Adrenocortical Carcinoma: Symptoms, Types, Causes and Treatment

Adrenocortical carcinoma (ACC) is a rare but aggressive cancer arising from the cortex of the adrenal gland. Despite its rarity, ACC poses significant challenges due to its late diagnosis, variable symptoms, and limited treatment options. In this comprehensive article, we’ll explore the key aspects of ACC, including symptoms, classification, underlying causes, and the latest approaches to treatment. Whether you’re a patient, caregiver, or healthcare professional, understanding these elements can empower you with knowledge to navigate this complex disease.

Symptoms of Adrenocortical Carcinoma

Recognizing the symptoms of ACC can be challenging, as they vary significantly depending on whether the tumor produces excess hormones or simply grows as a non-functioning mass. Sometimes, symptoms are subtle and overlooked until the disease has advanced, making early detection especially difficult.

Symptom	Description	Frequency/Context	Source(s)
Abdominal pain	Discomfort or pain in the abdomen	Common, often initial sign	1 4 5 9
Weight loss	Unintentional reduction in body weight	Frequent in advanced disease	1 9
Weakness	Generalized fatigue and muscle weakness	Common	1 9
Abdominal mass	Palpable or visible lump in the abdomen	Non-functioning or large ACC	1 4 5 9
Hormonal excess	Cushing's, virilization, feminization	Functioning tumors	2 3 5 12
Edema	Swelling, especially of lower extremities	Associated with mass effects	1
Metastatic signs	Symptoms from spread to other organs	Advanced/metastatic disease	1 5 9

Table 1: Key Symptoms

Common Symptoms and Their Variability

ACC symptoms are broadly divided into two groups: those caused by hormone overproduction and those resulting from the mass effect of the tumor.

• Hormone-related symptoms: Many ACCs are "functioning," meaning they secrete excess steroid hormones. This can cause:

  • Cushing’s syndrome: Features include rapid weight gain, easy bruising, muscle weakness, high blood pressure, and skin changes—resulting from overproduction of cortisol 2 3 12.
  • Virilization: Especially in women and children, excess androgens may cause deepening of the voice, increased body hair, acne, and menstrual irregularities 3 11 12.
  • Feminization: Rarely, some tumors secrete estrogens, leading to gynecomastia in men 8 12.
  • Mineralocorticoid excess: Presents with high blood pressure and low potassium levels 8.

• Mass effect symptoms: Non-functioning tumors often grow large before detection, leading to:

  • Abdominal pain or discomfort
  • A palpable abdominal mass
  • Digestive symptoms such as dyspepsia
  • Lower extremity swelling (edema) due to vascular compression 1 4 5.

Pediatric Presentation

In children, ACC can manifest with early signs of puberty (precocious puberty), rapid growth, or sudden changes in secondary sexual characteristics. Early detection is crucial, especially in regions with higher genetic susceptibility 3.

Metastatic Disease Symptoms

As ACC progresses, it may spread to the lungs, liver, bones, or lymph nodes, causing additional symptoms such as cough, bone pain, or jaundice 1 5 9.

Types of Adrenocortical Carcinoma

ACC is not a uniform disease—its classification is based on hormone production, molecular features, and clinical behavior. Understanding these types helps inform both diagnosis and treatment.

Type	Defining Feature	Clinical Implication	Source(s)
Functioning	Produces excess hormones	Overt endocrine symptoms	2 3 5 12
Non-functioning	Does not produce excess hormones	Mass effect, late diagnosis	4 5 10
Pediatric ACC	Occurs in children	Often virilizing, better prognosis in some cases	3 11
Molecular subtypes	Defined by genetic and epigenetic changes	Prognostic significance	6 7 14

Table 2: Classification of ACC

Functioning vs. Non-Functioning Tumors

• Functioning ACCs: These tumors secrete steroid hormones (cortisol, androgens, estrogens, or aldosterone), leading to distinct endocrine syndromes. Around 60% of adult ACCs are functioning 2 5 12.
  • Common syndromes include Cushing’s and virilization 2 3 12.
• Non-functioning ACCs: These do not secrete hormones and often present as large abdominal masses—found incidentally or due to mass effects 4 5 10. Non-functioning tumors are more common in older men and tend to be detected at advanced stages 10.

Pediatric vs. Adult ACC

• Pediatric ACC: More likely to produce androgens, leading to virilizing symptoms. In certain regions (e.g., Brazil), genetic predisposition increases incidence 3. Some pediatric cases, especially virilizing tumors, have better outcomes than non-functional or cortisol-secreting ACC 11.
• Adult ACC: More heterogeneous, with varying hormone profiles and generally poorer overall survival, especially when diagnosed late 1 11 12.

Molecular and Genetic Subtypes

Recent genomic studies have revealed that ACC can be stratified into distinct molecular subgroups, which correlate with prognosis:

• Aggressive subtypes: Characterized by numerous mutations, DNA methylation alterations, and worse outcomes 6 7.
• Indolent subtypes: Exhibit specific microRNA deregulation and have relatively better prognosis 6 7.

These insights pave the way for personalized medicine approaches in the future.

Causes of Adrenocortical Carcinoma

While the exact causes of ACC remain incompletely understood, research has identified several genetic, molecular, and environmental contributors—shedding light on why and how this rare cancer develops.

