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Adrenal Cortex Cancer

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Description: Adrenal cortex cancer is a rare and aggressive malignancy that originates in the outer layer of the adrenal glands responsible for hormone production.
Type: Adrenal cortex cancer is a type of cancer that originates in the outer layer of the adrenal glands. It can be sporadic or inherited. The genetic transmission can occur in familial conditions such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and multiple endocrine neoplasia type 1 (MEN1), which are inherited in an autosomal dominant pattern.
Signs And Symptoms: Adrenocortical carcinoma may present differently in children and adults. Most tumors in children are functional, and virilization is by far the most common presenting symptom(s), followed by Cushing's syndrome and precocious puberty. Among adults presenting with hormonal syndromes, Cushing's syndrome alone is most common, followed by mixed Cushing's and virilization (glucocorticoid and androgen overproduction). Feminization and Conn syndrome (mineralocorticoid excess) occur in less than 10% of cases. Rarely, pheochromocytoma-like hypersecretion of catecholamines has been reported in adrenocortical cancers. Nonfunctional tumors (about 40%, authorities vary) usually present with abdominal or flank pain, varicocele, and renal vein thrombosis or they may be asymptomatic and detected incidentally.All patients with suspected ACC should be carefully evaluated for signs and symptoms of hormonal syndromes. For Cushing's syndrome (glucocorticoid excess), these include weight gain, muscle wasting, purple lines on the abdomen, a fatty "buffalo hump" on the neck, a "moon-like" face, and thinning, fragile skin. Virilism (androgen excess) is most obvious in women, and may produce excess facial and body hair, acne, enlargement of the clitoris, deepening of the voice, coarsening of facial features, cessation of menstruation. Conn syndrome (mineralcorticoid excess) is marked by high blood pressure, which can result in headache and hypokalemia (low serum potassium, which can in turn produce muscle weakness, confusion, and palpitations), low plasma renin activity, and high serum aldosterone. Feminization (estrogen excess) is most readily noted in men, and includes breast enlargement, decreased libido, and impotence.
Prognosis: ACC, generally, carries a positive prognosis, with an overall 5-year survival rate of about 50%. Five-year disease-free survival for a complete resection of a stage I–III ACC is about 30%. The most important prognostic factors are age of the patient and stage of the tumor. Poor prognostic factors include mitotic activity, venous invasion, weight of 50 g or more, diameter of 6.5 cm or more, Ki-67/MIB1 labeling index of 4% or more, and p53 positive.In its malignancy, adrenocortical carcinoma is unlike most tumours of the adrenal cortex, which are benign (adenomas) and only occasionally cause Cushing's syndrome.
Onset: Adrenal cortex cancer, or adrenocortical carcinoma, is a rare cancer that originates in the outer layer of the adrenal glands. The onset of this cancer can vary widely among individuals, with no specific known triggers or age range for when it typically begins. Some cases may have a genetic predisposition, and it can occur at any age, though it is most commonly diagnosed in adults between the ages of 30 and 50.
Prevalence: Adrenal cortex cancer, also known as adrenocortical carcinoma, is a rare malignancy. Its annual incidence is estimated to be approximately 1 to 2 cases per million people worldwide.
Epidemiology: Adrenocortical carcinoma is a rare and aggressive cancer. It affects the adrenal cortex, the outer part of the adrenal glands. The incidence is estimated at 1 to 2 cases per million people annually. It can occur at any age but has two peak incidence periods: in children under 5 and adults in their 40s and 50s. It's more common in females than males.
Intractability: Adrenal cortex cancer, also known as adrenocortical carcinoma, is a rare and aggressive form of cancer. The disease is often considered intractable due to its tendency to be diagnosed at an advanced stage, which complicates treatment. Surgery is the primary treatment option, but complete resection is not always possible. Additionally, the cancer may not respond well to chemotherapy or radiation therapy. Thus, prognosis is generally poor, and long-term survival rates are low.
Disease Severity: Adrenal cortex cancer, also known as adrenocortical carcinoma, is a rare and aggressive cancer that originates in the outer layer of the adrenal glands. The disease severity can range from localized tumors to advanced stages where cancer has spread to other parts of the body. Prognosis typically depends on the stage at diagnosis; early-stage cancers may have a better outcome, while advanced cancers are often more challenging to treat effectively.
Healthcare Professionals: Disease Ontology ID - DOID:660
Pathophysiology: The main etiologic factor of ACC is unknown, although families with Li–Fraumeni syndrome, caused by an inherited inactivation mutation in TP53, have increased risk. Several genes have been shown to be recurrently mutated, including TP53, CTNNB1, MEN1, PRKAR1A, RPL22, and DAXX. The telomerase gene TERT is often amplified while ZNRF3 and CDKN2A are often homozygously deleted. The genes h19, insulin-like growth factor II (IGF-II), and p57kip2 are important for fetal growth and development. They are located on chromosome 11p. Expression of the h19 gene is markedly reduced in both nonfunctioning and functioning adrenal cortical carcinomas, especially in tumors producing cortisol and aldosterone. Also, a loss occurs of activity of the p57kip2 gene product in virilizing adenomas and adrenal cortical carcinomas. In contrast, IGF-II gene expression has been shown to be high in adrenal cortical carcinomas. Finally, c-myc gene expression is relatively high in neoplasms, and it is often linked to poor prognosis.Bilateral adrenocortical tumors are less common than unilateral. The majority of bilateral tumours can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenocortical disease, which can be sporadic or part of Carney complex, and primary bilateral macro nodular adrenal hyperplasia.Metastasis is most commonly to the liver and lung.
Carrier Status: Adrenal cortex cancer, also known as adrenocortical carcinoma, does not typically have a well-defined carrier status like some hereditary genetic conditions. However, in certain cases, there may be a hereditary component, such as in familial cancer syndromes like Li-Fraumeni syndrome or Beckwith-Wiedemann syndrome. Genetic counseling and testing may be recommended for individuals with a family history of related cancers.
Mechanism: Adrenocortical carcinoma (ACC) is a rare and aggressive cancer originating from the cortex of the adrenal gland. The mechanisms and molecular pathways involved in ACC are complex and not fully understood, but several key aspects have been identified.

