Adrenocortical Carcinoma
Disease Details
Family Health Simplified
- Description
- Adrenocortical carcinoma is a rare and aggressive cancer originating in the outer layer of the adrenal glands, responsible for hormone production.
- Type
- Adrenocortical carcinoma is a rare type of cancer that originates in the outer layer of the adrenal glands, known as the adrenal cortex. The genetic transmission of adrenocortical carcinoma can be sporadic or inherited. When inherited, it is often associated with genetic syndromes such as Li-Fraumeni syndrome or Beckwith-Wiedemann syndrome. The inheritance pattern in these syndromes can be autosomal dominant.
- 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
- Adrenocortical carcinoma typically has an onset that is difficult to pinpoint with precision due to its slow-growing nature. It can occur at any age but is most commonly diagnosed in adults aged 30 to 50 years. In children, it may present around the age of 3 to 4 years. The disease often remains asymptomatic until it has reached an advanced stage, complicating early detection.
- Prevalence
- The exact prevalence of adrenocortical carcinoma is not well established, but it is considered a rare cancer. It is estimated to occur in about 1 to 2 people per million annually. It can occur at any age but tends to peak in children under 5 and adults in their 40s and 50s.
- Epidemiology
- Adrenocortical carcinoma (ACC) is a rare cancer originating in the cortex of the adrenal gland. The incidence rate is estimated to be around 1-2 cases per million people per year. It can occur at any age but has bimodal peaks, commonly affecting children under 5 years old and adults in their 40s-50s. It appears to be more common in women than in men. Although rare, ACC can sometimes be associated with genetic syndromes such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and multiple endocrine neoplasia type 1.
- Intractability
- Adrenocortical carcinoma (ACC) can be particularly challenging to treat due to its aggressive nature and tendency to be diagnosed at an advanced stage. Although not universally intractable, outcomes often depend on early detection and the completeness of surgical resection. When diagnosed early, surgery can be potentially curative. However, for advanced cases, the prognosis is generally poor and treatment options are limited, involving a combination of surgery, mitotane therapy, and sometimes chemotherapy or radiation. Overall, managing ACC can be difficult, especially in advanced stages.
- Disease Severity
- Adrenocortical carcinoma is a rare and aggressive cancer originating in the adrenal cortex. The disease severity ranges from localized tumors with potential for surgical removal to advanced metastatic disease with a poor prognosis. The severity often depends on the stage at diagnosis, with early detection offering better outcomes. Treatment options and survival rates are significantly affected by how far the cancer has spread at the time of diagnosis.
- Healthcare Professionals
- Disease Ontology ID - DOID:3948
- 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
- Adrenocortical carcinoma is not typically associated with a specific carrier status as it is a rare cancer of the adrenal cortex. Most cases are sporadic, although it can occasionally be linked to genetic syndromes such as Li-Fraumeni syndrome or Beckwith-Wiedemann syndrome. There isn't a carrier status in the traditional sense as seen with some hereditary conditions.
- Mechanism
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Adrenocortical carcinoma (ACC) is a rare and aggressive cancer originating in the cortex of the adrenal gland. The mechanisms and molecular underpinnings of ACC are complex and involve various genetic and molecular alterations:
1. **Mechanism:**
- ACC typically arises due to uncontrolled proliferation of adrenal cortical cells. This can be driven by mutations that affect cell cycle regulation, apoptosis, and cellular differentiation.
2. **Molecular Mechanisms:**
- **Genetic Mutations:** Key genetic mutations involved in ACC include alterations in the TP53 gene, which encodes the tumor suppressor protein p53. Mutations in the CTNNB1 gene, affecting the Wnt/β-catenin signaling pathway, are also common.
- **Epigenetic Changes:** Hypermethylation of tumor suppressor genes and global hypomethylation can contribute to the pathogenesis of ACC.
- **IGF2 Overexpression:** Overexpression of the IGF2 (insulin-like growth factor 2) gene is frequently observed in ACC and is thought to promote cell growth and proliferation.
- **TERT Promoter Mutations:** Mutations in the promoter region of the TERT gene, which encodes telomerase reverse transcriptase, can lead to increased telomerase activity and contribute to the immortality of cancer cells.
- **Alterations in the Wnt/β-catenin Pathway:** Mutations leading to activation of the Wnt/β-catenin signaling pathway are common in ACC and contribute to uncontrolled cell proliferation.
- **MicroRNAs (miRNAs):** Dysregulation of microRNAs, which are small non-coding RNAs that regulate gene expression, can also play a role in the development and progression of ACC.
Understanding these mechanisms is crucial for developing targeted therapies and improving the prognosis for patients with adrenocortical carcinoma. - 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
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Adrenocortical carcinoma (ACC) is a rare and aggressive cancer originating in the adrenal cortex. Due to its rarity and severity, treatment options can be limited and may include compassionate use or off-label/experimental treatments. Here are some possibilities:
1. **Mitotane:** While it is an FDA-approved drug specifically for ACC, it may be used in combination with other treatments in experimental protocols.
2. **Targeted Therapies and Immunotherapy:**
- **Pembrolizumab** and **nivolumab:** Both are immune checkpoint inhibitors that may be used off-label for ACC.
- **Lenvatinib**: This is a small-molecule tyrosine kinase inhibitor with potential off-label use in ACC.
