by Consuelo Buttigliero and Elisabetta Greco
DEFINITION W
It is a malignant neoplasm affecting the adrenal cortex.
EPIDEMIOLOGY
• age :there are two peaks of incidence. The primary is around age 50, while the secondary smaller peak is before five years of life.
perche due picchi?
There is no explanation of this bimodal distribution by age in literature.
Giving that sex hormones and gonadotropin could be involved in the pathogenesis of this cancer (see after), it can be explained by a similar hormones profile: in both groups (children before 5 years and adults around 50), there is no activation of Hypothalamic-pituitary-gonadic axis, leading to high gonadotropin levels. Different studies misured urinary and plasmatic gonadotropin levels in children showing they are increased before 2 years of age; while in women at the onset of menopause, the lack of female sex steroid hormones normally produced by the ovaries results in a loss of negative feedback and high circulating concentrations of gonadotrophins.
• sex: predilection for females (65-90%).
• incidence: 0.1 cases per 100000 accounting for about 3% of endocrine neoplasms.
SYMPTOMS
Adrenal cortical carcinoma can be functioning or not. Non functioning tumours may present with symptoms related to the compression of abdominal organs or to metastatic disease, so their diagnosis could be late.
Giving that adrenal cortex synthesizes essential steroids (glucocorticoids; androgens and mineralocorticoids), that regulate diverse biological processes such as blood pressure, glucose metabolism, immune surveillance and sexual development, signs and symptoms of functioning adrenal cancer include:
• Virilisation, acne, deep voice, facial hair, due to high levels of androgens;
• Hypertension, facial hyperemia, mostly due to mineralcorticoid effect ;
• Sign and symptoms of Cushing Syndrome
• gynecomastia in men and metrorrhagia in post-menopausal in women, due to estrogens.
DIAGNOSIS
In most cases the differential diagnosis between adenoma and carcinoma can be difficult and requires integration of clinical, biochemical and histological findings.
• Histopathology: The diagnosis has been classical based on Weiss score system
• Imaging: TC scans and MRI of ACC typically demonstrate a large (larger than 5 cm) inhomogeneously enhancing suprarenal mass. Calcification are present in 30% of the tumours on TC. Adjacent organs are frequently displaced.
• Laboratory tests: Increased urinary cortisol excretion associated with undetectable ACTH plasma levels. DHEAS is often elevated. Other steroids such as 17-OH-progesterone delta-4-androstenedione and estrogens can be overproduced by the tumour. 24 hours urinary excretion of 17-ketogenic and 17-ketostyeroids may be elevated.
PATHOGENESIS
esiste un punto specifico della corticale da cui originano? ci sono diversi strati, fate una scheda Adrenals sotto tissues e trovate qualche figura che illustri i vari strati
The adrenal cortex is composed of the outer zona glomerulosa, middle zona fasciculata and inner zone reticularis. In adition, a thin stem cell zone is believed to be situated outermost, adjacent to the adrenal capsule, enabling continuous self-renewal of the adrenal cortex by centripetal migration. The same stem cells seem, in many instances to give rise to adrenocortical neoplasia.
As in the majority of tumours, pathogenesis is still undiscovered. Many authors have investigated molecular alterations that would lead to inactivation of the tumor suppressor genes and activation of the oncogenes. The most studied is IGF-II: Receptors for IGF-I and IGF-II are present in adrenal tissues and strong overexpression of intact IGF-I receptors has been shown in ACC. The mitogenic effect of IGF-II is dependent on the IGF-I receptor, as reported by Logie et al.(1999), who demonstrated that IGF-II is involved in the H295R cell line (derived from an ACC) proliferation and acts through the IGF-I receptor. IGF-II effects are restricted to tumors and plasma IGF-II concentrations are usually in the normal range. Many other genes are involved, for example p53, β-catenin and ACTH receptor. This receptor has been found downregulated in non functioning carcinomas suggesting a role in differentiation.
Cercate di capire come è regolata l'espressione del R per l'ACTH o l'IGF-I. Se si riuscisse ad up-regolare il ACTH-R il tumore non verrebbe
ACTH receptor is up-regulated by its own ligand. Its transcription is regulated by SF-1 and AP-1 which are inductor of its promoter, while Dax 1 is an inhibitor of the same region. It is still unknown how SF-1 is regulated. Despite an extensive search, no activating ACTH receptor mutations have been found in adrenal tumors, excluding the ACTH receptor as a relevant oncogene in adrenal tumorigenesis. However, the ACTH receptor may act as a differentiation factor as suggested by LOH in adrenal carcinomas with an undifferentiated tumor type.
