Adrenocortical Carcinoma

Adrenocortical Carcinoma – 18 Interesting Facts

Adrenocortical carcinoma is a very rare malignant tumor arising from the adrenal cortex
Approximately 60% of cases are hormonally active, typically presenting with symptoms related to excess adrenal steroid hormones such as those seen in hypercortisolism (Cushing syndrome), hyperaldosteronism, or androgen excess ¹ ²
Approximately 30% of cases are hormonally inactive or minimally active, instead presenting with nonspecific symptoms related to tumor bulk (eg, abdominal pain, back pain, early satiety, weight loss) ¹
Approximately 10% to 15% of cases overall are discovered incidentally during surgery or imaging for another complaint ³
Presumptive diagnosis is based on a thorough history and physical examination, imaging studies, and hormonal evaluation; histopathological confirmation (typically facilitated by surgical resection) is necessary for definitive diagnosis ²
Biochemical hallmarks of Cushing syndrome caused by adrenocortical carcinomas are adrenocorticotropic hormone-independent hypercortisolism and frequent concomitant hypersecretion of other steroids (precursors, androgens, or both) ⁴ ⁵
Differential diagnosis includes adrenocortical adenoma, adrenal metastases, pheochromocytoma, polycystic ovary syndrome, and other causes of Cushing syndrome and hyperaldosteronism
Management depends on size of tumor, presence of local or distant metastasis, secretory profile, and general status of patient
Open adrenalectomy with locoregional lymphadenectomy and possible en bloc removal of adjacent structures is the treatment of choice for localized disease whenever radical resection is feasible; adjuvant external beam radiotherapy or mitotane can be considered if there is high risk of recurrence ²
Adjuvant mitotane appears to improve recurrence-free survival and overall survival in patients without distant metastasis but at high risk of progression; however, no benefit has been seen in patients at low to intermediate risk for progression ⁶ ⁷ ⁸ ⁹
Minimally invasive surgery with laparoscopy can be considered in selected patients, with some studies suggesting comparable outcomes compared to open surgery ² ¹⁰ ¹¹
Management options for metastatic disease include expectant management, surgical resection, other local therapies, and systemic therapy ²
Expectant management can be considered for indolent disease or if patient declines active treatment
Surgery can be considered depending on resectability of primary tumor and metastases; if not initially feasible, resection may be reconsidered pending response to systemic therapy ¹¹
Local therapies (eg, stereotactic body radiation therapy, ablative therapies, liver-directed therapies) can be considered depending on presence and site of dominant metastatic lesions
Preferred regimens for systemic therapy consist of cisplatin or carboplatin with etoposide, with or without doxorubicin, and with or without mitotane; other recommended regimens include mitotane monotherapy, and pembrolizumab with or without mitotane
Medical management of hormone excess may be required perioperatively and in advanced disease; corticosteroid replacement to prevent adrenal insufficiency is required whenever mitotane is administered, and may be required lifelong ²
Prognosis varies with age, histologic grade, and stage at diagnosis; complete surgical resection is potentially curative for localized disease (though results are often suboptimal due to technical difficulty), while advanced and metastatic disease is associated with poor prognosis ¹²

Pitfalls

Due to risk of needle track seeding, do not perform needle biopsy of suspected adrenocortical carcinoma; proceed to open resection if masses are suspicious ¹³
- In addition to risk of needle track seeding from the biopsy, cytology specimens from fine-needle aspiration do not reliably distinguish benign adrenal masses from adrenocortical carcinomas
- Biopsies of adrenal masses are reserved to evaluate the possibility of metastasis to the adrenal gland and only after pheochromocytoma has been excluded with proper biochemical testing ² ³ ¹⁴
Patients with adrenocortical carcinomas and hypercortisolism are at risk of adrenal crisis after surgical resection if corticosteroids are not administered perioperatively ³ ⁶
Mitotane therapy can be associated with significant toxicity and requires careful therapeutic monitoring ¹ ² ⁹
Even with large adrenocortical carcinomas, signs or symptoms of steroid hormone excess can be absent and blood levels of hormones can be minimally elevated ¹³¹⁴
- Steroid hormone synthesis by adrenocortical carcinomas is relatively inefficient compared with synthesis by the normal adrenal gland, often resulting in elevated levels of several steroid hormone precursors but only modestly elevated hormone levels ⁵

Introduction

Adrenocortical carcinoma is a rare, aggressive primary malignancy arising from the adrenal cortex
Approximately 60% of adrenocortical carcinomas are hormonally active ¹
- Hypercortisolism is the most frequent endocrine abnormality, but the hallmarks are concomitant secretion of androgens and multiple steroids ⁵

Classification

Primary adrenal tumors
- Adrenocortical adenoma ¹
  - Benign tumor arising from adrenal cortex, majority of which are nonfunctioning
  - Common; prevalence of up to 3% to 10% on imaging ¹
- Adrenocortical carcinoma
  - Malignant tumor arising from cells of the adrenal cortex
  - Very rare; annual incidence is estimated to be 1 to 2 per million ¹
  - 60% are functional, and most express multiple hormones ²
- Pheochromocytoma ⁶
  - Tumor with malignant potential arising from chromaffin cells of the adrenal medulla
  - Annual incidence of approximately 2 to 8 per million ⁶
  - Secretes catecholamines and catecholamine metabolites
Classification according to biologic activity
- Functioning/hormonally active (approximately 60%); most express multiple hormones ²
  - Cortisol secreting
  - Aldosterone secreting
  - Androgen secreting
  - Estrogen secreting
- Nonfunctioning/hormonally inactive
TNM staging system for adrenocortical carcinoma ¹⁵
- Primary tumor (T)
  - TX: primary tumor cannot be assessed
  - T0: no evidence of primary tumor
  - T1: tumor 5 cm or less in greatest dimension, no extra-adrenal invasion
  - T2: tumor greater than 5 cm, no extra-adrenal invasion
  - T3: tumor of any size with local invasion but not invading adjacent organs (kidney, diaphragm, great vessels, pancreas, spleen, liver)
  - T4: tumor of any size with invasion of adjacent organs (kidney, diaphragm, great vessels, pancreas, spleen, liver) or large blood vessels (renal vein or vena cava)
- Regional lymph nodes (N)
  - NX: regional lymph nodes cannot be assessed
  - N0: no regional lymph node metastasis
  - N1: regional lymph node metastasis
- Distant metastases (M)
  - M0: no distant metastases
  - M1: distant metastases
- Anatomic stage/prognostic groups
  - Adrenal tumors
    - Stage I: T1, N0, M0
    - Stage II: T2, N0, M0
    - Stage III: T1, N1, M0; T2, N1, M0; T3, any N, M0; T4, any N, M1
    - Stage IV: any T, any N, M1