### Mechanism:
1. **Tumorigenesis**: ACC involves the transformation of adrenal cortical cells into malignant cells, leading to uncontrolled growth and potential metastasis.

2. **Hormonal Dysfunction**: ACC can result in excess production of adrenal hormones, leading to clinical syndromes like Cushing's syndrome (excess cortisol) or virilization (excess androgens).

### Molecular Mechanisms:
1. **Genetic Mutations**: Several genetic alterations are frequently observed in ACC, including:
- **TP53**: Mutations in the TP53 gene, which encodes the tumor suppressor p53, are common. This mutation impairs the cell's ability to undergo apoptosis in response to DNA damage.
- **CTNNB1**: Mutations in the CTNNB1 gene lead to the activation of the Wnt/β-catenin signaling pathway, promoting cell proliferation.

2. **IGF2 Overexpression**: The insulin-like growth factor 2 (IGF2) gene is often overexpressed in ACC. IGF2 enhances cell growth and inhibits apoptosis, contributing to tumor development.

3. **Epigenetic Changes**: Alterations in DNA methylation and histone modifications can affect gene expression patterns in ACC, leading to oncogene activation and tumor suppressor gene silencing.

4. **Signaling Pathway Dysregulation**: Various signaling pathways are implicated in ACC progression, including:
- **mTOR Pathway**: Activation of the mammalian target of rapamycin (mTOR) pathway promotes cell growth and survival.
- **Notch Pathway**: Dysregulation of the Notch signaling pathway is involved in cell differentiation and proliferation in ACC.

Overall, ACC involves a combination of genetic mutations, epigenetic changes, and dysregulated signaling pathways that drive its aggressive nature and resistance to conventional therapies.
Treatment: The only curative treatment is complete surgical excision of the tumor, which can be performed even in the case of invasion into large blood vessels, such as the renal vein or inferior vena cava. The 5-year survival rate after successful surgery is 50–60%, but unfortunately, many patients are not surgical candidates. A 2018 systematic review suggests that laparoscopic retroperotenial adrenalectomy appears to reduce late morbidity, time to oral fluid or food intake and time to ambulation when compared to laparoscopic transperitoneal adrenalectomy, however there is uncertainty about these effects due to very low-quality evidence. For outcomes such as all-cause mortality, early morbidity, socioeconomic effects, and operative and postoperative parameter, the evidence is uncertain about the effects of either interventions over the other.Radiation therapy and radiofrequency ablation may be used for palliation in patients who are not surgical candidates. Minimally invasive surgical techniques remain controversial due to the absence of long-term data, with a particular concern for rates of recurrence and peritoneal carcinomatosis.Chemotherapy regimens typically include the drug mitotane, an inhibitor of steroid synthesis, which is toxic to cells of the adrenal cortex, as well as standard cytotoxic drugs. A retrospective analysis showed a survival benefit for mitotane in addition to surgery when compared to surgery alone.The two most common regimens are cisplatin, doxorubicin, etoposide (EDP) + mitotane, and streptozotocin + mitotane. The FIRM-ACT trial demonstrated higher rates of response and longer progression-free survival with EDP + mitotane than with streptozotocin + mitotane.
Compassionate Use Treatment: For adrenal cortex cancer, compassionate use treatments and off-label or experimental treatments may include:

1. **Mitotane**: Although it is the standard treatment for adrenocortical carcinoma, it is sometimes used in varied dosing regimens beyond standardized guidelines, qualifying as off-label.