Cause/Factor	Description	Impact/Context	Source(s)
Genetic mutations	TP53, CTNNB1, ZNRF3, IGF-2, MEN1	Tumor initiation/progression	6 7 12 14
Hereditary syndromes	Li-Fraumeni, Beckwith-Wiedemann	Increased risk in children	3 12 14
Hormonal influences	Fetal adrenal cortex gene expression	Tumorigenesis	11 12 14
Environmental factors	Largely unknown, under investigation	Unclear	14

Table 3: Causes and Risk Factors

Genetic and Molecular Causes

• Somatic mutations: Common driver genes implicated in ACC include:
  • TP53 (tumor suppressor gene): Mutations are particularly frequent in pediatric cases and in certain populations (e.g., Southern Brazil) 3 6 12 14.
  • CTNNB1 (β-catenin pathway): Constitutive activation promotes cell proliferation 6 12 13.
  • ZNRF3, IGF-2, MEN1: Contribute to tumorigenesis through various pathways 6 7 12 14.
• Hereditary syndromes:
  • Li-Fraumeni syndrome: Associated with germline TP53 mutations, conferring a high risk for ACC in children 3 14.
  • Beckwith-Wiedemann syndrome: Linked to abnormal IGF-2 expression and ACC risk in children 12 14.

Developmental and Hormonal Factors

• Fetal adrenal cortex gene expression: Aberrant activation of developmental genes in the adrenal cortex may contribute to malignant transformation 11 12 14.
• Autocrine and paracrine signals: Dysregulation of local hormone signaling within the adrenal gland is also being investigated 11.

Environmental and Other Factors

• Environmental exposures: At present, no definitive environmental risk factors have been linked to ACC, though ongoing research seeks to clarify this area 14.
• Other unknowns: Most ACCs occur sporadically, without a clear familial or environmental link.

Treatment of Adrenocortical Carcinoma

Treating ACC is challenging due to its aggressive nature and frequent late-stage diagnosis. Multidisciplinary management and individualized treatment plans are essential for optimizing outcomes.

Treatment	Indication/Stage	Outcome/Notes	Source(s)
Surgery	Localized or resectable tumors	Only curative option	1 4 10 12 16
Mitotane	Adjuvant or unresectable/metastatic ACC	Main adjuvant/first-line drug	10 12 13 16
Chemotherapy	Advanced/metastatic disease, progression	EDP-M (etoposide, doxorubicin, cisplatin, mitotane) is standard	13 16 17 18
Radiation	Palliative/local control of recurrence	Limited role	10 16 17
Emerging therapies	Targeted drugs, immunotherapy	Under investigation	15 19
Follow-up	All stages post-treatment	Essential due to high recurrence	12 16

Table 4: Treatment Modalities in ACC

Surgery: The Mainstay of Cure

• Complete surgical resection is the only chance for cure in localized ACC. Surgery should be performed by experienced adrenal oncologic surgeons, aiming for complete (R0) removal including affected lymph nodes 1 4 10 12 16.
• In cases of recurrent or isolated metastases, repeated surgery may be considered if complete removal is feasible 4 16.

Adjuvant and Systemic Therapies

• Mitotane: A unique adrenolytic drug, mitotane is the main adjuvant therapy post-surgery for high-risk patients and is standard for inoperable, residual, or metastatic ACC 10 12 13 16.
  • Side effects can be significant, requiring careful monitoring.
• Combination chemotherapy: In advanced or progressive cases, regimens such as EDP-M (etoposide, doxorubicin, cisplatin, plus mitotane) or streptozotocin plus mitotane are utilized 13 16 17 18.
  • Responses are modest, and many patients experience eventual progression.

Role of Radiation and Local Therapies

• Radiation therapy: May be used for palliation or local control of unresectable or recurrent tumors, though its effectiveness is limited 10 16 17.
• Other local therapies: Radiofrequency ablation or chemoembolization may be considered for selected cases 16 17.

Emerging and Investigational Treatments

• Targeted therapies: Drugs targeting IGF-1 receptor, β-catenin pathway, angiogenesis, and cell cycle regulators (e.g., CDK1 inhibitors like cucurbitacin E) are under study, showing potential in preclinical and early clinical trials 15 19.
• Immunotherapy and gene therapy: These are promising areas, though still experimental 15.

Importance of Multidisciplinary Care and Follow-up

• Team approach: Due to ACC’s complexity, management at specialized centers with multidisciplinary expertise is strongly recommended 8 16.
• Close follow-up: Recurrence is common, especially within the first 2–3 years post-surgery. Regular imaging and hormone assessments are vital for early detection of relapse 12 16.

Conclusion

Adrenocortical carcinoma is a formidable disease due to its rarity, variable presentation, and aggressive behavior. However, advances in genetics, diagnostics, and multidisciplinary care are gradually improving outcomes and opening new therapeutic avenues.

Main points covered:

• Symptoms: ACC may present with hormone excess (Cushing’s, virilization), abdominal pain, mass, and signs of metastasis; pediatric presentations often feature early puberty.
• Types: Tumors are classified as functioning or non-functioning, with additional distinctions based on age (pediatric/adult) and molecular subtypes.
• Causes: Key drivers include mutations in TP53, CTNNB1, and other genes, with hereditary syndromes increasing risk in certain populations.
• Treatment: Complete surgical resection offers the best chance for cure; adjuvant mitotane and chemotherapy are mainstays for advanced disease; emerging targeted therapies and rigorous follow-up are critical to improving survival.

By staying informed and seeking care at experienced centers, patients and clinicians can work together to achieve the best possible outcomes in the fight against ACC.