Clinical Presentation

History

Adrenocortical carcinomas that produce active adrenal hormones (approximately 60%) can present with a variety of symptoms related to the particular constellation of hormones secreted in excess; it is characteristic for symptoms to develop rapidly ¹
- Glucocorticoid-secreting tumors (most common hormone excess in adrenocortical carcinoma, resulting in Cushing syndrome)
  - Weight gain, hirsutism, weakness, easy bruising
  - Depressed mood, anxiety, irritability
  - Fatigue
  - May have recent onset of diabetes mellitus and hypertension with hypokalemia
    - Very high cortisol levels saturate the renal HSD11B2 system, resulting in glucocorticoid-mediated mineralocorticoid receptor activation ¹
- Androgen-secreting tumors
  - Female patients report oligo-/amenorrhea, hirsutism, deepening of voice
  - Isolated hyperandrogenism in male patients is often unrecognized
- Estrogen-secreting tumors
  - In male patients, gynecomastia and reduced libido
  - In female patients, breast tenderness and uterine bleeding
- Aldosterone-secreting tumors
  - Muscle weakness, fatigue
  - May have recently discovered hypertension with hypokalemia
Adrenocortical carcinomas that secrete minimal or nonactive precursor hormones (approximately 30%) are most often associated with symptoms caused by tumor bulk, such as abdominal pain, back pain, flank pain, early satiety, and weight loss ¹
- Adrenocortical carcinomas are generally large tumors, measuring approximately 12 cm at presentation ¹⁶
Uncommonly (approximately 10%-15% of cases), adrenocortical carcinomas are discovered incidentally ³
- Strongly suspect adrenocortical carcinomas in adrenal tumors larger than 4 cm that are radiographically heterogeneous with irregular margins, show local invasion, or both ³

Physical examination

Physical findings vary according to adrenal steroid secreted in excess
- Glucocorticoid-secreting tumors
  - Characteristic cushingoid appearance may be seen with cortisol-secreting tumors
    - Findings include moon facies, centripetal obesity, and dorsocervical fat pad fullness
  - Proximal muscle weakness is common
  - Various skin findings include hirsutism (in female patients), acne, ecchymoses, and wide purple striae, particularly prominent over the abdomen
  - Hypertension is seen when very high cortisol levels saturate renal HSD11B2, resulting in mineralocorticoid receptor activation ¹
- Androgen-secreting tumors
  - Female patients with androgen-secreting tumors may show signs such as hirsutism and male pattern baldness
- Estrogen-secreting tumors
  - Male patients with estrogen-secreting tumors may have gynecomastia and testicular atrophy
- Aldosterone-secreting tumors
  - Hypertension is usually observed in patients with aldosterone-secreting tumors
Examination also may be normal

Causes

Primary adrenocortical carcinomas result from multiple and diverse molecular oncogenic events
- Most are sporadic
- Somatic events implicated thus far include mutations in TP53 (tumor suppressor gene), overexpression of IGF2, or activation of the Wnt/β-catenin signaling pathway ¹⁷ ¹⁸
Hereditary tumors can arise in the context of inherited genetic syndromes ²

Risk factors and/or associations

Age

Bimodal age distribution with peaks in childhood and in the fifth and seventh decades of life ¹⁹

Sex

Occurs slightly more frequently in female individuals ⁶ ²⁰

Genetics

Some arise in the context of inherited genetic syndromes ¹⁴
- Li-Fraumeni syndrome
  - Autosomal dominant inherited cancer predisposition syndrome caused by germline mutations in TP53 gene
  - Approximately 10% of all patients with Li-Fraumeni syndrome develop adrenocortical carcinomas, which occur at a median age of 3 years ²¹ ²² ²³
- Beckwith-Wiedemann syndrome
  - Overgrowth disorder caused by imprinting abnormalities in the chromosomal region of 11p15
  - Associated with an increased risk of embryonal malignancies (eg, hepatoblastoma, Wilms tumor)
    - Adrenal cytomegaly is common; progression to adrenocortical carcinoma is infrequent
- Lynch syndrome
  - Autosomal dominant condition caused by mutations in various DNA mismatch repair genes, with high predisposition to colorectal and endometrial carcinomas, as well as others
  - Lifetime risk of adrenocortical carcinoma is approximately 3% ²⁴
- Familial adenomatous polyposis
  - Autosomal dominant condition caused by mutations in APC gene
  - Lifetime risk is difficult to ascertain owing to limited data
- Multiple endocrine neoplasia type 1
  - Adrenal tumors, both benign and malignant, occur in 14%; lifetime risk of malignant adrenocortical carcinoma is 1% to 2% ²⁵
Germline TP53 mutations have been found in 50% to 65% of childhood cases ²⁶

Ethnicity/race

Majority of patients in the United States are White people (84.7% of all cases in 1 series) ²⁷