- **Steroidogenesis inhibitors**: Agents like metyrapone and ketoconazole, while not specifically approved for ACC, can be used off-label to manage symptoms.
3. **Chemotherapy Combinations:** Although established regimens such as Etoposide, Doxorubicin, Cisplatin (EDP) with Mitotane are standard, other combinations could be considered experimental in the context of clinical trials.
4. **Clinical Trials:** Participation in clinical trials can provide access to novel therapies that are still under investigation but show promise for treating ACC. These could include new chemotherapy agents, targeted therapies, or innovative immunotherapies.
5. **Hormone Receptor Modulators:** Off-label use of drugs like tamoxifen or other hormonal agents might be considered in specific cases where tumors exhibit hormone receptor positivity.
6. **Genomic and Molecular Targeted Therapy:** Treatments based on specific genetic mutations identified in the tumor (e.g., TP53, CTNNB1) can involve off-label or investigational use of drugs targeting these molecular pathways.
For any novel or experimental approach, consultation with a medical oncologist experienced in treating ACC is essential. - Lifestyle Recommendations
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For adrenocortical carcinoma, lifestyle recommendations are not a primary approach for treatment but can support overall health and well-being. Here are some general lifestyle recommendations:
1. **Follow Medical Advice:** Adhere closely to the treatment plan outlined by healthcare providers, including surgery, chemotherapy, or radiation as prescribed.
2. **Balanced Diet:** Consume a nutritious diet rich in fruits, vegetables, lean proteins, and whole grains to support overall health and recovery.
3. **Regular Exercise:** Engage in moderate physical activity, as tolerated, to maintain strength and improve mood. Consult with a healthcare provider before starting any exercise regimen.
4. **Stress Management:** Practice stress-reducing techniques like meditation, yoga, or deep-breathing exercises to improve emotional well-being.
5. **Avoid Smoking and Limit Alcohol:** Refrain from smoking and limit alcohol intake to reduce additional health risks.
6. **Regular Follow-ups:** Maintain regular follow-up appointments with healthcare providers to monitor health, manage side effects, and detect any recurrence early.
These recommendations can improve the quality of life and overall health for patients dealing with adrenocortical carcinoma. - Medication
- For adrenocortical carcinoma, the primary medication used is mitotane. Mitotane is an adrenolytic agent that helps to control symptoms by reducing cortisol production and targeting adrenal cancer cells. Other medications may include cytotoxic chemotherapy agents like etoposide, doxorubicin, and cisplatin, often combined with mitotane for more aggressive treatment. Depending on the case, additional treatments such as radiation therapy and surgery might also be considered.
- Repurposable Drugs
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Adrenocortical carcinoma (ACC) is a rare and aggressive cancer originating in the cortex (outer layer) of the adrenal glands. Repurposable drugs for ACC include:
1. **Mitotane**: Originally developed for Cushing’s syndrome, Mitotane is used for treating ACC and works by inhibiting adrenal steroidogenesis.
2. **Etoposide**: Traditionally used for small cell lung cancer and testicular cancer, this drug can be effective when combined with other chemotherapies for ACC.
3. **Doxorubicin**: An anthracycline antibiotic used in various cancers, it is part of the standard chemotherapy regimen for ACC.
4. **Cisplatin**: Often used for various types of cancer, it may be used in combination with other drugs for ACC chemotherapy.
5. **Streptozocin**: Originally for pancreatic cancer, it is used for its effectiveness in certain endocrine tumors, including ACC.
Repurposing drugs is an expanding field, potentially offering new therapeutic avenues for difficult-to-treat conditions such as ACC. - Metabolites
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Adrenocortical carcinoma (ACC) is a rare and aggressive cancer originating in the cortex of the adrenal gland. The following are key metabolites associated with ACC:
1. **Hormones:**
- **Cortisol:** Overproduction can lead to Cushing's syndrome.
- **Aldosterone:** Excess can cause hypertension and low potassium levels, leading to Conn's syndrome.
- **Androgens:** Elevated levels can result in virilization and hirsutism, especially in women.
- **Estrogens:** Overproduction can cause feminization in men, such as gynecomastia.
2. **Metanephrines:**
- Though more specific to pheochromocytoma, metanephrines can sometimes be assessed to rule out other adrenal tumors.
3. **Dehydroepiandrosterone sulfate (DHEA-S):**
- Elevated levels can be indicative of adrenocortical carcinoma.
These metabolites are often measured in various diagnostic tests to confirm ACC and assess the extent of hormone production by the tumor. - Nutraceuticals
- Currently, there is limited evidence on the effectiveness of nutraceuticals in treating adrenocortical carcinoma (ACC). Nutraceuticals, which are products derived from food sources with extra health benefits, have not been well-studied in the context of ACC. For patients with ACC, conventional treatments such as surgery, chemotherapy, and targeted therapy are the primary approaches recommended by healthcare professionals. Always consult with a healthcare provider before considering any alternative or supplementary treatments.
- Peptides
- Adrenocortical carcinoma (ACC) is a rare and aggressive cancer originating in the cortex of the adrenal gland. Research into peptides and nanotechnology for ACC includes the investigation of peptide-based therapeutic agents that can target specific pathways involved in tumor growth and metastasis. Nanoparticles are also being explored as drug delivery systems to improve the efficacy and precision of treatments while minimizing side effects. These advanced approaches aim to enhance targeted delivery, enable controlled drug release, and improve overall treatment outcomes for ACC patients.