Prognostic Role of Overt Hypercortisolism in Completely Operated Patients with Adrenocortical Cancer

Adrenocortical carcinoma (ACC) is a malignant endocrine tumour. The rarity of the disease has stymied therapeutic development. Age distribution shows two peaks: the first and fifth decades of life, with children and women more frequently affected. Although 60-70% of ACCs are biochemically found to overproduce hormones, it is not clinically apparent in many cases. If present, endocrine symptoms include signs of hypercortisolaemia, virilisation or gynaecomastia. ACC carries a poor prognosis, and a cure can be achieved only by complete surgical resection. Mitotane is used both as an adjuvant treatment and also in non-operative patients. The role of radio-and chemotherapy is still controversial. The post-operative disease free survival is low and oscillates around 30% due to high tumour recurrence rate. The diagnosis is based on tumour histological assessment with the use of the Weiss score, however urinary steroid profiling (if available) can serve to differentiate between ACC and other adrenal tumours. Conventional prognostic markers in ACC include stage and grade of disease, and, as currently reported, the presence of hypercortisolaemia. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers, among which alterations of the IGF system, the Wnt pathway, p53 and molecules involved in cancer cell invasion properties and angiogenesis seem to be very promising. We here summarise our own experience related to the management of ACC and present a literature overview. We have not aimed to include a detailed summary of the molecular alterations biology described in ACC, as this has already been addressed in other papers. StreszczenieRak kory nadnercza (ACC) jest złośliwym guzem endokrynnym. Rzadkość jego występowania przyczyniła się do spowolnienia rozwoju nowych opcji terapeutycznych. Zachorowalność występuje dwuszczytowo: w pierwszej oraz piątej dekadzie życia, przy czym zachorowalność dotyczy częściej kobiet i dzieci. Mimo że 60-70% ACC jest zwykle czynna hormonalnie, to klinicznie nie zawsze jest to oczywiste. W przypadku guzów aktywnych hormonalnie mamy do czynienia z objawami hiperkortyzolemii, wirylizacji czy ginekomastii. ACC jest nowotworem o złym rokowaniu, a jego wyleczenie może być osiągnięte poprzez całkowitą resekcję zmiany. Mitotan znajduje zastosowanie zarówno w leczeniu adjuwantowym jak i w przypadkach guzów nieresekcyjnych. Natomiast rola radio-oraz chemioterapii pozostaje nadal kontrowersyjna. Przeżywalność po zabiegu operacyjnym oscyluje w granicach 30% i wiąże się z wysokim odsetkiem nawrotów. Rozpoznanie stawiane jest na podstawie analizy histopatologicznej przy użyciu Weiss score, jednakże analiza wydalania steroidów w moczu (o ile jest dostępna) może pomóc w rozróżnieniu pomiędzy ACC a gruczolakiem nadnercza, a także innymi guzami nadnercza. Głównymi czynnikami prognostycznymi są: stopień zróżnicowania i zaawansowania nowotworu i, według ostatnich doniesień, obecność hiperko...

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“…Co ciekawe kliniczna jawność hiperkortyzolemii zdaje się nie mieć wpływu na skuteczność terapii adjuwantowej mitotanem [35].…”

Section: Patogeneza I Aspekty Molekularneunclassified

“…In summary, clinically relevant hypercortisolism has now been shown to be a new prognostic factor in patients with completely resected ACC receiving adjuvant mitotane. Interestingly, the efficacy of adjuvant mitotane does not seem to be influenced by overt hypercortisolism [35].…”

Section: Prognostic Markersmentioning

confidence: 99%

Rak kory nadnercza (ACC) — przegląd piśmiennictwa i doświadczenia własne

Dworakowska

Drabarek

Wenzel

et al. 2015

Endokrynologia Polska

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“…Approximately 50% of ACC in adults are hormone-secreting tumors that produce cortisol (Cushing's syndrome) or androgen or multiple steroids [4]. Cortisol excess negatively influences the outcome of ACC patients with early [5] and advanced stages [6,7] of disease. The adverse prognosis associated with secreting tumors is due to cortisol-related comorbidities, including hypertension, hypokaliemia, hyperglycemia, and infections.…”

Section: Introductionmentioning

confidence: 99%

Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study

Fiorentini¹,

Fragni²,

Perego³

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context: Patients with adrenocortical carcinoma (ACC) frequently suffer from cortisol excess, which portends a negative prognosis. Rapid control of cortisol hypersecretion and tumor growth are the main goals of ACC therapy. Abiraterone acetate (AA) is a potent inhibitor of 17alpha-hydroxylase/17,20-lyase, a key enzyme of adrenal steroidogenesis.Objective: To investigate the therapeutic use of AA in preclinical models of ACC.Design: AA antisecretive and antiproliferative effects were investigated in vitro using NCI-H295R and SW13 ACC cell lines and human primary ACC cell cultures, as well as in vivo using immunodeficient mice.Methods: Steroid secretion, cell viability and proliferation were analyzed in untreated and AA-treated ACC cells. The ability of AA to affect the Wnt/beta-catenin pathway in NCI-H295R cells was also analyzed.Progesterone receptor (PgR) gene was silenced by the RNA interference approach. The antitumor efficacy of AA was confirmed in vivo in NCI-H295R cells xenografted in immunodeficient mice.Results: AA reduced the secretion of both cortisol and androgens, increased production of progesterone and induced a concentration-dependent decrease of cell viability in the NCI-H295R cells and primary secreting ACC cultures. AA also reduced beta-catenin nuclear accumulation in NCI-H295R cells. AA administration to NCI-H295R-bearing mice enhanced progesterone levels and inhibited tumor growth. The cytotoxic effect of AA was prevented by either blocking PgR or by gene silencing.Conclusion: AA is able to inhibit hormone secretion and growth of ACC both in vitro and in vivo. It also reduces beta-catenin nuclear accumulation. The cytotoxic effect of AA appears to require PgR.

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“…и в обзорной статье A. Berruti и со-авт. [10,11]. Отмечено, что повышенная выработка кортизола при АКР характерна для пациентов более молодого возраста.…”

Section: Discussionunclassified

“…Стадия процесса, пол пациента, степень дифференцировки опухоли значения не име-ли. В исследовании [11] проведен анализ данных 524 больных, ни у одного из которых не было метастазов. Рецидив после хирургического лечения был зареги-стрирован у 339 (64,7 %) пациентов, умерли 204 (38,9 %).…”

Section: Discussionunclassified