Diagnostic Procedures

Primary diagnostic tools

Suspect diagnosis in patients who present with clinical manifestations of adrenal hormone excess or symptoms and signs secondary to local tumor growth
- Up to 60% of tumors in adults and 80% to 95% of tumors in children are associated with symptoms of hormone excess ¹⁴
  - Hormonally active tumors frequently display concomitant hypersecretion of several steroid hormones, including precursors and/or androgens ⁵
- Approximately 30% of adults present with symptoms related to tumor mass ¹⁴
- Approximately 10% to 15% of tumors in adults are asymptomatic and are discovered incidentally during surgery or imaging for another issue ³
Order hormonal evaluation in all patients with suspected adrenocortical carcinoma to determine the secretory activity and adrenocortical origin of tumor; this includes evaluation for hyperaldosteronism, Cushing syndrome, and pheochromocytoma, and it is guided in part by clinical symptoms ¹²⁵²⁸
- For evaluation of sex steroid and steroid precursor excess in all patients: ³
  - Measure adrenal androgens (eg, DHEA-S [dehydroepiandrosterone sulfate], androstenedione, testosterone, 17-hydroxyprogesterone)
- For evaluation of cortisol excess (hypercortisolemia) in all patients:
  - Obtain baseline electrolytes, cortisol, and ACTH in all patients ²
  - Obtain 1 of the following tests to screen for hypercortisolemia and detect subclinical or overt Cushing syndrome: ⁴²⁹
    - 1 mg overnight dexamethasone test
    - 24-hour urine free cortisol (at least 2 measurements)
    - Late night (midnight) salivary cortisol (at least 2 measurements)
  - Cushing syndrome unlikely with concordant normal results
  - Any abnormal result should be repeated with same test or another to confirm (referral to an endocrinologist is recommended at this point) ⁴
  - If concordant abnormal results are obtained, proceed to formally localize, beginning with morning ACTH level ⁴
    - Obtain 8 AM morning ACTH level
    - Note that the biochemical hallmark of Cushing syndrome caused by adrenocortical carcinoma is ACTH-independent hypercortisolism ⁵
      - Therefore, ACTH level is suppressed (ie, less than 10 pg/mL) when an adrenocortical carcinoma secretes excess cortisol ¹
    - Morning ACTH step can be skipped if hypercortisolism is excluded (concordant normal results) ³
    - Refer patients with discordant or consistently abnormal results to an endocrinologist ⁴
- For evaluation of aldosterone excess (primary aldosteronism) in patients with hypertension, hypokalemia, or both
  - Serum aldosterone and plasma renin activity
- For male patients and postmenopausal patients with symptoms of estrogen excess
  - Serum estradiol
- For exclusion of pheochromocytoma in all patients
  - Plasma free fractionated metanephrines or 24-hour urine collection for fractionated metanephrines
  - Mainly serves to prevent unexpected complications during surgery or treatment ¹⁴
- Finding that multiple hormones are produced and secreted in excess increases suspicion for malignancy ²
- Results of the hormonal evaluation serve diagnostic purposes but also provide baseline values to estimate the extent of residual tumor or development of tumor recurrence after surgery ¹ ⁵
Order an adrenal protocol CT or MRI of the abdomen and pelvis in all patients with suspected adrenocortical carcinoma to confirm tumor presence (if not already found on prior imaging) and evaluate tumor characteristics (eg, size, heterogeneity, margin characteristics, extent, resectability). ²³
- Adrenal-focused imaging may be prompted by clinical presentation or prior imaging (performed without adrenal protocol) indicative of adrenal tumor
- Radiographic evaluation may be performed in parallel with hormonal evaluation but should not be contingent on abnormal hormone testing, as adrenocortical carcinoma may be hormonally inactive/nonfunctioning
If tumor found with malignant characteristics suspicious for adrenocortical carcinoma, order fluorodeoxyglucose F 18 PET-CT and chest CT to assess for metastases and complete staging ²
- Lung and liver are the most likely sites of metastases
- MRI of brain or bone scan are not routinely indicated but may be obtained if there are signs or symptoms suggestive of cerebral or skeletal metastases ²⁸
Obtain pathology specimen (usually at surgical resection) to confirm histopathologic diagnosis
- Histopathology report should provide the Weiss score (as a histologic assessment of the likelihood of malignancy) and the prognostic Ki67 index ²⁸
  - Note: malignancy status of the adrenal cortex is technically verified by determining the presence of local or distant spread ⁹
- Image-guided needle biopsy of the adrenals is usually highly discouraged; however, it may be considered in patients with history of malignancy in whom adrenal metastasis from another primary site is suspected and histologic proof is required to inform oncologic management ²³²⁸
  - Needle biopsy carries risk of seeding the needle track; additionally, cytology specimens from fine-needle aspiration do not reliably distinguish benign adrenal masses from adrenocortical carcinomas
Stage tumor according to the American Joint Committee on Cancer TNM staging criteria for adrenal tumors ¹⁵
Other possible testing
- If hormonal workup result is negative, consider analyzing urinary steroid metabolites or steroid precursors
  - Adrenocortical carcinomas may secrete excessive amounts of adrenal steroid precursors that are not detected in traditional assays
    - Increased secretion of urinary metabolites of several steroids, and precursors of androgens, glucocorticoids, or mineralocorticoids can be detected even in the absence of a clinically or biochemically overt steroid excess using methods such as gas chromatography–mass spectrometry
  - Urine steroid metabolomics, via high-performance liquid or gas chromatography/mass spectrometry, may aid in the discrimination of benign from malignant adrenal tumors ²⁰ ³⁰
- Evaluate patient (especially those aged younger than 40 years) and probe family history for the possibility of genetic syndromes; may require additional molecular diagnostic testing of the patient for Lynch syndrome ²
- Consider molecular analysis of tumor tissue for mismatch repair defects or high microsatellite instability and tumor mutational burden testing ²