2. **PD-1/PD-L1 Inhibitors**: Drugs like pembrolizumab and nivolumab, which target the PD-1/PD-L1 pathway, are primarily approved for other cancers but may be used experimentally for adrenal cortex cancer.

3. **IGF-1R Inhibitors**: These inhibitors target the insulin-like growth factor receptor, which is being explored in clinical trials due to its potential effectiveness against this cancer type.

4. **Ketoconazole**: Typically an antifungal, this drug can be used off-label to manage hormone overproduction in adrenocortical carcinoma.

5. **Cabozantinib**: An FDA-approved drug for certain other cancers, it is being studied for use in adrenocortical carcinoma due to its multiple kinase inhibition properties.

6. **mTOR Inhibitors**: Drugs like everolimus and temsirolimus are also being investigated in clinical trials for potential efficacy against adrenal cortex cancer through disruption of cellular growth pathways.

Access to these treatments often requires enrollment in clinical trials or special compassionate use programs, as they are not standard therapies for adrenal cortex cancer.
Lifestyle Recommendations: For adrenal cortex cancer, the following lifestyle recommendations may be helpful:

1. **Healthy Diet**: Focus on a balanced diet rich in fruits, vegetables, whole grains, and lean proteins. This can support overall health and immune function.

2. **Regular Exercise**: Engage in regular physical activity tailored to your ability and energy levels, which can help maintain strength and reduce fatigue.

3. **Avoid Smoking and Limit Alcohol**: Smoking and excessive alcohol consumption can adversely affect overall health and potentially interfere with treatment effectiveness.

4. **Stress Management**: Practice stress-relieving techniques such as meditation, yoga, or deep-breathing exercises to help manage anxiety and emotional stress.

5. **Regular Medical Checkups**: Adhere to regular follow-ups with your healthcare provider for monitoring and early detection of any changes or recurrences.

6. **Stay Informed**: Educate yourself about the condition and treatment options while staying in close communication with your healthcare team to make informed decisions.

7. **Support Systems**: Engage with support groups or counseling services to cope with the psychological impact of the disease.

Follow all medical advice and recommendations from your healthcare providers to optimize treatment and manage symptoms effectively.
Medication: Adrenal cortex cancer, also known as adrenocortical carcinoma, often requires a combination of treatments. Mitotane is a medication specifically used to treat this type of cancer. It works by suppressing adrenal function and has direct cytotoxic effects on adrenocortical cells. Other treatments may include surgery, radiation therapy, and chemotherapy, depending on the stage and characteristics of the cancer. If you need more detailed information, consult a medical professional.
Repurposable Drugs: One of the repurposable drugs for adrenal cortex cancer is **mitotane**. Originally developed for treating adrenocortical carcinoma, mitotane can be used off-label for this purpose due to its adrenal gland cytotoxic effects.
Metabolites: Adrenal cortex cancer, also known as adrenocortical carcinoma, can affect the production and levels of various metabolites. Commonly affected metabolites include:

1. **Cortisol**: Elevated levels due to overproduction by the tumor.
2. **Aldosterone**: Can be elevated if the tumor produces this hormone.
3. **Androgens and Estrogens**: These sex hormones may also be overproduced, leading to symptoms of virilization or feminization.
4. **Dehydroepiandrosterone (DHEA)**: Levels might be increased if the tumor is functioning.

Please refer to specific clinical studies and diagnostic guidelines for a comprehensive analysis of metabolite alterations in adrenal cortex cancer.
Nutraceuticals: Adrenal cortex cancer is a rare and aggressive cancer originating in the outer layer of the adrenal glands. The role of nutraceuticals in treating or managing adrenal cortex cancer is not well-established. Nutraceuticals are products derived from food sources that offer extra health benefits in addition to their basic nutritional value. While general good nutrition can be important for patients undergoing cancer treatment, there is currently limited scientific evidence supporting the effectiveness of specific nutraceuticals in treating adrenal cortex cancer. It's essential for patients to consult with their healthcare provider before using any nutraceuticals.
Peptides: Adrenal cortex cancer (adrenocortical carcinoma) often involves the investigation of specific peptide markers for diagnosis and treatment monitoring. One such peptide is adrenocorticotropic hormone (ACTH), which can be elevated in cases of functioning adrenal tumors. Other peptide markers and signaling pathways are also under study for their roles in the development and progression of this cancer. Research into nanoparticle-based therapies is ongoing, seeking to improve targeted delivery of treatments and diagnostic imaging techniques.