layer. This study showed a lack of stain- ing with this preimmune antiserum. In contrast, intense ET-1 immunoreactivity was detected in the cytoplasm of cancer cells as well as in endothelial cells from various vessels with the antiserum raised against ET-1. Of note, other routine immunohistochemical studies revealed a labelling that was positive for synaptophysin, vimentin, neuron-specific enolase and cytokeratin. These charac- teristics, including notably cytokeratin were in favour of an adrenocortical carcinoma.
Discussion
A typical case of a patient with Cushing’s syndrome due to adrenocortical carcinoma has been reported. Immunohistochemical studies showed for the first time an expression of ET-1 by adrenocortical carcinoma cells.
Diagnosis of Cushing’s syndrome was suspected on clinical grounds and was confirmed by the endocrine assessment showing a hypercortisolism that did not suppress on low-dose dexamethasone. An adrenal origin was obvious upon the basis of low plasma ACTH and the evidence of a large adrenal mass on CT Scan. The size of the tumour suggested malignancy. Indeed, in a recent series (2), mean tumour size of adrenocortical carcino- ma was 12.0 ± 6 cm and a weight of more than 100 g was highly suspicious of malignancy (14). In the present case, a surgery of left adrenal was performed in another institution more than 10 years earlier with a diagnosis of oncocytoma. Whether this diagnosis was in connection with the current tumour remains equivocal in considera- tion of the poor prognosis of adrenocortical carcinoma. However, this hypothesis cannot be ruled out because adrenocortical carcinoma has been reported as a hetero- geneous disease with some patients surviving for more than 10 years and others dying after a few months (1). As previously reported (2), the prognosis also depends on the staging with a 5-year survival rate of 60% for stage I tumours (possibly this stage initially in our patient) and 0% for stage IV (the current stage).
In any case, response rates to mitotane and/or chemotherapy remain low in metastatic patients, espe- cially in the elderly as in the present case. The over- expression of ET-1 as we have now demonstrated in our patient may open new therapeutic perspectives in view of the recent development of ET-1 receptor antagonists. Indeed, ET-1 has been implicated by various ways in tumorigenesis. As recently reviewed, functions of ET-1 in cancer progression mediated by ETA receptors could involve cell proliferation, cell survival, angiogenesis and development of metastases (5, 6). ET-1 receptor antago- nists (such as bosentan or atrasentan) also proved to be efficacious on various cancer cell lines to counter ET-1 effects (5, 6, 13, 15). Moreover, a recent randomized phase II, placebo-controlled trial conducted in 288 patients with prostate adenocarcinoma showed that atrasentan was able to delay progression of this can- cer (13).
In conclusion, we showed ET-1 overexpression in a case of adrenocortical carcinoma. Further studies are now required to evaluate ET-1 expression in series and the efficacy of ET-1 receptor antagonists in this cancer.
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Prof. Julian Donckier Internal Medicine and Endocrinology University Hospital of Mont-Godinne B-5530 Yvoir, Belgium Tel. : 0032-81-42.32.81
Fax : 0032-81-42.32.83
E-mail : julian.donckier@mint.ucl.ac.be