mutational burden testing ²

Laboratory

Standard 1 mg overnight dexamethasone suppression test ²⁵
- 1 of 3 preferred tests recommended to screen for hypercortisolism in all patients, regardless of symptoms, who have suspected adrenocortical carcinoma; preferred test to screen for hypercortisolism in patients with adrenal incidentaloma ³¹
- Most sensitive laboratory test to detect autonomous cortisol secretion (95% at a cortisol threshold of 1.8 mcg/dL), compared with the 24-hour urine free cortisol test or late night salivary cortisol, which can miss more cases of mild hypercortisolism ³
- High negative predictive value but false positives common
- 1 mg of dexamethasone is taken orally by the patient between 11 PM and 12 AM, and serum cortisol level is obtained at 8 AM the next morning ³²
- Cortisol level 1.8 mcg/dL or lower after dexamethasone excludes cortisol hypersecretion ³²
- Elevated levels indicate hypercortisolemia; confirm by repeating the test or obtaining one of the other screening tests (24-hour urine free cortisol or late night salivary cortisol)
- If cortisol excess is confirmed, follow-up serum ACTH levels are required to establish adrenal autonomy
24-hour urine free cortisol
- Additional preferred test used to screen for hypercortisolemia in patients with suspected adrenocortical carcinoma ²
  - Less sensitive than the 1 mg overnight dexamethasone test but is helpful to estimate the degree of hypercortisolemia
  - May be cumbersome for patients to collect
  - Due to sample variability, at least 2 collections are needed
- Reference range is assay specific
- Elevated levels indicate hypercortisolemia; confirm by repeating the test or obtaining one of the other screening tests (overnight dexamethasone suppression test or late night salivary cortisol)
- If cortisol excess is confirmed, follow-up serum ACTH levels are required to establish adrenal autonomy
Late night (midnight) salivary cortisol ²⁵²⁹
- Additional preferred test used to screen for hypercortisolemia in patients with suspected adrenocortical carcinoma
- High sensitivity and specificity
- Easy for patients to perform and collect
- Due to intra-patient variability, at least 2 collections are needed
- Reference range is assay specific
- Test performance and interpretation is predicated on assumption of normal circadian cortisol secretion variation; should not be performed in patients such as night-shift workers who experience frequent disruptions in normal day/night cycles
- Elevated levels indicate hypercortisolemia; confirm by repeating the test or obtaining one of the other screening tests (overnight dexamethasone suppression test or 24-hour urine free cortisol)
- If cortisol excess is confirmed, follow-up serum ACTH levels are required to establish adrenal autonomy
Serum ACTH ³³
- Baseline ACTH levels should be obtained for all patients ²
- Obtain morning ACTH level as follow-up testing if result of initial hypercortisolemia screening and confirmatory testing are positive ²
- Elevated morning ACTH level (greater than 20 pg/mL) is indicative of ACTH-dependent hypercortisolemia (eg, due to ACTH-secreting pituitary adenoma or ectopic ACTH-producing tumor); intermediate values (between 10 pg/mL and 20 pg/mL) are less clear but often also reflect ACTH dependence
  - Elevated ACTH levels generally exclude adrenal gland as a source of excessive cortisol production
  - Additional specialized studies needed for further localization; refer to endocrinologist if not yet done already
- Low ACTH (less than 10 pg/mL) is indicative of ACTH-independent hypercortisolemia (ie, primary adrenal disease)
  - Most patients with cortisol-secreting adrenal tumors will have suppressed serum ACTH (less than 10 pg/mL) ¹⁴
Serum electrolytes
- Indicated to screen for hyperaldosteronism in all patients
- Hypokalemia is often found with mineralocorticoid excess
Serum aldosterone to plasma renin activity ratio
- Aldosterone-producing adrenocortical carcinoma is rare and generally associated with severe hypertension and marked hypokalemia ⁵
  - Screening for hyperaldosteronism by measuring plasma aldosterone level and plasma renin activity (or direct renin level) is recommended in all hypertensive and/or hypokalemic patients with adrenal masses
- Indicated when manifestations of hyperaldosteronism are present (hypokalemia or hypertension) ²
- Not routinely required for asymptomatic patients ⁶
- Aldosterone to plasma renin activity ratio greater than 30 with a plasma aldosterone level greater than 10 ng/dL is consistent with hyperaldosteronism ²
- Indicated if positive result of confirmatory testing is required
Catecholamine metabolites
- Plasma free fractionated metanephrines or 24-hour urinary fractionated metanephrines ²
  - Indicated to screen for pheochromocytoma in all patients without clearly established diagnosis of an adrenocortical carcinoma before surgery ² ⁶
  - If clinical suspicion is low and levels are less than 2 times the upper reference limit, pheochromocytoma is usually excluded ²
Sex steroids and precursors ³
- Serum DHEA-S
  - Indicated in all patients with suspected adrenocortical carcinoma ¹
  - May identify hormone excess requiring treatment and can be used as baseline for follow-up after treatment ¹⁴
- Hypersecretion of sex steroids is common in patients with adrenocortical carcinoma ⁵
  - Estrogen excess should be ascertained in male patients (especially in cases of gynecomastia) and postmenopausal patients. Baseline 17-hydroxyprogesterone levels are frequently increased, as well as androstenedione and DHEA-S, leading to increased plasma testosterone in female individuals
- Serum estradiol
  - Indicated in postmenopausal patients and in male patients with signs of estrogen excess (ie, gynecomastia)
- Serum testosterone
  - Indicated in all female patients with suspected adrenocortical carcinoma
- Serum androstenedione
- Serum 11-deoxycortisol
Other serum hormones
- Serum steroid paneling by liquid chromatography–mass spectrometry can discriminate adrenocortical carcinomas from other adrenal tumors and thus serve as a useful tool in differential diagnosis ³⁴
  - Steroid paneling shows that adrenocortical carcinomas characteristically secrete several steroids and steroid intermediates without biological activity in very high amounts
  - Cortisol precursor 11-deoxycortisol is the most discriminating steroid intermediate between adrenocortical carcinomas and nonmalignant adrenal lesions