ACTHR is a seventransmembrane domain receptor belonging to the G-protein-coupled receptor superfamily leading to activation of the adenylate cyclase pathway and consecutive activation of protein kinase A.
Interestingly, it has been shown that LH, FSH (their elevation is considered a risk factor: see after), TSH, HCG, NE activates the same signaling pathway, through different beta-adrenergic receptor. So, tumour adenilate cyclase could be a target to investigate, being the crossroad between these hormonal pathways (ACTH and gonadotropin).
PATIENT RISK FACTORS
Vascular
Genetic
Acquired
Tobacco : risk was elevated 5-fold among current cigarette smokers, with risks further increased among those who smoked > 20 cigarettes/day. cosa fa il fumo?
Nicotine is an activator of hypothalamic-pituitary-adrenocortical axis. It could acts as a promoting factor in the pathogenesis of tumour.
It has also been shown that tobacco smokers have higher plasma levels of FSH in premenopause.
Hormonal
Genetic
Gonadotropin-induced adrenocortical neoplasia : it has been demonstrated in nude mice that chronic gonadotropin elevation, caused by either gonadectomy or hCG administration, signals a population of cells in the adrenal subcapsular region that causes the development of sex steroid-producing adrenocortical neoplasms.
There are two inherited cancer syndrome which present ACC with high frequence: Li-Fraumeni Syndrome and Beckwith-Wiedemann Syndrome.
cosahanno in comune dal punto di vista molecolare?
The first one is due to germline p53 mutation; while the second is associated with dysregulation of a group of growth controlling genes on chromosome 11, including defects in maternal imprinting, with paternal disomy of the IGF2 gene.
There is a molecular link between these two syndromes: in other tissues (liver especially) has been shown that activation of insulin-like growth factor II signaling is upregulated by mutant type p53.
Acquired
Oral contraceptives before age 25
aumentano le gonadotropine?
Oral contraceptives inhibit the hypotalamic-pituitary-gonadal axis manteining costant low levels of gonadotropin. It is possible that after therapy suspension there is not an immediate riactivation of ovary function (low sexual steroid hormons), leading to compensatory increased levels of FSH and LH. This is why a unfrequent cause of secondary amennorhea is suspension of oral contraceptives. We couldn't find any confirm in litterature.
COMPLICATIONS
• Cardiovascular diseases, Hypertension
• Invasion of inferior vena cava.
PROGNOSIS
It is largerly dependent on the grade of tumour and stage of diagnosis. The mortality rate is 67-94%. Mean survival interval from diagnosis lies between 4 and 30 months.
Many tumours are locally invasively and 15-67% metastasized at time of initial presentation. The most common sites of metastasis are liver, lung, retroperitoneum and lymph nodes.
Some factors of tumour invasivity, such as metalloproteinases have been studied.
This family of endopeptidase is able to degrading all components of the extracellular matrix .This characteristic allows tumour to overcome the basement membrane, to grow and metastasize. The pivotal role of these proteins in tumour progression is confirmed by the development of their inhibitors (tetracycline derivatives and bisphosphonates) in cancer therapies.
THERAPIES
• Surgical excision is the mainstay of current therapy, also for localized metastasic tumours;
• Chemotherapy is used if surgical cure is not possible: the best protocol is Etoposide, Doxorubicin, Cisplatin with Mitotane (overall response rate 53.5%). This molecule is a derivative of DDT and has been used for years in Cushing Syndrome in canines because of its properties of inhibiting steroid hormones production. The molecular mechanism is still unknown, but a recent study proposes its role as an inhibitor of apoptosis.
Acc is resistant to the majority of chemioterapic agents. This could be explained by high levels of MDR1 expression by tumour cells. MDR1 is a drug efflux-pomp that transports out of the cells Hydrophobic cytotoxic agents. The development of highly specific inhibitors to drug efflux-pomp could lead to the development of much more effective chemotherapy protocols.
• New Therapies: they consist in small-molecule inhibitors that can target generalized tumour pathways (e.g. angiogenesis) or ACC-specific signalling pathways driving this cancer.
A recent study proposed peroxisome proliferator-activated receptor γ (PPARgamma) agonist rosiglitazone , because of its property to decrease the growth of H295 cells in vitro. It acts as a VEGF inhibitor and a specific molecular target inhibitor, as shown in breast and prostate cancers where it, respectively, determines ablation of cyclin D1 and bcl-2. It also inhibits metalloproeinase 2 and activates p21 and p27 (cell cycle inhibitors).
se vi è rimasta ancora qualche energia c'e' un nesso tra PPAR e qualcuno dei meccanismi che avete trovato prima?
We found that PPAR γ are involved in gonadotropin and HCG regulation: in particular, HCG is downregulated, while LH effect (on thecal cells) is repressed