Imaging

CT or MRI of the abdomen and pelvis with adrenal protocol
- Will confirm presence of adrenal tumor if not already visualized on prior imaging (performed without adrenal protocol)
- Guidelines do not indicate a preference between CT and MRI; either may be obtained ² ²⁸
- Standard imaging modalities to determine the size, heterogeneity, lipid content (MRI), contrast washout (CT), margin characteristics, extent, and resectability of adrenal gland tumors
- CT imaging characteristics of adrenocortical carcinomas ³⁵
  - Typically larger than 4 cm and heterogenous with irregular margins, central necrosis, and/or local invasion ¹³
  - Calcifications are present in 30% of cases ¹³
  - Hemorrhage is common when the tumor is larger than 6 cm ¹³
  - Adrenal masses raise concern for malignant tumor if unenhanced CT attenuation is greater than 10 Hounsfield units ³⁵
    - If Hounsfield units are 10 or less on unenhanced CT, tumor is likely benign; can manage as adrenal adenoma with no further imaging necessary
    - If Hounsfield units are greater than 10 on unenhanced CT, proceed to enhanced CT with washout
      - Contrast is administered with 15-minute delayed imaging to calculate contrast washout ³⁶
      - Greater than 60% washout in 15 minutes indicates tumor is likely benign
      - Less than 60% washout in 15 minutes indicates tumor is likely malignant
    - MRI with and without contrast may be obtained as an alternative to enhanced CT with washout as a follow-up study
- MRI imaging characteristics include:
  - On T1-weighted imaging: adrenocortical carcinoma is heterogeneously isointense to slightly hypointense to the liver but is hyperintense if hemorrhage is present
  - On T2-weighted imaging: adrenocortical carcinoma is heterogeneous and hyperintense
  - MRI may be superior to CT scans at identifying local invasion and involvement of the inferior vena cava
CT of the chest (with or without contrast)
- Generally performed for staging of regional and distant metastases
- Obtain in all patients with high suspicion for adrenocortical carcinoma (ie, adrenal tumor with malignant characteristics on imaging) as part of staging workup ²
Fluorodeoxyglucose F 18 PET
- Generally performed for staging of regional and distant metastases
- Obtain in all patients with high suspicion for adrenocortical carcinoma (ie, adrenal tumor with malignant characteristics on imaging) as part of staging workup ²
- May also be useful for distinguishing potentially malignant lesions from benign tumors if radiologically indeterminate ²⁸ ³⁷

Other diagnostic tools

Histopathologic analysis of tissue specimen (most often obtained at time of surgical resection) is necessary to confirm the diagnosis with certainty
Tumor is classified based on anatomic site and histologic characteristics
- Distinction of primary adrenocortical tumors from nonadrenal tumors is aided by positive result on immunostaining for steroidogenic factor 1 and melan-A (Mart1) markers, but absence of staining for cytokeratins and chromogranin A
Weiss system is the most widely used tool for differentiating malignant adrenal carcinomas from benign adrenal adenomas and is based on a combination of 9 histologic criteria that are applied on tumor sections
- Histopathologic parameters assessed include (1 point for each):
  - Greater than 5 mitoses per 50 high-power field
  - High nuclear grade
  - Atypical mitotic figures
  - Less than 25% of tumor cells are clear
  - Diffuse architecture encompassing more than 33% of the tumor
  - Venous invasion (smooth muscle in the wall)
  - Sinusoidal invasion (no smooth muscle in the wall)
  - Capsular invasion
  - Necrosis
- Scoring system
  - Score of 0 to 2 defines adrenocortical adenoma
  - Score of 3 to 6 may indicate malignancy
  - Score greater than 6 defines adrenocortical carcinoma

Differential Diagnosis

Most common

Adrenocortical adenoma
- Benign tumor of the adrenal cortex
- Like adrenocortical carcinomas, it may be an incidental finding or can present with symptoms and signs related to hormone hypersecretion
- Differentiated primarily on basis of imaging characteristics
  - Adrenal tumor is usually benign if it is less than 4 cm in diameter, is homogenous, has smooth margins, and has lipid-rich appearance on CT or MRI ²
  - Can be presumed to be benign if unenhanced CT attenuation 10 Hounsfield units or less or if there is signal loss on opposed-phase chemical-selective MRI ³⁵
Adrenal metastases
- Adrenal glands are a common site of metastases from breast, lung, and renal cell carcinomas, as well as melanoma and lymphoma
- Like some adrenocortical carcinomas, metastatic disease to the adrenals may present with symptoms or signs secondary to local tumor growth, or more commonly, they may be discovered as an incidental finding
- Differentiated primarily on basis of imaging characteristics; however, cannot be definitively determined with the use of imaging alone ³⁵
  - CT and MRI features are generally nonspecific; however, metastatic tumors are often bilateral
  - Fluorodeoxyglucose F 18 PET can accurately differentiate benign adenoma from malignant adrenal masses
  - When metastasis to the adrenal gland is very likely based on clinical context and this determination affects selection of therapy for the primary cancer, percutaneous CT-guided fine-needle aspiration biopsy may be done after pheochromocytoma has been excluded
Pheochromocytoma
- Catecholamine-secreting tumors of the adrenal medulla that appear as adrenal masses on abdominal imaging
- Like some adrenocortical carcinomas, pheochromocytomas may be found incidentally during surgery or imaging for another complaint
- Unlike adrenocortical carcinoma, typically presents with palpitations, headache, sweating, anxiety, and hypertension
- Differentiated on basis of history and formally by finding elevated plasma free or 24-hour urine fractionated metanephrines
Other causes of Cushing syndrome
- As with a cortisol-secreting adrenal carcinoma, presents with weight gain, centripetal obesity, buffalo hump, hirsutism, proximal muscle weakness, easy bruising, and purple striae
- Causes include:
  - Medically prescribed corticosteroids
  - Pituitary adenoma that autonomously secretes corticotropin, leading to increased cortisol production
  - Ectopic corticotropin hormone–secreting neoplasm (eg, small cell lung carcinoma, bronchial or thymic carcinoids, pancreatic neuroendocrine tumors)
  - Ectopic corticotropin-releasing hormone syndrome
  - Cortisol-secreting benign adrenocortical adenoma
  - Bilateral adrenal hyperplasia or dysplasia (rare)
- Differentiated based on many possible investigations (including serum corticotropin, inferior petrosal sinus sampling, various imaging modalities), which should be ordered and interpreted under the guidance of an endocrinologist and a multidisciplinary team consultation
Other causes of hyperaldosteronism
- As with an aldosterone-secreting adrenocortical carcinoma, manifestations include hypertension and hypokalemia
- Most common cause is adrenocortical adenoma or bilateral adrenal hyperplasia
- Differentiated on basis of imaging studies combined with adrenal vein sampling for aldosterone and cortisol ²
Polycystic ovary syndrome
- Chronic endocrine and reproductive disorder with anovulation and hyperandrogenemia, with common symptoms of oligomenorrhea, acne, and hirsutism ³⁸
- When not evaluated carefully, the symptoms of androgen-secreting adrenocortical carcinoma can be erroneously attributed to a common disorder such as polycystic ovary syndrome
- Clinical clue helpful to diagnosis of adrenocortical carcinoma is the concomitant existence of cushingoid phenotype with signs of marked androgen excess or along with cancer-related symptoms (eg, anorexia, cachexia, mass effect)
- Long-standing hirsutism and anovulation that gradually develop along with weight gain is characteristic of polycystic ovary syndrome, whereas rapid onset and quickly worsening hirsutism and menstrual irregularities, possibly with signs of virilization, are more characteristic of an adrenocortical carcinoma ³⁸
- Polycystic ovary syndrome and androgen-secreting tumors are distinguished by imaging, with CT or MRI of adrenal glands that shows a large, suspicious (inhomogeneous, invading) adrenal mass; ultimately, a definitive diagnosis requires histologic confirmation of surgically resected specimen ⁹

Treatment Goals

Eradicate or debulk tumor, and normalize hormone levels

Admission criteria

Admit patients for surgical resection

Recommendations for specialist referral

Refer patients to a multidisciplinary specialist center for diagnosis, staging, treatment, and counseling about prognosis ¹
- Refer to an endocrinologist for initial diagnosis and management of hormone-related symptoms
- Refer to an oncologist for cytotoxic chemotherapy
- Refer to an endocrine surgeon for adrenalectomy
  - For optimal outcomes, surgery should be undertaken at multidisciplinary centers where a high volume of adrenalectomies for adrenal cancer are done ¹¹
- Refer to radiation oncology for assessment of radiotherapy as a treatment option, determination of dose/scheduling, and administration
- Refer to palliative care to help manage symptoms, mediate side effects of treatment, and improve quality of life in patients with advanced disease (stage IV), or who require chemotherapy, regardless of cancer stage ³⁹

Treatment Options

Overview ² ⁴⁰

Localized adrenocortical carcinoma ²¹¹
- Surgery is the treatment of choice and should be attempted whenever a radical resection is feasible ⁵ ¹¹
- Resect tumor via open adrenalectomy and remove radiographically or clinically evident lymph nodes
  - Laparoscopic resection is associated with increased risk for local recurrence and peritoneal spread
  - Administer hydrocortisone during surgery and postoperatively to patients with hypercortisolemia to prevent postoperative adrenal insufficiency and adrenal crisis ³ ⁶
- If invasion is suspected, en bloc removal of adjacent structures (eg, liver, kidney, pancreas, spleen, diaphragm) may also be required for a complete resection
- Goal is complete resection to negative margins at index surgery ¹¹
- Consider external beam radiotherapy or adjuvant mitotane if there is a high risk of recurrence (positive margins, rupture of capsule, large size, or high grade)
  - Adjuvant mitotane is not routinely indicated for completely resected tumors with low risk for disease recurrence ⁶
  - Whenever mitotane is administered, prescribe replacement doses of corticosteroids (hydrocortisone or prednisone) to prevent adrenal insufficiency (lifelong replacement may be required) ²
Metastatic adrenal carcinoma ²
- Consider observation with imaging and measurement of relevant biomarkers (if functional) every 3 months if clinically indolent
- Consider resection of primary tumor and metastases if more than 90% removable, particularly if functional ¹¹
  - Administer hydrocortisone during surgery and postoperatively to patients with glucocorticoid excess to prevent adrenal crisis or insufficiency ⁶
- Consider additional local therapies (eg, stereotactic body radiation therapy, ablative therapies, liver-directed therapies) depending on presence and site of dominant metastatic lesions
- Otherwise, begin systemic therapy (clinical trials are preferred)
  - Preferred regimens
    - Cisplatin or carboplatin with etoposide, with or without doxorubicin, and with or without mitotane
  - Other recommended regimens
    - Mitotane monotherapy
    - Pembrolizumab with or without mitotane
  - Whenever mitotane is administered, prescribe replacement doses of corticosteroids (hydrocortisone with or without fludrocortisone) to prevent adrenal insufficiency; may be needed for the patient’s lifetime ²
    - Fludrocortisone is usually added depending on the blood pressure, serum potassium levels, and plasma renin activity ⁶
- Surgical resection, if not initially feasible, may be reconsidered pending response to systemic therapy; systemic therapy serves a neoadjuvant role in this setting ¹¹
- Local therapies may also have a role in palliation of unresectable metastatic disease or be used when surgery is declined ¹ ⁴¹
Hormone excess (therapy may be required before surgery and in advanced disease)
- Treat electrolyte abnormalities or hypertension caused by mineralocorticoid excess before surgery ¹⁴
- Treat hypercortisolism with mitotane, ketoconazole, mifepristone, metyrapone, or etomidate ¹
  - May be administered either alone or in combination with mitotane; combination treatment may be required to rapidly and/or effectively attenuate hypercortisolism ⁹
- Treat mineralocorticoid excess or androgen excess with spironolactone ¹
- Treat estrogen excess with aromatase inhibitors such as anastrozole or a selective estrogen receptor modulator (ie, tamoxifen) ¹

Rationale

Surgical resection eradicates tumors and/or reduces tumor burden
Treatment with mitotane controls symptoms related to hormone secretion and may control progression of tumor
Other forms of adjuvant therapy have potential to delay progression in advanced disease

Outcomes

Complete surgical resection is associated with superior outcomes in adrenocortical carcinoma ⁴²
- Surgical results are often suboptimal, however, owing to difficulty of achieving adequate surgical margins
- Margin-free complete resection provides the only means to achieve long-term survival; however, local recurrence will develop in more than half of these cases ¹⁴
- Locoregional lymphadenopathy enhances survival benefit in patients undergoing curative-intent resection ⁴³
Adjuvant therapy with mitotane may improve postoperative outcomes
- In patients without distant metastasis but at high risk of progression, postoperative mitotane appears to improve recurrence-free survival and overall survival ⁷ ⁸
- Mitotane was not shown to be beneficial in patients at low to intermediate risk for recurrence in the randomized ADIUVO trial ⁴⁴ ⁴⁵ ⁴⁶
- ADIUVO-2, comparing the effect of adjuvant mitotane vs mitotane combined with systemic chemotherapy in patients with locoregional adrenocortical cancer at high risk of recurrence after initial surgical resection, is ongoing ⁴⁷ ⁴⁸
Adjuvant radiation therapy may be associated with improved survival in patients without distant metastases, particularly in patients with high risk of recurrence ⁴⁹
Addition of systemic chemotherapy for patients with advanced disease may offer modest response rates
- In patients with metastatic disease, response rates to systemic therapy are as follows: ²
  - Approximately 10% to 30% partial response rate with mitotane monotherapy
  - Approximately 49% objective response rates for combination therapy with cisplatin/etoposide with or without doxorubicin with or without mitotane
  - Approximately 23% objective response rates with pembrolizumab ⁵⁰
Molecularly targeted therapy has not been shown to have significant benefits in unselected populations to date ²⁰ ⁵¹

Drug therapy

Table

Drug therapy: adrenocortical carcinoma.

Medications	Common regimens	Life-threatening or dose-limiting adverse reactions	Notable or nonemergent adverse reactions	Special considerations
Adrenal cytotoxic agents
Mitotane	• Mitotane monotherapy • Carboplatin + etoposide ± doxorubicin ± mitotane • Cisplatin + etoposide ± doxorubicin ± mitotane • Pembrolizumab ± mitotane	• Adrenal crisis or insufficiency • Bone marrow suppression • Gastrointestinal toxicity • Hepatotoxicity • Neurotoxicity • Ovarian macrocysts	• Decreased blood free testosterone in males • Depression • Hypercholesterolemia • Hypertriglyceridemia • Hypothyroidism • Rash	• Requires plasma concentration monitoring • Higher doses of hydrocortisone for adrenal insufficiency are necessary with mitotane due to increased glucocorticoid clearance; some require additional fludrocortisone • Mitotane may increase hormone binding protein plasma concentrations; consider when interpreting hormonal assay results • Perform adenosine diphosphate-induced aggregometry testing before surgery or dental procedures; mitotane can cause platelet dysfunction disorders and routine in vitro bleeding time is not sufficient to assess bleeding risk • Effective contraception required during and after therapy for as long as mitotane plasma concentrations are detectable for females of reproductive potential
Alkylating agents – platinums
Carboplatin	• Carboplatin + etoposide ± doxorubicin ± mitotane	• Anaphylaxis • Bleeding • Bone marrow suppression • Infection • Nausea/vomiting • Nephrotoxicity • Ototoxicity • Peripheral neuropathy	• Alopecia • Asthenia • Electrolyte loss • Increased hepatic enzymes • Secondary malignancy	• Avoid coadministering nephrotoxic or ototoxic agents
Cisplatin	• Cisplatin + etoposide ± doxorubicin ± mitotane	• Anaphylaxis • Bone marrow suppression • Nausea/vomiting • Nephrotoxicity • Ocular toxicity • Peripheral neuropathy	• Injection site reaction • Ototoxicity • Secondary malignancy	• Avoid coadministering nephrotoxic or ototoxic agents • Ensure adequate hydration • Effective contraception required during and after cisplatin therapy for 14 months for females of reproductive potential and for 11 months for males with female partners of reproductive potential
PD-1 (programmed death receptor-1) blocking antibodies
Pembrolizumab	• Pembrolizumab ± mitotane	• Adrenal insufficiency • Anaphylaxis • Colitis • Diabetic ketoacidosis • Exfoliative dermatitis • Hepatitis • Hyperthyroidism • Hypophysitis • Hypothyroidism • Infusion-related reactions • Myocarditis • Nephritis • Neurotoxicity • Pneumonitis • Thyroiditis	• Abdominal pain • Anorexia • Constipation • Cough • Diarrhea • Dyspnea • Fatigue • Fever • Myalgia • Nausea • Pain • Pruritus • Rash	• Effective contraception required during and after therapy for 4 months for females of reproductive potential
Topoisomerase II inhibitors – anthracyclines
Doxorubicin	• Carboplatin + etoposide ± doxorubicin ± mitotane • Cisplatin + etoposide ± doxorubicin ± mitotane	• Bone marrow suppression • Cardiac arrhythmias • Cardiomyopathy • Tumor lysis syndrome	• Alopecia • Nausea/vomiting • Radiation sensitization/recall • Secondary malignancy	• Can cause red discoloration of urine for 1 to 2 days after administration • Effective contraception required during and after therapy for 6 months for females of reproductive potential and males with female partners of reproductive potential
Topoisomerase II inhibitors – epipodophyllotoxins
Etoposide	• Carboplatin + etoposide ± doxorubicin ± mitotane • Cisplatin + etoposide ± doxorubicin ± mitotane	• Anaphylaxis • Bone marrow suppression	• Secondary malignancy	• Effective contraception required during and after therapy for at least 6 months for females of reproductive potential and for 4 months for males with female partners of reproductive potential

Citation: Data from Lysodren (Mitotane). Package Insert. HRA Pharma Rare Diseases; January 2024. Carboplatin. Package Insert. Fresenius Kabi USA, LLC; May 2021. Cisplatin. Package Insert. Accord Healthcare, Inc.; February 2020. Keytruda (Pembrolizumab). Package Insert. Merck Sharp and Dohme Corp; January 2024. Doxorubicin. Package Insert. Mylan Institutional LLC; December 2018. Etopophos (Etoposide Phosphate). Package Insert. Bristol Myers Squibb; May 2019.

Nondrug and supportive care

Tailored to meet each patient’s needs based on age, performance status, disease status, specific surgical approach and therapeutic agents used, and risk of complications

Postoperative issues

Hypotension and electrolyte abnormalities (especially potassium) may develop after adrenalectomy and require close monitoring
Diet is advanced as permitted when bowel resection is necessary ⁵²
Pancreatic resection may require drain management and monitoring of glucose homeostasis ⁵²
For patients with hypercortisolemia, corticosteroids are required after adrenal surgery and for several months thereafter in a tapering manner ⁵²
- Even with unilateral adrenalectomy, contralateral adrenal suppression occurs owing to suppression of both adrenocorticotropin and relative atrophy of the contralateral adrenal cortex
- Educate patients regarding steroid requirements, sick day management, and the need to seek health care for illnesses lasting more than 3 days or for recurrent emesis

Procedures

Adrenalectomy and related procedures

General explanation

Open adrenalectomy and locoregional lymphadenectomy are the standard treatments for all patients with localized and local advanced tumors when complete resection can be achieved ⁶¹¹
- Patients with locally advanced tumor require en bloc resection of surrounding peritumoral/periadrenal retroperitoneal fat and adjacent organs (eg, wall of the vena cava, liver, spleen, colon, pancreas, stomach) and lymphadenectomy
- Open adrenalectomy and lymphadenectomy can be considered to reduce tumor burden in metastatic disease if more than 90% are removable ²
Laparoscopic adrenalectomy is a potential option to remove small tumors (less than 6 cm) without preoperative evidence for local invasion or lymphadenopathy based on preoperative imaging when a surgeon has sufficient experience in these types of surgeries ³⁵³⁵⁴
- However, the laparoscopic approach is controversial because while some studies suggest outcomes may be comparable between open and laparoscopic adrenalectomy in selected cases, others have reported lower rates of positive resection margins and longer disease-free survival with open surgery ¹⁰ ⁵⁵ ⁵⁶
- Laparoscopic approaches may incur an increased risk for local recurrence and peritoneal spread
- National Comprehensive Cancer Network guidelines state that if tumor is deemed resectable via laparoscopy, a minimally invasive approach can be considered; decision for surgical approach (open vs laparoscopic) should be based on tumor size, suspicion for malignancy, and local surgical expertise ²
Preoperative treatment of manifestations of hormonal excess should be instituted as needed (eg, correction of serum potassium levels; blood pressure control; adrenolytic therapy with ketoconazole, mitotane, or metyrapone) ¹ ¹⁴
For patients with adrenocortical carcinoma and hypercortisolism undergoing surgery, administer perioperative corticosteroids to prevent postoperative adrenal crisis ³

Indication

Suspected or confirmed diagnosis of adrenocortical carcinoma

Contraindications

Widespread metastatic disease at the time of initial diagnosis

Complications

Adrenal insufficiency
Hemorrhage
Infection
Injury to nearby organs or vasculature

Special populations

Children
- Children with suspected adrenocortical carcinoma should be evaluated and managed in collaboration with a pediatric endocrinologist ⁵⁷
- Treatment is similar to that in adults; however, children may not be able to tolerate the treatment-related toxicity associated with mitotane plus chemotherapy ²⁶

Monitoring

Postoperative follow-up
- Follow-up after surgical resection with history, physical examination, biochemical markers (if tumor was initially hormonally functional), and imaging every 3 months for the first 2 years; interval may be extended thereafter, but continued surveillance is necessary for at least 5 years ² ⁵⁸
- Close follow-up is particularly important after seemingly complete surgery for stage I to stage III adrenocortical carcinoma, because surgery for tumor recurrence is an important treatment option
Medical therapy follow-up
- Medical treatment with mitotane requires drug monitoring (target concentration 14-20 mg/L) and periodic clinical assessment to ensure adequate hydrocortisone replacement ²
- Follow-up during mitotane therapy consists of measuring mitotane levels monthly until stable, then every 3 months; and CBC, liver function tests, thyroid function tests, cholesterol levels, and biochemical markers every 3 months ¹

Complications and Prognosis

Complications

Cushing syndrome
- Hypertension
- Hyperglycemia
- Hyperlipidemia
- Osteoporosis
Hyperaldosteronism
- Hypertension
- Hypokalemia
Locoregional recurrence
Distant metastasis; most common sites are the lung, liver, peritoneum, and less commonly, bones
Adrenocortical carcinoma can also cause deep vein thrombosis or pulmonary embolism because of hypercoagulable state related to cortisol excess or underlying malignancy ⁵

Prognosis

Prognosis varies with age, histologic grade, and stage at diagnosis ¹²
- Cure is possible with complete surgical resection; 5-year overall survival may be up to 90% in patients with completely resected localized tumors ²⁸
- Median overall survival of all patients is 3 to 4 years ¹⁹
- Median survival is about 15 months in patients with metastatic disease; however, long-term survival is seen in a subgroup of patients ²⁸
Survival statistics
- Extent of the disease at the time of diagnosis, as assessed by the European Network for the Study of Adrenal Tumors Staging Score, is a major determinant of survival ⁵⁹
- Survival is strongly influenced by tumor stage ⁵⁹at diagnosis and completeness of surgical removal, with a 5-year stage-dependent survival of 81%, 61%, 50%, and 13% from stage 1 to stage 4, respectively
- Median survival times were 24.1, 6.08, 3.47, and 0.89 years for stages I, II, III, and IV, respectively, in 1 series ⁶⁰
Other prognostic factors
- Older age, ⁶¹ cortisol-secreting tumors, ⁶² and incomplete resection ⁶³ are also factors associated with lower survival rates
- In children, age older than 4 years, tumor greater than 5 cm, Cushing syndrome at diagnosis, incomplete resection, and higher stage are associated with poorer prognosis ⁵⁷

References

1.Else T et al: Adrenocortical carcinoma. Endocr Rev. 35(2):282-326, 2014

Adrenocortical Carcinoma – 18 Interesting Facts

Pitfalls

Introduction

Classification

Clinical Presentation

History

Physical examination

Causes

Risk factors and/or associations

Age

Sex

Genetics

Ethnicity/race

Diagnostic Procedures

Primary diagnostic tools

Laboratory

Imaging

Other diagnostic tools

Differential Diagnosis

Most common

Treatment Goals

Admission criteria

Recommendations for specialist referral

Treatment Options

Nondrug and supportive care

Procedures

Adrenalectomy and related procedures

Special populations

Monitoring

Complications and Prognosis

Complications

Prognosis

References

Share this:

Like this:

Related Posts

Related Posts:

Recent Post

features

Categories

Weekly Newsletter